Macrocyclic diamine derivatives as ENT inhibitors and their combination with adenosine receptor antagonists for the treatment of cancer

Abstract

The present invention relates to macrocyclic diamine derivatives of Formula II, including pharmaceutically acceptable salts and solvates thereof. The compounds of the present invention are inhibitors of ENT family transporters, particularly ENT1, and are useful as therapeutic compounds for the treatment of cancer. The present invention also relates to the combination of a macrocyclic diamine derivative with an adenosine receptor antagonist for the treatment of cancer. JPEG2023521351000310.jpg36123

Description

[Technical Field]

[0001] The present invention relates to macrocyclic diamine derivatives, including pharmaceutically acceptable salts and solvates thereof. The compounds of the present invention are inhibitors of ENT family transporters, particularly ENT1, and are useful as therapeutic compounds, particularly in the treatment of cancer. The present invention also relates to the combination of the macrocyclic diamine derivatives of the present invention with an adenosine receptor antagonist for the treatment of cancer. [Background technology]

[0002] The equilibrative nucleoside transporter (ENT) family, also known as SLC29, is a group of plasma membrane transport proteins that transport nucleoside substrates into cells. Four ENTs, designated ENT1, ENT2, ENT3, and ENT4, are known.

[0003] One of the endogenous substrates of ENT is adenosine, a potent physiological and pharmacological regulator of numerous functions. Adenosine-mediated cell signaling occurs via four known G protein-coupled adenosine receptors, A1, A2A, A2B, and A3. By influencing the concentration of adenosine available to these receptors, ENT plays an important regulatory role in various physiological processes, including regulating coronary blood flow, inflammation, and neurotransmission (Griffith DA and Jarvis SM, Biochim Biophys Acta, 1996, 1286, 153-181; Shryock JC and Belardinelli L, Am J Cardiol, 1997, 79(12A), 2-10; Anderson CM et al., J Neurochem, 1999, 73, 867-873).

[0004] Adenosine is also a potent immunosuppressive metabolite that is often found elevated in the extracellular tumor microenvironment (TME) (Blay J et al., Cancer Res, 1997, 57, 2602-2605). Extracellular adenosine is primarily generated by the conversion of ATP by the ectonucleotidases CD39 and CD73 (Stagg J and Smyth MJ, Oncogene, 2010, 2, 5346-5358). Adenosine activates four G protein-coupled receptor subtypes (A1, A2A, A2B, and A3). In particular, activation of A2A receptors is considered a major driver of innate and adaptive immune cell suppression, leading to the suppression of antitumor immune responses (Ohta and Sitkovsky, Nature, 2001, 414, 916-920) (Stagg and Smyth, Oncogene, 2010, 2, 5346-5358) (Antonioli L et al., Nature Reviews Cancer, 2013, 13, 842-857) (Cekic C and Linden J, Nature Reviews Immunology, 2016, 16, 177-192) (Allard B et al., Curr Op Pharmacol, 2016, 29, 7-16) (Vijayan D et al., Nature Reviews Cancer, 2017, 17, 709-724).

[0005] The applicant previously demonstrated in PCT / EP2019 / 076244 that adenosine, like ATP, significantly suppresses T cell proliferation and cytokine secretion (IL-2) and severely reduces T cell viability. The adenosine- and ATP-mediated suppression of T cell viability and proliferation was successfully restored by using an ENT inhibitor. Furthermore, using an ENT inhibitor in combination with an adenosine receptor antagonist not only restored the adenosine- and ATP-mediated suppression of T cell viability and proliferation, but also restored T cell cytokine secretion. These results indicated that an ENT inhibitor, alone or in combination with an adenosine receptor antagonist, may be useful in the treatment of cancer. Various drugs, such as dilazep, dipyridamole and draflazine, interact with ENTs to alter adenosine levels and have been developed for their cardioprotective or vasodilatory effects.

[0006] Currently, two nonselective ENT1 inhibitors (dilazep and dipyridamole) are on the market (Vlachodimou et al., Bio-Chemical Pharmacology, 2020, 172, 113747). However, their binding kinetics are unknown; more potent ENT inhibitors, especially ENT1 inhibitors, are still needed for cancer treatment, either alone or in combination with adenosine receptor antagonists. For this reason, the present research has focused on finding new and improved ENT1 inhibitors, and to that end, the Applicant provides herein macrocyclic diamine derivatives of Formula I and Formula II, as detailed below. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] PCT / EP2019 / 076244 [Non-patent literature]

[0008] [Non-Patent Document 1] Griffith DA and Jarvis SM, Biochim Biophys Acta, 1996, 1286, 153-181 [Non-patent document 2] Shryock JC and Belardinelli L,Am J Cardiol,1997,79(12A),2-10 [Non-patent document 3] Anderson CM et al., J Neurochem, 1999, 73, 867-873 [Non-patent document 4] Blay J et al.,Cancer Res,1997,57,2602-2605 [Non-Patent Document 5] Stagg J and Smyth MJ,Oncogene,2010,2,5346-5358 [Non-patent document 6] Ohta and Sitkovsky,Nature,2001,414,916-920 [Non-Patent Document 7] Antonioli L et al.,Nature Reviews Cancer,2013,13,842-857 [Non-patent document 8] Cekic C and Linden J,Nature Reviews,Immunology,2016,16,177-192 [Non-Patent Document 9] Allard B et al.,Curr Op Pharmacol,2016,29,7-16 [Non-Patent Document 10] Vijayan D et al.,Nature Reviews Cancer,2017,17,709-724 Summary of the Invention

[0009] Thus, the present invention provides compounds of formula I: [ka] [R in the formula x , R 1 , R 4 , U, V and ALK are defined below] or a pharmaceutically acceptable salt or solvate thereof.

[0010] The present invention also provides a compound of formula II: [ka] [R in the formula x , R 1 , R 4, U, V, X and n 1 are defined below] or a pharmaceutically acceptable salt or solvate thereof.

[0011] According to one embodiment, the compounds of the invention have formula IIa or IIa1 as defined below: Preferably, the compounds of the invention are selected from the compounds listed in Table 1 below.

[0012] In some embodiments, the compounds of the present invention contain one chiral center.

[0013] In some embodiments, the compounds of the present invention are racemic mixtures containing "R" and "S" isomers.

[0014] In some embodiments, the compounds of the present invention are "R" isomers.

[0015] In some embodiments, the compounds of the present invention are "S" isomers.

[0016] In some embodiments, the compounds of the present invention contain more than one chiral center. In some embodiments, each chiral center contains the same configuration. In some embodiments, each chiral center independently contains the "R" or "S" configuration.

[0017] The present invention also relates to a pharmaceutical composition comprising a compound of formula I or formula II according to the present invention and at least one pharmaceutically acceptable excipient.

[0018] In one embodiment, the pharmaceutical composition further comprises an adenosine receptor antagonist, hi one embodiment, the adenosine receptor antagonist is an A2A or A2B receptor antagonist.

[0019] In one embodiment, the adenosine receptor antagonist is:

[0020] 5-Bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine;

[0021] (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

[0022] 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;

[0023] 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile;

[0024] 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine;

[0025] 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine; and

[0026] 4-Hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide is selected from.

[0027] In another embodiment, the adenosine receptor antagonist is a compound of formula (III): [ka] [R in the formula 1 and R 2 are defined below] or a pharmaceutically acceptable salt or solvate thereof.

[0028] The present invention further relates to a method for inhibiting ENT1 in a patient in need thereof, which comprises administering to said patient an effective amount of a compound of formula I or formula II according to the present invention.

[0029] The present invention also relates to a method of treating cancer in a patient in need thereof, comprising administering to said patient an effective amount of a compound of formula I or formula II according to the present invention.

[0030] The present invention also relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a combination of a compound of Formula I or II of the present invention and an adenosine receptor antagonist. In one embodiment, the compound of Formula I or II of the present invention is administered before, concomitantly with, or after the administration of the adenosine receptor antagonist. In one embodiment, the adenosine receptor antagonist is an A2A or A2B receptor antagonist. In one embodiment, the adenosine receptor antagonist is selected from those listed above.

[0031] The present invention further relates to a kit of parts comprising: (a) a first part comprising an effective amount of a compound of Formula I or Formula II according to the present invention; and (b) a second part comprising an effective amount of an adenosine receptor antagonist.

[0032] In one embodiment, the adenosine receptor antagonist in the kit of parts is an A2A or A2B receptor antagonist, preferably selected from among those listed above. [Brief explanation of the drawings]

[0033] [Figure 1A]A graph of percent proliferation versus log concentration (M) is shown. Purified human T cells were activated with anti-CD3 / CD28 dynabeads in the presence of ATP (100 μM) as a source of adenosine for 96 hours, after which proliferation was assessed by CFSE dilution.

[0034] [Figure 1B] A graph of the logarithmic concentration of ENT1 inhibitor (M) versus percent proliferation is shown. The experiment was performed as in panel A, with the addition of HSA and AAG (2% and 0.1% final concentrations, respectively) to the culture medium.

[0035] [Figure 2A] Bar graphs of percent proliferation normalized to that without ATP are shown. Naive CD4+ T cells were cultured with allogeneic monocyte-derived dendritic cells at a 10:1 ratio for 96 hours in the presence of 300 μM ATP as a source of adenosine and the molecules Compound 2 (50 nM), Compound 11 (500 nM), or a matching concentration of DMSO. T cell proliferation was assessed by CFSE dilution and normalized to the levels observed in T cells activated in the absence of ATP.

[0036] [Figure 2B] Two bar graphs are shown, one showing TNF concentrations (pg / mL) and the other showing IFNγ (pg / mL). Experiments were performed as shown in Figure 2A, and supernatants were sampled for cytokine analysis by alphaLISA. ****=p<0.0001, ***=p<0.001, **=p<0.01, and *=p<0.05; obtained from one-way ANOVA with Tukey's multiple comparison test.

[0037] [Figure 3]Bar graphs of percent tetramer are shown. PBMCs from a healthy volunteer donor with a history of CMV infection and a known HLA-A*02 subtype were cultured for 7 days with a peptide derived from the immunodominant CMV antigen pp65 (NLVPMVATV) in combination with IL-2, IL-7, and the anti-PD1 antibody nivolumab. ATP, a source of adenosine, was added to the cultures along with the indicated ENT1 inhibitor molecule. The expansion of peptide-specific CD8+ T cell populations was monitored by flow cytometry using BV421-linked NLVPMVATV-MHC-I tetramers. **=p<0.01, *=p<0.05; derived from one-way ANOVA with Tukey's multiple comparison test from technical replicates within a single experiment.

[0038] [Figure 4] FIG. 1 consists of three graphs: A, B, and C, showing the evaluation of the antitumor efficacy of compound 8 in a syngeneic fibrosarcoma model. DETAILED DESCRIPTION OF THE INVENTION

[0039] It should be understood that both the foregoing and following descriptions are exemplary and explanatory only and are not intended to limit the invention as defined by the claims. In this specification, the use of the singular includes the plural unless otherwise specified. Furthermore, the use of the term "comprising" as well as other forms such as "comprises" and "comprised" is not limiting. Furthermore, the term "element" or "component" encompasses both elements and components that comprise one unit and elements and components that comprise more than one subunit, unless otherwise specified.

