Telomerase inhibitor compounds

Abstract

Telomerase inhibitor compounds are provided. Some compounds contain a lactone or lactam group covalently bonded to a phenyl ring, which is itself bonded to a pyrazole group. In other examples, a sulfonamide-containing moiety is covalently bonded to a phenyl ring, which is itself bonded to a pyrazole group. In some embodiments, the telomerase inhibitor compounds have an amide moiety and a vinyl sulfonamide group bonded to an aromatic group. In other examples, the inhibitor compounds have an isothiazolidine 1,1-dioxide core bonded to a phenyl group. Aspects of the present invention also include pharmaceutical compositions containing the telomerase inhibitor compounds of the present invention, as well as methods for treating telomerase-related diseases or conditions.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 444,467, filed February 9, 2023, the disclosure of which is incorporated herein by reference. [Background technology]

[0002] Introduction Telomerase is a ribonucleoprotein known to add telomere repeat sequences to the 3' ends of telomeres on chromosomes. One of the functions of telomeres is to protect the ends of chromosomal DNA from degradation by various biochemical processes. Telomerase is typically absent or present at low concentrations in normal somatic cells. Telomerase, on the other hand, is abundant in gametes, embryonic stem cells, male sperm cells, epidermal cells, certain immune cells, and most cancer cells. Without telomerase, repeated cell division gradually shortens telomeres, and when the Hayflick limit is reached, cells undergo senescence and cease cell division (Hayflick et al., doi:10.1016 / 0014-4827(61)90192-6). However, cancer cells use telomerase to continually replenish lost telomeres, allowing them to divide and proliferate repeatedly (Hanahan et al., doi:10.1016 / j.cell.2011.02.013). Therefore, telomerase has been identified as an excellent target for cancer therapeutics. It has been proposed that inhibiting telomerase could suppress cancer (Williams, doi:10.1038 / nm0113-6).

[0003] The genes encoding both the protein and RNA components of human telomerase have been cloned and sequenced. The telomerase holoenzyme consists of the telomerase protein component (known in human form as human telomerase reverse transcriptase, or hTERT) and the RNA component (known in human form as human telomerase RNA, or hTR). Much effort has been expended in the search for telomerase inhibitors. Identified telomerase inhibitors include small molecules and oligonucleotides. Given the close relationship between telomerase and cell proliferative disorders such as cancer, what is needed are compounds useful for inhibiting telomerase in proliferative cells and for the use of these compounds in the treatment of proliferative diseases such as cancer.

[0004] Hematologic malignancies are a type of cancer that begins in the cells of blood-producing tissues, such as the bone marrow, or in the cells of the immune system. Examples of hematologic malignancies include acute and chronic leukemia, lymphoma, multiple myeloma, and myeloproliferative neoplasms.

[0005] Myeloproliferative neoplasms (MPNs) are hematologic tumors that arise from neoplastic hematopoietic myeloid precursor cells in the bone marrow, such as precursors to red blood cells, platelets, and granulocytes. The proliferation of neoplastic precursor cells leads to the overproduction of any combination of white blood cells, red blood cells, and / or platelets, depending on the disease. These overproduced cells may also be abnormal and cause additional clinical complications. There are various types of chronic myeloproliferative disorders. The MPN disease spectrum includes essential thrombocythemia (ET), polycythemia vera (PV), chronic myelogenous leukemia (CML), myelofibrosis (MF), chronic neutrophilic leukemia, chronic eosinophilic leukemia, and acute myeloid leukemia (AML). Myelodysplastic syndromes (MDS) are a group of rare, heterogeneous clonal disorders of the hematopoietic system characterized by inefficient hematopoiesis leading to anemia and other cytopenias. They are severe, life-threatening conditions with a high risk of leukemia. MDS includes refractory anemia, refractory anemia with excess blasts, refractory cytopenia with multilineage dysplasia, refractory cytopenia with unilineage dysplasia, and chronic myelomonocytic leukemia (CMML). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Hayflick et al,doi:10.1016 / 0014-4827(61)90192-6 [Non-patent document 2] Hanahan et al,doi:10.1016 / j.cell.2011.02.013 [Non-patent document 3] Williams, doi:10.1038 / nm0113-6 Summary of the Invention [Means for solving the problem]

[0007] Telomerase inhibitor compounds are provided. Some compounds contain a lactone or lactam group covalently bonded to a phenyl ring, which is itself bonded to a pyrazole group. In other examples, a sulfonamide-containing moiety is covalently bonded to a phenyl ring, which is itself bonded to a pyrazole group. In some embodiments, the telomerase inhibitor compounds have an amide moiety and a vinyl sulfonamide group bonded to an aromatic group. In other examples, the inhibitor compounds have an isothiazolidine 1,1-dioxide core bonded to a phenyl group. Aspects of the present invention also include pharmaceutical compositions containing the telomerase inhibitor compounds of the present invention, as well as methods for treating telomerase-related diseases or conditions. [Brief explanation of the drawings]

[0008] [Figure 1] 1 shows in vitro data for telomerase inhibitor compounds. [Figure 2] 1 shows in vitro data for additional telomerase inhibitor compounds. [Figure 3]1 shows a third set of in vitro data for telomerase inhibitor compounds. [Figure 4] 1 shows a fourth set of in vitro data for telomerase inhibitor compounds. [Figure 5] 1 shows a fifth set of in vitro data for telomerase inhibitor compounds. [Figure 6] The imaging and observation plan is shown. [Figure 7] 1 shows the effect of telomerase inhibition for 3 weeks on bioluminescence signal (BLI) in LUC-MOLM13 tumor-bearing mice. [Figure 8] The effect of telomerase inhibition for 3 weeks on the bioluminescence signal (BLI) for all groups is shown. [Figure 9] 1 shows the effect of telomerase inhibition for 3 weeks on the bioluminescence signal (BLI) of oral administration group 5 (compound 3). [Figure 10] 1 shows the effect of telomerase inhibition for 3 weeks on the bioluminescence signal (BLI) of Group 6 (Compound 2). [Figure 11A] Shows the effect of administered telomerase inhibitors on bioluminescence signals in LUC-MOLM13 tumor-bearing mice on day 0. (a) Mean BLI in each group. [Figure 11B] (b) The effect of administered telomerase inhibitors on the bioluminescence signal of LUC-MOLM13 tumor-bearing mice on day 0. (b) Distribution of orthotopically growing LUC-MOLM13 tumors in each group. Fluorescence is visible in the upper chest. [Figure 12A] Shows the effect of administered telomerase inhibitors on bioluminescence signals in LUC-MOLM13 tumor-bearing mice on day 5. (a) Mean BLI in each group. [Figure 12B] The effect of administered telomerase inhibitors on bioluminescence signals in LUC-MOLM13 tumor-bearing mice on day 5. (b) Distribution of orthotopically growing LUC-MOLM13 tumors in each group, with little to no fluorescence. [Figure 13A] Shows the effect of administered telomerase inhibitors on bioluminescence signals in LUC-MOLM13 tumor-bearing mice on day 10. (a) Mean BLI in each group. [Figure 13B] (b) Distribution of orthotopically growing LUC-MOLM13 tumors in each group. [Figure 14A] Shows the effect of administered telomerase inhibitors on bioluminescence signals in LUC-MOLM13 tumor-bearing mice on day 15. (a) Mean BLI in each group. [Figure 14B] (b) Distribution of orthotopically growing LUC-MOLM13 tumors in each group. [Figure 15A] Shows the effect of administered telomerase inhibitors on bioluminescence signals in LUC-MOLM13 tumor-bearing mice on day 18. (a) Mean BLI in each group. [Figure 15B] (b) Distribution of orthotopically growing LUC-MOLM13 tumors in each group. [Figure 16A] Shows the effect of administered telomerase inhibitors on bioluminescence signals in LUC-MOLM13 tumor-bearing mice on day 21. (a) Mean BLI in each group. [Figure 16B] (b) Distribution of orthotopically growing LUC-MOLM13 tumors in each group. [Figure 17A] Shows the effect of administered telomerase inhibitors on bioluminescence signals in LUC-MOLM13 tumor-bearing mice at day 28. (a) Mean BLI in each group. [Figure 17B](b) Distribution of orthotopically growing LUC-MOLM13 tumors in each group. [Figure 18] 1 shows the effect of administered telomerase inhibitors on the lifespan of LUC-MOLM13 tumor-bearing mice. [Figure 19] 1 shows the effect of administered telomerase inhibitors on the mean body weight of LUC-MOLM13 tumor-bearing mice. [Figure 20A] Bioluminescence signals from tissues obtained from the effects of telomerase inhibitors on postmortem day 34 are shown: Group - Control. [Figure 20B] Bioluminescence data for group 7 (BIRB-1532) is shown. [Figure 20C] Bioluminescence data for Group 5 (compound 3) is shown. [Figure 20D] Bioluminescence data for Group 4 (Compound 1) is shown. [Figure 20E] Bioluminescence data for Group 6 (compound 2) is shown. [Figure 20F] Samples with tissue labels are shown: 1. Brain 2. Axillary lymph nodes 3. Eyeball 4. Branchial lymph nodes 5. Lung 6. Heart 7. Stomach 8. Liver 9. Kidney 10. Spleen 11. Cervical lymph nodes 12. Mesenteric lymph nodes 13. Inguinal lymph nodes 14. Digestive tract 15. Male reproductive organs. DETAILED DESCRIPTION OF THE INVENTION

[0009] Telomerase inhibitor compounds are provided. Some compounds contain a lactone or lactam group covalently bonded to a phenyl ring, which is itself bonded to a pyrazole group. In other examples, a sulfonamide-containing moiety is covalently bonded to a phenyl ring, which is itself bonded to a pyrazole group. In some embodiments, the telomerase inhibitor compounds have an amide moiety and a vinyl sulfonamide group bonded to an aromatic group. In other examples, the inhibitor compounds have an isothiazolidine 1,1-dioxide core bonded to a phenyl group. Aspects of the present invention also include pharmaceutical compositions containing the telomerase inhibitor compounds of the present invention, as well as methods for treating telomerase-related diseases or conditions.

[0010] Before the present invention is described in more detail, it is to be understood that this invention is not limited to particular embodiments described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0011] Where a range of values ​​is provided, unless the context expressly dictates otherwise, it is understood that each intervening value between the upper and lower limits of that range is also specifically disclosed to the tenth of the unit of the lower limit. Each smaller range between any stated value or intervening value within a stated range and any other stated value or intervening value within that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded, and each range in which either, neither, or both limits are included in the smaller range is also encompassed within the invention, subject to any specifically excluded limits in the stated range. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also encompassed within the invention.

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.Any method and material similar or equivalent to the method and material described herein can be used to implement or test this invention, but some potential and exemplary methods and materials can be described here.Any and all publications mentioned herein are incorporated by reference into this specification to disclose and describe the method and / or material for which the publication is cited.In the event of any discrepancy, it should be understood that the present disclosure shall prevail over any disclosure of the incorporated publication.

[0013] It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to "a droplet" includes a plurality of such droplets, a reference to "an individual entity" includes a reference to one or more individual entities, and so forth. It should be further noted that the claims may be drafted to exclude any element, e.g., any optional element. Accordingly, this declaration is intended to serve as a predicate basis for using exclusive language such as "solely," "only," and the like, or for using "negative" limitations in connection with the recitation of claim elements.

[0014] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of publication provided may be different from the actual publication date, which may need to be independently confirmed. In the event that the definition or scope of any term herein conflicts with the definition or use of that term in an application or reference incorporated herein by reference, the present application controls.

[0015] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features which may be readily separated from or combined with the features of any of the other various embodiments without departing from the scope or spirit of the invention. Any described methods can be carried out in the order described or in any other order which is logically possible.

[0016] definition "Alkyl" refers to a monovalent, branched or straight-chain, acyclic, saturated hydrocarbon group. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, cyclopentyl, and cyclohexyl. In some cases, the alkyl group has 1 to 24 carbon atoms, e.g., 1 to 12, 1 to 6, or 1 to 3 carbon atoms.

[0017] "Alkenyl" refers to a monovalent, branched or straight-chain, acyclic hydrocarbon group containing a carbon-carbon double bond. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, and tetracosenyl.

[0018] "Alkynyl" refers to a monovalent, branched or straight-chain, acyclic hydrocarbon group containing a carbon-carbon triple bond. Examples of alkynyl groups include ethynyl and n-propynyl.

[0019] "Cycloalkyl" refers to a monovalent, cyclic, saturated hydrocarbon group. Similarly, "cycloalkenyl" refers to a monovalent cyclic group having a carbon-carbon double bond, and "cycloalkynyl" refers to a monovalent cyclic group having a carbon-carbon triple bond.

[0020] "Heterocyclyl" refers to a monovalent cyclic group that contains a heteroatom (e.g., O, S, N) as a ring atom and that is not aromatic (i.e., distinguishing heterocyclyl groups from heteroaryl groups). Examples of heterocyclyl groups include piperidinyl, tetrahydrofuranyl, dihydrofuranyl, and thiocanyl.

[0021] "Aryl" refers to an aromatic group containing at least one aromatic ring, wherein each atom in the ring is a carbon atom, i.e., none of the ring atoms are heteroatoms (e.g., O, S, N). In some cases, the aryl group has, for example, a second aromatic ring fused to the first aromatic ring. Examples of aryl groups include phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, and benzophenone.

[0022] "Heteroaryl" refers to an aromatic group containing at least one aromatic ring, wherein at least one of the atoms in the aromatic ring is a heteroatom (e.g., O, S, N). Examples of heteroaryl groups include those derived by removing a hydrogen atom from pyridine, pyrimidine, furan, thiophene, or benzothiophene.

[0023] The term "substituted" refers to the removal of one or more hydrogens from an atom (e.g., a C or N atom) and its replacement with a different group. For example, a hydrogen atom on a phenyl (-CH) group can be replaced with a methyl group to form a -CHCHCH group. Thus, the -CHCHCH group can be considered a substituted aryl group. As another example, two hydrogen atoms on the second carbon of a propyl (-CHCHCH) group can be replaced with oxygen atoms to form a -CHC(O)CH group, which can be considered a substituted alkyl group. However, replacing a hydrogen atom on a propyl (-CHCHCH) group with a methyl group (e.g., to give -CHCH(CH)CH) is not considered a "substitution" as used herein because both the starting and ending groups are alkyl groups. However, if the propyl group is replaced with a methoxy group to form a -CHCH(OCH)CH group, the entire group is no longer considered an "alkyl" but rather a "substituted alkyl." Thus, to be considered a substituent, a substituent must be of a different type from the original group. Also, unless described as a substituent, a group is presumed to be unsubstituted. For example, the terms "alkyl" and "unsubstituted alkyl" are used interchangeably herein.

[0024] The term "substituted versions thereof" refers to naming that refers to both substituted and unsubstituted groups. For example, the phrase "alkyl, aryl, heteroaryl, halo, nitro, and substituted versions thereof" refers to alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, and nitro groups.

[0025] Examples of substituents include deuterium (D), alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, thiol, thioether, and substituted versions thereof.

[0026] In some cases, the substituent itself can be further substituted with one or more groups. For example, the group -CHCHCH can be considered a substituted aryl, i.e., an aryl group substituted with the alkyl group ethyl. Furthermore, the ethyl group can itself be substituted with a pyridyl group to form -CHCHCHCHN, where -CHCHCHCHN can also be considered a substituted aryl group as the term is used herein. In some cases, the substituent is not substituted with other groups.

[0027] Diradical groups are also described herein, i.e., diradical groups are in contrast to the monoradical groups, such as alkyl and aryl, described above. The term "alkylene" refers to the diradical form of an alkyl group; i.e., an alkylene group is a diradical, branched or straight-chain, cyclic or acyclic, saturated hydrocarbon group. Examples of alkylene groups include diylmethane (-CH2-, also known as a methylene group), 1,2-diylethane (-CH2CH2-), and 1,1-diylethane (i.e., a CHCH3 fragment in which the first atom has two single bonds to two other groups). The term "arylene" refers to the diradical form of an aryl group; for example, 1,4-diylbenzene refers to a CH4 fragment in which two hydrogens positioned para to each other have been removed and replaced with single bonds to other groups. The terms "alkenylene," "alkynylene," "heteroarylene," and "heterocyclene" are also used herein.

[0028] "Acyl" refers to a group of the formula -C(O)R, where R is alkyl, alkenyl, alkynyl, or substituted versions thereof. For example, the acetyl group has the formula -C(O)CH. "Carbonyl" refers to a diradical group of the formula -C(O)-.

[0029] "Alkoxy" refers to a group of the formula -O(alkyl). Similar groups can be derived from alkenyl, alkynyl, aryl, heteroaryl, and the like groups.

[0030] "Amino" refers to the group -NR X R Y where R X and R Y are each independently H or a non-hydrogen substituent. Examples of non-hydrogen substituents include alkyl groups (e.g., methyl, ethyl, isopropyl).

[0031] "Carbonyl" refers to a diradical group of formula -C(O)-.

[0032] "Carboxy" is used interchangeably with carboxyl and carboxylate and refers to the -CO2H group and salts thereof.

[0033] "Ether" refers to a diradical group of formula -O-. For example, when the ether group is attached to an alkyl group, the entire group is an alkoxy group (e.g., -OCH or methoxy). When the ether group is attached to a carbonyl group, the entire group is an ester group of formula -OC(O)-.

[0034] "Halo" and "halogen" refer to chloro, bromo, fluoro, and iodo groups.

[0035] "Nitro" refers to a group of the formula -NO2.

[0036] Unless otherwise specified, a reference to an atom is meant to include all isotopes of that atom. For example, a reference to H is 1 H, 2 H (i.e., D or deuterium) and 3 H (i.e., tritium), and references to C include 12 C and all other isotopes of carbon (e.g., 13 C) Unless otherwise specified, a group includes all possible stereoisomers.

[0037] As used herein, the terms "subject" and "patient" are used interchangeably.

[0038] "Imetelstat" is a compound with Chemical Abstract Services (CAS) registration number 868169-64-6.

[0039] "Imetelstat sodium" is the sodium salt of imetelstat.

[0040] Compounds of formula (I) A compound of formula (I) is provided, [ka] During the ceremony, X is O or NR X and R X is selected from the group consisting of H, D, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof; Each R 1 and R 2 is independently selected from the group consisting of H, D, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, thiol, thioether, and substituted versions thereof; R 9 is H, D, or alkyl; A is an optionally substituted 5- or 6-membered aromatic ring or an optionally substituted heterocycle.

[0041] In some cases, A is an optionally substituted 5- or 6-membered heteroaryl ring. In some cases, A is, for example, a 5- or 6-membered heterocyclic ring. In some cases, A is an aromatic ring further substituted at two adjacent points, for example, optionally forming a second ring fused to the first ring. For example, A can be an indole ring, i.e., a benzene ring fused to a 5-membered pyrrole ring. In this example, A can be considered a phenyl ring substituted at two adjacent points with -CH=CH-NH- groups to form a pyrrole ring fused to the parent benzene ring.

[0042] As mentioned above, each R 1 and R 2 is independently selected from the group consisting of H, D, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, thiol, thioether, and substituted versions thereof. For example, R 1 is alkyl, such as methyl, ethyl, n-propyl, i-propyl, etc. 1-6 In some cases, R 1 is methyl. In some cases, R 2 is H, D, alkyl or substituted alkyl. As noted above, R 3 is H, D, or alkyl. For example, R 3 can be H. In some cases, R 3 is methyl.

[0043] As stated above, X is O or NR X In some embodiments, X is O, in which case the inhibitor compound can be said to have a lactone group. In other examples, X is NR 6 and therefore the compound can be said to have a lactam group. 6is independently selected from the group consisting of H, D, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof. 6 is H, alkyl, or substituted alkyl, e.g., C such as methyl 1-6 It is alkyl.

[0044] As mentioned above, R 9 is H, D, or alkyl. In some cases, R 9 is H, D, or methyl.

[0045] In some cases, the compound has formula (Ia-A): [ka] During the ceremony, m is 0 or an integer from 1 to 5; Each R 3 are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof, provided that two adjacent R 3 The groups, together with the atoms to which they are attached, can form rings in a cyclic structure.

[0046] In some cases, the compound has formula (Ia): [ka] During the ceremony, m is 0 or an integer from 1 to 5; Each R 3 are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof, provided that two adjacent R 3The groups, together with the atoms to which they are attached, can form rings in a cyclic structure.

[0047] In formulas (Ia-A) and (Ia), the variable m is 0 or an integer from 1 to 5, for example, m is 0, or m is 1. 3 are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof, provided that two adjacent R 3 The groups, together with the atoms to which they are attached, can form rings in a cyclic structure.

[0048] Additionally, in some cases, the compound may have at least one R located in the ortho position, for example, as shown in formula (Ib-A): 3 having a group, [ka] During the ceremony, n is 0 or an integer from 1 to 4, E is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0049] In some cases, the compound has formula (Ib): [ka] During the ceremony, n is 0 or an integer from 1 to 4, E is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0050] In some embodiments, E is selected from the group consisting of alkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, heterocyclyl, and substituted versions thereof. For example, E can be a 5-membered heteroaryl group or a substituted heteroaryl group, e.g., E can be pyrazole or a substituted pyrazole. For example, the compound can have the formula (Ib-1-A): [ka] During the ceremony, R 4 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof; z is 0, 1, or 2; Each R 5 are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0051] In some embodiments of Formula (Ib-1-A), Each R 1 is H, R 2 is H or OH, n is 1 or 2, Each R 3 is located para or meta to the ring containing X, Each R 3 are independently selected from F, Cl, and COOH; R 4 is H, methyl, ethyl, n-propyl, i-propyl, or a substituted alkyl group having 2 or 3 carbon atoms; z is 0.

[0052] In some cases, the compound has formula (Ib-1): [ka] During the ceremony, R 4 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof; z is 0, 1, or 2; Each R 5 are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0053] In some embodiments of Formula (Ib-1-A) or (Ib-1), the E group is selected from the group consisting of triazole, substituted triazole, 6-membered aryl, 6-membered substituted aryl, 6-membered heteroaryl, and 6-membered substituted heteroaryl.

[0054] In some embodiments of Formula (I), the compound is represented by Formula (Ic-A): [ka] During the ceremony, p is 0 or an integer ranging from 1 to 4; G is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0055] In some embodiments of Formula (I), the compound is represented by Formula (Ic): [ka] During the ceremony, p is 0 or an integer ranging from 1 to 4; G is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0056] For example, in some examples of formula (Ic), the G group is selected from the group consisting of alkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, heterocyclyl, and substituted versions thereof.

[0057] In some cases, the compound has formula (Id-A): [ka] During the ceremony, q is 0 or an integer of 1 to 3; Ring B is a 5- or 6-membered aryl or heteroaryl ring.

[0058] In some cases, the compound has formula (Id): [ka] During the ceremony, q is 0 or an integer of 1 to 3; Ring B is a 5- or 6-membered aryl or heteroaryl ring.

[0059] As noted above, B is a 5- or 6-membered aryl or heteroaryl ring. For example, in some instances, ring B is heteroaryl, such as pyridine, pyrrole, imidazole, or pyrrolidine.

[0060] In some embodiments, the telomerase inhibitor compound of Formula (I) has a structure selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka]

[0061] Compound of formula (II) In some embodiments, the compound has formula (II): [ka] During the ceremony, n is 0, 1, 2, or 3; Each R 1 , R 2 , R 6 , R 7 , and R 9 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; Each R 3 , R 4 , R 5 , and R 8 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof.

[0062] R 1is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. For example, in some cases, R 1 is H, alkyl, or substituted alkyl. In some cases, R 1 is alkyl, such as methyl or ethyl. 1 is H.

[0063] Each R 2 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. 2 is H or alkyl, e.g., each R 2 is H.

[0064] R 3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. 3 is H.

[0065] R 4 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof. 4 is H or alkyl (e.g., methyl, ethyl). In some cases, R 4 is H or methyl.

[0066] R 5is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof. 5 is H or alkyl (e.g., methyl, ethyl). In some embodiments, R 5 is H or methyl.

[0067] n is 0, 1, 2, or 3, and each R 6 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. In some cases, n ranges from 1 to 3, and in some cases, for example, at least one R 6 is a halo. For example, in some cases n is 2 and each R 6 are independently halo, e.g., one R 6 is Cl and one R 6 is F.

[0068] R 7 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. 7 is H.

[0069] R 8 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof. 8 is H or alkyl (e.g., methyl, ethyl).

[0070] R 9is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. 9 is H or alkyl (e.g., methyl, ethyl).

[0071] In some embodiments, the telomerase inhibitor compound of Formula (II) has a structure selected from the group consisting of: [ka]

[0072] Compound of formula (III) Also provided is a compound of formula (III): [ka] During the ceremony, n is 0 or an integer ranging from 1 to 4; Each R 1 , R 4 , and R 5 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; R 2 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R 3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof.

[0073] In some embodiments, n is 0 or an integer ranging from 1 to 4. In some embodiments, n is 0. In some embodiments, n is 1 or 2.

[0074] Each R 1 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0075] R 2 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl. 2 is an aryl group or a substituted aryl group.

[0076] R 3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof. 3 is H.

[0077] R 4 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. 4 is H.

[0078] Each R 5 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. 5 is H.

[0079] In some embodiments, the telomerase inhibitor compound of Formula (III) has a structure selected from the group consisting of: [ka] [ka]

[0080] In some cases, the compound has the structure of formula (III), wherein R 2 is an aryl group or a substituted aryl group. In some cases, the compound is represented by formula (IIIa): [ka] During the ceremony, m is 0 or an integer ranging from 1 to 5; Each R 22 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0081] m is 0 or an integer ranging from 1 to 5. In some cases, m is 0. In some cases, m is 1 or 2.

[0082] Each R 22 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. 22 teeth,

[0083] In some cases, the compound has formula (IIIb): [ka] During the ceremony, m is 0 or an integer ranging from 1 to 5; Each R 22is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0084] m is 0 or an integer ranging from 1 to 5, and each R 22 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. In some embodiments, m ranges from 1 to 5, and may be, for example, at least one R 22 is a halo. For example, in some cases, m is 2 and one R 22 is Cl and one R 22 is F.

[0085] Compound of formula (IV) Also provided is a compound of formula (IV): [ka] During the ceremony, R 1 and R 2 are each independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof, with the proviso that R 1 and R 2 at least one of is aryl, heteroaryl, or a substituted version thereof; L 1 and L 2 are each independently absent, an alkylene group, or a substituted alkylene group; R 3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof; Each R 4 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0086] R 1 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof. 1 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. 1 is H.

[0087] R 2 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof. 2 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. 2 is H.

[0088] L 1 and L 2 Each of L is independently absent, an alkylene group, or a substituted alkylene group. 1 Group and L 2 The group is also referred to as a "linker" or "linking" group. When the L group is absent, the corresponding R group is directly covalently attached to the five-membered ring. The L group may be an alkylene group, which can be referred to as the diradical form of a (monoradical) alkyl group. Examples of alkylene groups that can be used as the L group herein include -CH2-, -CH2CH2-, -CH(CH3)CH2-, and -CH2CH2CH2-.

[0089] R 3is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof. 3 is H. In some embodiments, R 3 is alkyl, for example methyl.

[0090] Each R 4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. 4 is H.

[0091] In some embodiments, the telomerase inhibitor compound of formula (IV) has a structure selected from the group consisting of: [ka]

[0092] As mentioned above, R 1 and R 2 At least one of R is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. 1 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. For example, in some embodiments, the compound has formula (IVa): [ka] During the ceremony, x is 0 or an integer ranging from 1 to 5; Each R 11is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0093] x is 0 or an integer from 1 to 5, and each R 11 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. In some embodiments, x is 0. In some embodiments, x is an integer ranging from 1 to 5, and may also be, for example, at least one R 11 is a halo. For example, if x is 2 and one R 11 Let F be one R 11 can be Cl. In some cases, R 2 is H or alkyl, e.g., methyl.

[0094] L 1 is independently absent, an alkylene group, or a substituted alkylene group, and each R 4 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. 1 does not exist. In some cases, L 1 is represented by the formula -CH2-. In some cases, each R 4 is H.

[0095] R 2 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof. 2is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. For example, in some embodiments, the compound has formula (IVb): [ka] During the ceremony, y is 0 or an integer from 1 to 5; Each R 22 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0096] y is 0 or an integer from 1 to 5, and each R 22 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. In some embodiments, y is 0. In some instances, y is an integer ranging from 1 to 5, and may also be, for example, at least one R 22 is a halo. For example, in some cases, y is 2 and one R 22 is Cl and one R 22 is F.

[0097] Compound of formula (V) Also provided is a compound of formula (V): [ka] During the ceremony, R 1 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof; Each R 2 and R 3is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof;

[0098] n is 0 or an integer of 1 to 4.

[0099] For example, in some cases, R 3 Both groups are H, and therefore the compound has formula (Va). [ka]

[0100] As mentioned above, R 1 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof. 1 is alkyl, e.g., methyl. In some embodiments, n is 0, and thus the compound is R 2 It has no group.

[0101] In some embodiments, the telomerase inhibitor compound of Formula (V) has a structure selected from the group consisting of: [ka]

[0102] Compound of formula (VI) A compound of formula (VI) is provided: [ka] During the ceremony, n is 0, 1, 2, or 3; Each R 1 , R 2 , R 3 , R 5, R 6 , and R 8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; R 4 and R 7 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof.

[0103] R 1 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. For example, in some cases, R 1 is H, alkyl, or substituted alkyl. In some cases, R 1 is a carboxylic acid group (i.e., -COOH) or a salt thereof. In some cases, R 1 is cyano.

[0104] Each R 2 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. 2 is H or alkyl, e.g., each R 2 is H.

[0105] R 3is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. 3 is H.

[0106] R 4 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof. 4 is H or alkyl (e.g., methyl, ethyl). In some cases, R 4 is H or methyl.

[0107] n is 0, 1, 2, or 3, and each R 5 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. In some cases, n ranges from 1 to 3, and in some cases, for example, at least one R 5 is a halo. For example, in some cases, n is 2 and each R 5 are independently halo, e.g., one R 5 is Cl and one R 5 is F.

[0108] R 6 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. 6 is H.

[0109] R 7is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof. 7 is H or alkyl (e.g., methyl, ethyl).

[0110] R 8 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof. 8 is H or alkyl (e.g., methyl, ethyl).

[0111] In some cases, the compound has a structure selected from the group consisting of: [ka]

[0112] Compositions and Formulations Also provided are compositions comprising the compounds disclosed herein. For example, the compounds can be represented by Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (II), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (VI), as described above. In some cases, the composition comprises a racemic mixture of stereoisomers. In some embodiments, the composition is enriched in a particular stereoisomer, for example, the composition is enriched in a first enantiomer relative to a second enantiomer. The term "enantiomeric excess" is used herein to quantify the relative amount of a first enantiomer compared to a second enantiomer, and the enantiomeric excess is the absolute value of the difference between the mole fractions of each enantiomer. For example, if 70% of the compound is the first enantiomer and 30% of the compound is the second enantiomer, the enantiomeric excess is 40% (i.e., 70% minus 40%). In some embodiments, the composition has a first enantiomeric excess of 1% or more, e.g., 10% or more, 20% or more, 30% or more, or 40% or more. In some embodiments, the composition is an aqueous solution of the compound.