[0040] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. Where permitted, all patents, applications, published applications and other publications, gene accession numbers, and related sequence information available from databases such as the National Center for Biotechnology Information (NCBI) and other data referenced throughout this disclosure are incorporated by reference in their entirety for all purposes. Any conflict in the teachings of these patents and publications and this specification shall be resolved in favor of the latter.

[0041] definition Unless otherwise defined, all technical terms, notation, and other scientific terminology used herein are intended to have the meaning commonly understood by one of ordinary skill in the art to which this invention pertains. In some cases, terms having commonly understood meanings are defined herein for clarity and / or ease of reference, but the inclusion of such definitions herein should not necessarily be construed as representing a departure from what is commonly understood in the art. The techniques and procedures described or referred to herein are generally well understood and commonly employed by those of ordinary skill in the art using conventional methodology. Standard techniques may be used for chemical syntheses and chemical analyses. Procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-specified protocols and conditions unless otherwise noted.

[0042] For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0043] Unless otherwise specified, the following terms have the following meanings:

[0044] As used herein, the singular forms "a," "an," and "the" include the plural references unless the context clearly indicates otherwise. Unless otherwise specified, terms such as "including," "e.g.," and "including" are intended to convey inclusion without limitation.

[0045] As used herein, the term "comprising" specifically includes embodiments "consisting of" and "consisting essentially of" the listed elements, unless specifically stated otherwise.

[0046] The term "about" refers to and encompasses the indicated value, as well as a range above and below that value. In some embodiments, the term "about" refers to the specified value ±10%, ±5%, or ±1%. In some embodiments, the term "about" refers to the specified value(s) ±1 standard deviation of that value(s), if applicable.

[0047] The term "aldehyde" refers to the group --CHO.

[0048] The term "alkenyl" refers to an unsaturated hydrocarbyl group containing one or more carbon-carbon double bonds, which may be straight-chained or branched. Suitable alkenyl groups contain 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and even more preferably 2 to 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl, and the like.

[0049] The term "alkenylcarbonyl" refers to the group --(C.dbd.O)-alkenyl, where alkenyl is as defined herein.

[0050] The term "alkenylcarbonylamino" refers to the group --NH--(C.dbd.O)-alkenyl, where alkenyl is as defined herein.

[0051] The term "alkoxy" refers to the group --O-alkyl, where alkyl is as defined herein.

[0052] The term "ALK" or "Alk" or "alk" refers to an alkyl group (having the formula C, where n is a number greater than or equal to 1). n H 2n+1or a hydrocarbyl radical having, for example, 1 to 4 substituents such as halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amine in which two amino substituents are selected from alkyl, aryl, or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkyl Thio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g., SO2NH2), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g., CONH2), substituted carbamyl (e.g., CONHalkyl, CONHaryl, CONHaralkyl, or examples where there are two substituents on the nitrogen selected from alkyl, aryl, or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino, and heterocyclo, e.g., indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, etc. In the above cases, when the substituent is further substituted, it is intended that this is done by halogen, alkyl, alkoxy, aryl, or aralkyl. In some embodiments, ALK is optionally substituted C1-C8 alkyl.

[0053] In some embodiments, the alkyl group is substituted with OH, OAlk, CF3, NR2.

[0054] Generally, alkyl groups of the present invention contain 1 to 8 carbon atoms, and more preferably, alkyl groups of the present invention contain 1 to 6 carbon atoms. The alkyl groups can be straight-chained or branched. Suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0055] The term "alkylaminoalkyl" refers to the group -alkyl-NH-alkyl, where alkyl is as defined herein.

[0056] The term "alkylaminoalkylaminocarbonyl" refers to the group --(C.dbd.O)--NH-alkyl-NH-alkyl, where alkyl is as defined herein.

[0057] The term “(alkylaminoalkyl)(alkyl)aminocarbonyl” refers to the group —(C═O)—NR 1 R 2 refers to R 1 is an alkyl group, and R 2 is an -alkyl-NH-alkyl group, where alkyl is as defined herein.

[0058] The term "alkylaminoalkylcarbonyl" refers to the group --(C.dbd.O)-alkyl-NH-alkyl, where alkyl is as defined herein.

[0059] The term "alkylcarbonyl" refers to the group --(C.dbd.O)-alkyl, where alkyl is as defined herein.

[0060] The term "alkylcarbonylamine" refers to the group -NH-(C=O)-alkyl, where alkyl is as defined herein.

[0061] The term "alkylcarbonyloxyalkyl" refers to the group -alkyl-O-(C=O)-alkyl, where alkyl is as defined herein.

[0062] The term "alkylheteroaryl" refers to any heteroaryl substituted with an alkyl group, where alkyl is as defined herein.

[0063] The term "alkyloxyalkyl" refers to the group -alkyl-O-alkyl, where alkyl is as defined herein.

[0064] The term "alkyloxycarbonyl" refers to the group --(C.dbd.O)--O-alkyl, where alkyl is as defined herein.

[0065] The term "alkylsulfonyl" refers to the group -SO2-alkyl, where alkyl is as defined herein.

[0066] The term "alkylsulfonylaminoalkyl" refers to the group -alkyl-NH-SO2-alkyl, where alkyl is as defined herein.

[0067] The term "alkylsulfonealkyl" refers to the group -alkyl-SO2-alkyl, where alkyl is as defined herein.

[0068] The term "alkylsulfonimidoyl" refers to the group -S(=O)(=NH)-alkyl, where alkyl is as defined herein.

[0069] The term "alkylsulfoxide" refers to the group --(S.dbd.O)-alkyl, where alkyl is as defined herein.

[0070] The term "alkylsulfoxidealkyl" refers to the group -alkyl-SO-alkyl, where alkyl is as defined herein.

[0071] The term "alkylene," as used herein, refers to an alkyl group, as defined above, having a bond replacing a hydrogen atom of the alkyl group. An alkylene group has two points of attachment. Non-limiting examples of alkylene groups include -CH-, -CHCH-, -CHCHCH-, -CHCHCHCH-, -CH(CH)CHCH-, -CH(CH)-, and CHCH(CH)CH-. In one embodiment, an alkylene group has from 1 to about 6 carbon atoms. In another embodiment, an alkylene group has from about 3 to about 5 carbon atoms. In another embodiment, an alkylene group is branched. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is -CH-. In one embodiment, at least one hydrogen atom of the alkylene group is replaced by a substituent, such as halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which two amino substituents are selected from alkyl, aryl, or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkanol, alkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g., SO2NH2), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g., CONH2), substituted carbamyl (e.g., CONHalkyl, CONHaryl, CONHaralkyl, or examples where there are two substituents on the nitrogen selected from alkyl, aryl, or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino, and heterocyclo, for example, substituted with indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, etc.In the above cases, if the substituent is further substituted, it is intended that this is done by halogen, alkyl, alkoxy, aryl, or aralkyl. In another embodiment, at least one hydrogen atom of the alkylene group is substituted with OH, OAlk, CF3, NR2.

[0072] The term "alkyne" refers to a class of monovalent unsaturated hydrocarbyl groups in which the unsaturation occurs due to the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically and preferably have the same number of carbon atoms as listed above for alkyl groups. Non-limiting examples of alkynyl groups include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers, etc.

[0073] The term "alkynealkyl" refers to the group -alkyl-alkyne, where alkyl and alkyne are defined herein.

[0074] The term "amino" refers to the group -NH2.

[0075] The term "aminoalkyl" refers to the group -alkyl-NH2, where alkyl is as defined herein.

[0076] The term "aminoalkylaminocarbonyl" refers to the group -(C=O)-NH-alkyl-NH2, where alkyl is as defined herein.

[0077] The term "aminoalkylcarbonylamino" refers to the group -NH-(C=O)-alkyl-NH2, where alkyl is as defined herein.

[0078] The term "aminocarbonyl" or "aminocarboxy" refers to the group --(C.dbd.O)--NH.sub.2.

[0079] The term “(aminocarbonylalkyl)(alkyl)amino” refers to the group —NR1 R 2 refers to R 1 is an alkyl group, and R 2 is an -alkyl-(C=O)-NH2 group, where alkyl is as defined herein.

[0080] The term "aminocarbonylalkylamino" refers to the group -NH-alkyl-(C=O)-NH2, where alkyl is as defined herein.

[0081] The term "aminosulfonyl" refers to the group -SO2-NH2.

[0082] The term "aryl" refers to a polyunsaturated aromatic hydrocarbyl group having a single ring (i.e., phenyl) or multiple fused aromatic rings (e.g., naphthyl), which typically contains 5 to 12, preferably 5 to 10, atoms; more preferably, the aryl is a 5- or 6-membered aryl. Non-limiting examples of aryl include phenyl and naphthalenyl.

[0083] The term "arylalkyl" refers to the group -alkyl-aryl, where alkyl and aryl are as defined herein.

[0084] The term "aryloxyalkyl" refers to the group -alkyl-O-aryl, where alkyl and aryl are defined herein.

[0085] The term "carbonyl" refers to the group --(C.dbd.O)--.

[0086] The term "carbonylamino" refers to the group --NH--(C.dbd.O)--.

[0087] The term "cyano" refers to the group --CN.

[0088] The term "cyano" refers to the group -alkyl-CN.=, where alkyl is as defined herein.

[0089] The term "cycloalkyl" refers to a cyclic alkyl group, i.e., a monovalent saturated or unsaturated hydrocarbyl group having one or two ring structures. Cycloalkyl includes monocyclic and bicyclic hydrocarbyl groups. Cycloalkyl groups can contain three or more carbon atoms in the ring, and according to the present invention typically contain 3 to 10, more preferably 3 to 8, carbon atoms; even more preferably, cycloalkyl is a 5- or 6-membered cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0090] The term "cycloalkyloxy" refers to the group --O-cycloalkyl, where cycloalkyl is as defined herein.

[0091] The term "dialkylamino" refers to the group -NR 1 R 2 refers to R 1 and R 2 are both independently an alkyl group as defined herein.

[0092] The term "dialkylaminoalkyl" refers to the group -alkyl-NR 1 R 2 refers to R 1 and R 2 are both independently an alkyl group as defined herein.

[0093] The term “dialkylaminoalkylaminocarbonyl” refers to the group —(C═O)—NH-alkyl-NR 1 R 2 refers to R 1 and R 2 are both alkyl groups as defined herein.

[0094] The term “dialkylaminoalkylcarbonyl” refers to the group —(C═O)-alkyl-NR 1 R 2 refers to R1 and R 2 are both alkyl groups as defined herein.

[0095] The term "dihydroxyalkyl" refers to an alkyl, as defined herein, substituted with two hydroxyl (-OH) groups.

[0096] The term "halo" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0097] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced with halogen atoms.

[0098] The term "haloalkyloxy" refers to the group --O-haloalkyl, where alkyl is as defined herein.

[0099] The term "heteroaryl" refers to an aryl group, as defined herein, in which at least one carbon atom has been replaced by a heteroatom. In other words, it refers to an aromatic monocyclic or two-fused ring system containing 5 to 12 carbon atoms, typically 5 to 6 atoms, in which one or more carbon atoms have been replaced by oxygen, nitrogen, and / or sulfur atoms, and the nitrogen and sulfur heteroatoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Non-limiting examples of such heteroaryls include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0100] The term "heteroarylalkyl" refers to the group -alkyl-heteroaryl, where alkyl and heteroaryl are defined herein.

[0101] The term "heterocyclyl" or "heterocycle" refers to a non-aromatic, fully saturated or partially unsaturated cyclic group (e.g., a 3- to 7-membered monocyclic ring, a 7- to 11-membered bicyclic ring, or a total of 3 to 10 ring atoms) containing at least one heteroatom in at least one carbon atom-containing ring. Preferably, the heterocyclyl is a 5- or 6-membered heterocyclyl. Each ring of a heteroatom-containing heterocyclic group can have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, with the nitrogen and sulfur heteroatoms optionally being oxidized and the nitrogen heteroatom optionally being quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom in the ring or ring system, valence permitting. The rings of polycyclic heterocycles may be fused, bridged, and / or linked through one or more spiro atoms.Exemplary heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, azetidinyl, azocanyl, diazepanyl, diazocanyl, morpholin-4-yl, oxazepanyl, pyrrolidinyl, thiomorpholin-4-yl, tetrahydrofuranyl, tetrahydropyranyl, aziridinyl, oxiranyl, thiiranyl, 2-imidazolinyl, and pyrazolidinyl. Imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H-quinolidinyl, 2-oxopiperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioxiimidazolidinyl , 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 1-oxido-1-thiomorpholin-4-yl, 1-dioxide-1-thiomorpholin-4-yl, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolidinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, dihydrotriazolopyrazine, dihydroimidazopyrazine, hexahydropyrrolopyrrole, and hexahydropyrrolopyrazine.

[0102] The term "heterocyclylalkyl" refers to the group -alkyl-heterocyclyl, where alkyl and heterocyclyl are as defined herein.

[0103] The term "heterocyclylalkylaminocarbonyl" refers to the group --(C.dbd.O)--NH-alkyl-heterocyclyl, where alkyl and heterocyclyl are as defined herein.

[0104] The term "(heterocyclyl)(alkyl)aminoalkyl" refers to the group -alkyl-NR 1 R 2 refers to R 1 is an alkyl group, and R 2 is a heterocyclyl group, where alkyl and heterocyclyl are as defined herein.

[0105] The term "heterocyclylalkyloxyalkyl" refers to the group -alkyl-O-alkyl-heterocyclyl, where alkyl and heterocyclyl are defined herein.

[0106] The term "heterocyclylcarbonyl" refers to the group --(C.dbd.O)-heterocyclyl, where heterocyclyl is as defined herein.

[0107] The term "heterocyclyloxy" refers to the group --O-heterocyclyl, where heterocyclyl is as defined herein.

[0108] The term "heterocyclylsulfonyl" refers to the group -SO2-heterocyclyl, where heterocyclyl is as defined herein.

[0109] The term "hydroxy" or "hydroxyl" refers to the group --OH.

[0110] The term "hydroxyalkyl" refers to the group -alkyl-OH, where alkyl is as defined herein.

[0111] The term "hydroxyalkylaminoalkyl" refers to the group -alkyl-NH-alkyl-OH, where alkyl is as defined herein.

[0112] The term "hydroxycarbonyl" refers to the group -C(=O)-OH, where carbonyl is as defined herein. In other words, "hydroxycarbonyl" is equivalent to a carboxylic acid group.

[0113] The term "oxo" refers to a ═O substituent.

[0114] The term "sulfonylamino" refers to the group -NH-SO2.

[0115] The term "intermediate" or "intermediate compound" refers to a compound produced during chemical synthesis that is not itself the final product, but is used in further reactions to produce the final product. During a complex synthesis, there may be many different intermediate compounds between the starting material and the desired product.

[0116] The term "about" preceding a number includes up to plus or minus 10% of the value of said number. It should be understood that the value to which the term "about" refers is itself specifically and preferentially disclosed.

[0117] The term "administration" or variations thereof (e.g., "administering") means providing an active agent or ingredient, alone or as part of a pharmaceutically acceptable composition, to a patient whose condition, symptom, or disease is to be treated or prevented.

[0118] The term "antagonist" refers to a natural or synthetic compound that binds to a protein and blocks the biological activation of the protein, thereby blocking the action of the protein. The protein may be a receptor, i.e., a protein molecule that receives a chemical signal from outside the cell. Therefore, an "adenosine receptor antagonist" includes any chemical entity that, when administered to a patient, results in inhibiting or downregulating the biological activity associated with adenosine receptor activation in the patient, including any downstream biological effects that would otherwise result from the binding of the adenosine receptor to its natural ligand. Such adenosine receptor antagonists include any agent that can block adenosine receptor activation or any downstream biological effects of adenosine receptor activation.

[0119] The term "inhibitor" refers to a natural or synthetic compound that has the biological effect of inhibiting or significantly reducing or downregulating the expression of a gene and / or protein, or inhibiting or significantly reducing the biological activity of a protein. Thus, "ENT inhibitors" or "inhibitors of ENT family transporters" refer to compounds that have the biological effect of inhibiting or significantly reducing or downregulating the biological activity of an ENT family transporter.

[0120] The term "chemotherapy" refers to a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents) as part of a standardized chemotherapy regimen. Chemotherapy may be given with curative intent, or it may be aimed at extending life or alleviating symptoms. Chemotherapeutic agents may be selected from, for example, anti-cancer alkylating agents, anti-cancer antimetabolites, anti-cancer antibiotics, plant-derived anti-cancer agents, anti-cancer platinum coordination compounds, and any combination thereof.

[0121] The term "hormonal therapy" refers to the use of hormones in medical treatment. In one embodiment, the hormone therapy is tumor hormone therapy.

[0122] The term "human" refers to subjects of both genders and at any stage of development (i.e., neonate, infant, juvenile, adolescent, adult).

[0123] The term "patient" refers to a mammal, more preferably a human, who is awaiting or receiving medical care or who is / will be the subject of medical intervention.

[0124] The term "immunotherapy" refers to a therapy aimed at inducing and / or enhancing an immune response against a specific target, e.g., cancer cells. Immunotherapy can involve the use of checkpoint inhibitors, checkpoint agonists (also called T cell agonists), IDO inhibitors, PI3K inhibitors, adenosine receptor inhibitors, adenosine synthase inhibitors, adoptive transfer, therapeutic vaccines, and combinations thereof.

[0125] The term "pharmaceutically acceptable" means that the ingredients of a pharmaceutical composition are compatible with each other and not harmful to the subject to which it is administered.

[0126] The phrase "pharmaceutically acceptable carrier, diluent, excipient, and / or adjuvant" means a substance that does not produce adverse, allergic, or other untoward reactions when administered to animals, preferably humans. It can include any and all inert substances, such as solvents, cosolvents, antioxidants, surfactants, stabilizers, emulsifiers, buffers, pH adjusters, preserving agents (or preserving agents), antibacterial and antifungal agents, isotonicity agents, granulating agents or binders, lubricants, disintegrants, glidants, diluents or fillers, adsorbents, dispersing agents, suspending agents, coating agents, bulking agents, releasing agents, absorption delaying agents, sweeteners, flavoring agents, and the like. For human administration, formulations should meet sterility, pyrogenicity, systemic safety, and purity standards required by regulatory authorities, such as the FDA or EMA.

[0127] The terms "prevent," "preventing," and "prevention," as used herein, refer to a method of delaying or preventing the onset of a condition or disease, and / or its attendant symptoms, thereby barring a patient from acquiring the condition or disease or reducing the patient's risk of acquiring the condition or disease.

[0128] As used herein, the term "prodrug" refers to a pharmacologically acceptable derivative of a compound of formula (I), such as an ester or amide, whose biotransformation product in vivo yields a biologically active drug. Prodrugs are generally characterized by enhanced bioavailability and are rapidly metabolized in vivo to the biologically active compound.

[0129] The term "radiation therapy" refers to cancer treatment methods that employ various types of radiation, such as X-rays, gamma rays, neutrons, electron beams, proton beams, and radioactive sources. It is used as part of cancer treatment to control or kill malignant cells. Radiation therapy can be curative for several types of cancer when localized to one area of ​​the body. It can also be used as part of adjuvant therapy to prevent tumor recurrence after surgery to remove the primary malignant tumor. The three main categories of radiation therapy are: external beam radiation therapy (EBRT or XRT); brachytherapy or brachytherapy; and systemic radioisotope therapy (RIT) or unsealed radiotherapy.

[0130] The term "therapeutically effective amount" or "effective amount" or "therapeutically effective dose" refers to an amount or dose of an active ingredient intended to (1) delay or prevent the onset of cancer in a subject; (2) reduce the severity or incidence of cancer; (3) slow or halt the progression, progression, or worsening of one or more symptoms of cancer affecting the subject; (4) bring about an improvement in symptoms of cancer affecting the subject; or (5) cure the cancer affecting the subject, without causing significant undesirable or harmful side effects to the subject. A therapeutically effective amount can be administered before the onset of cancer for prophylactic or preventative action. Alternatively, or in addition, a therapeutically effective amount can be administered after the onset of cancer for therapeutic action.

[0131] The term "treating" or "treatment" refers to a therapeutic procedure aimed at preventing or slowing the progression of a targeted pathological condition or disease. A subject or mammal has been successfully "treated" for a disease, illness, or condition if, after undergoing treatment according to the present invention, the subject or mammal exhibits an observable and / or measurable reduction or absence of one or more of the following: a reduction in the number of cancer cells; and / or some alleviation of one or more of the symptoms associated with the particular disease or condition; a reduction in morbidity and mortality; and an improvement in quality of life issues. The above parameters for assessing successful treatment and disease improvement can be readily measured by routine procedures familiar to physicians.

[0132] The term "stem cell transplant" refers to a procedure that provides a patient with healthy hematopoietic cells (stem cells) to replace their own destroyed by disease or by radiation or high doses of anticancer drugs given as part of the procedure. Healthy stem cells can be obtained from the patient's blood or bone marrow, from a donor, or from the umbilical cord blood of a newborn. Stem cell transplants can be autologous (using the patient's own stem cells collected and stored before treatment), allogeneic (using stem cells donated by a non-identical twin), or syngeneic (using stem cells donated by an identical twin).

[0133] The term "subject" refers to a mammal, preferably a human. In one embodiment, the subject has been diagnosed with cancer. In one embodiment, the subject is a patient, preferably a human patient, awaiting or undergoing medical treatment, or has been / is / will be the subject of medical intervention, or is being followed for the development or progression of a disease, such as cancer. In one embodiment, the subject is a human patient being treated and / or is being followed for the development or progression of cancer. In one embodiment, the subject is male. In another embodiment, the subject is female. In one embodiment, the subject is an adult. In another embodiment, the subject is a child.