[0113] In certain embodiments, the disclosed compounds are useful for treating diseases or disorders.Therefore, pharmaceutical compositions comprising at least one disclosed compound are also described herein.For example, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of the disclosed compound (or its pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer) and a pharmaceutically acceptable excipient.

[0114] Pharmaceutical compositions containing the compounds of the present invention may be administered to a patient alone or in combination with other supplementary active ingredients. For example, one or more compounds according to the present disclosure may be administered to a patient with or without supplementary active ingredients. Pharmaceutical compositions may be prepared using any of a variety of processes, including, but not limited to, conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, encapsulating, and lyophilizing. Pharmaceutical compositions may take any of a variety of forms, including, but not limited to, sterile solutions, suspensions, emulsions, spray-dried dispersions, lyophilized products, tablets, microtablets, pills, pellets, capsules, powders, syrups, elixirs, or any other dosage form suitable for administration.

[0115] The compound or prodrug of the present disclosure can be administered to the subject by any convenient means that can bring about the desired alleviation of disease pathology or symptoms.Therefore, the compound or prodrug can be incorporated into various preparations for therapeutic administration.More specifically, the compound or prodrug can be combined with suitable pharmaceutically acceptable excipient, carrier or diluent to be formulated into pharmaceutical composition, and can be formulated into the preparation of solid, semi-solid, liquid or gas form such as tablet, capsule, powder, granule, ointment, cream, gel, foam, solution, suppository, injection, inhalant, aerosol, etc.

[0116] Formulations of pharmaceutical compositions are described, for example, in Remington's Pharmaceutical Sciences, by E.W. Martin, Mack Publishing Co., Easton, Pa., 19th Edition, 1995, which describes examples of formulations (and their components) suitable for pharmaceutical delivery of the disclosed compounds. Pharmaceutical compositions containing at least one of the compounds or prodrugs can be formulated for use in human or veterinary medicine. The specific formulation of the disclosed pharmaceutical compositions may vary, for example, depending on the mode of administration and / or the site of the subject being treated. In some embodiments, the formulation comprises a pharmaceutically acceptable excipient in addition to at least one active ingredient, such as a compound of the present disclosure. In other embodiments, other medicinal or pharmaceutical agents, e.g., having similar, related, or complementary effects on the disease or condition being treated, can also be included as active ingredients of the pharmaceutical composition.

[0117] Pharmaceutically acceptable carriers useful in the disclosed methods and compositions can vary depending on the particular mode of administration employed. In addition to biologically neutral carriers, the administered pharmaceutical composition can optionally contain non-toxic auxiliary substances (e.g., excipients), such as wetting or emulsifying agents, preservatives, and pH buffering agents.

[0118] The disclosed pharmaceutical compositions may be formulated as pharmaceutically acceptable salts of the disclosed compounds.

[0119] The term "unit dosage form," as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of a compound or prodrug calculated in an amount sufficient to produce a desired effect, in association with a pharmaceutically acceptable diluent, excipient, carrier, or vehicle. The specifications for the compound or prodrug will vary depending on the particular compound or prodrug employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the subject.

[0120] The dosage form of the disclosed pharmaceutical compositions can be determined by the selected mode of administration. For example, injectable solutions, topical, or oral dosage forms may be employed. Topical formulations include eye drops, ointments, sprays, and the like. Oral formulations may be liquid (e.g., syrups, solutions, suspensions) or solid (e.g., powders, pills, tablets, capsules). Methods for preparing such dosage forms are known or will be apparent to those skilled in the art.

[0121] Certain embodiments of the pharmaceutical composition comprising the compound or prodrug of the present invention can be formulated in a unit dosage form suitable for individual administration of precise doses.The amount of the active ingredient to be administered can vary depending on the subject to be treated, the severity of the affliction, and the method of administration, and is known to those skilled in the art.In certain examples, the formulation to be administered comprises the compound or prodrug disclosed herein in an amount effective to achieve the desired effect in the subject to be treated.

[0122] Each therapeutic compound can independently be in any dosage form as described herein and can be administered in various ways as described herein. For example, the compounds or prodrugs can be formulated as a single dosage unit (i.e., combined in one dosage form such as a capsule, tablet, powder, liquid, etc.) to form a combined formulation. Alternatively, if not formulated together in a single dosage unit, the individual compounds or prodrugs can be administered simultaneously with another therapeutic compound or sequentially, in any order.

[0123] The disclosed compounds can be administered alone as the sole active pharmaceutical agent, or in combination with one or more additional compounds or prodrugs of the present disclosure, or in combination with other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or at different times, or the therapeutic agents can be administered together as a single composition combining two or more therapeutic agents. Thus, the pharmaceutical compositions disclosed herein that contain a compound of the present disclosure optionally contain other therapeutic agents. Accordingly, certain embodiments relate to such pharmaceutical compositions, which further contain a therapeutically effective amount of an agent known to those skilled in the art.

[0124] In some embodiments, pharmaceutical compositions comprise a disclosed compound (e.g., a compound of Formula (I), (II), (III), (IV)), (V), or (VI), or any other formula described herein) together with a second telomerase inhibitor, e.g., imetelstat or imetelstat sodium. Imetelstat has been described as a telomerase inhibitor and has been studied for its ability to suppress various cancers, including pancreatic cancer (Burchett et al., PLoS One, 2014, 9(1), e85155, doi:10.1371 / journal.pone.0085155).

[0125] Treatment methods Also provided are methods for treating a patient with a telomerase-associated disease or condition. Such telomerase-associated conditions are characterized by increased telomerase activity, or expression or overexpression of telomerase in cells that do not express telomerase, express telomerase at very low levels, or have little or no telomerase activity. The method can include administering to the patient a compound as described above. In some cases, the telomerase-associated condition is cancer. In some cases, the condition is Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, or hepatic fibrosis.

[0126] In some cases, the cancer is a hematological malignancy. In some cases, the cancer is selected from the group consisting of acute and chronic leukemia, lymphoma, multiple myeloma and myelodysplastic syndrome, myeloproliferative neoplasm (MPN), essential thrombocythemia (ET), polycythemia vera (PV), chronic myelogenous leukemia (CML), myelofibrosis (MF), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS).

[0127] Essential thrombocythemia Circulating blood platelets retain small amounts of megakaryocyte-derived mRNA and the ability to synthesize fully functional proteins, but are anuclear (Gnatenko et al., Blood 101, 2285-2293 (2003)). Essential thrombocythemia (ET) is a subtype of myeloproliferative disorder characterized by increased megakaryocyte neoplastic proliferation, elevated numbers of circulating platelets, and significant thrombotic and hemorrhagic events, often neurological symptoms (Nimer, Blood 93, 415-416 (1999)). ET is seen with equal frequency in both sexes, although another peak incidence in women at age 30 may explain the apparent higher disease prevalence in women after this age. Although the molecular basis of ET has not yet been established, it has historically been considered a "clonal" disorder (El-Kassar et al., Blood 89, 128 (1997) "Evidence that ET is a clonal disorder with origin in a multipotent stem cell" PJ Fialkow, Blood 1981 58:916-919). Apart from the increased platelet volume seen in some ET platelets, these cells are morphologically indistinguishable from their normal counterparts. Currently, there are no functional or diagnostic tests for ET, and diagnosis must be made by excluding other underlying hematologic disorders. The estimated incidence of 2-3 cases per 100,000 people per year is consistent with other types of leukemia, but the low mortality associated with ET suggests a prevalence rate at least 10 times higher.

[0128] Current treatments for ET primarily focus on preventing thrombotic and hemorrhagic events and involve nonspecifically lowering platelet levels. Furthermore, many individuals with ET develop resistance to first-line treatments such as hydroxyurea or discontinue these medications entirely due to side effects.

[0129] polycythemia vera Patients with polycythemia vera (PV) exhibit a marked increase in red blood cell production. Treatment is directed at reducing the excess number of red blood cells. PV can present in later stages with a clinical manifestation resembling primary myelofibrosis, with cytopenia, bone marrow hypoplasia, and fibrosis. Janus kinase 2 (JAK2) mutations on chromosome 9, which enhance proliferation and survival of hematopoietic precursors in vitro, have been identified in most patients with PV. Patients with PV are at increased risk for cardiovascular and thrombotic events and progression to acute myeloid leukemia or primary myelofibrosis. Treatment for PV includes regular, chronic phlebotomy to maintain a hematocrit of less than 45% in men and less than 40% in women. Other treatments include hydroxyurea, interferon-alpha, and low-dose aspirin.

[0130] Myelofibrosis Myelofibrosis (MF), or primary myelofibrosis, is a myeloproliferative neoplasm in the same disease spectrum as ET. Patients with MF often have the JAK2 V617F mutation in their bone marrow. ET sometimes progresses to MF. Currently, JAK2 inhibition is considered the standard of care for MF in countries where the Janus kinase inhibitor ruxolitinib (Jakafi®) is approved. There is no evidence that JAK2 inhibitors, such as Jakafi®, selectively inhibit the proliferation of the disease-causing leukemic clone and therefore may not be "disease-modifying."

[0131] acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid lineage of blood cells. AML is the most common acute leukemia that develops in adults. In patients with AML, abnormal white blood cells rapidly multiply and accumulate in the bone marrow, interfering with the production of normal blood cells. Leukemia cells replace normal bone marrow, resulting in a decrease in red blood cells, platelets, and normal white blood cells. Symptoms of AML include fatigue, shortness of breath, easy bruising and bleeding, and an increased risk of infection. As an acute leukemia, AML progresses rapidly and, if left untreated, is typically fatal within weeks to months. The standard treatment for AML is chemotherapy aimed at inducing remission, and patients may also undergo hematopoietic stem cell transplantation.

[0132] Myelodysplastic syndromes Myelodysplastic syndromes (MDS) are a group of rare, heterogeneous clonal hematopoietic disorders characterized by inefficient hematopoiesis leading to anemia and other cytopenias, a high risk of leukemic transformation, and severe, life-threatening conditions. MDS includes refractory anemia, refractory anemia with excess blasts, refractory cytopenia with multilineage dysplasia, refractory cytopenia with unilineage dysplasia, and chronic myelomonocytic leukemia. Immature blood stem cells (blasts) do not develop into healthy red blood cells, white blood cells, or platelets. Blasts either die in the bone marrow or enter the bloodstream and die quickly, leaving less room for healthy white blood cells, red blood cells, and / or platelets to form in the bone marrow.

[0133] Myelodysplastic syndromes (MDS) are a group of blood disorders involving the failure of myeloid blood cell production. Patients with MDS often present with severe anemia, requiring frequent blood transfusions. Risk of bleeding and infection also arises due to the decreased or absent function of platelets and neutrophils, respectively. In some cases, the disease worsens, and patients develop cytopenias (low blood cell counts) due to progressive bone marrow failure. In some cases, the disease progresses to acute myeloid leukemia (AML). AML progression is considered to have occurred when the overall percentage of bone marrow blasts rises above certain cutoff values ​​(20% according to the WHO and 30% according to the FAB).

[0134] The compound can be administered in a therapeutically effective amount. Thus, administration can inhibit telomerase in the patient's cancer cells, thereby suppressing cancer. For example, cancer can be suppressed by inhibiting cancer cell division. In some cases, the disclosed telomerase inhibitor compound can be administered, and the method further includes administering a second telomerase inhibitor, such as imetelstat or imetelstat sodium.

[0135] "Treatment" means achieving at least an improvement in symptoms associated with a pathological condition afflicting a host, where improvement is used broadly to mean at least a decrease in a parameter associated with the condition being treated, e.g., the magnitude of the symptoms. "Treatment" therefore includes situations in which a pathological condition, or at least the symptoms associated therewith, are completely inhibited (e.g., prevented from occurring) or stopped (e.g., terminated), rendering the host no longer susceptible to the condition, or at least the symptoms that characterize it. Treatment therefore includes (i) prevention, i.e., reducing the risk of developing clinical symptoms, including not developing clinical symptoms, e.g., preventing the progression of the disease to a deleterious state; (ii) suppression, i.e., arresting the onset or further development of clinical symptoms, e.g., reducing or completely suppressing active disease; and / or (iii) palliative, i.e., causing regression of clinical symptoms.

[0136] The compounds of the present invention are used to treat diseases or disorders in subjects. The route of administration may be selected depending on various factors, including, but not limited to, the condition being treated, the formulation and / or device being used, and the subject being treated. Routes of administration useful in the disclosed methods include, but are not limited to, oral and parenteral routes, such as intravenous (iv), intraperitoneal (ip), rectal, topical, ocular, nasal, otic, intrathecal, and transdermal routes. Formulations of these dosage forms are described herein.

[0137] The effective amount of a compound or prodrug of the present invention will vary depending at least on the particular method of use, the subject being treated, the severity of the affliction, and the method of administration of the therapeutic composition. A "therapeutically effective amount" of a composition refers to the amount of a particular compound or prodrug sufficient to achieve the desired effect in the subject (e.g., patient) being treated. For example, this may be the amount of a compound of the present invention necessary to prevent, inhibit, reduce, or alleviate a disease or disorder in the subject. Ideally, a therapeutically effective amount of a compound or prodrug is an amount sufficient to prevent, inhibit, reduce, or alleviate a disease or disorder in the subject without causing substantial cytotoxic effects on normal host cells in the subject.

[0138] Therapeutically effective doses of compounds or prodrugs or pharmaceutical compositions of the present invention can be determined by one of ordinary skill in the art. For example, in some instances, the IC 50 A therapeutically effective dose of the compound or prodrug or pharmaceutical composition is administered with the intent of achieving a local (eg, tissue) or plasma concentration at least as high as

[0139] The specific dose level and frequency of administration for any particular subject may vary and will depend on a variety of factors, including the activity of the compound or prodrug of the invention, the metabolic stability and duration of action of the compound or prodrug, the age, body weight, general health, sex and diet of the subject, the method and time of administration, rate of excretion, drug combination, and the severity of the condition of the host being treated.

[0140] In some embodiments, multiple doses of the compound or prodrug are administered. The frequency of administration of the compound can vary depending on a variety of factors, such as the severity of symptoms, the condition of the subject, etc. For example, in some embodiments, the compound is administered monthly, twice monthly, three times monthly, every other week, once weekly (qwk), twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, every other day, daily (qd / od), twice daily (bds / bid), or three times daily (tds / tid), etc.

[0141] Embodiment Embodiments of the present invention include, but are not limited to, those described in the following clauses. 1. A compound of formula (I), [ka] During the ceremony, X is O or NR X and R X is selected from the group consisting of H, D, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof; Each R 1 and R 2 is independently selected from the group consisting of H, D, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, thiol, thioether, and substituted versions thereof; R 9 is H, D, or alkyl; A compound wherein A is an optionally substituted 5- or 6-membered aromatic ring or an optionally substituted heterocycle.

[0142] 2. The compound according to clause 1, wherein X is O.

[0143] 3.X is NR X 2. The compound according to clause 1, wherein

[0144] 4. The compound according to any one of clauses 1 to 3, wherein the compound is represented by formula (Ia-A): [ka] During the ceremony, m is 0 or an integer from 1 to 5; Each R 3are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof, provided that two adjacent R 3 Compounds in which the groups, together with the atoms to which they are attached, can form rings in a cyclic structure.

[0145] 5. The compound according to any one of clauses 1 to 3, wherein the compound is represented by formula (Ib-A): [ka] During the ceremony, n is 0 or an integer from 1 to 4, A compound wherein E is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0146] 6. The compound according to clause 5, wherein E is selected from the group consisting of alkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, heterocyclyl, and substituted versions thereof.

[0147] 7. The compound according to clause 6, wherein E is a 5-membered heteroaryl or substituted heteroaryl group.

[0148] 8. The compound according to clause 7, wherein E is pyrazole or substituted pyrazole.

[0149] 9. The compound according to clause 8, wherein the compound is represented by formula (Ib-1-A): [ka] During the ceremony, R 4is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof; z is 0, 1, or 2; Each R 5 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0150] 10. The compound according to clause 7, wherein E is selected from the group consisting of triazole, substituted triazole, 6-membered aryl, 6-membered substituted aryl, 6-membered heteroaryl, and 6-membered substituted heteroaryl.

[0151] 11. The compound according to any one of clauses 1 to 3, wherein the compound is represented by formula (Ic-A): [ka] During the ceremony, p is 0 or an integer ranging from 1 to 4; A compound wherein G is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0152] 12. The compound according to clause 11, wherein G is selected from the group consisting of alkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, heterocyclyl, and substituted versions thereof.

[0153] 13. The compound according to any one of clauses 1 to 3, wherein the compound is represented by formula (Id-A): [ka] During the ceremony, q is 0 or an integer of 1 to 3; Ring B is a 5- or 6-membered aryl or heteroaryl ring.

[0154] 14. The compound according to clause 13, wherein ring B is heteroaryl.

[0155] 15. The compound according to clause 14, wherein ring B is pyridine, pyrrole, imidazole or pyrrolidine.

[0156] 16. The compound of clause 1, wherein said compound has a structure selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka]

[0157] 17. A compound of formula (II), [ka] During the ceremony, n is 0, 1, 2, or 3; Each R 1 , R 2 , R 6 , R 7 , and R 9is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; Each R 3 , R 4 , R 5 , and R 8 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof.

[0158] 18.R 1 18. The compound according to clause 17, wherein

[0159] 19.Each R 2 19. The compound according to any one of clauses 17 to 18, wherein is H.

[0160] 20.R 3 20. The compound of any one of clauses 17 to 19, wherein is H.

[0161] 21.R 4 21. The compound of any one of clauses 17 to 20, wherein is H or alkyl.

[0162] 22.R 5 22. The compound of any one of clauses 17 to 21, wherein is H or alkyl.

[0163] 23. n is in the range of 1 to 3 and at least one R 6 23. The compound of any one of clauses 17 to 22, wherein is halo.

[0164] 24.R 7 24. The compound according to any one of clauses 17 to 23, wherein is H.

[0165] 25.R 825. The compound of any one of clauses 17 to 24, wherein is H or alkyl.

[0166] 26.R 9 26. The compound according to any one of clauses 17 to 25, wherein is H.

[0167] 27. The compound of clause 17, wherein said compound has a structure selected from the group consisting of: [ka] [ka]

[0168] 28. A compound of formula (III), [ka] During the ceremony, n is 0 or an integer ranging from 1 to 4; Each R 1 , R 4 , and R 5 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; R 2 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R 3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof.

[0169] 29. The compound according to clause 28, wherein the compound is represented by formula (IIIa): [ka] During the ceremony, m is 0 or an integer ranging from 1 to 5; Each R 22 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0170] 30. The compound according to clause 28, wherein said compound has formula (IIIb): [ka]

[0171] 31. m is in the range of 1 to 5 and there is at least one R 22 31. The compound of any one of clauses 29 to 30, wherein is halo.

[0172] 32. The compound according to any one of clauses 29 to 31, wherein n is 0.

[0173] 33.R 3 33. The compound according to any one of clauses 29 to 32, wherein is H.

[0174] 34.R 4 34. The compound according to any one of clauses 29 to 33, wherein is H.

[0175] 35.Each R 5 35. The compound according to any one of clauses 29 to 34, wherein is H.

[0176] 36. The compound according to clause 28, wherein said compound has a structure selected from the group consisting of: [ka] [ka]

[0177] 37. A compound of formula (IV), [ka] During the ceremony, R 1 and R 2 are each independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof, with the proviso that R 1 and R 2 at least one of is aryl, heteroaryl, or a substituted version thereof; L 1 and L 2 are each independently absent or an alkylene group; R 3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof; R 4 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0178] 38.R 1 38. The compound of clause 37, wherein is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

[0179] 39. The compound according to clause 38, wherein the compound is represented by formula (IVa): [ka] During the ceremony, x is 0 or an integer ranging from 1 to 5; Each R 11is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0180] 40. x is an integer between 1 and 5, and there is at least one R 11 39. The compound according to clause 39, wherein is halo.

[0181] 41.R 2 41. The compound according to any one of clauses 39 to 40, wherein is H or alkyl.

[0182] 42.L 1 42. The compound according to any one of clauses 39 to 41, wherein is absent.

[0183] 43.L 1 42. The compound according to any one of clauses 39 to 41, wherein is represented by the formula -CH2-.

[0184] 44.Each R 4 44. The compound according to any one of clauses 39 to 43, wherein is H.

[0185] 45.R 2 45. The compound of any one of clauses 39-40 or 42-44, wherein is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

[0186] 46. ​​The compound according to clause 37, wherein the compound is represented by formula (IVb), [ka] During the ceremony, y is 0 or an integer from 1 to 5; Each R 22is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

[0187] 47. y is an integer between 1 and 5, and at least one R 22 47. The compound according to clause 46, wherein is halo.

[0188] 48.R 1 48. The compound according to any one of clauses 46 to 47, wherein is H or alkyl.

[0189] 49.L 2 49. The compound according to any one of clauses 46 to 48, wherein is absent.

[0190] 50.L 2 49. The compound according to any one of clauses 46 to 48, wherein is represented by the formula -CH2-.

[0191] 51.R 3 51. The compound according to any one of clauses 46 to 50, wherein is H or alkyl.

[0192] 52.Each R 4 52. The compound according to any one of clauses 46 to 51, wherein is H.

[0193] 53. The compound according to clause 37, wherein said compound has a structure selected from the group consisting of: [ka]

[0194] 54. A compound of formula (V), [ka] During the ceremony, R 1is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof; Each R 2 and R 3 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; A compound wherein n is 0 or an integer of 1 to 4.

[0195] 55. The compound according to clause 54, wherein said compound has formula (Va). [ka]

[0196] 56.R 1 56. The compound according to any one of clauses 54 to 55, wherein is alkyl.

[0197] 57.R 1 57. The compound according to clause 56, wherein is methyl.

[0198] 58. The compound according to any one of clauses 54 to 57, wherein n is 0.

[0199] 59. The compound according to clause 54, wherein said compound has a structure selected from the group consisting of: [ka]

[0200] 60. A compound of formula (VI), [ka] During the ceremony, n is 0, 1, 2, or 3; Each R1 , R 2 , R 3 , R 5 , R 6 , and R 8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; R 4 and R 7 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof.

[0201] 61.R 1 61. The compound according to clause 60, wherein is cyano or carboxy.

[0202] 62.Each R 2 is H and R 3 62. The compound according to any one of clauses 60 to 61, wherein is H.

[0203] 63.R 4 63. The compound according to any one of clauses 60 to 62, wherein is H.

[0204] 64. n is 1, 2, or 3 and there is at least one R 5 64. The compound according to any one of clauses 60 to 63, wherein is halo.

[0205] 65.Each R 6 is H and R 8 65. The compound according to any one of clauses 60 to 64, wherein is H.

[0206] 66.R 7 66. The compound of any one of clauses 60 to 65, wherein is alkyl or substituted alkyl.

[0207] 67. The compound according to clause 60, wherein said compound has a structure selected from the group consisting of: [ka] [ka]

[0208] 68. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 67.

[0209] 69. The pharmaceutical composition according to clause 68, further comprising a second compound.

[0210] 70. The pharmaceutical composition according to clause 69, wherein the second compound is imetelstat or imetelstat sodium.

[0211] 71. A method of treating a patient with a telomerase-associated condition, comprising: A method comprising administering a pharmaceutical composition according to any one of clauses 68 to 70.

[0212] 72. The method of clause 71, wherein the compound is a telomerase inhibitor.

[0213] 73. The method of clause 72, wherein said telomerase-associated condition is cancer.

[0214] 74. The method of clause 73, wherein said cancer is a hematological malignancy.

[0215] 75. The method of clause 73, wherein said cancer is selected from the group consisting of acute and chronic leukemia, lymphoma, multiple myeloma and myelodysplastic syndrome, myeloproliferative neoplasm (MPN), essential thrombocythemia (ET), polycythemia vera (PV), chronic myeloid leukemia (CML), myelofibrosis (MF), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS).

[0216] 76. A method of treating a patient with a telomerase-associated condition, comprising: 68. A method comprising administering a compound according to any one of clauses 1 to 67.

[0217] 77. The method of clause 76, wherein the compound is a telomerase inhibitor.

[0218] 78. The method of clause 77, wherein said telomerase-associated condition is cancer.

[0219] 79. The method of clause 78, wherein said cancer is a hematological malignancy.

[0220] 80. The method of clause 79, wherein said cancer is selected from the group consisting of acute and chronic leukemia, lymphoma, multiple myeloma and myelodysplastic syndrome, myeloproliferative neoplasm (MPN), essential thrombocythemia (ET), polycythemia vera (PV), chronic myeloid leukemia (CML), myelofibrosis (MF), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS). [Example]

[0221] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental error and deviation should be accounted for. Unless otherwise specified, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Standard abbreviations may be used, such as bp (base pair(s)), kb (kilobase(s)), pl (picoliter(s)), s or sec (second(s)), min (minute(s)), h or hr (hour(s)), aa (amino acid(s)), nt (nucleotide(s)), etc.

[0222] Example 1 Synthesis of 3-methylene-5-(2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one [ka] Step 1: 2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)benzaldehyde: To a stirred solution of 2-bromobenzaldehyde (0.2 g, 1.08 mmol), 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine (0.365 g, 1.18 mmol) in 1,4-dioxane-HO (7 mL + 3 mL) was added KCO (0.447.5 g, 3.24 mmol). The reaction mixture was degassed with N for 10 min, and Pd(PPh) (0.125 g, 0.010 mmol) was added. The reaction mixture was stirred at 110 °C overnight. The reaction progress was monitored by TLC. After the starting material was reacted, it was diluted with HO (50 mL) and extracted with EtOAc (2 x 20 mL). The organic layers were combined, dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give 2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)benzaldehyde. Yield 0.14 g (45.45%). 1 H-NMR(300MHz,CDCl3)δ10.21(s,1H),7.97(dd,J=1.5,8.7Hz,1H),7.61(d,J=5.1Hz,3H),7.46(d,J=2 .7Hz,3H),4.31(t,J=6.3Hz,2H),3.70(t,J=4.5Hz,4H),2.86(t,J=6.6Hz,2H),2.51(t,J=4.8Hz,3H), LCMS: Retention time 1.08 min (91.27% purity), m / z 286.22 [M+H] + .

[0223] Step 2: Methyl 4-hydroxy-2-methylene-4-(2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)phenyl)butanoate To a stirred solution of 2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)benzaldehyde (0.2 g, 0.70 mmol) in THF (7 mL) was added 2-(bromomethyl)acrylate (0.138 g, 0.77 mmol), saturated NH4Cl (3 mL), and zinc (0.055 g, 0.84 mmol). The reaction mixture was then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2 x 50 mL). The organic layers were combined, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the crude compound. This was purified by silica gel column chromatography (eluent: 30% ethyl acetate in hexane) to give methyl 4-hydroxy-2-methylene-4-(2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)phenyl)butanoate. Yield: 0.18 g (66.6%). 1 H-NMR(300MHz,CDCl3)δ7.65(d,J=8.1Hz,1H),7.38(d,J=3.6Hz,2H),7.35-7.28(m,3H),6.25(d,J=1.2Hz,1H),5.6 5(s,1H),5.08(dd,J=3.0,8.7Hz,1H),4.37(t,J=5.7Hz,2H),3.79(s,7H),2.96(t,J=6.0Hz,2H),2.78-2.62(m,7H). LCMS: Retention time 1.79 min (96.97% purity), m / z 386.31 [M+H] + .

[0224] Step 3: 3-Methylene-5-(2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one: To a stirred solution of methyl 4-hydroxy-2-methylene-4-(2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)phenyl)butanoate (0.12 g 0.311 mmol) in DCM (10 mL) was added TFA (0.025 g) at room temperature and stirred for 16 hours. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was concentrated under reduced pressure to give the crude compound. The resulting crude product was purified by silica gel column chromatography (eluent: 15% EtOAc in hexane) to give 3-methylene-5-(2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one. Yield: 0.111g (26.08%). 1 H-NMR(300MHz,CDCl3)δ7.72(s,1H),7.67(s,1H),7.42-7.37(m,3H),7.36-7.27(m,1H),6.29(t,J=2.7Hz,1H),5.70-7.67(m,1H), 5.65-5.62(m1H),4.72(d,J=5.7Hz,2H),3.95(t,J=4.5Hz,4H),3.61(s,2H,),3.37-3.29(m,2H),3.10(bs,5H),3.00-2.91(m,2H). LCMS: retention time 1.88 min (97.72% purity), m / z 354.25 [M+H] + . [ka] Note: Both enantiomers were synthesized by chiral HPLC purification (the stereochemistry of both enantiomers was tentatively assigned). Peak 1 (top left structure): 1H-NMR(300MHz,CDCl3)δ8.01(s,1H),7.73(s,1H),7.39(d,J=5.7Hz,4H),6.14(t,J=2.4Hz,1H),5.81- 5.77(m,2H),4.58(t,J=6.0Hz,2H),3.80(bs,4H),3.46-3.37(m,2H).3.16(bs,4H),2.94-2.87(m,2H), LCMS: retention time 1.84 min (97.20% purity), m / z 354.30 [M+H] + . Peak 2 (top right structure): 1 H-NMR(300MHz,CDCl3)δ7.67(s,1H),7.63(s,1H),7.44-7.28(m,4H),6.30(t,J=2.7Hz,1H),5.70-5.63(m,2H),4.69 (t,J=6.0Hz,2H),3.93(t,J=4.5Hz,4H),3.61(t,J=5.7Hz,2H).3.37-3.29(m,1H),3.08(bs,4H),2.98-2.90(m,1H). LCMS: retention time 1.84 min (98.55% purity), m / z 354.30 [M+H] + .

[0225] Using this protocol, the following analogous compounds were synthesized: Methyl 4-hydroxy-2-methylene-4-(2-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)butanoate [ka] 1 H-NMR(300MHz,CDCl3)δ:7.70(s,1H),7.61(s,1H),7.44-7.30(m,4H),6.30(t,J=1.8Hz,1H),5.70-5.63(m,2H) ),4.72(q,J=6.3Hz,2H),3.62-3.57(m,2H),3.42-3.33(m,3H).2.96-2.89(m,1H),1.75(bs,4H),1.41(bs,2H). LCMS: retention time 1.92 min (99.04% purity), m / z 352.23 [M+H] + .

[0226] 3-methylene-5-(2-(1-(prop-2-yn-1-yl)-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)δ:7.70(s,1H),7.57(s,1H),7.44-7.31(m,4H),6.30(t,J=2.7Hz,1H),5.74 -5.66(m,2H),5.01(d,J=2.7Hz,2H),3.27-2.18(m,1H),2.97-2.89(m,1H),2.55(t,J=2.4Hz,1H). LCMS: Retention time 2.42 min (99.63% purity), m / z 279.16 [M+H] + .

[0227] 5-(2-(2-methyl-1H-imidazol-1-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)δ:7.62-7.50(m,3H),7.28(s,1H),7.21(s,1H),7.05-6.92(m,1H),6.31(s,1H),5.69(d,J= 2.1Hz,1H),5.29(t,J=7.2Hz,1H),5.11(t,J=7.5Hz,1H).3.17-2.84(m,1H),2.82-2.77(m,1H),2.77-2.69(m,3H). LCMS: retention time 069 min (99.29% purity), m / z 255.11 [M+H] + .

[0228] 5-(2-(2-methoxypyrimidin-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)8.51(s,2H),7.54-7.42(m,3H),7.42- 7.23(m,1H),6.31(t,J=2.7Hz,2H),5.68(t,J=2.4Hz,1H),5.47(q,J=6.6Hz,1H),4.08(s,3H),3.23-3.13(m,1H),2.95-2.87(m,1H); LCMS(m / z):282[M+H] + .

[0229] 5-(4'-methoxy-[1,1'-biphenyl]-2-yl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)7.47-7.35(m,3H),7.24-7.20(m,2H),6.99-6.95(m,2H),6.26(t ,J=2.7Hz,3H),5.62-5.57(m,2H),3.86(s,3H),3.13-3.031(m,1H),2.88-2.78(m,1H); Mass:354.3[M+H] + .

[0230] 3-methylene-5-(2-(1-propyl-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one: [ka] 1H-NMR(300MHz,CDCl3)δ:7.53-7.48(m,2H),7.44-7.41(m,1H),7.38-7.29(m,3H),6.29(t,J=3.0Hz,1H),5.75-5.70(m,1H),5. 66(t,J=2.4Hz,1H),4.13(t,J=6.9Hz,2H),3.26-3.18(m,1H),2.97-2.89(m,1H),1.94(q,J=7.5Hz,2H),0.96(t,J=7.5Hz,3H), LCMS: retention time 2.49 min (98.12% purity), m / z 283.19 [M+H] + .

[0231] 5-(2-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)δ:7.54-7.49(m,2H),7.42-7.39(m,1H),7.36-7.27(m,3H),6.27(t,J=2.7Hz,1H),5.7 1-5.64(m,2H),3.67-3.60(m,1H),3.26-3.17(m,1H),2.96-2.87(m,1H)1.20-1.15(m,2H),1.03-1.09(m,2H) LCMS(m / z):281.24[M+H]

[0232] 3-methylene-5-(2-(thiazol-2-yl)phenyl)dihydrofuran-2(3H)-one [ka] 1H-NMR (300 MHz, CDCl3) δ: 7.92 (d, J = 1.8 Hz, 1H), 7.68 (dd, J = 1.2 and 7.5 Hz, 1H), 7.57 (dd, J = 1.5 and 4.8 Hz, 1H), 7.53-7.46 (m, 1H), 7.46-7.39 (m, 2H), 6.31-6.24 (m, 2H), 5.65 (t, J = 2.4 Hz, 1H), 3.64-3.54 (m, 1H), 2.85-2.76 (m, 1H); LCMS(m / z):258.14[M+H]

[0233] 5-(2-(1-isopropyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one: [ka] 1 H-NMR(300MHz,CDCl3)δ:7.57-7.53(m,2H),7.43-7.41(m,1H),7.37-7.30(m,3H),6.30(t,J=2.7 Hz,1H),5.73-7.66(m,2H),4.62-4.53(m,1H),3.28-3.17(m,1H),2.99-2.89(m,1H),1.56(s,6H): LCMS: Retention time 2.79 min (98.25% purity), m / 283.24 [M+H] + .

[0234] 3-Methylene-5-(3'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)dihydrofuran-2(3H)-one [ka] 300MHz, CDCl3)7.58(d,J=3Hz,1H),7.56-7.51(m,3H),7.49-7.38(m,3H),7.28(d,J=1.5Hz,1H),6.2 8(t,J=3Hz,1H),5.64(t,J=2.4Hz,1H),5.47(q,J=6.6Hz,3H),3.14-3.04(m,1H),2.92-2.82(m,1H); LCMS(m / z):318[M+H]+ .

[0235] 5-(2-(6-methoxypyridin-3-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one: [ka] 1 H-NMR(300MHz,CDCl3)δ:8.15(d,J=2.1Hz,1H),7.63(dd,J=2.4,8.4Hz,1H),7.50-7.38(m,3H),7.23(d,J=1.5Hz,2H),6.87(dd,J=0. 6,8.7Hz,1H),6.28(t,J=2.7Hz,1H),5.65(t,J=2.4Hz,1H),5.51(q,J=6.6Hz,1H),4.01(s,3H),3.20-312(m,1H),2.92-2.84(m,1H); MS(m / z):281[M+H] + .

[0236] 5-(2-Methoxyphenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)δ:7.34-7.28(m,2H),6.99-6.91(m,1H),6.88(d,J=0.9Hz,1H),6.28(t,J=3Hz, 1H),5.72(q,J=2.4Hz,1H),5.62(t,J=2.4Hz,1H),3.83(s,3H),3.47-3.37(m,1H),2.88-2.79(m,1H); MS(m / z):204[M+H] + .

[0237] 3-methylene-5-(3-phenoxyphenyl)dihydrofuran-2(3H)-one: [ka] 1H-NMR(300MHz,CDCl3)δ:7.37-7.31(m,3H),7.15-7.04(m,1H),7.02-6.94(m,5H),6.30(t,J=3 .0Hz,1H),5.68(t,J=2.4Hz,1H),5.48(t,J=7.2Hz,1H),3.42-3.34(m,1H),3.33-2.86(m,1H), LCMS: Retention time 6.31 min (95.71% purity); m / z 267.1 [M+H] + .

[0238] 3-methylene-5-(4-phenoxyphenyl)dihydrofuran-2(3H)-one: [ka] 1 H-NMR(300MHz,CDCl3)δ:7.37-7.27(m,4H),7.15-7.02(m,1H),7.02-6.99(m,4H), 6.31(t,J=2.7Hz,1H),5.50(t,J=6.6Hz,1H),3.43-3.34(m,1H),2.97-289(m,1H), LCMS: retention time 2.72 min (94.91% purity), m / z 267.14 [M+H] + .

[0239] 3-methylene-5-(quinolin-8-yl)dihydrofuran-2(3H)-one: [ka] 1 H-NMR(300MHz,CDCl3)δ:8.89(q,J=1.8Hz,1H),8.18(dd,J=1.8 and 8.4Hz,1H),7.78(q,J=8.4Hz,2H),7.58-7.52(m,1H), 7.47-7.43(m,1H),6.60-6.58(m,1H),6.31(t,J=2.7Hz,1H),5.63(t,J=2.4Hz,1H),3.83-3.73(m,1H),2.94-2.85(m,1H): MS(m / z): 226.2 [M + H] + .

[0240] [ka] 5-(2-chloronaphthalen-1-yl)-3-methylenedihydrofuran-2(3H)-one: 1 H-NMR(300MHz,CDCl3)δ:7.91-7.83(m,2H),7.78(d,J=8.7Hz,1H),7.56-7.43(m,3H), 6.56(t,J=8.4Hz,1H),6.47(q,J=2.4Hz,1H),5.80(t,J=2.4Hz,1H),3.47-3.25(m,2H), LCMS: Retention time 2.68 min (97.47% purity), m / z 300.12 [M+H] + .

[0241] [ka] 5-(2-Methoxynaphthalen-1-yl)-3-methylenedihydrofuran-2(3H)-one: 1 H-NMR(300MHz,CDCl3)δ:7.86-7.81(m,3H),7.53(t,J=1.2Hz,1H),7.48(d,J=1.5Hz,1H),7.40-7.27(m, 1H),6.50(t,J=6.3Hz,1H),6.36(t,J=3.0Hz,1H),5.67(t,J=2.4Hz,1H),3.91(s,3H),3.42-3.21(m,2H): LCMS: retention time 2.57 min (96.48% purity), m / z 255.10 [M+H] + .

[0242] [ka] 5-(2-(1-methyl-1H-indazol-5-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one: 1H-NMR(300MHz,CDCl3)δ:8.09(s,1H),7.67(t,J=0.6Hz,1H),7.51-7.45(m,2H),7.43-7.38(m, 2H),7.32-7.25(m,2H),5.60-5.55(m,2H),4.15(s,3H),3.07-2.98(m,1H),2.91-2.82(m,1H). LCMS(m / z):305.17[M+H] + .

[0243] 3-methylene-5-(2-(1-propyl-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one: [ka] 1 H-NMR(300MHz,CDCl3)δ:7.53-7.48(m,2H),7.44-7.41(m,1H),7.38-7.29(m,3H),6.29(t,J=3.0Hz,1H),5.75-5.70(m,1H),5. 66(t,J=2.4Hz,1H),4.13(t,J=6.9Hz,2H),3.26-3.18(m,1H),2.97-2.89(m,1H),1.94(q,J=7.5Hz,2H),0.96(t,J=7.5Hz,3H), LCMS: retention time 2.49 min (98.12% purity), m / z 283.19 [M+H] +

[0244] 5-(2-(2-methyl-2H-indazol-5-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one: [ka] 1 H-NMR(300MHz,CDCl3)δ:7.93(s,1H),7.73(d,J=8.7Hz,2H),7.68-7.61(m,1H),7.54-7.46 (m,2H),7.46-7.37(m,2H),7.37-7.33(m,2H),7.31-7.28(m,1H),7.19(dd,J=3 and 9Hz,1H): LCMS(m / z):305.16[M+H] + . [ka]

[0245] tert-Butyl-6-(benzyloxy)-3-(4-methylene-5-oxotetrahydrofuran-2-yl)-1H-indole-1-carboxylate: 1 H-NMR(300MHz, CDCl3)δ:7.86(bs,1H),7.46(d,J=8.9Hz,3H),7.42-7.32(m,5H),6.96(dd,J=2.4 and 8.7Hz,1 H),6.35(t,J=3.0Hz,1H),5.77-5.72(m,2H),5.13(s,1H),3.81-3.45(m,1H),3.18-3.09(m,1H),1.65(s,9H), LCMS: retention time 3.12 min (99.71% purity), m / z 413.26 [M+H] + .

[0246] 5-(2-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one: [ka] 1 H-NMR(300MHz,CDCl3)δ:7.45-7.30(m,3H),7.30(s,1H),7.21-7.18(m,1H),6.27-6.21(m,1H),5.62(t,J=2.4Hz ,1H),5.54(q,J=6.6Hz,1H),3.95(s,3H),3.72(s,2H),3.16-3.07(m,1H),2.86-2.78(m,1H),2.63-2.54(m,1H), LCMS: retention time 2.63 min (96.31% purity), m / z 269.15 [M+H] + .

[0247] 3-methylene-5-(2-(1-phenethyl-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one: [ka] 1 H-NMR(400MHz,CDCl3):7.56(s,1H),7.55-7.37(m,1H),7.36-7.27(m,1H),7.24-7.17(m,4H),7.11(s,1H),7.09-7.07(m,2H),6.3 2-6.30(t,1H),5.66-5.65(t,1H),5.44-5.41(m,1H),4.43-4.39(t,2H),3.22-3.19(t,2H),3.05-2.99(m,1H),2.86-2.80(m,1H).

[0248] 5-(4-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR (400 MHz, CDCl 3): 7.525(s,1H),7.46(s,1H),7.32-7.30(d,J=8Hz,1H),7.18-7.16(d,J=8.4Hz,1H),7.12(s,1H),6.2 9-6.28(t,1H),5.70-5.65(m,2H),3.97(s,3H),3.24-3.16(m,1H),2.97-2.90(m,1H),2.36(s,3H).

[0249] 5-(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one: [ka] 1H-NMR (400MHz, CDCl3):7.50(s,1H),7.43(s,1H),7.22(s,1H),7.19-7.14(m,2H),6.30-6.2 9(t,1H),5.71-5.66(m,2H),3.97(s,3H),3.25-3.17(m,1H),2.95-2.88(m,1H),2.39(s,3H).

[0250] 5-(3-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1H-NMR (400MHz, CDCl3):7.38(s,1H),7.31-7.23(m,4H),6.25-6.23(t,1H),5.6 0-5.59(t,1H),3.90(s,3H),3.10-3.04(m,1H),2.82-2.76(m,1H),2.13(s,3H).

[0251] 5-(2-(1-methyl-1H-pyrazol-4-yl)-4-phenoxyphenyl)-3-methylenedihydrofuran-2(3H)-one: [ka] 1 H-NMR(300MHz,CDCl3)δ:7.48(d,J=10.5Hz,2H),7.38-7.32(m,3H),7.15-7.10(m,1H),7.03(d,J=7.8Hz,2H),6. 98-6.92(m,2H),6.29(t,J=2.4Hz,1H),5.67(t,J=9.0Hz,2H),3.94(s,3H),3.26-3.18(m,1H),3.01-2.94(m,1H). LCMS: retention time 2.65 min (99.57% purity), m / z 347.25 [M+H] + .

[0252] 5-(3-(1-methyl-1H-pyrazol-4-yl)-[1,1'-biphenyl]-4-yl)-3-methylenedihydrofuran-2(3H)-one: [ka] 1 H-NMR(300MHz,CDCl3)δ7.61-7.57(m,4H),7.52(t,J=1.8Hz,2H),7.49-7.42(m,2H),7.39-7.34(m,1H),6.31(t ,J=3.0Hz,1H),5.76(q,J=6.0Hz,1H),5.69(t,J=2.4Hz,1H),3.99(s,3H),3.31-3.20(m,1H),3.03-2.93(m,1H). LCMS: retention time 2.67 min (98.85% purity), m / z 331.21 [M+H] + .

[0253] 5-(4,5-dichloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one: [ka] 1H-NMR (400MHz, CDCl3):7.53-7.50(s,2H),7.48-7.46(s,1H),7.42-7.38(s,1H),6.35-6 .32(t,1H),5.7(t,1H),5.66-5.59(m,1H),4.0(s,3H),3.39-3.29(m,1H),2.8-2.6(m,1H).

[0254] 5-(1,1'-dimethyl-1H,1'H-[4,4'-bipyrazol]-5-yl)-3-methylenedihydrofuran-2(3H)-one [ka] 1H-NMR(300MHz, CDCl3)δ:7.40(dd,J=0.6 and 5.1Hz,2H),7.31(s,1H),6.33(t,J=2 .7Hz,1H),5.71-5.65(m,2H),3.91(s,6H),3.27-3.18(m,1H),3.13-3.02(m,1H). LCMS: retention time 1.55 min (95.51% purity), m / z 259.15 [M+H] + .

[0255] Synthesis of lactam analogues: [ka] Step 1: Synthesis of 4-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzaldehyde: To a stirred solution of 2-bromo-4-chlorobenzaldehyde (1 g, 4.5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.18 g, 5.46 mmol) in 1,4-dioxane (15 mL) was added potassium carbonate (1.5 g, 11.83 mmol) in water (10 mL). The resulting mixture was degassed for 5 minutes, and tetrakis(triphenylphosphine)-palladium (100 mg, 10% mol) was added. The reaction mixture was degassed again for 5 minutes. The reaction mixture was heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with water (2 × 30 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the crude material. This was purified by silica gel column chromatography (eluent: 35-50% ethyl acetate and petroleum ether) to give 4-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzaldehyde as a pale yellow solid (0.9 g, 89%). H-NMR (400 MHz, CDCl): 10.159 (s, 1H), 7.89-7.87 (d, J = 8.8 Hz, 1H), 7.6 (s, 1H), 7.49 (s, 1H), 7.26-7.22 (m, 2H), 3.99 (s, 3H), 2.43 (s, 3H).

[0256] Step 2: Synthesis of N-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzylidene)-2-methylpropane-2-sulfinamide: To a stirred solution of 4-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzaldehyde (0.6 g, 2.7 mmol) in tetrahydrofuran (10 mL) was added 2-methylpropane-2-sulfinamide (0.39 g, 3.26 mmol) and titanium isopropoxide (1.95 g, 6.8 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was quenched with water (50 mL) and the solid was filtered. The filtrate was extracted with ethyl acetate (2 × 25 mL). The organic layers were combined, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the crude material. Purification by column chromatography using silica mesh (35-40% ethyl acetate in petroleum ether as eluent) gave N-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzylidene)-2-methylpropane-2-sulfinamide as a pale yellow gum (550 mg, 62.5%).

[0257] Step 3: Synthesis of methyl 4-((tert-butylsulfinyl)amino)-4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate: To a stirred solution of N-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzylidene)-2-methylpropane-2-sulfinamide (0.4 g, 1.23 mmol) and methyl 2-(bromomethyl)acrylate (280 mg, 1.66 mmol) in THF (4 mL) was added zinc (290 mg, 4.48 mmol) and saturated NH4Cl in water (2 mL). The resulting mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After 50% consumption of the starting material by TLC, the reaction mixture was filtered and the filtrate was extracted with ethyl acetate (20 mL) and washed with water (2 x 10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the crude material as a dark yellow gum. Purification by column chromatography on silica gel using 5-10% MeOH in DCM as eluent gave (E)-N-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzylidene)-2-methylpropane-2-sulfinamide as a pale yellow gum (150 mg, 30%).

[0258] Step 4: Synthesis of methyl 4-amino-4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate: To a stirred solution of methyl 4-((tert-butylsulfinyl)amino)-4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate (0.15 g, 0.354 mmol) in diethyl ether (2 mL) and THF (2 mL) was added HCl (2 M in diethyl ether, 1.5 mL) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure at low temperature to give the product, methyl 4-amino-4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate, as an off-white gum (100 mg, 88%).

[0259] Step 5: Synthesis of 5-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenepyrrolidin-2-one: To a stirred solution of methyl 4-amino-4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate (0.1 g, 0.31 mmol) in MeOH (4 mL) was added K2CO3 (90 mg, 0.62 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM (20 mL) and washed with water (2 × 10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give crude 5-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenepyrrolidin-2-one as a pale yellow gum. The crude compound thus obtained was purified by column chromatography using silica mesh column chromatography (2-5% MeOH in DCM as eluent) to give N-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzylidene)-2-methylpropane-2-sulfinamide as an off-white gum (60 mg, 67%). 1 H-NMR (400 MHz, CDCl3) : 7.48(s,1H),7.40(s,1H),7.36-7.26(m,2H),6.13-6.07(m,2H),5.40(m, 2H),3.97(s,1H),4.97-4.94(m,1H),3.23-3.18(m,1H),2.7-2.6(m,1H). MS:287.9

[0260] Step 6: Synthesis of 5-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-1-methyl-3-methylenepyrrolidin-2-one To a stirred solution of N-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzylidene)-2-methylpropane-2-sulfinamide (50 mg, 0.31 mmol) in THF (4 mL) was added NaH (90 mg, 0.62 mmol) followed by iodomethane (22 mg, 0.62 mmol) at room temperature.

[0261] The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was quenched with water and extracted with ethyl acetate (2 × 10 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude product as a pale yellow gum. The crude material was purified by column chromatography on silica mesh (2–5% MeOH in DCM as eluent) to give 5-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-1-methyl-3-methylenepyrrolidin-2-one as an off-white gum (60 mg, 67%). 1H-NMR (400MHz, CDCl3):7.46(s,1H),7.39(s,1H),7.31-7.30(m,2H),7.07-7.04(m,1H),6.08(br s,1H),5.36(m,1H),4.61-4.78(m,1H),3.97(s,3H),3.24(m,1H),2.97-2.90(m,1H),2.36(s,3H). MS:302.2

[0262] Synthesis scheme for amide analogues: [ka] Step 1: tert-butyl 2-(4-bromo-1H-pyrazol-1-yl)acetate: To a stirred solution of 4-bromo-1H-pyrazole (3.0 g, 20.4 mmol) in DMF (25 mL) at 0 °C, sodium hydride (0.58 g, 24.49 mmol) was added and stirred for 30 min. Then, tert-butyl 2-bromoacetate (4.3 g, 22.45 mmol) and KI (3.38 g, 2.04 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 20 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (2 × 100 mL) and washed with water (2 × 50 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the crude material. It was purified by column chromatography using 30% ethyl acetate in hexane as an eluent to give tert-butyl 2-(4-bromo-1H-pyrazol-1-yl)acetate. Yield 4.5g (84.42%) 1 H-NMR (300MHz, CDCl3)δ:7.49(s,2H),4.77(s,2H),1.47(s,9H);LCMS: Retention time 2.55 minutes (99.67% purity), m / z206.98[M-18] -

[0263] Step 2: tert-butyl 2-(4-(2-formylphenyl)-1H-pyrazol-1-yl)acetate: To a stirred solution of (2-formylphenyl)boronic acid (0.76 g, 5.07 mmol), tert-butyl 2-(4-bromo-1H-pyrazol-1-yl)acetate (1 g, 5.07 mmol) in 1,4-dioxane (20 mL) was added potassium tert-butoxide (1.49 g, 15.21 mmol) over 30 minutes under a nitrogen purge. The reaction mixture was again degassed with nitrogen gas, and Pd(PhP) (0.29 g, 0.25 mmol) was added at room temperature. The reaction mixture was stirred at 110 °C for 16 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (2 × 100 mL) and washed with water (2 × 50 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude material. This was purified by column chromatography (eluent: 30% ethyl acetate and hexane) to give tert-butyl 2-(4-(2-formylphenyl)-1H-pyrazol-1-yl)acetate. Yield: 0.574 g (39.58%) 1 H-NMR(300MHz, CDCl3)δ:10.23(d,J=0.6Hz,1H),7.98(dd,J=0.9 and 7.8Hz,1H),7.68(s,1H),7.61-7.5 8(m,2H),7.47-7.43(m,2H),4.89(s,2H),1.49(s,9H);LCMS: Retention time 2.59 minutes (89.67% purity), m / z287.15[M+1] +

[0264] Step 3: Methyl 4-(2-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoate: To a stirred solution of tert-butyl 2-(4-(2-formylphenyl)-1H-pyrazol-1-yl)acetate (0.57 g, 2.00 mmol)) in dry THF (10 mL) was added methyl 2-(bromomethyl)acrylate (0.395 g, 2.2 mmol), saturated ammonium chloride (4 mL), and zinc (0.154 g, 2.4 mmol). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (2 × 100 mL) and washed with water (2 × 50 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude material. This was purified by column chromatography (eluent: 30% ethyl acetate in hexane) to give methyl 4-(2-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoate. Yield: 0.820 g (98%). 1 H-NMR(300MHz,CDCl3)δ:7.74-7.63(m,3H),7.37-7.28(m,3H),6.23(d,J=1.2Hz,1H),5.63(d, J=0.9Hz,2H),4.90(d,J=7.8Hz,2H),3.73(s,3H),2.79-2.63(m,2H)2.59(s,1H),1.48(s,9H).

[0265] Step 4: 2-(4-(2-(4-methylene-5-oxotetrahydrofuran-2-yl)phenyl)-1H-pyrazol-1-yl)acetic acid: To a stirred solution of methyl 4-(2-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoate (0.820 g, 2.12 mmol) in DCM (10 mL) was added trifluoroacetic acid (0.1 mL). The reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure, diluted with dichloromethane (2 × 100 mL), and washed with water (2 × 50 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the crude material. This was purified by column chromatography (15% ethyl acetate in hexane as eluent) to give 2-(4-(2-(4-methylene-5-oxotetrahydrofuran-2-yl)phenyl)-1H-pyrazol-1-yl)acetic acid, yield 0.750 g (90%). 1 H-NMR(300MHz,CDCl3)δ:7.54(s,2H),7.35-7.30(m,2H),7.19(bs,1H),6.20(s,1H),5.60(s,2H),5.2 9-4.94(m,4H),3.15(bs,1H)2.86(d,J=12.9Hz,1H).:LCMS: Retention time 4.24 minutes (99.09% purity), m / z299.10[M+1] +

[0266] Step 5: N,N-dibutyl-2-(4-(2-(4-methylene-5-oxotetrahydrofuran-2-yl)phenyl)-1H-pyrazol-1-yl)acetamide: To a stirred solution of 2-(4-(2-(4-methylene-5-oxotetrahydrofuran-2-yl)phenyl)-1H-pyrazol-1-yl)acetic acid (0.4 g, 1.47 mmol) in dichloromethane (10 mL) was added triethylamine (0.54 g, 5.3 mmol), dibutylamine (0.542 g, 5.3 mmol), and a 50% solution of propylphosphonic anhydride in ethyl acetate (0.64 g, 2.01 mmol) at 0° C. The reaction mixture was stirred at 50° C. for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, it was diluted with dichloromethane (2×100 mL) and washed with water (2×50 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the crude material. This was purified by prep HPLC to give N,N-dibutyl-2-(4-(2-(4-methylene-5-oxotetrahydrofuran-2-yl)phenyl)-1H-pyrazol-1-yl)acetamide. Yield: 0.420 g (84.63%). 1 H-NMR(300MHz,CDCl3)δ:7.55(s,1H),7.50(s,1H),7.37-7.33(m,1H),7.29-7 .26(m,2H),6.20(t,J=2.7Hz,1H),5.70(q,J=6.0Hz,1H),5.57(t,J=2.4Hz,1H ),5.69(t,J=2.1Hz,1H)5.57(t,J=2.4Hz,1H),4.95(s,2H),3.65-3.14(m,4H) ,2.87-2.77(m,1H),1.57-1.43(m,4H),1.43-1.32(m,4H),1.29-1.21(m,6H). LCMS: retention time 2.78 min (99.67% purity), m / z 410.26 [M+1] +

[0267] Using this scheme, the following similar compounds were synthesized: 3-methylene-5-(2-(1-(2-oxo-2-(piperidin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,DMSO-d6)δ:7.86(s,1H),7.61(s,1H),7.38(s,4H),6.12(s,1H),5.77(s,2H),5 .16(s,2H),3.75-3.65(m,1H),3.44(s,4H),2.88(d,J=18.0Hz,1H),1.57(s,4H),1.45(s,2H). LCMS: RT 2.36 min (99.42% purity), m / z 366.18 [M+H] + .

[0268] 3-methylene-5-(2-(1-(2-oxo-2-(4-phenylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,DMSO-d6)δ:7.89(s,1H),7.63(s,1H),7.39(s,4H),7.24(q,J=7.5Hz,2H),6.98(d,J=7.8Hz,2H),6.82(t,J=7.2Hz,1H), 6.12(t,J=2.7Hz,1H),5.82-5.75(m,2H),5.26(s,2H),3.65(q,J=4.2Hz,4H),3.47-3.38(m,1H),3.24-3.14(m,4H),2.92-2.83(m,1H). LCMS: retention time 2.55 min (99.58% purity), m / z 443.38 [M+H] + .

[0269] 3-methylene-5-(2-(1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one [ka] 1H-NMR(300MHz,CDCl3)δ7.87(s,1H),7.62(s,1H),7.38(s,4H),6.12(t,J=2.7Hz,1H),5.82-5.75(m,2H),5.0 7(s,2H),3.50(t,J=6.9Hz,2H),3.46-3.32(m,3H),2.91-2.84(m,1H),1.96-1.88(m,2H),1.83-1.75(m,2H). LCMS: retention time 2.19 min (98.27% purity), m / z 352.19 [M+H] + .

[0270] [ka] 3-methylene-5-(2-(1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one 1H-NMR(300MHz,CDCl3)δ7.817(s,1H),7.62(s,1H),7.38(s,4H),6.12(t,J=2.7Hz, 1H),5.81-2.77(m,1H),5.21(d,J=5.4Hz,2H),3.63-3.41(m,9H),2.92-2.83(m,1H). LCMS: Retention time 2.11 min (97.06% purity), m / z 366.26[M+H]+.

[0271] Synthesis of N-methyl-2-(4-(2-(4-methylene-5-oxotetrahydrofuran-2-yl)phenyl)-1H-pyrazol-1-yl)acetamide: [ka] Step 1: Synthesis of 2-(4-(2-formylphenyl)-1H-pyrazol-1-yl)-N-methylacetamide: To a stirred solution of 2-(4-(2-formylphenyl)-1H-pyrazol-1-yl)acetic acid (0.3 g, 1.30 mmol) and methylamine (0.170 g, 1.95 mmol) in DMF (5 mL) at 0 °C, DIPEA (0.504 g, 3.91 mmol) was added, followed by HATU (0.743 g, 1.95 mmol). The reaction mixture was stirred at room temperature (rt) for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2 × 50 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude compound. The resulting crude product was purified by SiO2 column chromatography (eluent: 15% ethyl acetate in hexane) to give 2-(4-(2-formylphenyl)-1H-pyrazol-1-yl)-N-methylacetamide as a brown gummy solid (0.3 g, 99.59%). 1 H-NMR(300MHz,CDCl3)δ:10.16(s,1H),8.07(s,1H),8.02-8.01(m,1H),7.87(d,J=7.8Hz,1 H),7.76(s,1H),7.73-7.67(m,1H),7.56-7.42(m,2H),5.75(s,2H),2.64(d,J=4.5Hz,3H).

[0272] Step 2: Synthesis of methyl 4-hydroxy-4-(2-(1-(2-(methylamino)-2-oxoethyl)-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate: To a stirred solution of 2-(4-(2-formylphenyl)-1H-pyrazol-1-yl)-N-methylacetamide (0.3 g, 1.23 mmol) in THF (2 mL) was added saturated ammonium chloride (5 mL) and zinc (0.096 g, 1.48 mmol). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×50 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the crude compound. The resulting crude product was purified by SiO column chromatography (eluent: 50% ethyl acetate in hexanes) to give methyl 4-hydroxy-4-(2-(1-(2-(methylamino)-2-oxoethyl)-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate as a brown gum (0.180 g, 42.66%). 1 H-NMR(300MHz,CDCl3)δ:8.17(bs,1H),8.08-7.92(m,2H),7.86(s,1H),7.58(s,1H),7.38(s,1H),7.33-7.23(m,2H),6.05(s,1H),5. 77(d,J=7.5Hz,1H),5.58(s,1H),5.15(d,J=4.5Hz,1H),4.80(t,J=6.9Hz,2H),3.62(s,3H),3.15-3.12(m,2H),2.64(d,J=4.5Hz,2H). LCMS: retention time 1.98 min (84.35% purity), m / z 344.22 [M+H] + .

[0273] Step 3: Synthesis of N-methyl-2-(4-(2-(4-methylene-5-oxotetrahydrofuran-2-yl)phenyl)-1H-pyrazol-1-yl)acetamide: To a stirred solution of methyl 4-hydroxy-4-(2-(1-(2-(methylamino)-2-oxoethyl)-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate (0.180 g, 0.52 mmol) in DCM (10 mL) at 0° C. was added trifluoroacetic acid (0.5 mL). The reaction mixture was then stirred at room temperature for 12 hours. The reaction progress was monitored by TLC. After completion of the reaction of the starting material, the reaction mixture was concentrated under reduced pressure to obtain the crude compound. The obtained crude product was purified by preparative HPLC to obtain N-methyl-2-(4-(2-(4-methylene-5-oxotetrahydrofuran-2-yl)phenyl)-1H-pyrazol-1-yl)acetamide as an off-white gummy solid (0.050 g, 30.9%). 1 H-NMR(300MHz,DMSO-d6)δ:7.99(s,1H),7.92(s,1H),7.63(s,1H),7.38(s,4H),6.13(s,1H),5 .83-5.77(m,2H),4.82(s,2H),3.46(d,J=6.3Hz,1H),2.91-2.85(m,1H),2.63(d,J=3.9Hz,3H). LCMS: retention time 2.04 min (99.85% purity), m / z 312.17 [M+H] + .