[0134] Compound - ENT inhibitor Thus, the present invention provides macrocyclic diamine derivatives that may be useful as ENT inhibitors. Thus, in one embodiment, the present invention provides compounds of formula I: [ka] [During the ceremony, R 1 teeth, [ka] selected from the group consisting of: Each R 2 are independently absent, halogen, -NHR 3 , -OR 3 , -R 3 , -C(O)R 3 , -CO2R 3 , C(O)N(R 3 )2, -CH2C(O)N(R 3 )2, -S(O)2R 3 or selected from the group consisting of -CN; or two occurrences of R 2 together with the atoms to which they are attached form a heterocyclyl or heteroaryl ring; Each R 3 is independently selected from absent, —H, oxo, ALK, phenyl, heterocyclyl, and heteroaryl; R 4 teeth, [ka] selected from the group consisting of: U is -C(O)-, alkylene, -O-, -N(R 3 )-, -C(O)O-, -C(O)N(R 3 )-, and [ka] selected from the group consisting of: Each R x are independently selected from alkylene; Each V is independently -C(R 3 )-, -N(R 3 )-, -N-, and -O-; Z is C or N; ALK may be unsubstituted alkyl or substituted alkyl, or two occurrences of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring. or a pharmaceutically acceptable salt or solvate thereof.

[0135] In one embodiment, the present invention therefore provides a compound of formula I [During the ceremony, R 1 teeth, [ka] and; Each R 2 are independently halogen, -OR 3 , -R 3 , -CO2R 3 , C(O)N(R 3 )2, -CH2C(O)N(R 3 )2, and -CN; Each R 3 is independently -H or ALK; R 4 teeth, [ka] and; U is -C(O)-, alkylene, -O-, -N(R 3 )-, -C(O)O-, -C(O)N(R 3 )-, and [ka] selected from the group consisting of: Each R x are independently selected from alkylene; Each V is independently -C(R 3 )-, -N(R 3 ), -N-, -O-; Z is C; or R 2 Z is N if is absent. to provide.

[0136] In another embodiment, the present invention also provides a compound of formula II: [ka] [During the ceremony, R 1 is ALK, cycloalkyl, heterocyclyl, [ka] selected from the group consisting of: Each R 2 are independently absent, halogen, -OR 3 , -R 3 , -CO2R 3 , C(O)N(R 3 )2, -CH2C(O)N(R 3 )2, -S(O)2R 3 or selected from the group consisting of -CN; or two occurrences of R 2 together with the atoms to which they are attached form a heterocyclyl or heteroaryl ring; Each R 3is independently selected from absent, —H, ALK, phenyl, and heteroaryl; R 4 teeth, [ka] selected from the group consisting of: X is selected from the group consisting of -CH2-, -CHF-, -CF2-; Each U independently represents -O-, -N(R 3 )-, -C(O)O-, -C(O)N(R 3 )-, [ka] selected from the group consisting of -C(O)-, -ON=C(H)-, and alkylene; Each R x is independently selected from alkylene; Each V is independently -C(R 3 )-, -N(R 3 )-, -N=, -O-; Z is C or N; n is a number 0 or 1, ALK may be unsubstituted alkyl or substituted alkyl, or two occurrences of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring. or a pharmaceutically acceptable salt or solvate thereof.

[0137] In another embodiment, the present invention also provides a compound of formula II [During the ceremony, R 1 teeth, [ka] and; Each R 2 are independently halogen, -OR 3 , -R 3 , -CO2R 3 , C(O)N(R 3 )2, -CH2C(O)N(R3 )2, and -CN; Each R 3 is independently -H or ALK; R 4 teeth, [ka] and; X is selected from the group consisting of -CH2-, -CHF-, -CF2-; Each U independently represents -O-, -N(R 3 )-, -C(O)O-, -C(O)N(R 3 )-, [ka] selected from the group consisting of —C(O)—, and alkylene; Each R x is independently selected from alkylene; Each V is independently -C(R 3 )-, -N(R 3 )—, —N═, and —O—; Each Z is independently C; or R 2 is non-existent and Z=N; n 1 is a number that is either 0 or 1. Also provided.

[0138] In one embodiment, the compound of formula II has formula IIa: [ka] wherein X is CH2, CHF or CF2, and R 1 , U and n 1 is defined herein. R 1 teeth, [ka] and; Each R 2 are independently halogen, -OR 3 , -R 3, -CO2R 3 , C(O)N(R 3 )2, -CH2C(O)N(R 3 )2, and -CN; Each R 3 is independently -H or ALK; R 4 teeth, [ka] and; X is selected from the group consisting of -CH2-, -CHF-, -CF2-; Each U independently represents -O-, -N(R 3 )-, -C(O)O-, -C(O)N(R 3 )-, [ka] selected from the group consisting of —C(O)—, and alkylene; Each R x is independently selected from alkylene; Each V is independently -C(R 3 )-, -N(R 3 )—, —N═, and —O—; Each Z is independently C; or R 2 is non-existent and Z=N; n 1 is a number that is either 0 or 1. or a pharmaceutically acceptable salt or solvate thereof.

[0139] In one embodiment, the compound of formula IIa has formula IIa1: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0140] In some embodiments, the compound of Formula II has Formula IIb: [ka] [In the formula, R 2 and U are defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0141] In some embodiments, R 1 teeth, [ka] is selected from the group consisting of:

[0142] In some embodiments, R 1 teeth, [ka] is selected from the group consisting of:

[0143] In some embodiments, R 1 teeth, [ka] is.

[0144] In some embodiments, R 1 teeth, [ka] is.

[0145] In some embodiments, each R 2 are independently absent, halogen, -OR 3 , -R 3 , -CO2R 3 , C(O)N(R 3 )2, -CH2C(O)N(R 3 )2, -S(O)2R 3 -CN; or two occurrences of R 2 together with the atoms to which they are attached form a heterocyclyl or heteroaryl ring;

[0146] In some embodiments, each R 2 are independently absent, halogen, -OR 3 , -R 3 , -CO2R 3 , C(O)N(R 3 )2, -CH2C(O)N(R 3 )2, -S(O)2R 3 and -CN.

[0147] In some embodiments, each R 2 are independently absent, halogen, -OR 3 , and -R 3 is selected from the group consisting of:

[0148] In some embodiments, each R 2 are independently absent, halogen, -OR 3 and hydrogen.

[0149] In some embodiments, each R 3 is independently selected from absent, —H, ALK, phenyl, and heteroaryl.

[0150] In some embodiments, each R 3 is independently selected from —H and methyl.

[0151] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0152] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0153] In some embodiments, U is —C(O)—, alkylene, —O—, —N(R3 )-, -C(O)O-, -C(O)N(R 3 )-, and [ka] is selected from the group consisting of:

[0154] In some embodiments, each R x is independently selected from alkylene.

[0155] In some embodiments, each V is independently —C(R 3 )-, -N(R 3 )-, -N-, and -O-.

[0156] In some embodiments, Z is C or N.

[0157] In some embodiments, the macrocyclic diamine derivatives of the present invention contain only one chiral center.

[0158] In some embodiments, the macrocyclic diamine derivatives of the present invention are racemic mixtures containing "R" and "S" isomers.

[0159] In some embodiments, the macrocyclic diamine derivatives of the present invention are "R" isomers.

[0160] In some embodiments, the macrocyclic diamine derivatives of the present invention are "S" isomers.

[0161] In some embodiments, the macrocyclic diamine derivatives of the present invention contain more than one chiral center.

[0162] In some embodiments, each chiral center independently comprises an "R" or "S" configuration. In some embodiments, each chiral center comprises the same configuration.

[0163] Particularly preferred compound structures of Formula II of the present invention are those listed in Table 1 below. Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 [Table 2-24] [Table 2-25] [Table 2-26] [Table 2-27]

[0164] The compounds in Table 1 were named using ChemBioDraw® Ultra version 12.0 (PerkinElmer).

[0165] In one embodiment, the present invention also relates to salts, solvates, enantiomers, isomers (including optical, geometric and tautomeric forms), polymorphs, multi-component complexes, liquid crystals, prodrugs, and isotopically labeled compounds of Formula I or Formula II and formulae substituting therein.

[0166] In one embodiment, the present invention relates to enantiomers and isomers (including optical, geometric, and tautomeric forms) of compounds of Formula I and formulae subordinate thereto. Indeed, compounds of Formula I or Formula II and formulae subordinate thereto may contain asymmetric centers and therefore may exist in different stereoisomeric forms. Accordingly, the present invention includes all possible stereoisomers, including racemates as well as individual enantiomers and non-racemic mixtures thereof. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, resolution of the final product or any convenient intermediate compound, or chiral chromatographic methods, each of which are known in the art. Resolution of the final product, intermediate compound, or starting material may be carried out by any suitable method known in the art.

[0167] In one embodiment, the present invention also relates to salts of the compounds of Formula I or Formula II and formulae substitutive therein. In particular, the compounds of the present invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of Formula I or Formula II include ammonium salts, aspartate, benzoate, besylate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, bitartrate, borate, calcium edetate, camsylate, citrate, clavulanate, cyclamate, dihydrochloride, edetate, edisylate, estolate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hybenzate, hydrabamine salts, hydrochloride / chloride salts, hydrobromide / bromide salts, hydroiodide / iodide salts, hydroxynaphthoate, isethionate, isothionate salts, Lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, methyl bromide, N-methylglucamate, methyl nitrate, methyl sulfate, mucate, panoate, naphthylate, 2-napsylate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate, pantothenate, phosphate / monohydrogenphosphate / dihydrogenphosphate, polygalacturonate, pyroglutamate, saccharate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, trifluoroacetate, valerate, and xinafoate. Preferred pharmaceutically acceptable acid addition salts include hydrochloride / chloride, hydrobromide / bromide, bisulfate / sulfate, nitrate, citrate, tosylate, esylate, and acetate. Suitable base salts are formed from bases which form non-toxic salts.Examples include aluminum, ammonia, arginine, benzathine, N-benzylphenethylamine, calcium, chloroprocaine, chlorine, N,N'-dibenzylethylenediamine, diethanolamine, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, ethylenediamine, glycine, lithium, lysine, magnesium, meglumine, N-methylglutamine, morpholine, 4-(2-hydroxyethyl)morpholine, olamine, ornithine, piperazine, potassium, procaine, sodium, tetramethylammonium hydroxide, tris(hydroxymethyl)aminomethane, tromethamine, and zinc salts. Hemisalts of acids and bases, such as hemisulfate hemicalcium salts, can also be formed. When the compounds of the present invention contain a hydrogen-donating heteroatom (e.g., NH), the present invention also encompasses salts and / or isomers formed by transferring the hydrogen atom to a basic group or atom within the molecule.

[0168] Pharmaceutically acceptable salts of compounds of Formula I or Formula II and subformulae therein may be prepared by one or more of these methods:

[0169] (i) reacting a compound of Formula I or Formula II with a desired acid;

[0170] (ii) reacting a compound of Formula I or Formula II with a desired base;

[0171] (iii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of Formula I or Formula II, or ring-opening a suitable cyclic precursor, such as a lactone or lactam, using a desired acid; or

[0172] (iv) Converting one salt of a compound of formula I or formula II into another by reaction with an appropriate acid or by a suitable ion exchange column.

[0173] All of these reactions are typically carried out in solution. The salt may precipitate from solution and be recovered by filtration or may be removed by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to nearly non-ionized.

[0174] In addition, although pharmaceutically acceptable salts are generally preferred with respect to salts of the compounds of the present invention, it should be noted that the present invention in its broadest sense also includes pharmaceutically unacceptable salts that may be used, for example, for isolating and / or purifying the compounds of the present invention. For example, salts formed with optically active acids or bases may be used to form diastereomeric salts that may facilitate the separation of optically active isomers of the compounds of Formula I or II above.

[0175] In one embodiment, the present invention also relates to solvates of the compounds of Formula I or II and their sub-formulas. The compounds of the present invention may be in the form of pharmaceutically acceptable solvates. The pharmaceutically acceptable solvates of the compounds of Formula I or II and their sub-formulas contain stoichiometric or substoichiometric amounts of one or more pharmaceutically acceptable solvent molecules, such as ethanol or water. The term "hydrate" refers to when the solvent is water.

[0176] In one embodiment, this invention also relates to prodrugs of compounds of Formula I or Formula II and formulae subscriptive thereto. For example, when an alcohol group is present, pharmaceutically acceptable esters may be employed, such as acetates, maleates, pivaloyloxymethyl esters, and the like, as well as esters known in the art for altering solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

[0177] Manufacturing Process Compounds of Formula I or Formula II can be prepared in a variety of ways using reactions known to those skilled in the art.

[0178] The present invention also relates to compounds of formula I: [ka] [In the formula, R X , R 1 , R 4 , U, V and ALK are defined below] Also provided is a process for preparing the compound or a pharmaceutically acceptable salt or solvate thereof.

[0179] The present invention also provides a compound of formula II: [ka] [In the formula, R X , R 1 , R 4 , X, U, V and n 1 are defined below] Also provided is a process for preparing the compound or a pharmaceutically acceptable salt or solvate thereof.

[0180] Purpose The present invention further relates to the use of the compounds of the present invention, or pharmaceutically acceptable salts and solvates thereof, as inhibitors of ENT family transporters. Thus, in a particularly preferred embodiment, the present invention relates to the use of the compounds of Formula I or Formula II and their subformulae, particularly those of Table 1 above, or pharmaceutically acceptable salts and solvates thereof, as inhibitors of ENT family transporters.

[0181] In one embodiment, the compounds of the invention are inhibitors of ENT1, ENT2, ENT3, and / or ENT4. In one embodiment, the compounds of the invention are inhibitors of ENT1 and ENT2. In one embodiment, the compounds of the invention are inhibitors of ENT1, preferably selective inhibitors of ENT1. In one embodiment, the compounds of the invention are selective inhibitors of ENT1 over other ENT family transporters, particularly over ENT2 and ENT4.

[0182] The present invention also provides a method for inhibiting an ENT family transporter, in particular ENT1, in a patient, preferably a warm-blooded animal, more preferably a human, in need thereof, which method comprises administering to the patient an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

[0183] The present invention further relates to the use of the compounds of the present invention as medicaments, i.e. for medical use.Accordingly, in one embodiment, the present invention provides the use of the compounds of the present invention for the manufacture of medicaments.In particular, the present invention provides the use of the compounds of the present invention for the manufacture of medicaments.

[0184] In particular, the present invention provides compounds of the present invention for use in the treatment and / or prevention of proliferative disorders, including cancer. Accordingly, in one embodiment, the present invention provides the use of a compound of the present invention for the manufacture of a medicament for treating and / or preventing cancer. The present invention also provides a method of treating cancer, comprising administering a therapeutically effective amount of a compound of the present invention to a mammalian species in need thereof.

[0185] The present invention also provides a method for delaying the onset of cancer in a patient, comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of the present invention.

[0186] Various cancers are known in the art. Cancers that can be treated using the methods of the present invention include solid and non-solid cancers, particularly benign and malignant solid tumors, and benign and malignant non-solid tumors. Cancers can be metastatic or non-metastatic. Cancers can be familial or sporadic.

[0187] In one embodiment, the cancer to be treated according to the present invention is a solid cancer. As used herein, the term "solid cancer" includes any cancer (also called a malignant tumor) that forms a discrete tumor mass, as opposed to a cancer (or malignant tumor) that diffusely infiltrates tissue without forming a mass.

[0188] Examples of solid tumors include biliary tract cancer, brain tumors (including glioblastoma and medulloblastoma), breast cancer, carcinoid, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, head and neck cancer, intraepithelial neoplasia (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastoma, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, and rectal cancer. , kidney cancer (including adenocarcinoma and Wilms' tumor), sarcoma (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma), testicular cancer, including germ cell tumors (seminomas, and non-seminomas, e.g., teratomas and choriocarcinomas), stromal tumors, germ cell tumors, thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma), and urothelial carcinoma.

[0189] In another embodiment, the cancer to be treated according to the present invention is a non-solid cancer. Examples of non-solid tumors include, but are not limited to, hematopoietic neoplasms. As used herein, hematopoietic neoplasm is a term that includes lymphoid disorders, bone marrow disorders, and AIDS-related leukemia.

[0190] Lymphatic system disorders include, but are not limited to, acute lymphocytic leukemia and chronic lymphoproliferative diseases (e.g., lymphoma, myeloma, and chronic lymphocytic leukemia). Lymphomas include, for example, Hodgkin's disease, non-Hodgkin's lymphoma, and lymphocytic lymphoma. Chronic lymphocytic leukemia includes, for example, T-cell chronic lymphocytic leukemia and B-cell chronic lymphocytic leukemia.

[0191] In specific embodiments, the cancer is selected from breast cancer, carcinoid cancer, cervical cancer, colon cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, gastric cancer, thyroid cancer, and urothelial cancer.

[0192] In a specific embodiment, the cancer is breast cancer. In a specific embodiment, the cancer is carcinoid cancer. In a specific embodiment, the cancer is cervical cancer. In a specific embodiment, the cancer is colorectal cancer. In a specific embodiment, the cancer is endometrial cancer. In a specific embodiment, the cancer is glioma. In a specific embodiment, the cancer is head and neck cancer. In a specific embodiment, the cancer is liver cancer. In a specific embodiment, the cancer is lung cancer. In a specific embodiment, the cancer is melanoma. In a specific embodiment, the cancer is ovarian cancer. In a specific embodiment, the cancer is pancreatic cancer. In a specific embodiment, the cancer is prostate cancer. In a specific embodiment, the cancer is kidney cancer. In a specific embodiment, the cancer is gastric cancer. In a specific embodiment, the cancer is thyroid cancer. In a specific embodiment, the cancer is urothelial carcinoma.

[0193] In another specific embodiment, the cancer is selected from the group consisting of leukemia and multiple myeloma.

[0194] Preferably, the patient is a warm-blooded animal, more preferably a human.

[0195] In one embodiment, the cancer to be treated according to the present invention is a solid cancer. As used herein, the term "solid cancer" includes any cancer (also called a malignant tumor) that forms a discrete tumor mass, as opposed to a cancer (or malignant tumor) that diffusely infiltrates tissue without forming a mass.

[0196] Examples of solid tumors include biliary tract cancer, brain tumors (including glioblastoma and medulloblastoma), breast cancer, carcinoid, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, head and neck cancer, intraepithelial neoplasia (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastoma, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, and rectal cancer. , kidney cancer (including adenocarcinoma and Wilms' tumor), sarcoma (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma), testicular cancer, including germ cell tumors (seminomas, and non-seminomas, e.g., teratomas and choriocarcinomas), stromal tumors, germ cell tumors, thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma), and urothelial carcinoma.

[0197] In another embodiment, the cancer to be treated according to the present invention is a non-solid cancer. Examples of non-solid tumors include, but are not limited to, hematopoietic neoplasms. As used herein, hematopoietic neoplasm is a term that includes lymphoid disorders, bone marrow disorders, and AIDS-related leukemia.

[0198] Lymphatic system disorders include, but are not limited to, acute lymphocytic leukemia and chronic lymphoproliferative diseases (e.g., lymphoma, myeloma, and chronic lymphocytic leukemia). Lymphomas include, for example, Hodgkin's disease, non-Hodgkin's lymphoma, and lymphocytic lymphoma. Chronic lymphocytic leukemia includes, for example, T-cell chronic lymphocytic leukemia and B-cell chronic lymphocytic leukemia.

[0199] In specific embodiments, the cancer is selected from breast cancer, carcinoid cancer, cervical cancer, colon cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, gastric cancer, thyroid cancer, and urothelial cancer.

[0200] In a specific embodiment, the cancer is breast cancer. In a specific embodiment, the cancer is carcinoid cancer. In a specific embodiment, the cancer is cervical cancer. In a specific embodiment, the cancer is colorectal cancer. In a specific embodiment, the cancer is endometrial cancer. In a specific embodiment, the cancer is glioma. In a specific embodiment, the cancer is head and neck cancer. In a specific embodiment, the cancer is liver cancer. In a specific embodiment, the cancer is lung cancer. In a specific embodiment, the cancer is melanoma. In a specific embodiment, the cancer is ovarian cancer. In a specific embodiment, the cancer is pancreatic cancer. In a specific embodiment, the cancer is prostate cancer. In a specific embodiment, the cancer is kidney cancer. In a specific embodiment, the cancer is gastric cancer. In a specific embodiment, the cancer is thyroid cancer. In a specific embodiment, the cancer is urothelial carcinoma.

[0201] In another specific embodiment, the cancer is selected from the group consisting of leukemia and multiple myeloma.

[0202] Preferably, the patient is a warm-blooded animal, more preferably a human.

[0203] In one embodiment, the subject receiving an ENT inhibitor of the present invention is being treated with an additional therapeutic agent in combination with the ENT inhibitor of the present invention or has received the additional therapeutic agent within about 14 days of administration of the ENT inhibitor of the present invention. In one embodiment, the additional therapeutic agent comprises an adenosine receptor antagonist.

[0204] In one embodiment, the subject has previously undergone at least one prior therapeutic treatment and has progressed after administration of the at least one prior therapeutic treatment and prior to administration of an ENT inhibitor of the present invention, hi one embodiment, the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplant, hormone therapy, and surgery.

[0205] In one embodiment, an ENT inhibitor of the present invention is administered prior to, concomitantly with, or following the administration of an additional therapeutic agent, such as an adenosine receptor antagonist.

[0206] The present invention also provides pharmaceutical compositions comprising a compound of Formula I or Formula II and formulae substitutable therein, or pharmaceutically acceptable salts and solvates thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.

[0207] Another object of the present invention is a medicament comprising, as active ingredient, at least one compound according to the invention, or the pharmaceutically acceptable salts and solvates thereof.