[0274] Synthesis of open chain amide analogues: 4-Hydroxy-4-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoic acid: [ka] Step 1: 4-hydroxy-4-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoic acid: To a stirred solution of methyl 4-hydroxy-4-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate (0.080 g, 2.7 mmol) in a mixture of THF (3 mL) and methanol (1 mL) at 0 °C, aqueous lithium hydroxide (0.014 g, 3.3 mmol, 1 mL of water) was added. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure. The reaction mixture was acidified with potassium hydrogen sulfate and extracted with 5% methanol and dichloromethane (2 × 50 mL). The organic layer was evaporated under reduced pressure to give the crude material. This was purified by column chromatography (10–15% methanol in dichloromethane as eluent) to give 4-hydroxy-4-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoic acid. Yield: 0.250g (64.9%, gummy) 1 H-NMR(300MHz,CDCl3)δ:7.65(d,J=8.1Hz,1H),7.48(d,J=11.4Hz,2H),7.38-7.32(m,1H),7.29-7.23(m,1H) ,7.20(dd,J=1.5 and 7.8Hz,1H),6.25(s,1H),5.87(bs,2H),5.16(t,J=6.6Hz,1H),3.85(s,3H),3.46(s,1H); LCMS(m / z):273[M+H] + .

[0275] Step 2: 4-hydroxy-N-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanamide: A solution of 4-hydroxy-4-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoic acid (0.1 g, 0.36 mmol) in DMF (6 mL), methylamine (0.248 g, 0.36 mmol), and N,N-diisopropylethylamine (0.47 g, 0.36 mmol) was added with stirring for 30 min. The reaction mixture was cooled to 0 °C, and HATU (0.209 g, 0.055 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was then diluted with cold water and extracted with dichloromethane (2 × 50 mL). The organic layer was evaporated under reduced pressure to give the crude material. This was purified by column chromatography (10–15% methanol in dichloromethane as eluent) to give 4-hydroxy-N-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanamide. Yield: 0.030g (54%). 1 H-NMR(300MHz,CDCl3)δ:7.67-7.65(m,1H),7.57-7.55(m,2H),7.36-7.28(m,1H),7.28-7.26(m,1H),7.25(d,J=1.2H) z,1H),6.07(s,1H),5.55(s,1H),5.13(s,1H),4.65(s,1H),3.96(s,3H),3.73(s,1H),2.83(s,3H),2.67-2.52(m,2H); LCMS(m / z):286[M+H] + .

[0276] Synthesis of additional compounds [ka] Step 1: Synthesis of 2-bromo-4-(hydroxymethyl)benzaldehyde: [ka] To a stirred solution of ethyl 3-bromo-4-cyanobenzoate (200 mg, 0.78 mmol) in THF (10 mL) was added DIBAL-H (0.59 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2 × 10 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by column chromatography using silica gel (mesh: 60-120) with 15-20% ethyl acetate and petroleum ether as eluent to give 2-bromo-4-(hydroxymethyl)benzaldehyde as an off-white gum (80 mg, 47.27%).

[0277] Step 2: Synthesis of 4-(hydroxymethyl)-2-(1-methyl-1H-pyrazol-4-yl)benzaldehyde: [ka] procedure: A suspension of 2-bromo-4-(hydroxymethyl)benzaldehyde (80 mg, 0.37 mmol), 1-methyl-1H-pyrazol-4-yl)boronic acid (60.89 mg, 0.48 mmol), and potassium carbonate (134.27 mg, 0.96 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was degassed for 5 minutes, and tetrakis(triphenylphosphine)palladium (8 mg, 10% mol) was added. The reaction mixture was degassed for an additional 5 minutes and heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2 × 10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give a crude mixture. This was purified by column chromatography on silica gel (mesh: 60-120) and the required compound was eluted with 15-20% ethyl acetate and petroleum ether to give 4-(hydroxymethyl)-2-(1-methyl-1H-pyrazol-4-yl)benzaldehyde as an off-white gum (60 mg, 59.67%).

[0278] Step 3: Synthesis of methyl 4-hydroxy-4-(4-(hydroxymethyl)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate [ka] To a stirred solution of 4-(hydroxymethyl)-2-(1-methyl-1H-pyrazol-4-yl)benzaldehyde (60 mg, 0.27 mmol) in tetrahydrofuran (10 mL) was added methyl 2-(bromomethyl)acrylate (59.60 mg, 0.33 mmol), saturated ammonium chloride (2 mL), and zinc (65.29 mg, 0.99 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2 × 10 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give methyl 4-hydroxy-4-(4-(hydroxymethyl)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate (60 mg, 69%).

[0279] Step 4: 5-(4-(hydroxymethyl)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] To a stirred solution of methyl 4-hydroxy-4-(4-(hydroxymethyl)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate (60 mg, 0.08 mmol) in dry dichloromethane (10 mL) was added trifluoroacetic acid (0.3 mL). The reaction mixture was stirred at room temperature overnight. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was evaporated under reduced pressure to obtain the crude compound, which was purified by column chromatography using silica gel (mesh 100-200). The desired compound was eluted with 30% ethyl acetate and hexane to give 5-(4-(hydroxymethyl)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one as an off-white gum (30 mg, 55%). 1 H-NMR (400MHz, CDCl3):7.52(s,1H),7.47(s,1H),7.44-7.36(d,1H),7.34(d,1H),7.32(s,1H),6.30(t ,1H),5.73-5.70(t,1H),5.67(s,1H),4.72(s,2H),3.97(s,3H),3.25-3.19(m,1H),2.95-2.89(m,1H). LCMS (M+H=285.1, 82.53%).

[0280] 5-(1,1'-dimethyl-1H,1'H-[3,4'-bipyrazol]-4-yl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR (400 MHz, CDCl3) : 7.74(s,1H),7.68(s,1H),7.39(s,1H),6.30-6.29(t,1H),5.70-5.68(m,1H),5. 56-5.52(t,1H),3.98(s,3H),3.91(s,3H),3.37-3.27(m,1H),3.02-2.95(m,1H).

[0281] Synthesis of (S)-3-acryloyl-4-benzyloxazolidin-2-one: [ka] To a stirred solution of (S)-4-benzyloxazolidin-2-one (250 mg, 1.41 mmol) in DCM (15 mL) was added DIPEA (364 mg, 2.82 mmol) and DMAP (2 mg, 0.014 mmol). The resulting mixture was cooled to 0 °C, and acryloyl chloride (191 mg, 2.16 mmol) was added. The resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was quenched with ice-cold water and extracted with diethyl ether (2 × 10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude mixture thus obtained was purified by column chromatography on silica gel (mesh: 100-200) and the required compound was eluted with 20-30% ethyl acetate in petroleum ether to give (S)-3-acryloyl-4-benzyloxazolidin-2-one as a pale yellow gum (36 mg, 12%). 1 H-NMR (400MHz, CDCl3):7.55-7.48(m,1H),7.35-7.32(m,1H),7.29-7.27(d,1H),7.25-7.21(m,2H),6.63-6 .58(m,1H),5.95-5.92(m,1H),4.76-4.72(m,1H),4.25-4.17(m,2H),3.37-3.33(m,1H),2.84-2.78(m,1H). LCMS (M+H=232.0, 98.82%).

[0282] Synthesis of methyl acryloylphenylalaninate: [ka] To a stirred solution of methyl phenylalaninate hydrochloride (250 mg, 1.16 mmol) in DCM (15 mL) was added DIPEA (300 mg, 2.32 mmol), followed by DMAP (3 mg, 0.016 mmol). The resulting mixture was cooled to 0 °C, and acryloyl chloride (160 mg, 1.74 mmol) was added. The resulting reaction mixture was stirred at RT for 16 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was quenched with ice-cold water and extracted with diethyl ether (2 × 10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the crude mixture. The desired compound was purified by column chromatography on silica gel (mesh: 100-200). The desired compound was eluted with 20-30% ethyl acetate in petroleum ether to give methyl acryloylphenylalaninate (40 mg, 15%) as a pale yellow gum. 1 H-NMR (400MHz, CDCl3):7.30-.26(m,2H),7.25-7.24(d,1H),7.09-7.07(d,1H),6.31-6.26(d,1H),6.12-6. 05(m,1H),6.00-5.98(brs,1H),5.68-5.66(d,1H),4.99-4.95(m,1H),3.74-3.71(s,3H),3.19-3.16(m,2H). LCMS (M+H=234.1, 92.74%).

[0283] Synthesis of methyl 2-acrylamido-2-phenylacetate: [ka] To a stirred solution of methyl 2-amino-2-phenylacetate hydrochloride (250 mg, 1.14 mmol) in DCM (20 mL) was added DIPEA (367.74 mg, 2.850 mmol), followed by DMAP (13.93 mg, 0.11 mmol). The reaction mixture was cooled to 0 °C, and acryloyl chloride (154.19 mg, 1.71 mmol) was added dropwise. The resulting reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was quenched with water (20 mL) and extracted with diethyl ether (2 × 20 mL). The organic layer was dried over Na SO , filtered, and the solvent was evaporated under reduced pressure to give a crude mixture. This was purified by column chromatography using silica gel (mesh: 100-200), and the required compound was eluted with 10-12% ethyl acetate and petroleum ether to give methyl 2-acrylamido-2-phenylacetate as a pale yellow solid (57.1 mg, 52.52%). 1 H-NMR (400MHz, CDCl3):7.39-7.29(m,5H),6.56-6.54(brs,1H),6.34-6.29(dd,1H),6.18-6.12(m,1H),5.70-5.65(m,2H),3.74(s,3H). LCMS (M+H=220.0, 91.53%).

[0284] Synthesis of 4-(1-methyl-1H-pyrazol-4-yl)-3-(4-methylene-5-oxotetrahydrofuran-2-yl)benzoic acid [ka] Step 1: Synthesis of methyl 3-formyl-4-(1-methyl-1H-pyrazol-4-yl)benzoate: [ka] To a stirred solution of methyl 4-bromo-3-formylbenzoate (0.2 g, 0.83 mmol) and 1-methyl-1H-pyrazol-4-yl)boronic acid (210 mg, 0.99 mmol) in 1,4-dioxane (7 mL) was added potassium carbonate (300 mg, 2.15 mmol) in water (4 mL). The resulting mixture was degassed for 5 minutes, and tetrakis(triphenylphosphine)-palladium (20 mg, 10% mol) was added. The reaction mixture was degassed for an additional 5 minutes and heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2 × 10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give a crude mixture. This was purified by column chromatography on silica gel (mesh: 60-120) and the required compound was eluted with 15-20% ethyl acetate and petroleum ether to give methyl 3-formyl-4-(1-methyl-1H-pyrazol-4-yl)benzoate as an off-white gum (180 mg, 90%).

[0285] Step 2: Synthesis of 3-formyl-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid: [ka] To a stirred solution of methyl 3-formyl-4-(1-methyl-1H-pyrazol-4-yl)benzoate (0.18 g, 1.75 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL) was added an aqueous solution of LiOH.HO (160 mg, 1.10 mmol) at room temperature, and the resulting reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was concentrated, diluted with water (25 mL), and washed with ethyl acetate (2 × 25 mL). The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2 × 25 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give 3-formyl-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (100 mg, 58.9%) as an off-white solid.

[0286] Step 3: Synthesis of tert-butyl 3-formyl-4-(1-methyl-1H-pyrazol-4-yl)benzoate: [ka] To a stirred solution of 3-formyl-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (100 mg, 0.43 mmol) in tetrahydrofuran (10 mL) was added BOC anhydride (142.2 mg, 0.65 mmol) followed by DMAP (5.30 mg, 0.04 mmol) at room temperature, and the resulting reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2 × 25 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give a crude mixture. Purification by column chromatography on silica gel (mesh 60-120) and elution with 35-40% ethyl acetate and petroleum ether afforded the desired compound as a pale yellow gum (100 mg, 80.4%).

[0287] Step 4: 3-(1-hydroxy-3-(methoxycarbonyl)but-3-en-1-yl)-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid: [ka] To a stirred solution of tert-butyl 3-formyl-4-(1-methyl-1H-pyrazol-4-yl)benzoate (100 mg, 0.34 mmol) in tetrahydrofuran (10 mL) was added methyl 2-(bromomethyl)acrylate (75.02 mg, 0.41 mmol), saturated ammonium chloride (2 mL), and zinc (82.1 mg, 1.257 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2 × 25 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give 3-(1-hydroxy-3-(methoxycarbonyl)but-3-en-1-yl)-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (100 mg, 86.67%).

[0288] Step 5: 4-(1-methyl-1H-pyrazol-4-yl)-3-(4-methylene-5-oxotetrahydrofuran-2-yl)benzoic acid: [ka] To a stirred solution of 3-(1-hydroxy-3-(methoxycarbonyl)but-3-en-1-yl)-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (100 mg, 0.335 mmol) in dry dichloromethane (10 mL) was added trifluoroacetic acid (0.3 mL). The reaction mixture was stirred overnight at room temperature. After disappearance of the starting material by TLC, the reaction mixture was evaporated under reduced pressure to give the crude compound. This was purified by column chromatography on silica gel (mesh 100-200). The required compound was eluted with 30% ethyl acetate and hexane to give 4-(1-methyl-1H-pyrazol-4-yl)-3-(4-methylene-5-oxotetrahydrofuran-2-yl)benzoic acid as an off-white gum (23 g, 70%). 1H-NMR(400MHz,DMSO):13.2(bS,1H),8.04(s,1H),8.01-7.90(t,2H),7.70-7.68(d,1H),7.54-7.52(m ,1H),6.15(s,1H)5.93-5.91(t,1H),5.19(s,1H),3.91(s,3H),3.52-3.46(m,1H),2.86-2.80(m,1H). LCMS (M+H=299.1, 90.15%).

[0289] Synthesis of 3-ethylidene-1-phenethylindolin-2-one and 1-methylspiro[indoline-3,2'-pyran]-2,4'(3'H)-dione [ka] Step 1: Synthesis of 1-methylindoline-2,3-dione: [ka] To a stirred solution of isatin (1.0 g, 6.80 mmol) in DMF (2 mL) was added NaH (0.163 g, 6.80 mmol) under an argon atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Methyl iodide (1.06 g) was added to the reaction mixture at 0 °C. Upon completion of the reaction, a non-polar spot was formed compared to the starting material, as observed by TLC. The reaction mixture was added to water (5 mL) and extracted with EtOAc (5 mL × 3). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 1-methylindoline-2,3-dione as a crude product. The crude product was purified by silica gel column chromatography (100-200 mesh) using 15-20% ethyl acetate in pet ether as the eluent to give the desired product (0.80 g) as an orange solid.

[0290] Step 2: Synthesis of 3-ethylidene-1-phenethylindolin-2-one: [ka] To a stirred solution of 1-methylindoline-2,3-dione (0.1 g, 0.621 mmol) in THF (2.0 mL) was added but-3-yn-2-one (0.063 g, 0.931 mmol) and triphenylphosphine (33 mg, 0.124 mmol) under an argon atmosphere. The mixture was stirred at room temperature until the reaction was complete. After completion of the reaction (a non-polar spot was formed on TLC compared to the starting material 1-methylindoline-2,3-dione), the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (100-200 mesh) using 7-12% ethyl acetate and pet ether as eluents to give the desired product (0.02 g each) as an off-white solid.

[0291] The formation of the product 1 Confirmed by 1 HNMR and LCMS.

[0292] Synthesis of 3-ethylidene-1-phenethylindolin-2-one: 1 HNMR(400MHz,CDCl3):δ=7.44-7.04(m,1H),7.37-7.35(m,1H),7.16-7.13(m,1H),6.90-6.88(d,1H,J=7.6Hz ),5.15(d,1H,J=2.0Hz),4.73(d,1H,J=2.4Hz),3.22(s,3H),3.04(d,1H,J=18.4Hz),2.89(d,1H,J=18.4Hz). LC-MS: 99.81%. m / z 230.9 [M+1]+

[0293] 1-Methylspiro[indoline-3,2'-pyran]-2,4'(3'H)-dione: 1 HNMR(400MHz,CDCl3):δ=7.44(d,1H,J=0.8Hz),7.48-7.26(m,2H),7.09-7.05(m,1H), 7.09-7.05(m,1H),6.89(d,1H,J=8.0Hz),3.23(s,3H),3.18(d,1H),2.68-2.63(m,1H), m / z230.9[M+1] +LC-MS, purity by LC-MS-99.74%.

[0294] 1'-Benzyl-5-methylene-3H-spiro[furan-2,3'-indoline]-2',4(5H)-dione [ka] 1 HNMR(400MHz, CDCl3):δ=7.37-7.27(m,7H),7.12-7.08(m,1H),6.78(d,1H,J=8.0Hz ),5.18(d,1H,J=2.8Hz),4.90(q,2H,J=15.2Hz),4.77(d,1H,J=2.4Hz),3.10(d,1H,J =18.4Hz), 2.94(d,1H,J=18.8Hz), m / z 305.9[M + +H]

[0295] 1-Benzylspiro[indoline-3,2'-pyran]-2,4'(3'H)-dione [ka] 1 HNMR (400MHz, CDCl3): δ=7.50(d,1H,J=6.8Hz),7.48(d,1H,J=17.2Hz),7.36-7.27(m,6H),6.76(d,1H,J=8.0Hz),5. 65(d,1H,J=6.4Hz),4.95(q,2H,J=15.6Hz),3.27(d,1H,J=14.0Hz),2.75(d,1H,J=16.8Hz),2.89(d,1H,J=18.4Hz). m / z 305.9 [M+1]; purity by LC: 99.84%.

[0296] Synthesis of N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)ethenesulfonamide [ka] Step 1: Synthesis of tert-butyl 2-bromobenzylcarbamate: [ka] To a solution of (2-bromophenyl)methanamine (1.0 g, 0.005 mol) and Boc anhydride (1.29 g, 0.0059 mol) in DCM (10 mL) was added EtN (0.54 g, 0.0059 mol). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (a non-polar spot was formed on TLC compared to the starting material), the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated under reduced pressure to give crude tert-butyl 2-bromobenzylcarbamate as a semi-solid. This was purified by silica gel column chromatography (100-200 mesh) using 28-30% ethyl acetate in pet ether as eluent to give the desired product (1.74 g) as a colorless gum. Product formation was confirmed by TLC.

[0297] Step 2: Synthesis of tert-butyl 2-(1-methyl-1H-pyrazol-4-yl)benzylcarbamate [ka] Under a nitrogen atmosphere, tert-butyl 2-(1-methyl-1H-pyrazol-4-yl)benzylcarbamate (1.74 g, 0.006 mol) and Pd(dppf)Cl 2.To a mixture of DCM (0.25 g, 0.0003 mol) in 1,4-dioxane and water (13:6 mL) was added K2CO3 (2.1 g, 0.015 mol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.26 g, 0.006 mol). The reaction mixture was degassed with nitrogen for 5 minutes. The reaction mixture was stirred at 80 °C for 2 hours. After completion of the reaction (TLC showed the formation of a polar spot compared to the starting material tert-butyl 2-(1-methyl-1H-pyrazol-4-yl)benzylcarbamate), the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude tert-butyl 2-(1-methyl-1H-pyrazol-4-yl)benzylcarbamate. This was isolated by silica gel column chromatography (100-200 mesh) using 15-20% ethyl acetate and pet ether as eluent to give the desired product (0.9 g) as an off-white gum. Product formation was confirmed by TLC.

[0298] Step 3: Synthesis of (2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanamine [ka] To a stirred solution of tert-butyl 2-(1-methyl-1H-pyrazol-4-yl)benzylcarbamate (0.05 g, 0.0001 mol) in DCM (10 mL) was added TFA (2 mL) at 0° C. The resulting mixture was stirred at room temperature. After completion of the reaction (TLC showed the formation of a polar spot compared to the starting material tert-butyl 2-(1-methyl-1H-pyrazol-4-yl)benzylcarbamate), the reaction mixture was quenched with water (15 mL) and extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated under reduced pressure to give (2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanamine as a TFA salt (semi-solid). The pure product was isolated by silica gel column chromatography (100-200 mesh) using 18-20% ethyl acetate in pet ether as the eluent to give the desired product (0.02 g) as an off-white semi-solid. Product formation was confirmed by TLC.

[0299] Step 4: Synthesis of N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)ethenesulfonamide: [ka] To a stirred solution of (2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanamine (0.3 g, 0.001 mol) in DCM (3 mL) was added TEA (0.48 g, 0.004 mol). The reaction mixture was cooled to 0° C., and 2-chloroethanesulfonyl chloride (0.36 g, 0.002 mol) was added. The resulting mixture was allowed to stir at 0° C. for 1 hour. After completion of the reaction (formation of a non-polar spot on TLC compared to the starting material (2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanamine), the reaction mixture was quenched with water and extracted with DCM. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the desired compound as a crude product. This was purified by silica gel column chromatography (100-200 mesh) using 60-70% ethyl acetate in pet ether as the eluent to give the desired product (0.05 g) as an off-white semi-solid. 1HNMR (400MHz, CDCl3): δ=7.57(d,2H,J=4.4Hz),7.41(d,2H,J=6.8Hz),7.34-7.36(m,3H),6.43(q,1H,J= 9.6Hz),6.25(d,1H,J=16.8Hz),5.93(d,1H,J=9.6Hz),4.35(bs,1H),4.27(d,1H,J=6.0Hz),3.98(s,3H), LC-MS, Purity by LC-MS - 99.25% m / z 278.3 [M+1] + .

[0300] Synthesis of N-(1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)ethenesulfonamide [ka] Step 1: Synthesis of 1-(2-bromophenyl)ethanamine: [ka] To a solution of 1-(2-bromophenyl)ethanone 1 (3.0 g, 0.015 mol) in methanolic NH₃ (0.26 g, 0.150 mol) was added titanium isopropoxide (5.99 g, 0.021 mol). The reaction mixture was stirred at room temperature for 5 h. Upon completion of the reaction, NaBH₄ was added slowly over 1 h at room temperature. After completion of the reaction (a polar spot was formed on TLC compared to the starting material), the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give the crude product. This was purified by silica gel column chromatography (100-200 mesh) using 15-20% ethyl acetate in pet ether as the eluent to give 1-(2-bromophenyl)ethanolamine (2.54 g) as an off-white semi-solid.

[0301] Step 2: Synthesis of tert-butyl 1-(2-bromophenyl)ethylcarbamate [ka] To a mixture of (2-bromophenyl)methanamine (0.5 g, 0.004 mol) and di-tert-butyl dicarbonate (1.04 g, 0.0047 mol) in DCM (5 mL) was added TEA (0.44 g, 0.0043 mol). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (a non-polar spot was formed on TLC compared to the starting material), the reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude tert-butyl 1-(2-bromophenyl)ethylcarbamate. This was purified by silica gel column chromatography (100-200 mesh) using 16-20% ethyl acetate in pet ether as eluent to give the desired product (0.87 g) as an off-white semi-solid.

[0302] Step 3: Synthesis of tert-butyl 1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethylcarbamate [ka] Under a nitrogen atmosphere, to a mixture of tert-butyl 1-(2-bromophenyl)ethylcarbamate (0.87 g, 0.0040 mol) and Pd(dppf)Cl.DCM (0.16 g, 0.0002 mol) in 1,4-dioxane and water (8 mL) was added KCO (1.39 g, 0.010 mol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.84 g, 0.004 mol). The reaction mixture was degassed with nitrogen for 5 minutes. The reaction mixture was stirred at 80 °C for 3 hours. Upon completion (a polar spot was formed on TLC compared to the starting material), the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give tert-butyl 1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethylcarbamate as a crude product. The pure product was isolated by silica gel column chromatography (100-200 mesh) using 18-25% ethyl acetate and pet ether as eluent to give the desired product (0.81 g) as an off-white semi-solid. Product formation was confirmed by TLC.

[0303] Step 4: Synthesis of N-(1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)ethenesulfonamide: [ka] To a stirred solution of tert-butyl 1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethylcarbamate (0.09 g, 0.30 mmol) in DCM (2 mL) was added trifluoroacetic acid (1.0 mL) at 0° C. The resulting reaction mixture was allowed to stir at ambient temperature for 2 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL), cooled to 0° C., and TEA (0.29 g, 1.82 mmol) was added slowly at 0° C. under a nitrogen atmosphere. 2-Chloroethanesulfonyl chloride (0.03 g, 0.30 mmol) was added at 0° C. The resulting mixture was allowed to stir at 0° C. for 1 hour. After completion of the reaction, water was added to the reaction mixture and it was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the desired product as a crude material. This was isolated by silica gel column chromatography (100-200 mesh) using 60-70% ethyl acetate and pet ether as eluent to give the desired product (0.05 g) as an off-white semi-solid.

[0304] The formation of the product 1 Confirmed by 1 HNMR and LCMS. 1 HNMR (400MHz, CDCl3): δ=7.52(d,2H,J=2.8Hz),7.40(d,1H,J=7.6Hz),7.34(t,1H,J=6.8Hz),7.29-7.22(m,2H),6.16(q,1H,J=10Hz) ),6.02(d,1H,J=16.8Hz),5.66(d,1H,J=10.0Hz),4.92(q,1H,J=6.8Hz),4.68(d,1H,J=6.4Hz),3.98(s,3H),1.45(d,3H,J=6.8Hz). LC-MS-97.58%.m / z292.2[M+1]+

[0305] 5-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenepyrrolidin-2-one [ka] 1H-NMR (400MHz, CDCl3):7.42-7.40(m,1H),7.36(s,1H),7.32-7.26(m,2H),6.07-6. 04(m,2H),5.40(s,1H),4.8(m,1H),3.97(s,3H),3.23-3.18(m,1H),2.7-2.6(m,1H), m / z: 287.9 ​​(M+H)

[0306] 5-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-1-methyl-3-methylenepyrrolidin-2-one [ka] 1 H-NMR (400MHz, CDCl3):7.43-7.42(m,2H),7.41-7.40(m,1H),7.31(s,1H),7.04-7.02(m,1H),6.07- 6.04(m,1H),5.40(s,1H),4.6(m,1H),4.01(s,3H),3.23-3.18(m,1H),2.75(s,3H),2.6-2.5(m,1H). m / z: 301.9 (M+H).

[0307] Synthesis of methyl(vinylsulfonyl)-L-tryptophanate [ka] Step 1: Synthesis of methyl L-tryptophanate: [ka] To a stirred solution of L-tryptophan (500 mg, 2.44 mmol) in MeOH (10 mL) was added H2SO4 (300 mg, 2.93 mmol) at 0 °C. The resulting reaction mixture was then stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was evaporated under reduced pressure at low temperature. The crude product was purified by column chromatography on silica gel (mesh: 100-200). The desired compound was eluted with 50-60% ethyl acetate and petroleum ether to give methyl L-tryptophanate (420 mg, 78%) as a thick yellow gum.

[0308] Step 2: Synthesis of methyl(vinylsulfonyl)-L-tryptophanate: [ka] To a stirred solution of methyl L-tryptophanate (200 mg, 0.92 mmol) in DCM (10 mL), DIPEA (180 mg, 1.38 mmol) was added, followed by DMAP (11 mg, 0.09 mmol). The reaction mixture was then cooled to 0°C, and 2-chloroethane-1-sulfonyl chloride (195 mg, 1.19 mmol) was added dropwise. The resulting reaction mixture was then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure at low temperature. The resulting crude product was purified by column chromatography on silica gel (mesh: 100-200). The desired compound was eluted with 30-40% ethyl acetate and petroleum ether to give methyl (vinylsulfonyl)-L-tryptophanate (100 mg, 20%) as a pale yellow solid. 1H-NMR-CDCl3:8.15(bs,1H),7.56-7.54(d,1H),7.37-7.35(d,1H),7.21-7.09(m,3H),6.33-6.26(m, 1H),6.15-6.11(d,1H),5.75-5.73(m,1H),4.33-4.28(m,1H),3.68(s,3H),3.32-3.31(m,2H).LCMS(M + 1=309.1,87.12%).

[0309] Synthesis of methyl 4-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylene-4-(methylsulfonamido)butanoate [ka] Step 1: Synthesis of 3-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzaldehyde: [ka] To a stirred solution of 2-bromo-3-chlorobenzaldehyde (0.3 g, 1.37 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.34 g, 1.64 mmol) in 1,4-dioxane (10 mL) was added potassium carbonate (0.47 g, 3.42 mmol) in water (5 mL), and the resulting mixture was degassed for 5 minutes. Tetrakis(triphenylphosphine)-palladium (30 mg, 10% mol) was then added and degassed for an additional 5 minutes. The reaction mixture was heated at 90 °C for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with water (2 × 30 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (mesh: 60-120). The required compound was eluted with 35-50% ethyl acetate and petroleum ether to give 3-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzaldehyde as a pale yellow solid (0.3 g, 96%).

[0310] Step 2: Synthesis of (E)-N-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzylidene)-2-methylpropane-2-sulfinamide [ka] To a stirred solution of 3-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzaldehyde (0.3 g, 1.35 mmol) in tetrahydrofuran (10 mL) was added 2-methylpropane-2-sulfinamide (0.22 g, 1.76 mmol) and titanium isopropoxide (1.0 mL, 3.37 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was quenched with water (50 mL) and the solid was filtered. The resulting filtrate was extracted with ethyl acetate (2 × 25 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica mesh (mesh: 60-120). The required compound was eluted with 35-40% ethyl acetate and petroleum ether to give (E)-N-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzylidene)-2-methylpropane-2-sulfinamide as a pale yellow gum (0.24 g, 54%).

[0311] Step 3: Synthesis of methyl 4-((tert-butylsulfinyl)amino)-4-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate [ka] To a stirred solution of (E)-N-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzylidene)-2-methylpropane-2-sulfinamide (0.24 g, 0.74 mmol) and methyl 2-(bromomethyl)acrylate (0.18 mL, 0.96 mmol) in THF (4 mL) was added zinc (174 mg, 2.671 mmol) and saturated NH4Cl in water (1 mL), and the resulting mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After 50% consumption of the starting material by TLC, the reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (150 mL) and washed with water (2 x 10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the crude product as a dark yellow gum. The crude product was purified by column chromatography on silica mesh (mesh: 60-120) and the required compound was eluted with 5-6% MeOH in DCM to give methyl 4-((tert-butylsulfinyl)amino)-4-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate as a pale yellow solid (0.24 g, 75%).