[0208] Typically, for pharmaceutical use, the compounds of the present invention can be formulated as pharmaceutical compositions containing at least one compound of the present invention and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant, and optionally one or more additional pharmaceutically active compounds, details of which are provided below.

[0209] By way of non-limiting example, such formulations may be in a form suitable for administration orally, parenterally (e.g., by intravenous, intramuscular or subcutaneous injection, or intravenous infusion), topically (including intraocularly), by inhalation, skin patch, implant, suppository, etc. Such suitable dosage forms, which may be solid, semi-solid or liquid depending on the mode of administration, as well as methods for their preparation and carriers, diluents and excipients will be apparent to those skilled in the art; reference is made to the latest edition of Remington's Pharmaceutical Sciences.

[0210] Some preferred, but non-limiting examples of such preparations include tablets, pills, powders, lozenges, pre-formulated tablets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions for bolus and / or continuous administration, and sterile packaged powders (which are often reconstituted before use), which may be formulated using carriers, excipients, and diluents that are inherently suitable for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils, and mineral oils, or suitable mixtures thereof. The formulations may optionally contain other substances commonly used in pharmaceutical formulations, such as lubricants, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrating agents, bulking agents, fillers, preservatives, sweeteners, flavoring agents, flow conditioners, release agents, etc. The compositions may also be formulated so as to provide immediate, sustained, or delayed release of the active compound(s) contained therein.

[0211] The pharmaceutical compositions of the present invention are preferably in unit dosage form and may be suitably packaged, for example, in a box, blister, vial, bottle, sachet, ampule, or any other suitable single-dose or multi-dose holder or container (which may be appropriately labeled), optionally with one or more leaflets containing product information and / or instructions for use.

[0212] Depending on the condition to be prevented or treated and the route of administration, the active compounds of the invention may be administered as a single daily dose, may be administered in one or more divided daily doses, or may be administered essentially continuously, for example, by infusion.

[0213] formulation Combination with adenosine receptor antagonists The present invention further relates to the combination of an ENT inhibitor of formula I or formula II or a formula substitutable therefor as defined above according to the invention with an adenosine receptor antagonist.

[0214] Thus, the present invention provides a combination:

[0215] The present invention relates to such combinations comprising an effective amount of an ENT inhibitor of formula I or formula II or any of the formulae subordinate thereto as defined above, and (b) an effective amount of an adenosine receptor antagonist.

[0216] In the context of the present invention, the term "combination" preferably means that the ENT inhibitor and the A2AR antagonist coexist.Therefore, the combination of the present invention can be present as a composition that contains all components in one and the same mixture (for example, a pharmaceutical composition), or can be present as a kit of parts, where different components form different parts of such a kit of parts.The administration of the ENT inhibitor and the A2AR antagonist can be simultaneous, or can be staggered by administration at similar or different times (i.e., administration of each component at similar or different times), in similar or different dosage forms, at the same administration site or different administration sites.

[0217] The present invention further relates to a method of treating cancer, comprising administering to a patient in need thereof a combination of an adenosine receptor antagonist and an ENT inhibitor of the present invention.

[0218] The above embodiments relating to the ENT inhibitors of the present invention also apply to the combinations of the present invention. In particular, in one embodiment, the ENT inhibitor in the combinations of the present invention may have formula I or formula II of the sub-formulas defined above.

[0219] The combinations of the present invention comprise at least one adenosine receptor antagonist as a second component.

[0220] As defined above, "adenosine receptor antagonist" refers to a compound that, when administered to a patient, results in inhibiting or down-regulating the biological activity associated with adenosine receptor activation in the patient, including any downstream biological effects that would otherwise result from the binding of the adenosine receptor to its natural ligand. Such adenosine receptor antagonists include any agent that can block adenosine receptor activation or any downstream biological effects of adenosine receptor activation.

[0221] Adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors for which adenosine is the endogenous ligand. Four types of adenosine receptors are known in humans: A1, A2A, A2B, and A3; each is encoded by a different gene (ADOARA1, ADORA2A, ADORA2B, and ADORA3, respectively).

[0222] In one embodiment, the adenosine receptor antagonist is an antagonist of an A1 receptor, an A2A receptor, an A2B receptor, an A3 receptor, or a combination thereof.

[0223] In one embodiment, the adenosine receptor antagonist is an antagonist of an A2A receptor, an A2B receptor, or a combination thereof. In one embodiment, the adenosine receptor antagonist is an A2A or A2B receptor antagonist.

[0224] In one embodiment, the adenosine receptor antagonist is an antagonist of the A2A receptor (A2AR antagonist). In one embodiment, the adenosine receptor antagonist is an antagonist of the A2B receptor (A2BR antagonist).

[0225] In one embodiment, the adenosine receptor antagonist is a selective antagonist for the A2A receptor over other adenosine receptors, hi one embodiment, the adenosine receptor antagonist is a selective antagonist for the A2A receptor over the A2B receptor.

[0226] In one embodiment, the adenosine receptor antagonist is a selective antagonist for the A2B receptor over other adenosine receptors, hi one embodiment, the adenosine receptor antagonist is a selective antagonist for the A2B receptor over the A2A receptor.

[0227] In a specific embodiment, the combination of the present invention comprises at least one A2A receptor antagonist as defined herein and at least one ENT inhibitor of formula I or formula II as defined above.

[0228] A2A receptor antagonists In one embodiment, the combination of the present invention comprises at least one A2AR antagonist.

[0229] "A2AR antagonist" refers to a compound that, when administered to a patient, results in inhibiting or down-regulating the biological activity associated with activation of the A2A receptor in the patient, including any downstream biological effects that would otherwise result from binding of the A2A receptor to its natural ligand. Such A2AR antagonists include any agent that can block activation of the A2A receptor or any downstream biological effects of A2A receptor activation.

[0230] Examples of A2AR antagonists include preladenant (SCH-420,814), bipadenant (BIIB-014), tozadenant (SYK-115), ATL-444, istradefylline (KW-6002), MSX-3, SCH-58261, SCH-412,348, SCH-442,416, ST-1535, caffeine, VER-6623, VER-6947, VER-7835, ZM-241,385, and theophylline. It also includes A2AR antagonists disclosed in WO2018 / 178338, WO2011 / 121418, WO2009 / 156737, WO2011 / 095626 or WO2018 / 136700, the contents of which are incorporated herein by reference.

[0231] In one embodiment, the A2AR antagonist is a thiocarbamate derivative, particularly a thiocarbamate derivative as disclosed in WO2018 / 178338. More preferably, the A2AR antagonist is a thiocarbamate derivative of formula (III) as described below.

[0232] Thus, in a specific embodiment, the present invention provides:

[0233] (b) an ENT inhibitor of formula I or II or a formula subordinate thereto as defined above according to the present invention; and (b) a thiocarbamate derivative of formula (III) as described in WO2018 / 178338, which is an A2AR antagonist: [ka]

[0234] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 is defined as follows:

[0235] Thus, in a preferred embodiment, the A2AR antagonist is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0236] R 1 represents a 5- or 6-membered heteroaryl, or a 5- or 6-membered aryl, wherein the heteroaryl or aryl group is optionally substituted with one or more substituents selected from C-C alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R 1 represents a 5-membered heteroaryl; more preferably R 1 represents frills;

[0237] R 2 represents a 6-membered aryl or a 6-membered heteroaryl;

[0238] the heteroaryl or aryl group is optionally substituted with one or more substituents selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, and alkylsulfonalkyl;

[0239] The above substituents may be oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl optionally substituted with one or more substituents selected from alkylsulfonyl and alkylsulfonealkyl;

[0240] Alternatively, the heteroaryl or aryl group is optionally substituted with two substituents which, together with the atoms to which they are attached, represent oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, and alkylsulfonyl and alkylsulfonealkyl, and optionally substituted with one or more substituents selected from alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl.

[0241] In one embodiment, a preferred A2AR antagonist of formula (III) is of formula (IIIa): [ka] have or

[0242] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0243] R 1is a 5- or 6-membered heteroaryl, or a 5- or 6-membered aryl, wherein the heteroaryl or aryl group is optionally substituted with one or more substituents selected from C-C alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R 1 represents a 5-membered heteroaryl; more preferably R 1 represents frills;

[0244] X 1 and X 2 each independently represents C or N;

[0245] R 1’ is X 1 is non-existent if is N; or X 1 If C is R 1’ represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino or alkylsulfonalkyl;

[0246] The above substituents may be oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl optionally substituted with one or more substituents selected from alkyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl;

[0247] R 2’ represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino or alkylsulfonalkyl;

[0248] The above substituents may be oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl optionally substituted with one or more substituents selected from alkyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl;

[0249] Alternatively, R 1’ and R 2’and, together with the atoms to which they are bonded, represent oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoa forming a 5- or 6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl ring, or a 5- or 6-membered heterocyclyl ring optionally substituted with one or more substituents selected from alkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl;

[0250] R 3’ is X 2 is non-existent if is N; or X 2 If C is R 3’ represents H or halo, preferably H or F;

[0251] R 4’ represents H or halo, preferably H or F;

[0252] R 5’ represents H or halo, preferably H or F.

[0253] In one embodiment, a preferred A2AR antagonist of formula (IIIa) is of formula (IIIa-1): [ka] have or

[0254] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 1’ , R 2’ , R 3’ , R 4’ and R 5’ is as defined in formula (IIIa).

[0255] In one embodiment, a preferred A2AR antagonist of formula (IIIa-1) is a compound of formula (IIIa-1a): [ka] have or

[0256] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0257] R 1 and R 3’ is as defined in formula (IIIa);

[0258] R 1”is oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyl It represents an alkyl or heterocyclyl group substituted with one or more groups selected from oxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

[0259] In one embodiment, a preferred A2AR antagonist of formula (IIIa-1) is a compound of formula (IIIa-1b): [ka] have or

[0260] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0261] R 1 and R 3’ is as defined in formula (IIIa);

[0262] R 1’ represents H or halo, preferably H or F;

[0263] R2” is oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyl It represents an alkyl or heterocyclyl group substituted with one or more groups selected from oxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

[0264] In one embodiment, preferred A2AR antagonists of formula (IIIa-1) are those of formula (IIIa-1c) or (IIIa-1d): [ka] have or

[0265] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0266] R 1 and R 3’ is as defined in formula (IIIa);

[0267] R 1’ represents H or halo, preferably H or F;

[0268] R 2’ represents H or halo, preferably H or F;

[0269] R 1i and R 1ii each independently represent hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl, or alkylsulfonealkyl;

[0270] R 2i and R 2iieach independently represents hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl, or alkylsulfonealkyl.

[0271] In one embodiment, preferred A2AR antagonists of formula (IIIa) are those of formula (IIIa-2) or (IIIa-3): [ka] have or

[0272] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 2’ , R 3’ , R 4’ and R 5’ is as defined in formula (IIIa).