[0312] Step 4: Synthesis of methyl 4-amino-4-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate hydrochloride: [ka] To a stirred solution of 4-((tert-butylsulfinyl)amino)-4-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate (0.15 g, 0.354 mmol) in diethyl ether (2 mL) was added 2 M HCl in diethyl ether (1.5 mL, 10 V) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure at low temperature to give the product as methyl 4-amino-4-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate hydrochloride (0.12 g, 95%).

[0313] Step 5: Synthesis of methyl 4-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylene-4-(methylsulfonamido)butanoate: [ka] To a stirred solution of methyl MsCl (24 mg, 0.21 mmol) in DCM (10 mL) was added TEA (42 mg, 0.42 mmol). The reaction mixture was cooled to 0 °C. 4-Amino-4-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenebutanoate hydrochloride (50 mg, 0.14 mmol) in DCM (5 mL) and TEA (0.1 mL) was added to the above reaction mixture at 0 °C, and then warmed to room temperature. The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM (20 mL) and washed with water (2 × 10 mL). The organic layer was dried over Na SO , filtered, and the solvent was evaporated under reduced pressure to give a crude material. The crude product thus obtained was purified by column chromatography using silica mesh (mesh 60-120) and the required compound was eluted with 50-60% ethyl acetate in pet ether to give methyl 4-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylene-4-(methylsulfonamido)butanoate as an off-white solid (12 mg, 21%). 1 H-NMR (400MHz, CDCl3):7.49-7.46(m,2H),7.36(m,1H),7.33-7.31(m,1H),6.18(brs,2H),5.41-5.40(d, 1H),4.84-4.82(m,1H),4.02(s,3H),3.72(s,3H),3.12-3.02(m,1H),2.60-2.54(m,1H),2.49-2.45(m,1H) m / z: 397.9 (M+H)

[0314] Methyl(vinylsulfonyl)-D-phenylalaninate [ka] 1 H-NMR-CDCl3:7.32-7.27(m,3H),7.16-7.14(m,2H),6.31-6.24(m,1H),6.17-6.13(m,1H) ,5.81-5.78(m,1H),4.84-4.82(d,1H),4.27-4.21(m,1H),3.73(s,3H),3.15-3.04(m,1H). LCMS (M+H=270.0, 82.13%).

[0315] Methyl acryloyl-L-tryptophanate [ka] 1 H-NMR-CDCl3:8.15(brs,1H),7.52-7.50(m,1H),7.36-7.34(d,1H),7.20-7.16(m,1H),7.12-7.08(m,1H),6.977-6.97 2(d,1H),6.30-6.25(m,1H),6.13-6.01(m,2H),5.66-5.63(m,1H),5.06-5.01(m,1H),3.702(s,3H),3.38-3.36(m,2H). LCMS (M+H=273.0, 92.13%).

[0316] Methyl (S)-2-phenyl-2-(vinylsulfonamido)acetate [ka] 1 H-NMR-CDCl3:7.37-7.32(m,5H),6.34-6.28(m,1H),6.15-6.11(m,1H),5.77-5.75(m,1H),5.51-5.49(d,1H),5.09-5.07(m,1H),3.74(s,3H). LCMS (M+H=254.0, 93.14%).

[0317] Synthesis of 3-benzylidene-5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one [ka] Step 1: Synthesis of 1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethan-1-one: [ka] To a stirred solution of 2-bromoacetophenone (1 g, 5.024 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g, 6.53 mmol) in 1,4-dioxane (15 mL) was added potassium carbonate (1.805 g, 13.06 mmol) in water (15 mL). The resulting mixture was degassed for 5 minutes, after which tetrakis(triphenylphosphine)-palladium (100 mg, 10% mol) was added and degassed for another 5 minutes. The resulting reaction mixture was heated at 70 °C for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (25 mL) and washed with water (2 × 20 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (mesh: 60-120). The required compound was eluted with 25-30% ethyl acetate and petroleum ether to give 1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethan-1-one as a pale yellow gum (1.1 g, 98%).

[0318] Step 2: Synthesis of 2-bromo-1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethan-1-one: [ka] To a stirred solution of 1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethan-1-one (1.1 g, 5.49 mmol) in THF (50 mL) was added phenyltrimethylammonium tribromide (2.26 g, 6.04 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to give crude methyl 4-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoate (170 mg, 90%) as a yellow gum. The crude product was purified by column chromatography on silica gel (mesh: 230-400) and the desired compound was eluted with 2-4% ethyl acetate and petroleum ether to give 2-bromo-1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethan-1-one as an off-white solid (750 mg, 49%).

[0319] Step 3: Synthesis of ethyl 2-(diethoxyphosphoryl)-4-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-oxobutanoate: [ka] To a stirred solution of 2-bromo-1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethan-1-one (750 mg, 0.54 mmol) in THF (10 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (783 mg, 3.49 mmol) followed by K2CO3 (558 mg, 4.03 mmol) at room temperature, and the reaction mixture was stirred at 70 °C for 16 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product as a pale yellow gum. The crude product was purified by column chromatography on silica gel (mesh: 100-200). The desired compound was eluted with 70-80% ethyl acetate and petroleum ether to give ethyl 2-(diethoxyphosphoryl)-4-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-oxobutanoate as a pale yellow gum (400 mg, 35%).

[0320] Step 4: Synthesis of diethyl (5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-oxotetrahydrofuran-3-yl)phosphonate: [ka] To a stirred solution of ethyl 2-(diethoxyphosphoryl)-4-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-oxobutanoate (400 mg, 0.95 mmol) in MeOH (10 mL) was added potassium borohydride (77 mg, 1.42 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure to give the crude product as a pale yellow gum. The crude product was purified by column chromatography on silica gel (mesh: 100-200). The required compound was eluted with 2-3% MeOH in DCM to give diethyl (5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-oxotetrahydrofuran-3-yl)phosphonate as a pale yellow gum (130 mg, 36%).

[0321] Step 5: Synthesis of (Z)-3-benzylidene-5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one: [ka] To a stirred solution of (5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-oxotetrahydrofuran-3-yl)phosphonate (130 mg, 0.34 mmol) in THF (10 mL) was added benzaldehyde (48 mg, 0.44 mmol), followed by K2CO3 (72 mg, 0.51) at room temperature, and the reaction mixture was stirred at 70 °C for 16 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product as a pale yellow gum. The obtained crude product was purified by column chromatography using silica gel (mesh: 100-200), and the required compound was eluted with 10-15% ethyl acetate and petroleum ether to obtain (Z)-3-benzylidene-5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one as a pale yellow gum (24 mg, 17%). 1 H-NMR-CDCl3:7.87-7.85(d,1H),7.64-7.62(m,1H),7.57-7.55(m,2H),7.54-7.52(m,3H),7.50-7.45(m,4H),7.44-7. 39(m,6H),5.85-5.81(m,1H),5.78-5.74(m,1H),3.95(s,3H),3.50-3.35(m,1H),3.34-3.33(m,1H),3.25-3.14(m,2H). LCMS (M+H=331.2, 95.5%).

[0322] (R)-3-Acryloyl-4-benzyloxazolidin-2-one [ka] To a stirred solution of (R)-4-benzyloxazolidin-2-one (250 mg, 1.41 mmol) in DCM (20 mL) was added DIPEA (273.4 mg, 2.11 mmol), followed by DMAP (18 mg, 0.14 mmol). The reaction mixture was cooled to 0°C, and acryloyl chloride (154.19 mg, 1.71 mmol) was added dropwise. The resulting reaction mixture was then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure at low temperature. The resulting crude product was purified by column chromatography on silica gel (mesh: 100-200). The required compound was eluted with 30-40% ethyl acetate and petroleum ether to give (R)-3-acryloyl-4-benzyloxazolidin-2-one as a pale yellow gum (45 mg, 14%). 1 H-NMR-CDCl3:7.55-7.48(m,1H),7.36-7.32(m,2H),7.44-7.39(m,1H),7.29-7.28(m,1H),7.23-7.21(m,2H),6. 63-6.58(m,1H),5.95-5.92(m,1H),4.76-4.72(m,1H),4.26-4.18(m,2H),3.37-3.33(m,1H),2.84-2.78(m,1H). LCMS (M+H=232.0, 99.14%).

[0323] 5-(4,5-difluoro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1H-NMR (400MHz, CDCl3):7.49(s,1H),7.45(s,1H),7.26-7.25(d,1H),7.13(m,1H),6.32-6.31( t,1H)5.70-5.69(t,1H),5.63-5.60(t,1H),3.97(s,3H),3.25-3.10(m,1H),2.89-2.82(m,1H). LCMS (M+H=291.0, 98.09%).

[0324] 3-methylene-5-(2-(6-methylpyridin-3-yl)phenyl)dihydrofuran-2(3H)-one [ka] 1 H-NMR (400MHz, CDCl3):8.44(s,1H),7.58-7.56(d,1H),7.51-7.40(m,4H),7.24(s,1H),6.28-6.2 7(d,1H)5.64-5.63(d,1H),5.52-5.48(t,1H),3.16-3.09(m,1H),2.90-2.85(m,1H),2.63(s,3H). LCMS (M+H=266.0, 96.75%).

[0325] 5-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR (400MHz, CDCl3):7.90(s,1H),7.73(s,1H),7.48-7.45(t,1H),7.43-7.38(m,3H),7.33-7 .31(d,1H),6.32(s,1H),5.07(s,1H),5.66-5.63(m,1H),3.26-3.20(m,1H),2.97-2.93(d,1H). LCMS (M+H=291.0, 97.15%).

[0326] 5-(4-fluoro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(400MHz, CDCl3):7.53(s,1H),7.49(s,1H),7.42-7.39(s,1H),7.07-7.00(m,2H ),6.31(s,1H),5.69-5.61(m,2H),3.98(s,3H),3.26-3.20(m,1H),2.95-2.89(m,1H). LCMS (M+H=272.9, 99.12%).

[0327] 3-Methylene-5-(2-morpholinopyridin-3-yl)dihydrofuran-2(3H)-one [ka] 1 H-NMR(400MHz,CDCl3):8.37-8.35(m,1H),7.68-7.66(m,1H),7.10-7.06(s,1H),7.36-7.35(m,1H),5.84-5.80(m,1H) ),5.74-5.73(m,1H),3.89-3.81(m,4H),3.51-3.45(m,1H),3.26-3.20(m,2H),3.07-3.01(m,2H),2.95-2.90(m,1H). LCMS (M+H=261.0, 96.93%).

[0328] 5-(2-(6-methoxypyridin-3-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1H-NMR (400MHz, CDCl3):8.10-8.09(d,1H),7.57-7.54(m,1H),7.50-7.38(m,3H),7.24-7.23(m,1H),6.84-6.82(d ,1H),6.28-6.27(t,1H),5.64-5.63(t,1H),5.55-5.52(t,1H),3.99(s,3H),3.17-3.11(m,1H),2.90-2.84(m,1H). LCMS (M+H=282.1, 99.23%).

[0329] 5-(2-(2-methoxypyrimidin-5-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR (400MHz, CDCl3):8.51(s,2H),7.53-7.42(m,3H),7.24(s,1H),6.31-6.30(t,1H),5.68-5.6 7(t,1H),5.48-5.45(t,1H),4.08(s,3H),3.49-3.48(d,1H),3.21-3.14(m,1H),2.94-2.88(m,1H). LCMS (M+H=283.2, 97.22%).

[0330] 3-(1-methyl-1H-pyrazol-4-yl)-4-(4-methylene-5-oxotetrahydrofuran-2-yl)benzoic acid [ka] 1 H-NMR(400MHz,DMSO):13.4(bs,1H),7.95(s,1H),7.89-7.87(d,2H),7.62(d,1H),7.44-7.42(d,1 H),6.13(s,1H),5.86-583(m,1H),5.77(s,1H),3.90(s,3H),3.50-3.40(m,1H),2.86-2.81(m,1H). LCMS (M+H=299.1, 94.55%).

[0331] 3-methylene-5-(2-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one [ka] 1 H-NMR (400MHz, CDCl3):7.56-7.55(m,2H),7.44-7.41(m,1H),7.38-7.33(m,2H),7.31-7.29(m,1H),6.30-6.29(m,1H),5.72-5.67(m,1) H),5.68-5.66(m,1H),5.04-5.0(m,1H),4.19-4.11(m,3H),4.09-3.94(m,1H),3.25-3.18(m,1H),2.97-2.91(m,1H),2.54-2.38(m,2H). LCMS (M+H=311.1, 96.59%).

[0332] 5-(Isoquinolin-1-yl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)δ:8.50(d,J=6Hz,1H),8.28(dJ=9Hz,1H),7.88(dJ=9Hz,1H),7.75- 7.64(m,1H),6.37-6.33(m,2H),5.79-5.74(m,1H),4.06-3.97(m,1H),3.36-3.27(m,1H), m / z 226.11[M+H] + .

[0333] 5-(2-(1-methyl-1H-pyrazol-3-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1H-NMR(300MHz,CDCl3)δ:7.54-7.51(m,1H),7.48-7.45(m,1H),7.41-7.40(m,1H),7.37-7.34(m,2H),6.44(d,J=3H) z,1H),6.27(t,J=3Hz,1H),6.20-6.10(1H,m),5.61(t,J=3Hz),3.95(s,3H),3.54-3.46(m,1H),2.86-2.78(m,1H). m / z 255.17[M+H] + .

[0334] 5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenepyrrolidin-2-one [ka] 1 H-NMR(300MHz,CDCl3)δ:7.48-7.25(m,6H),6.09-6.06(m,1H),5.38(bs,1H),5.01-4.97(m,1H),3.98(s,3H),3.26-3.20(m,1H),2.74-2.61(m,1H), m / z 254.24[M+H] + .

[0335] 1-methyl-5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenepyrrolidin-2-one [ka] 1 H-NMR(300MHz,CDCl3)δ:7.48(s,1H),7.37-7.26(m,4H),7.13-7.10(m,1H),6.06(s,1H),5.33- 5.29(m,1H),4.85-4.81(m,1H),3.98(s,3H),3.35-3.14(m,1H),2.70(s,3H),2.66-2.59(m,1H), m / z 268.21[M+H] + .

[0336] 5-(5-methyl-2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(400MHz,CDCl3):8.62(s,1H),7.90(s,1H),7.56(s,1H),7.26-7.24(d,1H),7.19(brs,1H),6.54(s,2H),6.12 (brs,1H),5.79-5.76(m,2H),4.28-4.24(m,2H),3.54-3.53(m,4H),2.73-2.671(m,2H),2.41(brs,4H),2.32(s,3H). LCMS (M+H=368.1).

[0337] N-methyl-N-(1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)ethenesulfonamide [ka] 1 HNMR (400MHz, CDCl3): δ=7.66(s,1H),7.55(s,1H),7.46-7.44(m,1H),7.37(s,3H),6.15(d,1H,J=16.4Hz),6.02-5.95 (m,1H),5.87(d,1H,J=10Hz),5.50-5.45(q,1H,J=9.6Hz),4.026(d,3H,J=4.0Hz),2.58(s,3H),1.54(d,3H,J=6.8Hz). m / z306.1[M+1] +

[0338] 2-(4-(2-(4-methylene-5-oxotetrahydrofuran-2-yl)phenyl)-1H-pyrazol-1-yl)-N-(oxetan-3-yl)acetamide [ka] 1HNMR (400MHz, CDCl3): δ=7.72(s,1H),7.60(s,1H),7.47-7.44(m,1H),7.43-7.38(m,2H),7.38-7.27 (m,1H),7.21-7.20(m,1H),6.33(t,1H,J=2.8Hz),5.72-7.67(m,2H),5.10-5.01(m,1H),4.93(t,2H,J =14.4Hz),4.87(s,2H),4.54-4.50(m,2H),3.30-3.23(m,1H),3.04-2.97(m,1H). LCMS: m / z 354.1 [M + +H]; (93.11% purity).

[0339] Additional compounds synthesized 3-methylene-5-(2-(1-(2,2,2-trifluoroethyl)-4-yl)phenyldihydrofuran-2(3H)-one [ka] 1 H-NMR (400 MHz, CDCl 3): 7.64-7.61(d,2H),7.46-7.41(m,1H),7.40-7.38(s,2H),7.35-7.25(m,1H),6.31-6.2 9(t,1H),5.68-5.64(m,2H),4.81-4.79(m,2H),3.24-3.16(m,1H),2.97-2.96(m,1H).

[0340] 5-(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1H-NMR (400MHz, CDCl3):7.50(s,1H),7.43(s,1H),7.22(s,1H),7.19-7.14(m,2H),6.30-6.2 9(t,1H),5.71-5.66(m,2H),3.97(s,3H),3.25-3.17(m,1H),2.95-2.88(m,1H),2.39(s,3H).

[0341] 5-(2-methyl-6-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] LCMS: m / z: 269.31 (M+1)

[0342] 5-(5-(4-methoxyphenyl)-1-methyl-1H-pyrazol-3-yl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR (400MHz, CDCl3):7.69-7.65(m,2H),6.94-6.90(m,2H),6.46(s,1H),6.36-6.35(t,1H),5.8 1-5.79(t,1H),5,62-5,58(m,1H),3.96(s,3H),3.83(s,3H),3.45-3.39(m,1H),3.25-3.20(m,1H).

[0343] 5-(1',2-dimethyl-1'H,2H-[3,4'-bipyrazol]-5-yl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR (400MHz, CDCl3):7.72-7.65(d,2H),6.35-6.27(m,2H),5.79(brs,1H),5.59-5.56(t,1H),3.92(s,6H),3.20-3.17(m,1H),2.95-2.44(d,1H).

[0344] 5-(4'-fluoro-[1,1'-biphenyl]-2-yl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR (400 MHz, CDCl3) : 7.48-7.36(m,3H),7.32-7.22(m,3H),7.16-7.11(m,2H),6.3(t,1H),5.62(t,1H),5.58-5.50(m,1H),3.12-3.02(m,1H),2.90-2.80(m,1H).

[0345] 5-(4-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR (400 MHz, CDCl3) : 8.7(s,1H),8.6(d,1H),7.64-7.62(s,2H),7.3(d,1H),6.36-6.32(s,1H),5 .78-5.72(m,2H),4.0-3.98(s,3H),(3.35-3.25(m,1H),3.22-3.12(m,1H). LCMS-(M+H=256.28, 98.5%).

[0346] 5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-methylenedihydrofuran-2(3H)-one: [ka] 1 H-NMR (400 MHz, CDCl3) :8.62-8.58(d,1H),8.16-8.14(s,1H),7.922-7.82(m,2H),7.44-7.38(m,1H),6.04-6.02( t,1H),6.0-5.58(m,1H),5.56(s,1H),3.98(s,3H),3.53-3.50(m,1H),2.90-2.70(m,1H). LCMS (M+H=256.78, 99%)

[0347] 5-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR (400 MHz, CDCl3) : 8.61-8.52(m,2H),7.59-7.55(m,2H),7.38(d,1H),6.3(t,1H),5.74-5.72(m,2H),4.0(s,3H),3.22-3.12(m,1H),2.80-2.72(m,1H).

[0348] 5-(2-(1-methyl-1H-indol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka]

[0349] 1 H-NMR(300MHz,CDCl3)δ:7.50-7.24(m,6H),7.05(d,J-=6Hz,1H),6.22-6.12(m,2H),5.62-5 .48(m,2H),3.82(s,3H),2.89-2.65(m,2H),LCMS: Retention time 2.65 minutes (97.74% purity),m / z304.16[M+H] + .

[0350] 5-(2-(1-ethyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)δ:7.51(d,J=12Hz,2H),7.44-7.41(1H,m),7.38-7.29(m,3H),6.29(t,J=3Hz,1H),5.73(q,J=6Hz),5.66(t,1 H,3Hz),4.23(q,J=9Hz,2H),3.27-3.17(m,1H),2.98-2.89(m,1H),1.56(t,J=6Hz,3H)LCMS: Retention time 2.65 minutes (96.9% purity), m / z269.16[M+H] + .

[0351] 5-(2-(1-isobutyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)δ:7.69(s,1H),7.55(s,1H),7.47-7.38(3H,m),7.32-7.29(m,1H),6.32(t,J=3Hz,1H),5.71(t,J=6Hz),5.68-5.63(m,1H) ),4.06(d,J=6Hz,2H),3.29-3.19(m,1H),3.03-2.93(m,1H),2.25-2.21(1H,m),0.95(d,J=6Hz,6H)LCMS: Retention time 2.65 minutes (96.9% purity), m / z297.2[M+H] + .

[0352] 3-methylene-5-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)dihydrofuran-2(3H)-one [ka] 1H-NMR (300 MHz, CDCl3), mixture of rotamers δ: 7.50-7.38 (m, 3H), 7.10 (t, J = 6 Hz, 1H), 6.29 and 6.21 (2t, J = 3 Hz, 1H), 5.68 and 5.60 (2t, J = 3 Hz, 1H), 5.38 and 5.35 (2t, J = 3 Hz, 1H), 3.96 and 3.9 4(2s,3H),3.33-3.30(m,1H),6.32(t,J=3Hz,1H),5.71(t,J=6Hz),5.68-5.63(m,1H),4.0 6(d,J=6Hz,2H),3.29-3.19(m,1H),2.80-2.55(m,1H),2.18-2.11(m,6H),m / z283.2[M+H] + .

[0353] 5-(2-(1-benzyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)δ:7.58-7.26(m,11H),6.29-6.28(m,1H),5.72-5.63(m,4H),3.21-3.13(m,1H),2.93-2.85(m,1H),m / z331.18[M+H] + .

[0354] 5-(2-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)δ:7.56-7.51(m,3H),7.46-7.40(m,1H),7.29-7.28(m,1H),6.29-6.24(m,2 H),5.64(d,J-3Hz,1H),5.38(t,J=6Hz,1H),3.13-3.04(m,1H),2.80-2.71(m,1H),m / z255.57[M+H] + .

[0355] 5-(2-(1-methyl-1H-indazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)δ:7.71(bs,1H),7.56-7.34(m,7H),6.21(t,J=3Hz,1H),5 .53(t,3Hz,1H),5.53(bm,1H),4.13(s,3H),2.98-2.78(m,2H),m / z305.18[M+H] + . [ka]

[0356] (S)-5-(2-(1-methyl-1H-indol-5-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one 1 H-NMR(300MHz,CDCl3)δ:7.53-7.32(m,6H),7.17-7.12(m,2H),6.52-6.51(m,1H),6.23-6.21(m,1H),5. 70-5.65(m,1H),5.56(t,J=3Hz,1H),3.85(s,1H),3.01-2.98(m,1H),2.88-2.78(m,1H)m / z304.15[M+H] + .

[0357] (R)-5-(2-(1-methyl-1H-indol-5-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one 1 H-NMR(300MHz,CDCl3)δ:7.53-7.32(m,6H),7.17-7.12(m,2H),6.52-6.51(m,1H),6.23-6.21(m,1H),5. 70-5.65(m,1H),5.56(t,J=3Hz,1H),3.85(s,1H),3.01-2.98(m,1H),2.88-2.78(m,1H),m / z304.15[M+H] + .

[0358] tert-Butyl 2-(4-(2-(4-methylene-5-oxotetrahydrofuran-2-yl)phenyl)-1H-pyrazol-1-yl)acetate [ka] 1 H-NMR(300MHz,CDCl3)δ:7.57(d,J=6Hz,2H),7.46-7.30(m,4H),6.26(t,J=3Hz,1H),5.72(t,J=6Hz,1H) ,5.65(t,J=3Hz,1H),4.86(s,2H),3.27-3.21(m,1H),2.94-2.81(m,1H),1.47(s,9H),)m / z355.25[M+H] + .

[0359] 3-methylene-5-(2-phenoxyphenyl)dihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)δ:7.44(dd,J=3Hz,1H),7.37-7.24(m,3H),7.16-7.10(m,2H),7.00-6.97(m,2H),6.88-6 .85(m,1H),6.27(t,J=3Hz,1H),5.80(t,J=6Hz,1H),5.62(t,J=3Hz,1H),3.41-3.33(m,1H),2.94-2.81(m,1H). M / z 267.19[M+H] + .

[0360] 3-methylene-5-(2-(thiophen-2-yl)phenyl)dihydrofuran-2(3H)-one [ka] 1H-NMR(300MHz,CDCl3)δ:7.46-7.36(m,5H),7.12-7.09(m,1H),7.04-7.02(m,1H),6.28(t,J=3Hz,1 H),5.79(t,J=6Hz,1H),5.64(t,J=3Hz,1H),3.73-3.16(m,1H),2.890-2.87(m,1H),m / z257.10[M+H] + .

[0361] 3-Methylene-5-(2-(2-morpholinoethoxy)phenyl)dihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)δ:7.29(t,2H),6.99-6.87(m,2H),6.27(t,J=3Hz,1H),5.71(t,J=6Hz,1H),5.62(t,J=3Hz,1H),4.16- 4.09(m,2H),3.75-3.69(m,4H),3.46-3.43(m,1H),2.94-2.84(m,1H),2.79-2.75(m,2H),2.56-2.53(m,4H),m / z304.25[M+H] + .

[0362] Synthesis of (S)-2-phenyl-2-(vinylsulfonamido)acetic acid [ka] Step 1: Methyl (S)-2-phenyl-2-(vinylsulfonamido)acetate: To a solution of methyl (S)-2-amino-2-phenylacetate hydrochloride (0.3 g, 1.487 mmol) in DCM (10 mL) was added TEA (0.9 mL, 6.691 mmol) and 2-chloroethanesulfonyl chloride (0.15 mL, 1.487 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with DCM (2 × 30 mL) and washed with water (2 × 30 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure, followed by purification by column chromatography. The required compound was eluted with 80% ethyl acetate and hexane to give methyl (S)-2-phenyl-2-(vinylsulfonamido)acetate. Yield: 0.329 g (86.80%).

[0363] Step 2: (S)-2-phenyl-2-(vinylsulfonamido)acetic acid: To a stirred solution of methyl (S)-2-phenyl-2-(vinylsulfonamido)acetate (0.329 g, 1.288 mmol) in THF (3 mL) and water (3 mL) was added NaOH (0.077 g, 1.932 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with DCM (2 × 30 mL) and washed with water (2 × 30 mL). The aqueous layer was acidified with 1 N HCl and extracted with 20% MeOH / DCM. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give (S)-2-phenyl-2-(vinylsulfonamido)acetic acid. Yield 0.1 g (32.25%). 1 HNMR(400MHz,dmso)δ8.02(d,J=48.6Hz,1H),7.41-7.26(m,5H),6.58(dd,J= 16.1,9.9Hz,1H),5.97(d,J=16.3Hz,1H),5.86(d,J=9.7Hz,1H),4.72(s,1H). MS(m / z):240[MH] + .

[0364] Synthesis of (S)-N,2-diphenyl-2-(vinylsulfonamido)acetamide [ka] Step 1: Methyl (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate: To a solution of methyl (S)-2-amino-2-phenylacetate hydrochloride (1 g, 4.959 mmol) in DCM (10 mL) was added TEA (2.073 mL, 14.877 mmol) and (Boc)2O (1.365 mL, 5.950 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with DCM (2 × 50 mL) and washed with water (2 × 50 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure, followed by purification by column chromatography. The required compound was eluted with 10% ethyl acetate and hexane to give methyl (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate. Yield: 1.1 g (83.65%).

[0365] Step 2: (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid: To a stirred solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate (1.1 g, 4.150 mmol) in THF (10 mL) and water (10 ml) was added LiOH.HO (0.209 g, 4.98 ml) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with EtOAc (100 mL) and washed with water (2 × 50 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid. Yield 0.85 g (81.49%).

[0366] Step 3: tert-Butyl (S)-(2-oxo-1-phenyl-2-(phenylamino)ethyl)carbamate: To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (0.4 g, 1.593 mmol) in DCM (15 mL) was added aniline (0.148 g, 1.593 mmol), HoBt (0.258 g, 1.911), and NMM (0.161 g, 1.593 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. EDC.HCl (0.305 g, 1.593 mmol) was then added, and the reaction mixture was stirred at 0 °C for 3 h and at room temperature for 12 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with DCM (2 × 50 mL) and washed with water (2 × 50 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure, followed by purification by column chromatography. The desired compound was eluted with 50% ethyl acetate and hexane to give tert-butyl (S)-(2-oxo-1-phenyl-2-(phenylamino)ethyl)carbamate. Yield 0.3 g (57.69%).

[0367] Step 4: (S)-2-Amino-N,2-diphenylacetamide hydrochloride: To a stirred solution of tert-butyl (S)-(2-oxo-1-phenyl-2-(phenylamino)ethyl)carbamate (0.3 g, 0.920 mmol) in DCM (5 mL) was added 4 M HCl in 1,4-dioxane (3 ml) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was evaporated under reduced pressure, washed with diisopropyl ether, and evaporated to give (S)-2-amino-N,2-diphenylacetamide hydrochloride. Yield 0.22 g (91.28%).

[0368] Step 5: (S)-N,2-Diphenyl-2-(vinylsulfonamido)acetamide: To a stirred solution of (S)-2-amino-N,2-diphenylacetamide hydrochloride (0.220 g, 0.837 mmol) in DCM (10 mL) was added TEA (0.525 mL, 3.766 mmol) and 2-chloroethanesulfonyl chloride (0.096 mL, 0.920 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with DCM (2 × 30 mL) and washed with water (2 × 30 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure and purified by column chromatography. The required compound was eluted with 20% ethyl acetate and hexane to give (S)-N,2-diphenyl-2-(vinylsulfonamido)acetamide. Yield: 0.08g (30.30%). 1 HNMR(400MHz,cdcl3)δ7.49(s,1H),7.46-7.34(m,7H),7.30(t,J=7.9Hz,2H),7.13(t,J=7.4Hz,1H),6.33(dd,J =16.5,9.8Hz,1H),6.15(d,J=16.5Hz,1H),5.87(d,J=5.7Hz,1H),5.79(d,J=9.8Hz,1H),5.04(d,J=5.9Hz,1H). MS(m / z):316.9[M+H] + .

[0369] Synthesis of (S)-N-(2-morpholino-2-oxo-1-phenylethyl)ethenesulfonamide [ka] 1HNMR(400MHz,cdcl3)δ7.43-7.28(m,5H),6.18(dd,J=16.5,9.7Hz,1H),6.12-6.04(m,2H),5.66(d,J=9.7Hz,1H),5.2 3(d,J=7.3Hz,1H),3.78-3.45(m,5H),3.43-3.31(m,1H),3.24-3.15(m,1H),3.14-3.04(m,1H).MS(m / z):310.9[M+H] + .

[0370] (S)-N-(2-oxo-1-phenyl-2-(pyrrolidin-1-yl)ethyl)ethenesulfonamide [ka] 1 HNMR(400MHz,cdcl3)δ7.41-7.29(m,5H),6.20-6.06(m,2H),6.02(d,J=16.5Hz,1H),5.61(d,J=9.7Hz,1H),5.08(d,J =7.2Hz,1H),3.62-3.52(m,1H),3.51-3.38(m,2H),2.99(dt,J=9.4,6.7Hz,1H),1.98-1.72(m,4H).MS(m / z):295[M+H] + .

[0371] N-(1-(4-chlorophenyl)-2-oxo-2-(pyrrolidin-1-yl)ethyl)ethenesulfonamide [ka] 1 HNMR(400MHz,cdcl3)δ7.32(q,J=8.5Hz,4H),6.21(dd,J=16.5,9.8Hz,1H),6.08(d,J=7.6Hz,2H),5.68(d,J=9.8Hz,1H) ,5.05(d,J=7.1Hz,1H),3.61-3.52(m,1H),3.44(td,J=13.3,7.3Hz,2H),2.97(dt,J=9.6,6.6Hz,1H),2.00-1.73(m,4H). MS(m / z):329.1[M+H]+ .

[0372] N-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-oxo-2-(pyrrolidin-1-yl)ethyl)ethenesulfonamide [ka] 1 HNMR(400MHz,cdcl3)δ7.75(s,1H),7.65(s,1H),7.44(dd,J=4.0,1.5Hz,2H),7.33(dd, J=9.7,6.0Hz,1H),7.18(d,J=7.6Hz,1H),6.19(dd,J=16.5,9.8Hz,1H),6.11(d,J=7.2H z,1H),6.04(d,J=16.5Hz,1H),5.62(d,J=9.8Hz,1H),5.08(d,J=7.2Hz,1H),3.95(s,3H) ),3.63-3.54(m,1H),3.51-3.40(m,2H),3.04(dt,J=9.4,6.6Hz,1H),1.96-1.74(m,4H). MS(m / z):375.5[M+H] + .

[0373] N-(1-(2-chlorophenyl)-2-oxo-2-(pyrrolidin-1-yl)ethyl)ethenesulfonamide [ka] 1 HNMR(400MHz,cdcl3)δ7.44-7.36(m,2H),7.31-7.27(m,2H),6.33(dd,J=16.5,9.8Hz,1H),6.15(d,J=16.5Hz,1H),6.10(d,J=7.3Hz,1H),5. 71(d,J=9.8Hz,1H),5.57(d,J=7.4Hz,1H),3.56(dt,J=12.2,5.4Hz,2H),3.47-3.36(m,1H),2.89(dt,J=10.0,7.0Hz,1H),1.99-1.68(m,4H). MS(m / z):329.1[M+H] + .

[0374] (R)-N-(2-oxo-1-phenyl-2-(pyrrolidin-1-yl)ethyl)ethenesulfonamide [ka] 1HNMR(400MHz,cdcl3)δ7.39-7.30(m,5H),6.15(dd,J=16.5,9.7Hz,1H),6.09(d,J=7.1Hz,1H),6.02(d,J=16.5Hz,1H),5.61( d,J=9.7Hz,1H),5.08(d,J=7.2Hz,1H),3.62-3.53(m,1H),3.50-3.39(m,2H),2.99(dt,J=9.3,6.7Hz,1H),1.95-1.73(m,4H). MS(m / z):295.3[M+H] + .

[0375] (S)—N-(1-oxo-3-phenyl-1-(pyrrolidin-1-yl)propan-2-yl)ethenesulfonamide [ka] 1 HNMR(400MHz,cdcl3)δ7.33-7.22(m,3H),7.22-7.15(m,2H),6.32(dd,J=16.5,9.8Hz,1H) ,6.16-6.08(m,1H),5.75(d,J=9.8Hz,1H),5.47(d,J=9.5Hz,1H),4.22(td,J=8.6,6.7Hz,1 H),3.47-3.37(m,1H),3.29(ddd,J=11.9,11.3,6.5Hz,2H),3.07-2.93(m,2H),2.59(dt,J =9.7,6.5Hz,1H),1.75(ddd,J=14.7,12.0,3.1Hz,2H),1.58(ddd,J=16.9,8.7,4.8Hz,1H). MS(m / z):309.2[M+H] + .

[0376] N-(1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-oxo-2-(pyrrolidin-1-yl)ethyl)ethenesulfonamide [ka] 1 HNMR(400MHz,cdcl3)δ7.98(s,1H),7.58(s,1H),7.40(d,J=7.6Hz,1H),7.35(d,J=4.0Hz,2H ),7.32-7.27(m,1H),6.47(dd,J=16.5,9.9Hz,1H),6.09(d,J=16.5Hz,1H),5.74(d,J=9.9Hz, 2H),5.29(d,J=9.0Hz,1H),4.00(s,3H),3.42(dd,J=12.1,6.5Hz,1H),3.34(dd,J=12.0,7.0 Hz,1H),2.94(dd,J=9.9,6.1Hz,1H),2.59-2.51(m,1H),1.71(ddd,J=15.2,13.0,7.6Hz,4H).

[0377] Synthesis of 2-benzyl-4-hydroxy-5-methyleneisothiazolidine 1,1-dioxide [ka] Step 1: N-benzyl-2,2-dimethoxyethan-1-amine: To a solution of phenylmethanamine (1 g, 9.331 mmol) in DMF (10 mL) was added K2CO3 (3.869 mL, 27.993 mmol) and 2-bromo-1-1-dimethoxyethane (1.1 mL, 9.331 mmol) at 0 °C. The reaction mixture was stirred at 80 °C for 16 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with EtOAc (2 × 50 mL) and washed with water (2 × 50 mL) and brine solution (2 × 50 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure, followed by purification by column chromatography. The required compound was eluted with 10% ethyl acetate and hexane to give N-benzyl-2,2-dimethoxyethan-1-amine. Yield: 1.281 g (70.30%).

[0378] Step 2: N-benzyl-N-(2,2-dimethoxyethyl)ethenesulfonamide: To a stirred solution of N-benzyl-2,2-dimethoxyethan-1-amine (1.281 g, 6.560 mmol) in DCM (20 mL) was added TEA (4.114 mL, 29.52 mmol) and 2-chloroethanesulfonyl chloride (0.754 mL, 7.216 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with DCM (2 × 50 mL) and washed with water (2 × 50 mL). The organic layer was dried over Na SO , filtered, and the solvent was evaporated under reduced pressure and purified by column chromatography. The required compound was eluted with 6% ethyl acetate and hexane to give N-benzyl-N-(2,2-dimethoxyethyl)ethenesulfonamide. Yield: 0.872g (46.58%).

[0379] Step 3: N-benzyl-N-(2-oxoethyl)ethenesulfonamide: To a stirred solution of N-benzyl-N-(2,2-dimethoxyethyl)ethenesulfonamide (0.3 g, 1.051 mmol) in THF (1.8 mL) was added 3 M HCl (1.8 mL) at room temperature. The reaction mixture was stirred at room temperature and 70 °C for 3 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with EtOAc (2 × 30 mL) and washed with water (2 × 50 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure and purified by column chromatography. The required compound was eluted with 40% ethyl acetate and hexane to give N-benzyl-N-(2-oxoethyl)ethenesulfonamide. Yield: 0.226 g (90.03%).

[0380] Step 4: 2-benzyl-4-hydroxy-5-methyleneisothiazolidine 1,1-dioxide: To a stirred solution of N-benzyl-N-(2-oxoethyl)ethenesulfonamide (0.132 g, 0.551 mmol) in DCM (10 mL) was added DABCO (0.006 g, 0.0551 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 4 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was evaporated under reduced pressure and purified by column chromatography. The desired compound was eluted with 40% ethyl acetate and hexane to give 2-benzyl-4-hydroxy-5-methyleneisothiazolidine 1,1-dioxide. Yield 0.05 g (37.87%). 1 HNMR(400MHz,cdcl3)δ7.41-7.29(m,5H),6.26(t,J=2.0Hz,1H),6.00(t,J=1.9Hz,1H),4.80(s,1H),4.2 3(s,2H),3.37(dd,J=10.3,6.6Hz,1H),2.98(dd,J=10.3,4.6Hz,1H),2.42(s,1H).MS(m / z):240.1[M+H] + .

[0381] 4-Hydroxy-5-methylene-2-phenylisothiazolidine 1,1-dioxide [ka] Step 1: N-(2,2-Dimethoxyethyl)aniline: To a solution of aniline (1 g, 10.737 mmol) in THF (10 mL) was added NaH (0.644 g, 16.105 mmol) and 2-bromo-1-1-dimethoxyethane (1.522 mL, 12.884 mmol) at 0 °C. The reaction mixture was stirred at 70 °C for 16 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was quenched with ice-cold water (2 × 50 mL) and extracted with EtOAc (2 × 50 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure, followed by purification by column chromatography. The required compound was eluted with 2% ethyl acetate and hexane to give N-(2,2-dimethoxyethyl)aniline. Yield: 0.684 g (35.14%).

[0382] Step 2: N-(2,2-Dimethoxyethyl)-N-phenylethenesulfonamide: To a stirred solution of N-(2,2-dimethoxyethyl)aniline (0.684 g, 3.774 mmol) in DCM (10 mL) was added TEA (2.367 mL, 16.983 mmol) and 2-chloroethanesulfonyl chloride (0.4 mL, 4.151 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with DCM (2 × 50 mL) and washed with water (2 × 50 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure and purified by column chromatography. The required compound was eluted with 25% ethyl acetate and hexane to give N-(2,2-dimethoxyethyl)-N-phenylethenesulfonamide. Yield: 0.861g (84.16%).

[0383] Step 3: N-(2-oxoethyl)-N-phenylethenesulfonamide: To a stirred solution of N-(2,2-dimethoxyethyl)-N-phenylethenesulfonamide (0.312 g, 1.149 mmol) in THF (1.87 mL) was added 3 M HCl (1.87 mL) at room temperature. The reaction mixture was stirred at room temperature and 70 °C for 3 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with EtOAc (2 × 30 mL) and washed with water (2 × 30 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure and purified by column chromatography. The required compound was eluted with 30% ethyl acetate and hexane to give N-(2-oxoethyl)-N-phenylethenesulfonamide. Yield 0.236 g (91.11%).

[0384] Step 4: 4-Hydroxy-5-methylene-2-phenylisothiazolidine 1,1-dioxide: To a stirred solution of N-(2-oxoethyl)-N-phenylethenesulfonamide (0.130 g, 0.577 mmol) in DCM (10 mL) was added DABCO (0.006 g, 0.0577 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 4 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was evaporated under reduced pressure and purified by column chromatography. The desired compound was eluted with 40% ethyl acetate and hexane to give 4-hydroxy-5-methylene-2-phenylisothiazolidine 1,1-dioxide. Yield 0.05 g (38.46%). 1 HNMR(400MHz,cdcl3)δ7.44-7.37(m,2H),7.35(t,J=4.4Hz,2H),7.25-7.21(m,1H),6.32(t,J=2.1Hz,1H),6.07(t,J=1 .9Hz,1H),5.04(dt,J=8.1,6.4Hz,1H),4.00(dd,J=9.7,6.5Hz,1H),3.63(dd,J=9.7,5.0Hz,1H),2.58(d,J=8.3Hz,1H). MS(m / z):226.1[M+H] + .

[0385] 4-Hydroxy-2-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-methyleneisothiazolidine 1,1-dioxide [ka] 1 HNMR(400MHz,dmso)δ8.09(s,1H),7.85(s,1H),7.64(d,J=7.7Hz,1H),7.55(d,J=7.9Hz,1H),7.42(t,J=7.2Hz,1H),7.32(t,J=7.6Hz,1H),6 .34(d,J=5.1Hz,1H),6.21(s,1H),6.06(s,1H),4.93(d,J=6.2Hz,1H),3.85(s,3H),3.69(dd,J=9.6,6.9Hz,1H),3.27(dd,J=9.7,5.4Hz,1H). MS(m / z):306.2[M+H] + .

[0386] 4-Hydroxy-2-methyl-5-methylene-3-phenylisothiazolidine 1,1-dioxide [ka] Step 1: 2-((tert-butyldimethylsilyl)oxy)-1-phenylethan-1-amine: To a stirred solution of 2-amino-2-phenylethan-1-ol (1 g, 7.289 mmol) in DCM (20 mL) was added imidazole (1.240 g, 18.222 mmol) and TBDMS-Cl (1.318 g, 8.746 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with DCM (2 × 50 mL) and washed with water (2 × 50 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give 2-((tert-butyldimethylsilyl)oxy)-1-phenylethan-1-amine. Yield 1.6 g (87.33%).

[0387] Step 2: N-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)ethenesulfonamide: To a stirred solution of 2-((tert-butyldimethylsilyl)oxy)-1-phenylethan-1-amine (1 g, 3.976 mmol) in DCM (15 mL) was added TEA (2.49 ml, 17.892 mmol) and 2-chloroethanesulfonyl chloride (0.457 ml, 4.373 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with DCM (2×50 mL) and washed with water (2×50 mL). The organic layer was dried over NaSO, filtered, the solvent was evaporated under reduced pressure and purified by column chromatography. The desired compound was eluted with 20% ethyl acetate and hexane to give N-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)ethenesulfonamide. Yield 0.6 g (44.18%).

[0388] Step 3: N-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-N-methylethenesulfonamide: To a stirred solution of N-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)ethenesulfonamide (0.5 g, 1.463 mmol) in ACN (10 mL) was added KCO (0.606 g, 4.389 mmol) and CHI (0.091 mL, 2.926 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 4 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with DCM (2 × 30 mL) and washed with water (2 × 30 mL). The organic layer was dried over NaSO, filtered, the solvent was evaporated under reduced pressure and purified by column chromatography. The desired compound was eluted with 15% ethyl acetate and hexane to give N-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-N-methylethenesulfonamide. Yield 0.5 g (96.15%).

[0389] Step 4: N-(2-hydroxy-1-phenylethyl)-N-methylethenesulfonamide: To a stirred solution of N-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-N-methylethenesulfonamide (0.5 g, 1.406 mmol) in DCM (10 mL) was added 4 M HCl in 1,4-dioxane (2 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the solvent was evaporated under reduced pressure to give N-(2-hydroxy-1-phenylethyl)-N-methylethenesulfonamide. Yield 0.3 g (88.49%).

[0390] Step 5: N-Methyl-N-(2-oxo-1-phenylethyl)ethenesulfonamide: To a stirred solution of N-(2-hydroxy-1-phenylethyl)-N-methylethenesulfonamide (0.2 g, 0.828 mmol) in DCM (10 mL) was added DMP (0.703 g, 1.656 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with DCM (2 × 50 mL) and washed with water (2 × 50 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure and purified by column chromatography. The required compound was eluted with 20% ethyl acetate and hexane to give N-methyl-N-(2-oxo-1-phenylethyl)ethenesulfonamide. Yield 0.19 g (95.95%).

[0391] Step 6: 4-Hydroxy-2-methyl-5-methylene-3-phenylisothiazolidine 1,1-dioxide: To a stirred solution of N-methyl-N-(2-oxo-1-phenylethyl)ethenesulfonamide (0.19 g, 0.794 mmol) in DCM (20 mL) was added DABCO (0.0088 g, 0.079 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was evaporated under reduced pressure and purified by column chromatography. The desired compound was eluted with 40% ethyl acetate and hexane to give 4-hydroxy-2-methyl-5-methylene-3-phenylisothiazolidine 1,1-dioxide. Yield: 0.03 g (15.78%). 1HNMR(400MHz,cdcl3)δ7.48-7.35(m,5H),6.30(dd,J=4.7,2.4Hz,1H),5.98(t,J=2 .1Hz,1H),4.68(s,1H),3.89(d,J=7.2Hz,1H),2.54(s,3H),2.38(d,J=13.7Hz,1H). MS(m / z):240.1[M+H] + .

[0392] Synthesis of 4-hydroxy-2-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-5-methyleneisothiazolidine 1,1-dioxide [ka] Step 1: N-(2-Bromobenzyl)-2,2-dimethoxyethan-1-amine: To a solution of (2-bromophenyl)methanamine (0.5 g, 2.687 mmol) in ACN (20 mL) was added K2CO3 (1.114 g, 8.061 mmol) and 2-bromo-1-1-dimethoxyethane (0.317 mL, 2.687 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with EtOAc (2 × 50 mL) and washed with water (2 × 50 mL) and brine solution (2 × 50 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure and purified by column chromatography. The required compound was eluted with 8% ethyl acetate and hexane to give N-(2-bromobenzyl)-2,2-dimethoxyethan-1-amine. Yield: 0.3g (40.76%).

[0393] Step 2: 2,2-Dimethoxy-N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)ethan-1-amine: To a solution of N-(2-bromobenzyl)-2,2-dimethoxyethan-1-amine (0.3 g, 1.094 mmol) in 1,4-dioxane (4 mL) and HO (1 mL) was added KCO (0.378 g, 2.735 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.273 g, 2.687 mmol) at room temperature. The reaction mixture was degassed with nitrogen for 10 minutes. Tetrakis (0.126 g, 0.1094) was then added and again degassed with nitrogen for 10 minutes. The reaction mixture was stirred at 90 °C for 16 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with EtOAc (2 x 50 mL) and washed with water (2 x 50 mL) and brine solution (2 x 50 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure and purified by column chromatography. The required compound was eluted with 25% ethyl acetate and hexane to give 2,2-dimethoxy-N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)ethan-1-amine. Yield 0.2 g (66.44%).

[0394] Step 3: N-(2,2-Dimethoxyethyl)-N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)ethenesulfonamide: To a stirred solution of 2,2-dimethoxy-N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)ethan-1-amine (0.2 g, 0.726 mmol) in DCM (10 mL) was added TEA (0.455 ml, 3.267 mmol) and 2-chloroethanesulfonyl chloride (0.083 ml, 0.798 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with DCM (2×30 mL) and washed with water (2×30 mL). The organic layer was dried over Na2SO4, filtered, the solvent was evaporated under reduced pressure and purified by column chromatography. The desired compound was eluted with 15% ethyl acetate and hexane to give N-(2,2-dimethoxyethyl)-N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)ethenesulfonamide. Yield 0.08 g (30.18%).

[0395] Step 4: N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-N-(2-oxoethyl)ethenesulfonamide: To a stirred solution of N-(2,2-dimethoxyethyl)-N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)ethenesulfonamide (0.08 g, 0.218 mmol) in THF (1.8 mL) was added 3 M HCl (1.8 ml) at room temperature. The reaction mixture was stirred at room temperature and 70 °C for 3 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with EtOAc (2 × 30 mL) and washed with water (2 × 50 mL). The organic layer was dried over NaSO, filtered, the solvent was evaporated under reduced pressure and purified by column chromatography. The desired compound was eluted with 45% ethyl acetate and hexane to give N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-N-(2-oxoethyl)ethenesulfonamide. Yield 0.06 g (85.83%).

[0396] Step 5: 4-Hydroxy-2-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-5-methyleneisothiazolidine 1,1-dioxide: To a stirred solution of N-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-N-(2-oxoethyl)ethenesulfonamide (0.06 g, 0.187 mmol) in DCM (6 mL) was added DABCO (0.002 g, 0.0187 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was evaporated under reduced pressure and purified by column chromatography. The required compound was eluted with 30% ethyl acetate and hexane to give 4-hydroxy-2-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-5-methyleneisothiazolidine 1,1-dioxide. Yield 0.015g (25%) 1 HNMR(400MHz,cdcl3)δ7.65(s,1H),7.57(s,1H),7.44-7.28(m,4H),6.27(t,J=2.0Hz,1H),6.01(t,J=1.9Hz,1H),4.79(ddd,J=8.5,4.4,2. 0Hz,1H),4.27(d,J=3.1Hz,2H),3.94(s,3H),3.33(dd,J=10.2,6.5Hz,1H),2.95(dd,J=10.3,4.6Hz,1H),1.82(s,1H).MS(m / z):320.1[M+H] + .

[0397] 4-Methoxy-5-methylene-2-phenylisothiazolidine 1,1-dioxide [ka] Step 1: 4-Methoxy-5-methylene-2-phenylisothiazolidine 1,1-dioxide: To a stirred solution of 4-hydroxy-5-methylene-2-phenylisothiazolidine 1,1-dioxide (0.15 g, 0.665 mmol) in ACN (10 mL) was added K2CO3 (0.460 g, 3.325 mmol) and CHI (0.124 mL, 1.995 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with DCM (2 × 30 mL) and washed with water (2 × 30 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure and purified by column chromatography. The required compound was eluted with 20% ethyl acetate and hexane to give 4-methoxy-5-methylene-2-phenylisothiazolidine 1,1-dioxide. Yield: 0.01g (6.28%). 1 HNMR(400MHz,cdcl3)δ7.44-7.31(m,4H),7.22(t,J=7.1Hz,1H),6.36(s,1H),6.02(s,1H),4. 67-4.61(m,1H),3.98(dd,J=9.7,6.1Hz,1H),3.72(dd,J=9.7,3.9Hz,1H),3.51-3.48(s,3H). MS(m / z):240.1[M+H] + .

[0398] 4-Methoxy-2-methyl-5-methylene-3-phenylisothiazolidine 1,1-dioxide [ka] Step 1: 4-Methoxy-2-methyl-5-methylene-3-phenylisothiazolidine 1,1-dioxide: To a stirred solution of 4-hydroxy-2-methyl-5-methylene-3-phenylisothiazolidine 1,1-dioxide (0.06 g, 0.250 mmol) in ACN (10 mL) was added K2CO3 (0.173 g, 1.25 mmol) and CHI (0.046 mL, 0.75 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with DCM (2 × 30 mL) and washed with water (2 × 30 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure and purified by column chromatography. The desired compound was eluted with 20% ethyl acetate and hexane to give 4-methoxy-2-methyl-5-methylene-3-phenylisothiazolidine 1,1-dioxide. Yield 0.015 g (23.80%). 1 HNMR(400MHz,cdcl3)δ7.45-7.36(m,5H),6.34(t,J=1.9Hz,1H),5.92(t,J=1.8Hz, 1H),4.33(dt,J=5.7,2.0Hz,1H),4.05(d,J=5.7Hz,1H),3.31(s,3H),2.55(s,3H). MS(m / z):254.5[M+H] + .

[0399] 4-Hydroxy-2-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-methyleneisothiazolidine 1,1-dioxide [ka] 1HNMR(400MHz,cdcl3)δ7.76(s,1H),7.64(s,1H),7.44(s,1H),7.41-7.31(m,2H),7.18(d,J=7.5Hz,1H),6.34(s,1H),6 .09(s,1H),5.07(s,1H),4.04(dd,J=9.5,6.5Hz,1H),3.95(s,3H),3.66(dd,J=9.5,4.9Hz,1H),2.70(d,J=7.3Hz,1H). LCMS(m / z):306.2[M+H] + .

[0400] Synthesis of 4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanenitrile [ka] In the formula, R 1 and R 2 is H, D, alkyl, cycloalkyl, and R 1 and R 2 can join together to form rings in a cyclic structure. [ka] Step 1: 2-(Hydroxymethyl)acrylonitrile: To a solution of diethyl(cyanomethyl)phosphonate (5 g, 28.248 mmol) in water (20 mL) was added aqueous HCHO (3.389 g, 112.992 mmol) and K2CO3 (7.016 g, 50.846 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ether (2 × 200 mL) and washed with water (2 × 100 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure, followed by purification by column chromatography. The desired compound was eluted with 20% ethyl acetate and hexane to give 2-(hydroxymethyl)acrylonitrile. Yield 2.1 g (89%).

[0401] Step 2: 2-(Bromomethyl)acrylonitrile: To a stirred solution of 2-(hydroxymethyl)acrylonitrile (2.1 g, 25.301 mmol) in diethyl ether (20 mL) was added PBr3 (1.19 mL, 12.65 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ether (2 × 100 mL) and washed with water (2 × 100 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure, followed by purification by column chromatography. The desired compound was eluted with 20% ethyl acetate and hexane to give 2-(bromomethyl)acrylonitrile. Yield 2 g (54%).

[0402] Step 3: 2-((phenylsulfonyl)methyl)acrylonitrile: To a stirred solution of 2-(bromomethyl)acrylonitrile (2 g, 13.698 mmol) in methanol (20 mL) was added sodium phenylsulfinate (3.36 g, 20.547 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (2 × 100 mL) and washed with water (2 × 50 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure, followed by purification by column chromatography. The desired compound was eluted with 40% ethyl acetate in hexane to give 2-((phenylsulfonyl)methyl)acrylonitrile. Yield 0.62 g (21%).

[0403] Step 4: 2-((tributylstannyl)methyl)acrylonitrile: To a stirred solution of 2-((phenylsulfonyl)methyl)acrylonitrile (0.62 g, 2.991 mmol) in benzene (6 mL) was added AIBN (0.049 g, 0.299 mmol) and tributylstannane (1.306 g, 4.487 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 3 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was evaporated under reduced pressure and purified by column chromatography. The desired compound was eluted with 10% ethyl acetate and hexane to give 2-((tributylstannyl)methyl)acrylonitrile. Yield: 0.40 g (37%).

[0404] Step 5: 4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanenitrile: To a stirred solution of 4-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzaldehyde (0.1 g, 0.453 mmol) in benzene (2 mL), AIBN (0.0074 g, 0.045 mmol) and 2-((tributylstannyl)methyl)acrylonitrile (0.484 g, 1.359 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 16 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was evaporated under reduced pressure and purified by column chromatography. Acetonitrile (6 mL) and concentrated hydrochloric acid (0.5 mL) were added to the reaction mixture at 0°C. It was stirred for 10 minutes, then extracted with EtO (2 x 50 ml) and washed with saturated NaHCO solution. The organic layer was treated with DBU (0.5 ml) for 10 minutes. The reaction mixture was evaporated under reduced pressure and purified by column chromatography. The desired compound was eluted with 35% ethyl acetate and hexane to give 4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanenitrile. Yield: 0.105g (80.76%). 1HNMR(400MHz,cdcl3)δ7.56(d,J=8.4Hz,1H),7.51(d,J=2.4Hz,2H),7.36-7.27(m,2H),5.95(s,1H) ),5.78(s,1H),5.21(dt,J=8.2,4.2Hz,1H),3.96(s,3H),2.60-2.54(m,2H),2.19(d,J=3.7Hz,1H). MS(m / z):288.1[M+H] + .

[0405] 5-(4-chloro-2-(1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] Synthesis scheme: [ka] Step 1: Synthesis of 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole: [ka] procedure: To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (400 mg, 2.68 mmol) and DHP (248.37 mg, 2.95 mmol) in toluene (5 mL) was added TFA (0.01 mL, 0.13 mmol). The resulting reaction mixture was heated at 80 °C for 2 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (2 × 10 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a pale yellow oil (600 mg, 75%).

[0406] Step 2: Synthesis of 4-chloro-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde: [ka] procedure: To a stirred solution of 2-bromo-4-chlorobenzaldehyde (0.3 g, 1.37 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein (226 mg, 1.78 mmol) in 1,4-dioxane (15 mL) was added potassium carbonate (500 mg, 3.57 mmol) in water (5 mL). The resulting mixture was degassed for 5 minutes, and tetrakis(triphenylphosphine)-palladium (30 mg, 10% mol) was added. The reaction mixture was again degassed for another 5 minutes. The resulting reaction mixture was heated at 70°C for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (2 × 10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (mesh: 60-120) using 25-30% ethyl acetate and petroleum ether as eluent to give 4-chloro-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde as a pale yellow solid (380 mg, 95%).

[0407] Step 3: Synthesis of methyl 4-(4-chloro-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoate: [ka] procedure: To a stirred solution of 4-chloro-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde (300 mg, 1.03 mmol) and methyl 2-(bromomethyl)acrylate (241 mg, 1.34 mmol) in THF (20 mL) was added zinc (243 mg, 3.71 mmol) and saturated NH4Cl in water (1 mL). The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (20 mL) and washed with water (2 x 10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give methyl-4-(4-chloro-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoate as a colorless gum (350 mg, 86%).

[0408] Step 4: Synthesis of 5-(4-chloro-2-(1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one: [ka] procedure: To a stirred solution of methyl 4-(4-chloro-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoate (300 g, 0.77 mmol) in DCM (15 mL) was added trifluoroacetic acid (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure to give a brown gum. The crude product was purified by preparative HPLC to give 5-(4-chloro-2-(1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one as an off-white gum (15 mg, 6%). 1H-NMR (400MHz, CDCl3):7.69(s,2H),7.40-7.33(m,2H),6.31-6.30(t,1H),5.68-5.63(m,2H),3.23-3.16(m,1H),2.92-2.84(m,1H). LCMS (M+H=275.0, 96.42%).

[0409] 5-(5-chloro-2-(1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one: [ka] 1 H-NMR(400MHz,CDCl3):7.67(s,2H),7.445-7.440(m,1H),7.36-7.33(m,1H),7.27-7.24(m,1H), 6.33-6.31(t,1H),5.69-5.65(m,1H),5.64-5.62(m,1H),,3.19-3.17(m,1H),2.91-2.89(m,1H). LCMS (M+H=275.1, 90.58%)

[0410] 5-(5-fluoro-2-(1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one: [ka] 1 H-NMR (400MHz, CDCl3):7.67(s,2H),7.30-7.27(m,1H),7.18-7.15(m,1H),7.09-7.0 4(m,1H),6.32-6.30(t,1H),5.68-5.62(m,2H),3.22-3.15(m,1H),2.89-2.61(m,1H). LCMS (M+H=259.1, 90.21%)

[0411] 5-(3-chloro-2-(1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR (400MHz, CDCl3):7.62(s,2H),7.58-7.46(m,1H),7.44-7.32(m,2H),6.28-6.2 6(m,1H),5.63-5.62(t,1H),5.48-5.45(m,1H),3.11-3.04(m,1H),2.81-2.66(m,1H). LCMS (M+H=275.0, 98.22%)

[0412] 5-(4,5-difluoro-2-(1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one: [ka] 1 H-NMR(400MHz, CDCl3):7.72(s,2H),7.29-7.24(m,1H),7.16-7.11(m,1H),6.33-6.2 3(t,1H),5.70-5.69(t,1H),5.61-5.55(m,1H),3.49-3.16(m,1H),2.89-2.81(m,1H). LCMS (M+H=277.0, 95.34%).

[0413] 5-(4,5-dichloro-2-(1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR (400MHz, CDCl3):7.68(s,2H),7.53(s,1H),7.42(s,1H),6.33-6.32(t,1 H),5.70-5.69(t,1H),5.62-5.58(m,1H),3.23-3.17(m,1H),2.88-2.82(m,1H). LCMS(M + +H):309.14,(96.44%).

[0414] 4-Hydroxy-5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] Step 1: [ka] procedure: To a stirred solution of 5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one (0.087 g, 0.31 mmol) in dioxane (5 mL) and water (1 mL) was added selenium dioxide (0.053 g, 0.47 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 24 hours. The progress of the reaction was monitored by TLC. After completion of the reaction of the starting material, it was diluted with HO (50 mL) and extracted with EtOAc (2×20 mL). The organic layers were combined and dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude compound. The resulting crude product was purified by SiO column chromatography (eluent: 5% methanol and DCM) to give 4-hydroxy-5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one as a brown solid (0.015 g, 17.4%). 1 H-NMR(300MHz,CDCl3)δ7.60(d,J=12.0Hz,2H),7.38-7.31(m,4H),6.50(d,J=2.1Hz, 1H),6.00(d,J=1.8Hz,1H),5.55(d,J=4.2Hz,1H),4.84(t,J=2.1Hz,1H),3.96(s,3H), LCMS: retention time 2.03 min (90.38% purity), m / z 271.14 [M+H] + .