[0273] Particularly preferred A2AR antagonists of formula (III) are those listed below:

[0274] 3-(2-(4-(4-((1H-1,2,3-triazol-4yl)methoxy-2-fluorophenyl)piperazin-1-yl)ethyl)-5-amino-(8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0275] 5-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)methyl)-1,3,4-oxadiazol-2(3H)-one

[0276] 5-amino-3-(2-(4-(3-fluoropyridin-4-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0277] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetamide

[0278] (S)-5-Amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0279] (R)-5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)-piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0280] (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0281] (+)-5-Amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0282] (-)-5-Amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0283] 5-Amino-8-(furan-2-yl)-3-(2-(4-(4-(2-hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0284] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)phenoxy)acetic acid

[0285] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)phenoxy)acetamide

[0286] 5-Amino-3-(2-(4-(4-(2,3-dihydroxypropoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0287] 5-amino-3-(2-(4-(4-(2-aminoethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0288] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)benzamide

[0289] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-methylbenzamide

[0290] 5-Amino-8-(furan-2-yl)-3-(2-(4-(4-(2-morpholinoethoxy)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0291] 5-Amino-3-(2-(4-(4-(2-(dimethylamino)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0292] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)benzenesulfonamide

[0293] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-methylbenzenesulfonamide

[0294] 5-Amino-8-(furan-2-yl)-3-(2-(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0295] 5-Amino-8-(furan-2-yl)-3-(2-(4-(4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0296] 3-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)benzamide

[0297] 5-Amino-8-(furan-2-yl)-3-(2-(4-(3-(2-hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0298] 5-Amino-3-(2-(4-(2-fluoro-4-(2-oxo-2-(piperazin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0299] 5-amino-3-(2-(4-(2-fluoro-4-(piperidin-4-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0300] 5-amino-3-(2-(4-(2-fluoro-4-(piperazine-1-carbonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0301] 5-amino-3-(2-(4-(2-fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0302] 5-Amino-3-(2-(4-(2-fluoro-4-(piperazin-1-ylsulfonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0303] 5-Amino-3-(2-(4-(2-fluoro-4-(methylsulfonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0304] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-aminoethyl)-3-fluorobenzamide

[0305] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylamino)ethyl)benzamide

[0306] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3-fluorobenzamide

[0307] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide

[0308] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-3-fluorobenzamide

[0309] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)acetic acid

[0310] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3,5-difluorophenoxy)acetic acid

[0311] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoic acid

[0312] (S)-2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoic acid

[0313] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-2-methylpropanoic acid

[0314] 3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)propanoic acid

[0315] 4-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)butanoic acid

[0316] 2-(3-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,6-difluorophenoxy)acetic acid

[0317] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetic acid

[0318] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorobenzoic acid

[0319] 2-((2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)amino)acetamide

[0320] 2-((2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)(methyl)amino)acetamide

[0321] 5-amino-3-(2-(4-(2-fluoro-4-(piperidin-4-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0322] 5-amino-3-(2-(4-(2-fluoro-4-(pyrrolidin-3-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0323] 3-(2-(4-(4-((1H-1,2,4-triazol-3-yl)methoxy)-2-fluorophenyl)piperazin-1-yl)ethyl)-5-amino-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0324] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-(methylamino)ethyl)acetamide

[0325] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-(dimethylamino)ethyl)acetamide

[0326] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-aminoethyl)acetamide

[0327] (R)-2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoic acid

[0328] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)acetamide

[0329] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-methyl-N-(2-(methylamino)ethyl)benzamide

[0330] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3-fluoro-N-methylbenzamide

[0331] (R)-4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(1-(dimethylamino)propan-2-yl)-3-fluorobenzamide

[0332] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-methyl-N-(2-(methylamino)ethyl)acetamide

[0333] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-2-methylpropanoic acid

[0334] (S)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propanoic acid

[0335] (R)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propanoic acid

[0336] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-(methylamino)ethyl)acetamide

[0337] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-(dimethylamino)ethyl)acetamide

[0338] 5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2,4-difluoro-N-methylbenzamide

[0339] 4-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)butanoic acid

[0340] 3-(2-(4-(5-((1H-tetrazol-5-yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-5-amino-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0341] 5-amino-3-(2-(4-(2-fluoro-4-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0342] 5-Amino-3-(2-(4-(2,4-difluoro-5-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0343] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methyl(oxetan-3-yl)amino)ethyl)benzamide

[0344] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-((2-hydroxyethyl)amino)ethyl)benzamide

[0345] 2-Amino-N-(2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)acetamide

[0346] (S)-2-Amino-N-(2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)-3-methylbutanamide

[0347] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetic acid ethyl ester

[0348] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetonitrile

[0349] 5-Amino-8-(furan-2-yl)-3-(2-(4-(pyridin-4-yl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0350] 5-Amino-8-(furan-2-yl)-3-(2-(4-(pyrimidin-4-yl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0351] 5-Amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0352] 5-Amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfonyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0353] 5-Amino-3-(2-(4-(6-fluoro-2-oxoindolin-5-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0354] 5-Amino-3-(2-(4-(2-fluoro-4-(S-methylsulfonimidoyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0355] 5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2,4-difluorobenzamide

[0356] 5-Amino-3-(2-(4-(5-fluoro-2-methylpyridin-4-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0357] 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0358] 5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0359] 5-Amino-3-(2-(4-(2-fluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0360] 5-amino-3-(2-(4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0361] 5-amino-3-(2-(4-(2-fluoro-4-(3,3,3-trifluoro-2-hydroxypropoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0362] 5-Amino-3-(2-(4-(2-fluoro-5-(2-hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0363] 5-Amino-3-(2-(4-(2,4-difluoro-5-(morpholin-2-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0364] 5-Amino-3-(2-(4-(2,4-difluoro-5-(morpholin-3-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0365] 5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0366] 5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0367] 5-amino-3-(2-(4-(2,4-difluoro-5-(((3R,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0368] 5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0369] (S)-5-Amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0370] (R)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0371] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-morpholinoethyl)acetamide

[0372] 5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(morpholin-3-ylmethyl)benzamide

[0373] 5-amino-3-(2-(4-(2-fluoro-4-(morpholin-3-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0374] 5-amino-3-(2-(4-(2-fluoro-4-(morpholin-2-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0375] 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0376] 5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0377] 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0378] 5-amino-3-(2-(4-(2-fluoro-4-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0379] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-morpholinoethyl)acetamide

[0380] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-morpholinoethyl)benzamide

[0381] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(morpholin-3-ylmethyl)benzamide

[0382] 5-Amino-3-(2-(4-(4-(azetidin-3-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0383] (S)-5-Amino-3-(2-(4-(2,4-difluoro-5-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0384] (R)-5-Amino-3-(2-(4-(2,4-difluoro-5-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0385] 5-Amino-3-(2-(4-(2,4-difluoro-5-(((1s,4s)-1-oxidetetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0386] 5-Amino-3-(2-(4-(2,4-difluoro-5-(((1r,4r)-1-oxidetetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0387] (S)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(2-(methylsulfinyl)ethyl)benzamide

[0388] (R)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(2-(methylsulfinyl)ethyl)benzamide

[0389] (S)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methyl-N-(2-(methylsulfinyl)ethyl)benzamide

[0390] (R)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methyl-N-(2-(methylsulfinyl)ethyl)benzamide

[0391] 5-Amino-3-(2-(4-(2,4-difluoro-5-(1-oxidothiomorpholine-4-carbonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0392] 5-Amino-3-(2-(4-(2,4-difluoro-5-(1-oxidothiomorpholino)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0393] (R)-5-amino-3-(2-(4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0394] (S)-5-Amino-3-(2-(4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0395] 5-amino-3-(2-(4-(2-fluoro-4-(((1s,4s)-1-oxidetetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0396] 5-amino-3-(2-(4-(2-fluoro-4-(((1r,4r)-1-oxidetetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0397] (S)-4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylsulfinyl)ethyl)benzamide

[0398] (R)-4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylsulfinyl)ethyl)benzamide

[0399] 5-amino-3-(2-(4-(2-fluoro-4-(1-oxidothiomorpholine-4-carbonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0400] 5-amino-3-(2-(4-(2-fluoro-4-(1-oxidothiomorpholino)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0401] (S)-5-Amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0402] (R)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0403] (S)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4-difluorobenzamide

[0404] (R)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4-difluorobenzamide

[0405] 5-Amino-3-(2-(4-(4-(azetidin-3-yloxy)-2-fluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0406] 5-Amino-3-(2-(4-(5-(azetidin-3-yloxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one

[0407] (S)-5-Amino-3-(2-(4-(2,4-difluoro-5-(3-(methylsulfinyl)propoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one.

[0408] In one embodiment, the A2AR antagonist of formula (III) is:

[0409] (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (compound 7),

[0410] (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (compound 8a), and

[0411] (-)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (compound 8b) is selected from.

[0412] In a specific embodiment, the A2AR antagonist of formula (III) is:

[0413] (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (Compound 7); and

[0414] (+)-5-Amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (Compound 8a) is selected from.

[0415] In a preferred embodiment, the A2AR antagonist of formula (III) is (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (compound 8a).

[0416] In another preferred embodiment, the A2AR antagonist of formula (III) is (-)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (compound 8b).

[0417] The embodiments of the present invention relating to salts, solvates, enantiomers, isomers (including optical, geometric and tautomers), polymorphs, multi-component complexes, liquid crystals, prodrugs and isotopically labeled ENT inhibitors also apply to the A2AR antagonists of formula (III) and formulae substitutive thereto, as detailed above.

[0418] In another embodiment, the A2AR antagonist is an A2AR antagonist disclosed in WO2011 / 121418. In particular, the A2AR antagonist is the compound of Example 1 of WO2011 / 121418, i.e., 5-bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine, also known as NIR178: [ka] is.

[0419] In another embodiment, the A2AR antagonist is an A2AR antagonist disclosed in WO2009 / 156737. In particular, the A2AR antagonist is the compound of Example 1S of WO2009 / 156737, namely (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine, also known as CPI-444: [ka] is.

[0420] In another embodiment, the A2AR antagonist is an A2AR antagonist disclosed in WO2011 / 095626. In particular, the A2AR antagonist is compound (cxiv) of WO2011 / 095626, i.e., 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine, also known as AZD4635: [ka] is.

[0421] In another embodiment, the A2AR antagonist is an A2AR antagonist disclosed in WO2018 / 136700. In particular, the A2AR antagonist is the compound of Example 1 of WO2018 / 136700, namely 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile, also known as AB928: [ka] is.

[0422] In another embodiment, the A2AR antagonist is preladenant (SCH-420,814), i.e., 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine: [ka] is.

[0423] In another embodiment, the A2AR antagonist is bipadenant (BIIB-014), i.e., 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine: [ka] is.

[0424] In another embodiment, the A2AR antagonist is tozadenant (SYK-115), i.e., 4-hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide: [ka] is.

[0425] Thus, in one embodiment, the adenosine receptor antagonist is:

[0426] 5-Bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine;

[0427] (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

[0428] 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;

[0429] 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile;

[0430] 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine;

[0431] 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine; and

[0432] 4-Hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide is selected from.