[0415] 5-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(300MHz,CDCl3)δ7.66-7.58(m,2H),7.38-7.20(m,3H),6.50(bs,1H),6.01 (d,J=1.2Hz,1H),5.50(d,J=4.4Hz,1H),4.84(bs,1H),3.96(s,3H),3.0(bs,1H). LCMS(M + +H):326.8 (sodium adduct), (98.24%).

[0416] 5-Methyl-5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one

[0417] Synthesis scheme [ka] Step 1: Synthesis of 1-(-2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethan-1-one: [ka] procedure: To a stirred solution of 1-(2-bromophenyl)ethan-1-one (1 g, 5.02 mmol) and 1-(1-methyl-1H-pyrazol-4-yl)boronic acid (760 mg, 6.02 mmol) in 1,4-dioxane (20 mL) was added potassium carbonate (1.7 g, 12.55 mmol) in water (20 mL). The resulting mixture was degassed for 5 minutes, and tetrakis(triphenylphosphine)-palladium (500 mg, 10% mol) was added. The reaction mixture was again degassed for another 5 minutes. The resulting reaction mixture was heated at 70° C. for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×20 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the crude product. Purification by column chromatography on silica gel (mesh: 60-120) using 40-50% ethyl acetate and petroleum ether as eluent gave 1-(-2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethan-1-one as an off-white solid (820 mg, 82%).

[0418] Step 2: Synthesis of methyl 4-hydroxy-4-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenepentanoate: [ka] procedure: To a stirred solution of 1-(-2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethan-1-one (0.5 g, 2.50 mmol) and methyl 2-(bromomethyl)acrylate (580 mg, 3.24 mmol) in THF (10 mL) was added zinc (1.07 g, 16.25 mmol) and saturated NH4Cl in water (5 mL). The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (20 mL) and washed with water (2 x 10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the crude product. Purification by column chromatography using silica gel (mesh: 60–120) and 50–60% ethyl acetate and petroleum ether as eluent gave methyl 4-hydroxy-4-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenepentanoate as a light brown gum (150 mg, 20%).

[0419] Step 3: Synthesis of 5-methyl-5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one: [ka] procedure: To a stirred solution of methyl 4-hydroxy-4-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylenepentanoate (150 mg, 0.49 mmol) in DCM (10 mL) was added trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure to give the crude product. This was purified by column chromatography on silica gel (mesh: 60-120) using 40-50% ethyl acetate and petroleum ether as eluent to give 5-methyl-5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one as an off-white gum (64 mg, 47%). 1H-NMR (400MHz, CDCl3):7.73-7.72(d,1H),7.42-7.38(m,1H),7.369-7.367(m,2H),7.32-7.28(m,1H)7.168-7.1 65(d,1H),6.18-6.16(t,1H),5.53-5.52(t,1H),3.97(s,3H),3.10-3.04(m,1H),2.76-2.71(m,1H),1.6(s,3H). LCMS: 269.25(M + +H), 99.72% purity.

[0420] 5-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-methyl-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(400MHz,CDCl3):7.64-7.66(m,1H);7.43(s,1H);7.32-7.36(m,2H),7.17(d,1H,3Hz);6.1 7-6.19(m,1H);5.53-5.54(m,1H);3.96(s,3H);3.00-3.05(m,1H),2.70-2.75(m,1H);1.68(s,3H) LCMS(M+H):303.4,99.93%.

[0421] 5-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-methyl-2-methylenedihydrofuran-3(2H)-one Synthesis scheme [ka] Step 1: Synthesis of methyl 3-hydroxy-2-methylenebutanoate: [ka] procedure: To a stirred solution of acetaldehyde (5 g, 0.11 mmol) and methyl acrylate (19.2 g, 0.15 mmol) in 1,4-dioxane (20 mL) and water (20 mL) was added DABCO (19.2 g, 0.18 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with water (2 × 30 mL). The organic layer was dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude product as a yellow oil. The crude product was purified by column chromatography (silica gel: 60 + 120, 5–10% ethyl acetate in petroleum ether) to give methyl 3-hydroxy-2-methylenebutanoate as a pale yellow oil (8 g, 95%).

[0422] Step 2: Synthesis of methyl 3-bromo-2-methylenebutanoate: [ka] procedure: To a stirred solution of methyl 3-hydroxy-2-methylenebutanoate (8 g, 0.06147 mmol) in diethyl ether (30 mL) was added PBr (3 mL, 0.0307 mmol) dropwise at 0 °C. The resulting reaction mixture was stirred at 0 °C for 1 h. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was quenched with ice-cold water and extracted with diethyl ether (2 × 25 mL). The organic layer was dried over Na SO , filtered, and the solvent was evaporated under reduced pressure to give methyl 3-bromo-2-methylenebutanoate as a dark brown liquid (4 g, 35%).

[0423] Step 3: Synthesis of 4-chloro-2-(1-methyl-1H-pyrazol-4-yl)benzaldehyde: [ka] procedure: To a stirred solution of 2-bromo-4-chlorobenzaldehyde (400 mg, 1.82 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (496 mg, 2.36 mmol) in 1,4-dioxane (8 mL) was added potassium carbonate (656 mg, 4.74 mmol) in water (5 mL). The resulting mixture was degassed for 5 minutes, and tetrakis(triphenylphosphine)-palladium (40 mg, 10 mol%) was added. The reaction mixture was degassed for another 5 minutes. The resulting reaction mixture was heated at 70° C. for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (2×10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the crude product. This was purified by column chromatography on silica gel (mesh: 60-120) and the required compound was eluted with 25-30% ethyl acetate and petroleum ether to give 4-chloro-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde as a pale yellow solid (300 mg, 74%).

[0424] Step 4: Synthesis of methyl 4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-3-methyl-2-methylenebutanoate: [ka] procedure: To a stirred solution of 4-chloro-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde (300 mg, 1.36 mmol) and methyl 3-bromo-2-methylenebutanoate (360 mg, 1.76 mmol) in THF (10 mL) was added zinc (320 mg, 4.88 mmol) and saturated NH4Cl in water (1 mL). The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (20 mL) and washed with water (2 x 10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give the product methyl 4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-3-methyl-2-methylenebutanoate as a white gum (300 mg, 65%).

[0425] Step 5: 4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-3-methyl-2-methylenebutanoic acid: [ka] procedure: To a stirred solution of 4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-3-methyl-2-methylenebutanoic acid (150 mg, 0.47 mmol) in DCM (15 mL) was added trifluoroacetic acid (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure to give the crude product as a brown gum. This was purified by column chromatography (silica gel: 100-200, 25-30% ethyl acetate in petroleum ether) to give the desired product, 5-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-methyl-2-methylenedihydrofuran-3(2H)-one, as a pale yellow gum (28 mg, 21%). 1H-NMR (400MHz, CDCl3):7.53(s,1H),7.48(s,1H),7.35(m,1H),7.31-7.26(m,2H),6.3 1-6.28(m,1H),5.593-5.57(m,1H),3.99(s,3H),3.24-3.19(m,1H),1.29-1.28(d,3H). LCMS (M+H=303.1, 99.91%)

[0426] 5-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-cyclopropyl-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(400MHz,CDCl3):7.52-7.77(m,1H);7.36-7.39(m,1H);7.30-7.32(m,2H);6.35-6.37(m,1H);5.89(d,0.5H,3H z);5.80(d,0.5H,3Hz);560(d,0.5H,6Hz) and 5.78(d,0.5H,6Hz);4.07(s,3H);2.37-2.62(m,1H);0.01-0.58(m,5H). LCMS(M+H):329.4,97.53%.

[0427] 5-(4-chloro-2-(1H-pyrazol-4-yl)phenyl)-4-methyl-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(400MHz,CDCl3):7.65(bs,2H);7.28-7.36(m,3H);6.31(d,1H,J=1.5Hz),5 .80(d,1H,J=6Hz);5.57(d,1H,J=1.5Hz);;3.18-3.22(m,1H);0.75(d,3H,J=6Hz). LCMS(M+H):289.4,93%.

[0428] 5-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-methyl-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(400MHz,CDCl3):7.47(bs,1H);7.38(s,1H);7.35-7.36(m,1H);7.29-7.31(m,1H);7.18-7.20(m,1H);6.32 (d,1H,J=1.5Hz),5.80(d,1H,J=6Hz);5.60(d,1H,J=1.5Hz);3.97(s,3H);3.18-3.22(m,1H);0.80(d,3H,J=6Hz). LCMS (M+H) = 303.4, 96.81%.

[0429] 5-(5-chloro-2-(1H-pyrazol-4-yl)phenyl)-4-methyl-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(400MHz,CDCl3):7.67(bs,2H);7.31-7.38(m,2H);7.21-7.26(m,1H);6.32(d,1H,J= 1.5Hz),5.78(d,1H,J=6Hz);5.59(d,1H,J=1.5Hz);3.18-3.22(m,1H);0.80(d,3H,J=6Hz). LCMS (M+H) = 289.3, 96.81%.

[0430] 5-(5-fluoro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-methyl-3-methylenedihydrofuran-2(3H)-one [ka] 1H-NMR(400MHz,CDCl3):7.46(bs,1H);7.37(s,1H);7.35-7.36(m,1H);7.29-7.31(S,1H);7.20-7.26(m,1H);7.00-7.5(m,1 H);6.30(d,1H,J=1.5Hz);5.80(d,1H,J=6Hz);5.60(d,1H,J=1.5Hz);3.96(s,3H);3.17-3.220(m,1H);0.80(d,3H,J=6Hz). LCMS (M+H) = 287.3, 95.02%.

[0431] 5-(4,5-dichloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-methyl-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(400MHz,DMSO):8.02(s,1H);7.71(s,1H);7.66(s,1H);7.38(S,1H);6.18(d,J=3Hz,1H) ;5.99(d,1H,J=6Hz);5.80(d,1H,J=3Hz);3.89(s,3H);3.47-3.42(m,1H),0.69(d,3H,J=6Hz). LCMS(M + +H):337.5,97.08%.

[0432] 5-(5-fluoro-2-(1H-pyrazol-4-yl)phenyl)-4-methyl-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(400MHz,CDCl3):7.67(bs,2H);7.08-7.25(m,3H);6.30(d,1H,J=1.5Hz);5 .77(d,1H,J=6Hz);5.58(d,1H,J=1.5Hz);3.13-3.17(m,1H);0.80(d,3H,J=6Hz). LCMS (M+H) = 273.2, 97.7%.

[0433] 4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-3-methyl-2-methylenebutanoic acid [ka] procedure: To a stirred solution of methyl 4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-3-methyl-2-methylenebutanoate (300 mg, 0.89 mmol) in THF (10 mL) and MeOH (2 mL) was added LiOH.HO (76 mg, 1.79 mmol) in water (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure to give the crude product. It was diluted with water and washed with ethyl acetate (2 × 10 mL). The aqueous layer was acidified with 6N hydrochloric acid and extracted again with ethyl acetate (2 × 15 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give 4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-3-methyl-2-methylenebutanoic acid as an off-white solid (95 mg, 34%). 1 H-NMR(400MHz,CDCl3):12.25(brs,1H),7.88(brs,1H),7.59(s,1H),7.57-7.50(d,1H),7.30-7.22(m,1H) ,7.24-7.23(d,1H),5.91(brs,2H),4.80-4.79(d,1H),3.89(s,3H),2.99-2.96(t,1H),1.04-1.03(d,3H). LCMS(M + +H:321.1, 90.13% purity).

[0434] 4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanenitrile [ka] 1 HNMR(400MHz,CDCl3)δ7.56(d,J=8.4Hz,1H),7.51(d,J=2.4Hz,2H),7.36-7.27(m,2H),5.95(s,1H) ),5.78(s,1H),5.21(dt,J=8.2,4.2Hz,1H),3.96(s,3H),2.60-2.54(m,2H),2.19(d,J=3.7Hz,1H). MS(m / z):288.1[M+H] + .

[0435] 5-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(400MHz, CDCl3):7.97(s,1H),7.66(s,1H),7.43-7.41(m,3H),6.12(t ,1H),5.85-5.75(m,2H),3.89(s,3H),3.50-3.40(m,1H),2.90-2.80(m,1H). HPLC: 98.18%.

[0436] 5-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR (400MHz, CDCl3):7.49(s,1H),7.45(s,1H),7.419-7.413(d,1H),7.33-7.30(d,1H),7.24-7. 21(d,1H),6.32-6.31(t,1H),5.69-5.64(m,2H),3.97(s,3H),3.25-3.18(m,1H),2.92-2.85(m,1H). LCMS: m / z: 289.25 (M+H): 97.96%)

[0437] 5-(2-chloro-6-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR (400MHz, CDCl3):7.83(s,1H),7.51(s,1H),7.47-7.46(d,1H),7.44-7.38(m,1H),7.30-7.28(m,1H) ),6.10-6.09(t,1H),5.93-5.89(m,1H),5.73(s,1H),3.86(s,3H),3.49-3.43(m,1H),3.16-3.08(m,1H). LCMS: m / z: 288.9 (M+H): 99.44%).

[0438] 5-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-methylenedihydrofuran-2(3H)-one [ka] 1 H-NMR(400MHz,CDCl3):7.46-7.44(m,2H),7.40(s,1H),7.35-7.32(m,2H),7.27-7.26(t,1H),( t,1H),5.63-5.62(t,1H),5.52-5.48(t,1H),3.99(s,3H),3.14-3.08(m,1H),2.80-2.74(m,1H) / LCMS: m / z: 289.25 (M+H): 98.52%).

[0439] 4-(2-(1-(tert-butyl)-1H-pyrazol-4-yl)-4-chlorophenyl)-4-hydroxy-2-methylenebutanoic acid [ka] 1H-NMR(400MHz,CDCl3):12.4-12.3(brs,1H),8.027(s,1H),7.65-7.59(m,2H),7.35-7.30(m,2H),6.07 6-6.072(d,1H),5.58(s,1H),5.27-5.21(brs,1H),5.05-4.95(brs,1H),2.6-2.51(m,2H),1.56(s,9H). LCMS: m / z 349.1 [M + +H]; (99.42% purity)

[0440] 4-(4-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoic acid [ka] 1 H-NMR (400MHz, CDCl3):12.5-12.3(brs,1H),8.01(s,1H),7.84(s,1H),7.70-7. 59(m,2H),7.45-7.35(m,2H),6.04(d,1H),4.91-4.85(m,1H),2.6-2.51(m,2H). LCMS: m / z 340.9 [M + -H]; (99.95% purity).

[0441] (4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoyl)glycine [ka] 1 H-NMR(400MHz,CDCl3):8.03(s,1H),7.64(s,1H),7.59(d,1H),7.35-7.30(m,2H),5.6 2(s,1H),5.24(d,1H),4.90-4.85(m,1H),3.88(s,3H),3.45(s,2H),2.70-2.40(m,2H). LCMS: m / z 361.9 [M + -H]; (98.15% purity).

[0442] 4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-N-methyl-2-methylenebutanamide [ka] 1 H-NMR(400MHz,CDCl3):8.03(s,1H),7.96(s,1H),7.70-7.55(m,2H),7.45-7.30(m,2H),5 .61(s,1H),5.37(d,1H),5.25(s,1H),4.90-4.85(m,1H),3.88(s,3H),2.70-2.40(m,5H). LCMS: m / z 317.8 [M + -H]; (98.83% purity).

[0443] 4-(4-chloro-2-(1-ethyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoic acid [ka] 1 H-NMR(400MHz,CDCl3):12.5-12.3(brs,1H),8.02(s,1H),7.65(s,1H),7.59(d,1H),7.35-7.30 (m,2H),6.06(d,1H),5.56(s,1H),4.91-4.85(m,1H),4.2(q,2H),2.6-2.51(m,2H),1.4(t,3H). LCMS: m / z 340.9 [M + -H]; (99.95% purity). 4-(4-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoic acid [ka] 1H-NMR(400MHz, CDCl3):12.45-12.35(brs,1H),8.02(s,1H),7.63(s,1H),7.56(d,1H),7.35-7.27(m,2H ),6.05(bs,1H),5.54(s,1H),4.91-4.85(m,1H),3.81-3.70(m,1H),2.6-2.41(m,2H),1.1-0.90(m,4H). MS: m / z 333.0 [M + -H].

[0444] 4-(4-chloro-2-(1-isopropyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoic acid [ka] 1 H-NMR(400MHz,CDCl3):12.45-12.3(brs,1H),8.03(s,1H),7.66(s,1H),7.59(d,1H),7.35-7.30(m,2H),6.07(d,1H) ,5.56(s,1H),5.31-5.20(bs,1H),4.98-4.91(m,1H),4.55-4.48(m,1H),2.6-2.51(m,2H),1.46(s,3H),1.45(s,3H). LCMS: m / z 335.0 [M + +H].

[0445] 4-(4-chloro-2-(1-cyclopentyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoic acid [ka] 1 H-NMR (400MHz, CDCl3):8.03(s,1H),7.66(s,1H),7.59(d,1H),7.35-7.30(m,2H),6.04(d, 1H),5.53(s,1H),4.98-4.91(m,1H),4.72-4.68(m,1H),2.6-2.51(m,2H),2.2-1.6(m,8H). LCMS: m / z 361.1 [M+ +H].

[0446] 4-(4-chloro-2-(1-(cyclobutylmethyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoic acid [ka] 1 H-NMR(400MHz,CDCl3):12.45-12.3(brs,1H),7.99(s,1H),7.66(s,1H),7.59(d,1H),7.35-7.30(m,2H),6.07(d,1H) ,5.56(s,1H),4.98-4.91(m,1H),4.55-4.48(m,1H),4.14(d,2H),2.8-2.65(m,1H),2.6-2.51(m,2H),2.2-1.6(m,6H). LCMS: m / z 361.1 [M + +H]; (97.82% purity).

[0447] 4-(4-chloro-2-(1-phenyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoic acid [ka] 1 H-NMR (400MHz, CDCl3):12.45-12.3(brs,1H),8,72(s,1H),7.99(s,1H),7.89(d,1H),7.66-7. 25(m,6H),6.07(d,1H),5.59(s,1H),5.35-5.30(bs,1H),5.15-5.05(m,1H),2.6-2.51(m,2H). LCMS: m / z 369.0 [M + +H]; (90.54% purity).

[0448] 4-(4-chloro-2-(1-(cyclohexylmethyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoic acid [ka] 1 H-NMR(400MHz,CDCl3):12.45-12.3(brs,1H),7.97(s,1H),7.66(s,1H),7.59(d,1H),7.35-7.27(m,2H),6.07 (s,1H),5.58(s,1H),5.25-5.20(bs,1H),4.98-4.91(m,1H),3.97(d,2H),2.6-2.51(m,2H),1.8-0.9(m,10H). LCMS: m / z 389.1 [M + +H]; (92.5% purity).

[0449] 4-(4-chloro-2-(1-(cyclopentylmethyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoic acid [ka] 1 H-NMR(400MHz,CDCl3):12.45-12.3(brs,1H),8.01(s,1H),7.65(s,1H),7.59(d,1H),7.35-7.27(m ,2H),6.07(s,1H),5.56(s,1H),4.98-4.91(m,1H),4.04(d,2H),2.6-2.51(m,2H),1.7-1.2(m,8H). LCMS: m / z 375.1 [M + +H]; (94.68% purity).

[0450] 4-(4,5-difluoro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoic acid [ka] 1H-NMR (400MHz, CDCl3): δ=7.46-7.44(m,2H),7.40(s,1H),7.35-7.26(m,2H),6.27- 6.26(t,1H),5.63-5.62(t,1H),3.99(s,3H),3.14-3.08(m,1H),2.80-2.74(m,1H). LCMS: m / z 309 [M + +H]; (93.51% purity)

[0451] 4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoic acid [ka] 1 H-NMR(400MHz,CDCl3):12.4-12.2(brs,1H),7.93(s,1H),7.58(s,2H),7.30-7.29(m,2H),6.0 76-6.072(d,1H),5.59(s,1H),5.3-5.2(brs,1H),3.99(s,3H),2.56-2.51(m,1H),2.28(m,1H). LCMS: m / z 307.1 [M + +H]; (92.99% purity)

[0452] 4-(4-chloro-2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanoic acid [ka] 1H-NMR (400MHz, CDCl3):7.60-7.58(d,1H),7.43-7.41(d,2H),7.34-7.31(m, 1H),7.17(d,1H),6.23(brs,2H),5.939-5.937(s,1H),5.34-5.31(m,1H),5.1 8(s,1H),4.37-4.34(m,2H),3.95(brS,5H),3.83-3.74(m,4H),3.16-3.10(m, 1H),3.05-2.99(m,1H),2.89(brs,4H),2.70-2.65(m,1H),2.44-2.39(m,1H). LCMS (M+H=406.2, 99.48%).

[0453] 4-Hydroxy-2-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-methyleneisothiazolidine 1,1-dioxide [ka] 1 HNMR(400MHz,CDCl3)δ7.76(s,1H),7.64(s,1H),7.44(s,1H),7.41-7.31(m,2H),7.18(d,J=7.5Hz,1H),6.34(s,1H),6 .09(s,1H),5.07(s,1H),4.04(dd,J=9.5,6.5Hz,1H),3.95(s,3H),3.66(dd,J=9.5,4.9Hz,1H),2.70(d,J=7.3Hz,1H). LCMS(m / z):306.2[M + +H].

[0454] 5-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-(2-fluorobenzylidene)dihydrofuran-2(3H)-one [ka] 1H-NMR(400MHz,CDCl3):7.53(s,1H);7.50(s,1H);7.31-7.39(m,5H);711-7.2 0(m,2H),5.73-5.76(m,1H);3.97(s,3H)3.39-3.46(1H,m);3.06-3.13(m,1H). MS(M + +H):383.1

[0455] 4-(4-chloro-2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanenitrile [ka] 1 HNMR(400MHz,CDCl3)δ8.068(s,1H),7.68(s,1H),7.61(d,J=8.4Hz,1H),7.40(d,J=8.4Hz,1H),7.31(m,1H),6.02(s, 1H),5.91(s,1H),5.64(s,1H),4.98-4.90(m,1H),4.44(bs,2H),3.15(bs,2H),2.60-2.54(m,2H),2.45-2.40(m,6H). LCMS(M + +H):345.6,98.28%.

[0456] 4-(4,5-difluoro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanenitrile [ka] 1 HNMR(400MHz,CDCl3)δ7.48-7.50(m,3H),7.12-7.07(m,1H),5.96(s,1H),5.80( s,1H),5.21-5.15(m,1H),3.96(s,3H),2.60-2.54(m,2H),2.15(d,J=3.6Hz,1H). LCMS(M + +H):289.9,97.62%.

[0457] 3-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methyl-5-methyleneisothiazolidine 1,1-dioxide [ka] 1 H-NMR(400MHz,CDCl3):7.2(s,2H);7.44-7.47(m,1H);7.35-7.39(m,2H);6.29(t, 1H),6.97(t,1H);4.72-4.74(m,1H);4.40(d,1H,J=6Hz);3.95(s,3H);2.41(s,3H). MS(M + +H):354.1

[0458] 4-Hydroxy-2-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-methyleneisothiazolidine 1,1-dioxide [ka] 1 H-NMR(400MHz,CDCl3):7.75(s,1H);7.63(s,1H);7.44(s,1H);7.32-7.38(m,2H);7.16-7.18(m,1H);6.33 (bs,1H);6.09(bs,1H);5.07(bs,1H);4.03-4.05(m,1H);3.94(s,3H);3.64-3.67(m,1H);2.69-2.67(m,1H) LCMS(M + +H):306.2,98.4%.

[0459] 4-Hydroxy-2-methyl-3-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-methyleneisothiazolidine 1,1-dioxide [ka] 1H-NMR(400MHz,CDCl3):7.50-7.56(m,3H);7.33-7.43(m,3H);6.28(t,1H);5.95(t,1H);4.7 5-4.79(m,1H);4.44-4.45(m,1H);3.94(s,3H);3.48(s,1H);2.83-2.83(m,1H);2.41(s,3H) LCMS(M + +H):320.1,98.54%.

[0460] 3-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-ethyl-4-hydroxy-5-methyleneisothiazolidine 1,1-dioxide [ka] 1 H-NMR(400MHz,CDCl3):7.61(s,2H);7.47-7.49(m,1H);7.37-7.38(m,1H);7.35(s,1H);6.26(t,1H);5 .92(t,1H);4.74(bs,1H);4.57(d,1H,J=6Hz);3.97(s,3H);3.03(m,1H);2.81-2.86(m,1H);0.95(t,3H) LCMS(M + +H):368.1,98.0%.

[0461] 4-(3-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanenitrile [ka] 1 HNMR(400MHz,CDCl3)δ7.55(d,J=7.6Hz,1H),7.46-7.32(m,4H),5.91(s,1H),5.72( s,1H),5.01-4.96(m,1H),3.99(s,3H),2.49(d,J=6.4Hz,2H),2.22(d,J=3.2Hz,1H). LCMS(M + +H):288.0,97.86%.

[0462] 4-(3-chloro-2-(1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanenitrile [ka] 1 HNMR(400MHz,CDCl3)δ7.60(m,2H),7.56(d,J=8Hz,1H),7.44(d,J=8Hz,1H),7.35( t,J=8Hz,1H),5.90(s,1H),5.71(s,1H),4.97(t,J=6.4Hz,1H),2.49(d,J=6Hz,2H). LCMS(M + +H):274.0,97.72%.

[0463] 4-(4-fluoro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanenitrile [ka] 1 HNMR(400MHz,CDCl3)δ7.62-7.48(m,3H),7.10-6.98(m,2H),5.95(s,1H),5.78( s,1H),5.23-5.19(m,1H),3.97(s,3H),2.54-2.50(m,2H),2.02(d,J=3.6Hz,1H). MS(m / z):272.3[M+H] + .

[0464] 5-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-(2-methylpropylidene)dihydrofuran-2(3H)-one [ka] 1H-NMR(400MHz,CDCl3):7.53(s,1H);7.47(s,1H);7.41-7.43(m,1H);7.28-7.40(m,3H);6.62-6.66(m,1H); 5.70-5.73(m,1H);3.97(s,3H);3.10-3.17(m,1H);2.78-2.85(m,1H);2.41-2.47(m,1H);1.02-1.12(m,6H) LCMS(M + +H):297.1,91.57%.

[0465] 5-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3-(4-fluorobenzylidene)dihydrofuran-2(3H)-one [ka] 1 H-NMR(400MHz,CDCl3):7.59(t,1H);7.56(s,1H);7.51(s,1H);7.44-7.46(m,2H);7.31-7.37( m,3H);7.10-7.15(m,1H);5.76-5.79(m,1H);3.97(s,3H);3.43-3.40(m,1H);3.09-3.15(m,1H) LCMS(M + +H):382.1,95.64%.

[0466] 4-(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-methylene-4-oxobutanenitrile [ka] 1 HNMR(400MHz,CDCl3)δ7.60(s,1H),7.47(s,1H),7.44-7.42(bs,1H),7.37-7.32(m,2H),6.05(s,1H),5.69(s,1H),3.96(s,3H),3.40(s,2H). LCMS(M + +H):286.1,95.15%.

[0467] 4-(4-chloro-2-(1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanenitrile [ka] 1 HNMR(400MHz,CDCl3)δ7.70-7.62(m,2H),7.57(d,J-6.4Hz,1H),7.40-7.30(m,2H),5.94(s,1H),5.77(s,1H),5.21-5.17(m,1H),2.64-2.50(m,2H). MS(m / z):274.2[M+H] + .

[0468] 4-(4-chloro-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)phenyl)-4-hydroxy-2-methylenebutanenitrile [ka] 1 HNMR(400MHz,CDCl3)δ7.62-7.54(m,3H),7.42-7.35(m,1H),7.30-7.25(m,1H),5.92(s,1H),5.77(s,1H),5.26-5 .19(m,1H),4.31(t,J=4.4Hz,1H),4.08-4.0(m,2H),3.52-3.46(bs,2H),3.07(t,J=6.4Hz,1H),2.60-2.48(m,2H). LCMS(M + +H):318.4,93.67%.

[0469] Example 2 Proliferation assay Ten thousand cells were seeded in 50 μl of solution into each well of a 96-well assay plate. Four different cell types were seeded separately, including a telomerase-positive cell line (MOLM-13) and telomerase-negative cell lines (Saos-2 and MRC-9). The required amounts of test compound, reference compound, and positive control (doxorubicin) were added in duplicate at six logarithmic concentrations starting at 100 μM. Ten μl of this 10x diluted compound stock was added to each well and adjusted to 100 μl with cell culture medium (RPMI 1640 for MOLM-13, DMEM with 10% FBS for Saos-2 and MRC-9, maintained at 37°C and 5% CO2 to maintain physiological pH). Untreated cells were assessed for IC2000 based on the lack of inhibition / cell death observed without treatment. 50 After 72 hours of incubation at 37°C with 5% CO2, 100 μl of Cell-TiterGlo reagent was added directly to each well, and the entire contents of the well were transferred to a white plate for reading. Luminescence was read and measured after 10 minutes of incubation. Doxorubicin (10 μM) was used as a positive control for cell death. Percent inhibition was calculated based on the percent decrease in luminescence compared to untreated control wells. IC 50 Values ​​were determined by fitting the percent inhibition data with GraphPad Prism (version 9.3.1) software.

[0470] Telomerase enzyme assay 0.4 x 10 cells per well of a 6-well plate 6Cells were seeded. 10x concentrated compounds at the required concentration were added in duplicate at 2 ml per well. Untreated cells served as a positive control. Heat-inactivated cells served as a negative control. Cells were incubated at 37°C in 5% CO2 for 72 hours, harvested, and telomerase activity was measured using the TeloTAGGG Telomerase PCR ELISAPLUS kit (Roche, UK). After 72 hours, samples were centrifuged, washed, and lysed (in the cold) with the lysis buffer provided with the kit. After 30 minutes in the cold, the lysate was centrifuged at 16,000 rpm for 20 minutes to obtain samples for PCR. Some cells were treated with RNAse and heat-inactivated; these served as a negative control with no telomerase activity. Untreated cells served as a positive control to measure the percent inhibition. The high control (positive control sample, provided with the kit) was used as a reference standard instead of the sample wells. PCR was performed using 30 μl of reaction mixture and 3 μl of cell extract, adjusted to a total volume of 50 μl with distilled water. The PCR reaction consisted of 30 cycles of denaturation, annealing, and polymerization, followed by extension and inactivation, and then a final 10-minute extension in a thermocycler, according to the kit instructions. PCR samples were then collected and subjected to ELISA using the kit protocol, with detection using HRP-TMB substrate conjugate. Finally, the reaction was stopped and read using a Synergy H1 microplate reader (BioTek Instrument, UK) at an absorbance of 450 nm and a reference wavelength of 690 nm. Percent inhibition was calculated based on complete telomerase inhibition in heat-inactivated cells and the absence of telomerase inhibition in untreated cells. IC 50 Values ​​were determined by fitting the percent inhibition data with GraphPad Prism (version 9.3.1) software.

[0471] The data obtained from such analyses are shown in Figures 1 and 2, and Figures 3, 4, and 5.

[0472] Example 3 Anticancer activity screening of compounds using an efficacy model using Luc-MOLM13 cell line 3.0 Test System: Species: Mouse Strain:NOD-SCID (NOD.CB17-Prkdcscid / NCrCrl) Gender: Male Age: 6-7 weeks old at the start of acclimatization Weight change range: 27~28g at the start of acclimatization Number of groups: 5 (with an additional 2 animals as a control group) Number of animals per group: 7 Total number of animals: 37

[0473] The NOD-SCID mouse is a standard laboratory rodent used for preclinical efficacy evaluation of adaptive therapy of test articles.

[0474] The animals were housed in a controlled animal room with a temperature of 22 ± 2°C, relative humidity of 40–70%, a daylight period of 12–12 h, and an air exchange rate of 10–12 times / h.

[0475] During the study, animals were housed (6 per cage) in Techniplast sterile polysulfone Green Line IVC mouse cages (GM500). The external dimensions of the cages were 7.75 inches (length) x 14.75 inches (width) x 5.25 inches (height). The cages were covered with a stainless steel grid-top mesh and provided spaces for water bottles and food. Autoclaved corncobs and paper strips were used as bedding and nesting material.

[0476] Laboratory floors and work surfaces were mopped with 0.03% sodium hypochlorite twice daily on weekdays and at least once daily on weekends.

[0477] 3.5 Food and water. The animals were fed gamma-irradiated pelleted food (Altromin, Germany) ad libitum. Autoclaved RO water was available ad libitum to all animals throughout the experiment in autoclaved water bottles.

[0478] 3.6 Acclimation. Animals were allowed to acclimate for 7 days before treatment initiation. A thorough physical examination was performed before animal selection. Animals without visible signs of illness were used in the study. During the acclimation period, all animals were observed cageside for clinical signs at least once daily.

[0479] Individual animals were identified by universal ear notching during the acclimation period and after randomization, and cages were also identified by cage cards.

[0480] The acclimatization cage card contained the following details: study protocol number, species and strain, sex, cage number, animal number, acclimatization start date, acclimatization end date, signature and date.The experimental cage card contained the following details: study protocol number, test item code, species and strain, sex, cage number, group number and dose, animal number, treatment start date, remarks, necropsy date, signature and date.

[0481] Randomization occurred one day prior to dosing based on body weight.

[0482] 4.0 Materials and Methods Animals: A total of 37 animals were used across groups (7 animals per group for test compounds, 1 animal each for control blank and control compound blank [both no cells]). LUC-MOLM13 cells: Cells were obtained from Creative Biolabs, NY 11967, USA (Cat. No. IOC-02P004). Reagents: LUC-MOLM13 medium (RPMI) was obtained from Gibco (Cat. No.-11875093); Luciferin potassium salt (CAS-NO: 115144-35-9) was procured from SRL Ltd., India.

[0483] Complete medium was prepared by adding 20% ​​Australian FBS (Corning, FBS product number 35-086-CV, catalog number 30029020) and 1 μg / mL puromycin (puromycin hydrochloride, Puromycin dihydrochloride: CAS 58-58-2, Sigma).

[0484] Preparation of compound formulations:

[0485] Doses 50mg / Kg, 25mg / Kg, and 10mg / Kg. Dose volume 0.1 mL [Table 1] Dose volume 0.1 mL

[0486] 5.1 Cell Culture. We used the LUC-MOLM13 cell line supplied by Creative Biolabs. Cells were cultured in antibiotic-free RPMI medium (supplemented with 20% Australian FBS) at 37°C under 5% CO2 until fully confluent. After 7–10 days, when the cells had entered the proliferation phase, they were passaged in 1 μg / ml puromycin-containing medium at a seeding density of 2 × 106 cells / 75 mm flask. Cells were cultured in large quantities, and luciferase signals were confirmed using imaging with an IVIS Spectral Imaging system. After confirmation by in vitro imaging, the cells were considered ready for inoculation into animals.

[0487] 5.2 Study Protocol. Efficacy studies were conducted using the LUC-MOLM13 cell line to evaluate tumor regression in male NOD-SCID mice for Compound 1, Compound 2, and Compound 3, as shown below. Individual animals were ear-marked. The study population and dosing schedule are described in Sections 5.3 and 5.6. Initially, compound doses were 50 mg / kg; however, due to overdosing and the death of several animals, the dose was reduced to 10 mg / kg for all test compounds except BIBR-1532. After test compound administration, study endpoints were evaluated according to the study protocol described in Section 5.3. [ka]

[0488] 5.2 Study design (shown in Figure 6). This study included seven groups: five groups containing vehicle, Compound 1, Compound 3, Compound 2, and the reference compound BIBR-1532, and two groups containing no cells (blank control and compound control). Each mouse was intravenously administered 1 million LUC-MOLM13 tumor cells in a total volume of 0.1 mL in DPBS, designated as day 0. Five minutes before imaging, luciferin (150 mg / kg body weight) was injected intravenously, and the mice were imaged 1-2 times every minute. From day 10 onward, the animals were administered the test compound orally at a dose of 50 mg / kg every other day.

[0489] Following administration of the test compound, study endpoints were assessed according to the study protocol described in Section 5.3.

[0490] (A) Efficacy test procedures Efficacy studies were conducted using the LUC-MOLM13 cell line to evaluate the inhibitory effects of Compound 1, Compound 3, and Compound 2 on the proliferation of leukemia cells in male NOD-SCID mice.

[0491] One million LUC-MOLM13 cells per 100 μL were suspended in DPBS and, after 7 days of acclimation, were inoculated intravenously into the lateral tail vein of 6-8 week-old NOD SCID male mice (fed animals) per mouse. This day was designated as day 0 of the study.

[0492] Luciferin (150 mg / Kg body weight) was injected (IP) 5 min before imaging, and 1–2 consecutive images of the mouse were taken every 1 min.

[0493] Each animal was ear-marked for identification. The study population and dosing schedule are described in Section 5.4. Each animal was weighed prior to dosing and dosed based on individual body weight.

[0494] Bioluminescence imaging for tumor assessment, along with regular weight monitoring, was performed on days 0, 5, 10, 15, 18, 21, and 28. The following observations were monitored regularly: body weight (weight loss rate), and the frequency of leukemic cells (LUC-MOLM13) in hematopoietic organs and non-lymphoid tissues using imaging with an IVIS Spectrum Imaging system to assess tumor burden.

[0495] Other observations included clinical signs and observations at the time of administration. Animals were euthanized after survival curve assessment, and tissues were collected from two animals from each group except for the Compound 1 group, in which tissues were collected from the remaining animal. Various tissues were collected, including the brain, axillary lymph nodes, eyes, branchial lymph nodes, lungs, heart, stomach, liver, kidneys, spleen, cervical lymph nodes, mesenteric lymph nodes, inguinal lymph nodes, gastrointestinal tract, and male reproductive tract. The growth kinetics of Luc-MOLM13 cells was monitored based on BLI along with the survival curve.

[0496] Procedural deviations will be included in the initial study plan for dosing presented in Section 5.3 based on the overall health of the animals.

[0497] (B) Protocol for pharmacokinetic studies in NOD-SCID mice: NOD-SCID mice were allowed to acclimate for 7 days. On the 8th day, the animals were orally administered 10 mg / Kg of Compound 2. Plasma was collected at various time points, 0.08, 0.25, 0.50, 1, 2, 4, 6, and 24 hours, and frozen at -80°C.

[0498] Plasma samples were removed from the freezer and allowed to thaw. Standard samples were used to generate a calibration curve.

[0499] The thawed samples were vortexed to ensure complete mixing. 50 μL of each sample was transferred to a ria vial, and 200 μL of acetonitrile containing the internal standard was added to all samples and vortexed.

[0500] The sample was kept on a shaker for 5 minutes to ensure the contents were thoroughly mixed, and then centrifuged at 10,000 rpm for 10 minutes at 20°C.

[0501] 20 μL of the supernatant was transferred to a vial and loaded into an autosampler for LC-MS / MS analysis.

[0502] The calibration curve range was 10–20,000.0 ng / mL. Calibration curve (CC) standard samples run alongside the samples met the acceptance criteria, demonstrating sufficient performance of the method in sample analysis.

[0503] NOTE: Satellite PK results in NOD-SCID mice are provided in Appendix 2.

[0504] 5.3 Protocol Deviation. The original plan was to administer 50 mg / kg orally every other day from Day 10 onward. However, based on several reports [7,8], administration was initiated from Day 8 onward. After the initial administration of 50 mg / kg on Day 8, deterioration in health was observed in most animals, and one animal in Group 5 died on Day 9. Therefore, the dose was reduced to 25 mg / kg in the Compound 1 and Compound 2 groups and 10 mg / kg in the Compound 3 group on Days 10 and 12, respectively. The BIBR-1532 dose was maintained at 50 mg / kg every other day. However, deaths were observed in Group 5 (one animal on Day 11), Group 6 (two animals on Day 12), and Group 4 (one animal each on Days 12 and 13). Considering the animals' health, administration of all test compounds and BIBR-1532 was discontinued for the following four days. From day 17 onwards, animals received 10 mg / Kg for all treatment groups (Group 4: Compound 1, Group 5: Compound 3, Group 6: Compound 2) and 50 mg / Kg for the reference standard every other day (Group 7: BIBR-1532).

[0505] 5.4 Dose. Animals in the G3 group were administered the vehicle and served as the vehicle control. Groups G4, G5, G6, and G7 were administered Compound 1, Compound 3, Compound 2, and BIBR-1532 (reference standard), respectively.

[0506] 5.5 Justification for Dose and Route of Administration Selection. Doses were selected based on the PK profiles of these compounds in Balb / c animals and the tolerability of the compounds in NOD-SCID mice.

[0507] [Table 2]

[0508] 5.7 Administration of Test Drugs. Test compounds Compound 1, Compound 3, Compound 2, and BIBR-1532 were administered orally as described in Sections 5.3 and 5.4.

[0509] 6.0 Calculations. Bioluminescence imaging levels (BLI (mean luminance)) data were captured from the device across each group of ROIs (regions of interest (ROIs)), and the mean radiance was calculated and levels compared to the vehicle control (Group 3) were determined.

[0510] 7.0 Results and Discussion. Based on bioluminescence imaging (BLI) assessment at day 28 between groups, there was variability in the level of reduced leukemia cell inhibition across the test groups compared to vehicle controls. Details are provided below.

[0511] 7.1 Body Weight. Body weight data for the NOD-SCID mice used in this study were monitored every other day, including the different treatment groups (vehicle control, 10 mg / kg for the three treatment groups, and 50 mg / kg for the reference standard). In each treatment group (Compound 1, Compound 3, and Compound 2 groups early in the study), initial animal losses due to overdosing indicated a decrease in body weight (two animals lost in Group 4: Compound 1, Group 5: Compound 3, and Group 6: Compound 2). Weight loss was observed in all groups, including the vehicle control, for several days after the start of the study. The exact reason is unclear, but it may be due to stress on the animals. (Subsequent administration of 10 mg / kg resulted in consistent body weights. All groups maintained relatively stable mean body weights throughout the second half of the study. No significant abnormalities in body weight were observed, suggesting good tolerability in all treatment groups at 10 mg / kg every other day. That is, after the initial overdose, body weights remained consistent throughout the experiment in all groups.

[0512] 7.2 Clinical Signs. All animals were observed for clinical signs at least once daily throughout the experiment. Based on initial observations at the high dose of 50 mg / Kg, there were few deaths along with tremor patterns across the group. Few animals stopped eating. Taking these observations into account, the dose was subsequently reduced to 10 mg / Kg, and the animals' health stabilized. Therefore, the initially observed clinical signs were due to overdosing, and the symptoms improved when the dose was reduced, followed by a stable health state.

[0513] 7.3 Leukemic Cell Burden. Bioluminescence imaging (BLI) assessment showed different levels of leukemic cells in each group compared to the vehicle control, with the following observations:

[0514] Compound 2 group showed the most significant reduction in leukemia cell burden, as well as favorable results in the animals' overall health.

[0515] Compound 3 group showed similar effects to BIBR-1532 in reducing leukemia cells, despite being administered at a lower dose.

[0516] Compound 1 was found to be inferior among all groups.

[0517] The mean BLI versus days showed a gradual increase in BLI with increasing days, indicating disease progression across groups, but disease progression was inhibited as days progressed in the treatment group with the reference standard (BIBR-1532) compared to the vehicle control group.

[0518] The interpretation of BLI among different groups is as follows:

[0519] Average brightness on day 0: After LUC-MOLM13 inoculation, animals showed a distribution of cells that appeared to be localized in the abdomen near the heart.

[0520] Average brightness on day 5: On day 5, bioluminescence had diminished to negligible levels, and no significant BLI was observed in most animals.

[0521] Average brightness on day 10: Bioluminescence reappeared on day 10 in most animals in group 3 (vehicle control), was prominent in groups 3 and 7, and was prominent only in the brain in group 4. Also, not all animals in each treatment group showed the appearance of a bioluminescent signal; some appeared as late as days 18 and 21.

[0522] Average brightness on day 15: On day 15, bioluminescence was prominent in groups 3 and 7, but in group 4 it was only prominent in the brain (similar to observations on day 10).

[0523] Average brightness on day 18: Bioluminescence showed significant regression across groups compared to controls, with significant regression in group 6 and no signal in any of the animals.

[0524] Average brightness on day 21: Bioluminescence signals were enhanced in Group 3 (vehicle control) and Group 7 (BIBR-1532), and tumor regression was observed with all test compounds, but this was most pronounced in Group 6. However, in Group 6 (Compound 2), few animals showed re-emergence of signal after day 18.

[0525] Average brightness on day 28: Bioluminescence signals were prominent in almost all groups, but the overall tumor regression was most pronounced by day 28 in Group 6 compared to Group 3 (vehicle control group).

[0526] 7.4 Tissue Imaging. Necropsy was performed 34 days after LUC-MOLM13 cell implantation. In the vehicle control group, bioluminescence from LUC-MOLM13 implants was significant and highest in the brain, axillary lymph nodes, branchial lymph nodes, and lungs. Animals showed significant tissue reactions in the Compound 2 group compared to the control group, consistent with the BLI observed on day 28. Lymph nodes showed a complete loss of bioluminescence compared to the control group.

[0527] 7.5 Survival curves. Early mortality due to compound overdose was observed in the treatment groups, but subsequent dose reductions achieved stabilization of overall health. From day 15 onward, compound-treated groups demonstrated greater protection compared to vehicle controls. Notably, compound 1 resulted in one death on day 31 and two deaths on day 34 in the treatment groups. Compound 3 and BIBR-1532 both resulted in one death on day 31 and one death on day 34, while compound 2, administered at 10 mg / kg, resulted in no deaths throughout the study period. When assessing overall group health, animals in group 6 (compound 2) exhibited the best health. Group 5 (compound 3) exhibited mortality similar to BIBR-1532, but at a significantly lower dose compared to the reference standard. By Day 28, the health of both the vehicle control and BIBR-1532 groups had deteriorated, with one death in the control group and most animals in both groups remaining moribund. Due to concerns about the animals' overall health, the study was terminated on Day 34. In summary, the survival curves showed a rapid deterioration in overall health in both the control vehicle and BIBR-1532 groups. However, animals in Group 6 (Compound 2), in contrast to the control vehicle group, remained fully alive and robustly healthy through Day 34 with no animals remaining moribund.

[0528] 8.0 Conclusions. Compound 2, a small molecule telomerase inhibitor, demonstrated significant tumor suppression as evidenced by both bioluminescence imaging of both animal and tissue samples. Notably, bioluminescence, particularly in lymph nodes, was completely abolished. This highlights the inhibitory effect of compound 2 on the growth of orthotopically growing LUC-MOLM13 tumors.

[0529] Compound 3 also stands out by demonstrating significant tumor burden suppression even at low doses, similar to BIBR-1532. In contrast, compound 1 performed poorly on study endpoints, resulting in lower survival rates and less tumor burden suppression compared to the other two compounds.

[0530] 9.0 Data. The experimental data of the study are shown in the figure.

[0531] Figures 7-10 show the effect of telomerase inhibition over a 3-week period on bioluminescence signal (BLI) in LUC-MOLM13 tumor-bearing mice. (7) Overall group; (8) Group 4 (compound 1) oral administration; (9) Group 5 (compound 3) oral administration; and (10) Group 6 (compound 2) oral administration.

[0532] Figures 11A-11B show the effect of administered telomerase inhibitors on the bioluminescence signal of LUC-MOLM13 tumor-bearing mice on day 0. (a) Mean BLI in each group, (b) distribution of orthotopically growing LUC-MOLM13 tumors in each group. Fluorescence in the upper chest is visible in Figure 11B.

[0533] Figures 12A-12B show the effect of administered telomerase inhibitors on bioluminescence signals in LUC-MOLM13 tumor-bearing mice on day 5. (a) Mean BLI in each group, (b) distribution of orthotopically growing LUC-MOLM13 tumors in each group. Figure 12B shows little to no fluorescence.

[0534] 13A-13B show the effect of administered telomerase inhibitors on bioluminescence signals in LUC-MOLM13 tumor-bearing mice on day 10. (a) Mean BLI in each group, (b) distribution of orthotopically growing LUC-MOLM13 tumors in each group.

[0535] 14A-14B show the effect of administered telomerase inhibitors on bioluminescence signals in LUC-MOLM13 tumor-bearing mice on day 15. (a) Mean BLI in each group, (b) distribution of orthotopically growing LUC-MOLM13 tumors in each group.

[0536] 15A-15B show the effect of administered telomerase inhibitors on bioluminescence signals in LUC-MOLM13 tumor-bearing mice on day 18. (a) Mean BLI in each group, (b) distribution of orthotopically growing LUC-MOLM13 tumors in each group.

[0537] 16A-16B show the effect of administered telomerase inhibitors on bioluminescence signals in LUC-MOLM13 tumor-bearing mice on day 21. (a) Mean BLI in each group, (b) distribution of orthotopically growing LUC-MOLM13 tumors in each group.

[0538] 17A-17B show the effect of administered telomerase inhibitors on bioluminescence signals in LUC-MOLM13 tumor-bearing mice at day 28. (a) Mean BLI in each group, (b) distribution of orthotopically growing LUC-MOLM13 tumors in each group.

[0539] FIG. 18 shows the effect of administered telomerase inhibitors on the lifespan of LUC-MOLM13 tumor-bearing mice.

[0540] FIG. 19 shows the effect of administered telomerase inhibitors on the mean body weight of LUC-MOLM13 tumor-bearing mice.

[0541] Figures 20A-20F show bioluminescence signals from tissues obtained from the effects of telomerase inhibitors on post-mortem day 34. Figure 20A shows group-control, Figure 20B shows group 7 (BIRB-1532), Figure 20C shows group 5 (compound 3), Figure 20D shows group 4 (compound 1), Figure 20E shows group 6 (compound 2), and Figure 20F shows representative tissue labeling. 1. Brain, 2. Axillary lymph node, 3. Eye, 4. Branchial lymph node, 5. Lung, 6. Heart, 7. Stomach, 8. Liver, 9. Kidney, 10. Spleen, 11. Cervical lymph node, 12. Mesenteric lymph node, 13. Inguinal lymph node, 14. Digestive tract, 15. Male reproductive organs.

[0542] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those skilled in the art, in light of the teachings of this invention, that certain changes and modifications can be made thereto without departing from the spirit or scope of the appended claims.

[0543] Thus, the foregoing merely illustrates the principles of the present invention. It will be appreciated by those skilled in the art that, although not explicitly described or shown herein, various modifications may be devised which embody the principles of the present invention and are within the spirit and scope of the present invention. Furthermore, all examples and conditional language recited herein are intended primarily to aid the reader in understanding the principles of the present invention and concepts provided by the inventors to further advance the art, and should not be construed as being limited to such specifically recited examples and conditions. Furthermore, all statements herein reciting principles, aspects, and embodiments of the present invention, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Furthermore, such equivalents are intended to include both currently known equivalents and equivalents developed in the future, i.e., any elements developed to perform the same function, regardless of structure. Furthermore, nothing disclosed herein is intended as a public dedication, regardless of whether such disclosure is expressly recited in the claims.

[0544] Accordingly, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention is embodied by the appended claims. For purposes of the claims, 35 U.S.C. 112(f) expressly defines a claim limitation as invoking only when the exact phrase "means for" or "step for" is recited at the beginning of that claim limitation; if such exact phrase is not used in the claim limitation, 35 U.S.C. 112(f) does not apply.

Claims

1. A compound of formula (I) 【Chemistry 282】 During the ceremony, X is O or NR Ｘ and R Ｘ is selected from the group consisting of H, D, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof; Each R １ and R ２ is independently selected from the group consisting of H, D, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, thiol, thioether, and substituted versions thereof; R ９ is H, D, or alkyl; A compound wherein A is an optionally substituted 5- or 6-membered aromatic ring or an optionally substituted heterocycle.

2. The compound of claim 1 , wherein X is O.

3. X is NR Ｘ 2. The compound of claim 1, wherein:

4. The compound is represented by formula (Ia-A), 【Chemistry 283】 During the ceremony, m is 0 or an integer from 1 to 5; Each R ３ are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof, provided that two adjacent R ３ 4. The compound of claim 1, wherein the groups, together with the atoms to which they are attached, can form rings in a cyclic structure.

5. The compound is represented by formula (Ib-A), 【Chemistry 284】 During the ceremony, n is 0 or an integer from 1 to 4; 4. The compound of any one of claims 1 to 3, wherein E is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

6. 6. The compound of claim 5, wherein E is selected from the group consisting of alkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, heterocyclyl, and substituted versions thereof.

7. 7. The compound of claim 6, wherein E is a 5-membered heteroaryl or substituted heteroaryl group.

8. 8. The compound of claim 7, wherein E is pyrazole or substituted pyrazole.

9. The compound is represented by formula (Ib-1-A), 【Chemical 285】 During the ceremony, R ４ is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof; z is 0, 1, or 2; Each R ５ is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

10. 8. The compound of claim 7, wherein E is selected from the group consisting of triazole, substituted triazole, 6-membered aryl, 6-membered substituted aryl, 6-membered heteroaryl, and 6-membered substituted heteroaryl.

11. The compound is represented by formula (Ic-A), 【Chemistry 286】 During the ceremony, p is 0 or an integer ranging from 1 to 4; 4. The compound of claim 1, wherein G is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

12. 12. The compound of claim 11, wherein G is selected from the group consisting of alkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, heterocyclyl, and substituted versions thereof.

13. The compound is represented by formula (Id-A), 【Chemistry 287】 During the ceremony, q is 0 or an integer from 1 to 3; 4. The compound of claim 1, wherein Ring B is a 5- or 6-membered aryl or heteroaryl ring.

14. 14. The compound of claim 13, wherein Ring B is heteroaryl.

15. 15. The compound of claim 14, wherein Ring B is pyridine, pyrrole, imidazole, or pyrrolidine.

16. The compound is 【Chemical 288】 【Chemistry 289】 【Chemistry 290】 【Chemistry 291】 【Chemistry 292】 【Chemistry 293】 10. The compound of claim 1 having a structure selected from the group consisting of:

17. A compound of formula (II) 【Chemistry 294】 During the ceremony, n is 0, 1, 2, or 3; Each R １ , R ２ , R ６ , R ７ , and R ９ is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; Each R ３ , R ４ , R ５ , and R ８ is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof.

18. R １ 18. The compound of claim 17, wherein is H.

19. Each R ２ 19. The compound of any one of claims 17 to 18, wherein is H.

20. R ３ 20. The compound of any one of claims 17 to 19, wherein is H.

21. R ４ 21. The compound of any one of claims 17 to 20, wherein is H or alkyl.

22. R ５ 22. The compound of any one of claims 17 to 21, wherein is H or alkyl.

23. n is in the range of 1 to 3, and at least one R ６ 23. The compound of any one of claims 17 to 22, wherein is halo.

24. R ７ 24. The compound of any one of claims 17 to 23, wherein is H.

25. R ８ 25. The compound of any one of claims 17 to 24, wherein is H or alkyl.

26. R ９ 26. The compound of any one of claims 17 to 25, wherein is H.

27. The compound is 【Chemistry 295】 18. The compound of claim 17 having a structure selected from the group consisting of:

28. A compound of formula (III): 【Chemistry 296】 During the ceremony, n is 0 or an integer ranging from 1 to 4; Each R １ , R ４ , and R ５ is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; R ２ is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R ３ is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof.

29. The compound is represented by formula (IIIa): 【Chemistry 297】 During the ceremony, m is 0 or an integer ranging from 1 to 5; Each R ２２ 29. The compound of claim 28, wherein is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

30. 29. The compound of claim 28, wherein the compound is represented by formula (IIIb): 【Chemistry 298】

31. m is in the range of 1 to 5, and at least one R ２２ 31. The compound of any one of claims 29 to 30, wherein is halo.

32. 32. The compound of any one of claims 29 to 31, wherein n is 0.

33. R ３ 33. The compound of any one of claims 29 to 32, wherein is H.

34. R ４ 34. The compound of any one of claims 29 to 33, wherein is H.

35. Each R ５ 35. The compound of any one of claims 29 to 34, wherein is H.

36. The compound is 【Chemistry 299】 [Chemical 300] 29. The compound of claim 28 having a structure selected from the group consisting of:

37. A compound of formula (IV), 【Chemical 301】 During the ceremony, R １ and R ２ are each independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof, with the proviso that R １ and R ２ at least one of is aryl, heteroaryl, or a substituted version thereof; L １ and L ２ are each independently absent or an alkylene group; R ３ is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, and substituted versions thereof; R ４ is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

38. R １ 38. The compound of claim 37, wherein is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

39. The compound is represented by formula (IVa): 【Chemical 302】 During the ceremony, x is 0 or an integer ranging from 1 to 5; Each R １１ 39. The compound of claim 38, wherein is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

40. x is an integer from 1 to 5, and at least one R １１ 40. The compound of claim 39, wherein is halo.

41. R ２ 41. The compound of any one of claims 39 to 40, wherein is H or alkyl.

42. L １ 42. The compound of any one of claims 39 to 41, wherein is absent.

43. L １ is the formula -CH ２ The compound according to any one of claims 39 to 41, wherein

44. Each R ４ 44. The compound of any one of claims 39 to 43, wherein is H.

45. R ２ The compound of any one of claims 39-40 or 42-44, wherein is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

46. The compound is represented by formula (IVb), 【Chemical 303】 During the ceremony, y is 0 or an integer from 1 to 5; Each R ２２ 38. The compound of claim 37, wherein is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof.

47. y is an integer from 1 to 5, and at least one R ２２ 47. The compound of claim 46, wherein is halo.

48. R １ 48. The compound of any one of claims 46 to 47, wherein is H or alkyl.

49. L ２ 49. The compound of any one of claims 46 to 48, wherein is absent.

50. L ２ is the formula -CH ２ The compound according to any one of claims 46 to 48, wherein

51. R ３ 51. The compound of any one of claims 46 to 50, wherein is H or alkyl.

52. Each R ４ 52. The compound of any one of claims 46 to 51, wherein is H.

53. The compound is 【Chemical 304】 38. The compound of claim 37, having a structure selected from the group consisting of:

54. A compound of formula (V) 【Chemical 305】 During the ceremony, R １ is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof; Each R ２ and R ３ is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; A compound wherein n is 0 or an integer of 1 to 4.

55. 55. The compound of claim 54, wherein the compound is represented by formula (Va): 【Chemical 306】

56. R １ 56. The compound of any one of claims 54 to 55, wherein is alkyl.

57. R １ 57. The compound of claim 56, wherein is methyl.

58. 58. The compound of any one of claims 54 to 57, wherein n is 0.

59. The compound is 【Chemical 307】 【Chemical 308】 55. The compound of claim 54, having a structure selected from the group consisting of:

60. A compound of formula (VI) 【Chemical 309】 During the ceremony, n is 0, 1, 2, or 3; Each R １ , R ２ , R ３ , R ５ , R ６ , and R ８ is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, alkoxy, amino, azido, carbonyl, carboxy, cyano, ether, halo, hydroxy, nitro, and substituted versions thereof; R ４ and R ７ is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, carbonyl, carboxy, and substituted versions thereof.

61. R １ 61. The compound of claim 60, wherein is cyano or carboxy.

62. Each R ２ is H and R ３ 62. The compound of any one of claims 60 to 61, wherein is H.

63. R ４ 63. The compound of any one of claims 60 to 62, wherein is H.

64. n is 1, 2, or 3, and at least one R ５ 64. The compound of any one of claims 60 to 63, wherein is halo.

65. R ６ is H and R ８ 65. The compound of any one of claims 60 to 64, wherein is H.

66. R ７ 66. The compound of any one of claims 60 to 65, wherein is alkyl or substituted alkyl.

67. The compound is 【Chemical 310】 【Chemical 311】 61. The compound of claim 60, having a structure selected from the group consisting of:

68. 68. A pharmaceutical composition comprising a compound according to any one of claims 1 to 67.

69. 69. The pharmaceutical composition of claim 68, further comprising a second compound.

70. 70. The pharmaceutical composition of claim 69, wherein the second compound is imetelstat or imetelstat sodium.

71. 1. A method of treating a patient for a telomerase-associated condition, comprising:

71. A method comprising administering a pharmaceutical composition according to any one of claims 68 to 70.

72. 72. The method of claim 71, wherein the compound is a telomerase inhibitor.

73. 73. The method of claim 72, wherein the telomerase-associated condition is cancer.

74. 74. The method of claim 73, wherein the cancer is a hematological malignancy.

75. 74. The method of claim 73, wherein the cancer is selected from the group consisting of acute and chronic leukemia, lymphoma, multiple myeloma and myelodysplastic syndrome, myeloproliferative neoplasm (MPN), essential thrombocythemia (ET), polycythemia vera (PV), chronic myelogenous leukemia (CML), myelofibrosis (MF), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS).

76. 1. A method of treating a patient for a telomerase-associated condition, comprising:

68. A method comprising administering a compound of any one of claims 1 to 67.

77. 77. The method of claim 76, wherein the compound is a telomerase inhibitor.

78. 78. The method of claim 77, wherein the telomerase-associated condition is cancer.

79. 79. The method of claim 78, wherein the cancer is a hematological malignancy.

80. 80. The method of claim 79, wherein the cancer is selected from the group consisting of acute and chronic leukemia, lymphoma, multiple myeloma and myelodysplastic syndrome, myeloproliferative neoplasm (MPN), essential thrombocythemia (ET), polycythemia vera (PV), chronic myelogenous leukemia (CML), myelofibrosis (MF), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS).

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