[0433] In one embodiment, the adenosine receptor antagonist is 5-bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine. In one embodiment, the adenosine receptor antagonist is (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine. In one embodiment, the adenosine receptor antagonist is 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine. In one embodiment, the adenosine receptor antagonist is 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile.

[0434] A2B receptor antagonists In one embodiment, the combination of the present invention comprises at least one A2BR antagonist.

[0435] "A2BR antagonist" refers to a compound that, when administered to a patient, results in inhibiting or down-regulating the biological activity associated with activation of the A2B receptor in the patient, including any downstream biological effects that would otherwise result from binding of the A2B receptor to its natural ligand. Such A2BR antagonists include any agent that can block activation of the A2B receptor or any downstream biological effects of A2B receptor activation.

[0436] Examples of A2BR antagonists include: bipadenant (BIIB-014), CVT-6883, MRS-1706, MRS-1754, PSB-603, PSB-0788, PSB-1115, OSIP-339,391, ATL-801, theophylline, and caffeine.

[0437] Specific combinations In one embodiment, the combination of the present invention comprises:

[0438] (a) an effective amount of an ENT inhibitor of Formula I or Formula II of the present invention or a formula substitutable therefor;

[0439] (b) an effective amount of an adenosine receptor antagonist, preferably an A2AR antagonist, preferably selected from the following:

[0440] (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[0441] (-)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[0442] 5-Bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine;

[0443] (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

[0444] 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;

[0445] 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile;

[0446] and pharmaceutically acceptable salts thereof.

[0447] In one embodiment, the combination of the present invention comprises:

[0448] (a) an effective amount of an ENT inhibitor of Formula I or Formula II of the present invention or a formula substitutable therefor;

[0449] (b) an effective amount of (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one as an A2AR antagonist.

[0450] In one embodiment, the combination of the present invention comprises:

[0451] (a) an effective amount of an ENT inhibitor of Formula I or Formula II of the present invention or a formula substitutable therefor;

[0452] (b) an effective amount of (-)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one as an A2AR antagonist.

[0453] Combination preparations and kits of parts The present invention further provides a combined preparation comprising the combination of the present invention. In particular, the present invention provides a combined preparation comprising: an effective amount of an adenosine receptor antagonist in combination with an effective amount of an ENT inhibitor of the present invention as defined above, together with a pharmaceutically acceptable excipient.

[0454] The present invention further relates to a combined pharmaceutical composition comprising the combination of the present invention. In one embodiment, the pharmaceutical composition comprises:

[0455] (a) an effective amount of an ENT inhibitor of the present invention according to Formula I or Formula II or any formula therebetween as defined above; (b) an effective amount of an adenosine receptor antagonist; and (c) at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.

[0456] The specific embodiments listed above regarding the adenosine receptor antagonists and ENT inhibitors of the present invention also apply in the context of the combined formulations and pharmaceutical compositions of the present invention.

[0457] In a preferred embodiment, the present invention provides a compound comprising: (a) an effective amount of an ENT inhibitor of the present invention, of formula I or II or a formula substitutable therefor, as defined above; and (b) an effective amount of a thiocarbamate derivative that is an A2AR antagonist, more preferably a thiocarbamate derivative of formula (III) as defined above. [ka]

[0458] or a pharmaceutically acceptable salt or solvate thereof;

[0459] (c) providing a combined pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.

[0460] In one embodiment, the combined preparation or pharmaceutical composition of the present invention further comprises an additional therapeutic agent.

[0461] The at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant for use in preparing the dosage form will be apparent to those skilled in the art, and reference is made to the latest edition of Remington's Pharmaceutical Sciences. Specific embodiments relating to formulations comprising an ENT inhibitor of the present invention also apply in the context of the combined formulations and pharmaceutical compositions of the present invention.

[0462] The present invention further relates to a kit-of-parts comprising the combination of the present invention. In one embodiment, the kit-of-parts of the present invention comprises:

[0463] (a) a first portion comprising an effective amount of an ENT inhibitor of Formula I or Formula II or any of the formulae substitutable therein as defined above according to the present invention;

[0464] (b) a second portion comprising an effective amount of an adenosine receptor antagonist.

[0465] The above embodiments relating to the ENT inhibitors and adenosine receptor antagonists of the present invention also apply to the kit-of-parts of the present invention.

[0466] In a preferred embodiment, the present invention provides:

[0467] (a) a first portion comprising an effective amount of an ENT inhibitor of Formula I or Formula II or any of the formulae substitutable therein as defined above according to the present invention;

[0468] (b) an effective amount of a thiocarbamate derivative that is an A2AR antagonist, more preferably a thiocarbamate derivative of formula (III) as defined above; [ka]

[0469] or a pharmaceutically acceptable salt or solvate thereof.

[0470] Depending on the ENT inhibitor and adenosine receptor antagonist, the first and second parts of the kit may be in the form of pharmaceutical compositions. The excipients, dosage forms and routes of administration of such pharmaceutical compositions will be clear to those skilled in the art (see the latest edition of Remington's Pharmaceutical Sciences), and may in particular be those listed above for the pharmaceutical compositions of the present invention.

[0471] In one embodiment, the kit-of-parts of the present invention further comprises an additional therapeutic agent.

[0472] In the context of the present invention, administration of the ENT inhibitor and adenosine receptor antagonist may occur simultaneously or staggered in time, either at the same or different administration sites, under similar or different dosage forms as further outlined below.

[0473] In one embodiment, the ENT inhibitor is administered before, concomitantly with, or after the administration of the adenosine receptor antagonist.In order to ensure that the individual mechanisms induced by the ENT inhibitor and the adenosine receptor antagonist are not adversely affected by each other, the adenosine receptor antagonist and the ENT inhibitor can be administered temporally (time-shifted), i.e., separately, and / or at different administration sites.This means that the adenosine receptor antagonist can be administered, for example, before, concomitantly with, or after the ENT inhibitor, or vice versa.Alternatively, or in addition, the adenosine receptor antagonist and the ENT inhibitor can be administered at different administration sites, or preferably, when administered at different times, can be administered at the same administration site.

[0474] In one embodiment, the adenosine receptor antagonist will be administered prior to and / or concomitantly with the ENT inhibitor. In one embodiment, the adenosine receptor antagonist will be administered prior to or on the same day as the administration of the ENT inhibitor. In another embodiment, the ENT inhibitor will be administered prior to and / or concomitantly with the adenosine receptor antagonist. In one embodiment, the ENT inhibitor will be administered prior to or on the same day as the administration of the adenosine receptor antagonist. In one embodiment, the adenosine receptor antagonist will be administered prior to and / or concomitantly with the ENT inhibitor and will be administered continuously thereafter. In another embodiment, the ENT inhibitor will be administered prior to and / or concomitantly with the adenosine receptor antagonist and will be administered continuously thereafter.

[0475] Depending on the condition to be prevented or treated and the form of administration, the ENT inhibitors and adenosine receptor antagonists may be administered as a single daily dose or in one or more divided daily doses.

[0476] It will be understood that the overall daily dosage of adenosine receptor antagonists and ENT inhibitors will be determined by the attending physician within the scope of sound medical judgment. The specific dose for any particular subject will depend on a variety of factors, such as the cancer being treated; the patient's age, weight, general health, sex, and diet; and similar factors well known in the medical field.

[0477] Another object of the present invention is the use of the combination as a medicament, i.e. for medical use. Thus, in one embodiment, the present invention provides the use of the combination of the present invention for the manufacture of a medicament. In particular, the present invention provides the use of the combined pharmaceutical composition of the present invention or the kit of the present invention for the manufacture of a medicament.

[0478] In particular, the present invention provides a combination, combined pharmaceutical composition or kit-of-parts of the present invention for use in the treatment and / or prevention of cancer. The present invention further provides the use of a combination, combined pharmaceutical composition or kit-of-parts of the present invention for the manufacture of a medicament for treating and / or preventing cancer. The present invention further provides a method of treating cancer, which comprises administering a therapeutically effective amount of a combination, combined pharmaceutical composition or kit-of-parts of the present invention to a mammalian species in need thereof.

[0479] In particular, the present invention provides a method of treating cancer, comprising administering to a patient in need thereof a combination of an adenosine receptor antagonist and an ENT inhibitor. The specific embodiments for the adenosine receptor antagonist and ENT inhibitor listed above also apply in the context of the treatment methods of the present invention.

[0480] The present invention also provides a method for delaying the onset of cancer in a patient, comprising administering to a patient in need thereof a pharmaceutically effective amount of the combination, combined pharmaceutical composition or kit-of-parts of the present invention. Enumeration of Embodiments 1. Compounds of Formula I: [ka] [During the ceremony, R 1 teeth, [ka] and; Each R 2 are independently halogen, -OR 3 , -R 3 , -CO2R 3 , C(O)N(R 3 )2, -CH2C(O)N(R 3 )2, and -CN; Each R 3 is independently -H or ALK; R 4 teeth, [ka] and; U is -C(O)-, alkylene, -O-, -N(R 3 )-, -C(O)O-, -C(O)N(R 3 )-, and [ka] selected from the group consisting of: Each R x are independently selected from alkylene; Each V is independently -C(R 3 )-, -N(R 3 ), -N-, -O-; Z is C; or R 2 Z is N if is absent. or a pharmaceutically acceptable salt or solvate thereof. 2. Compound of Formula II: [ka] [During the ceremony, R 1 teeth, [ka] and; Each R 2 are independently halogen, -OR 3 , -R 3 , -CO2R 3 , C(O)N(R 3 )2, -CH2C(O)N(R 3 )2, and -CN; Each R 3 is independently -H or ALK; R 4 teeth, [ka] and; X is selected from the group consisting of -CH2-, -CHF-, -CF2-; Each U independently represents -O-, -N(R3 )-, -C(O)O-, -C(O)N(R 3 )-, [ka] selected from the group consisting of —C(O)—, and alkylene; Each R x is independently selected from alkylene; Each V is independently -C(R 3 )-, -N(R 3 )—, —N═, and —O—; Each Z is independently C; or R 2 is non-existent and Z=N; n 1 is a number that is either 0 or 1. or a pharmaceutically acceptable salt or solvate thereof. 3.Formula IIa: [ka] [During the ceremony, R 1 teeth, [ka] and Each R 2 are independently halogen, -OR 3 , -R 3 , -CO2R 3 , C(O)N(R 3 )2, -CH2C(O)N(R 3 )2, and -CN; Each R 3 is independently -H or ALK; R 4 teeth, [ka] and; X is selected from the group consisting of -CH2-, -CHF-, -CF2-; Each U independently represents -O-, -N(R 3 )-, -C(O)O-, -C(O)N(R3 )-, [ka] selected from the group consisting of —C(O)—, and alkylene; Each R x is independently selected from alkylene; Each V is independently -C(R 3 )-, -N(R 3 )—, —N═, and —O—; Each Z is independently C; or R 2 is non-existent and Z=N; n 1 is a number that is either 0 or 1. or a pharmaceutically acceptable salt or solvate thereof. 4.Formula IIa1: [ka] or a pharmaceutically acceptable salt or solvate thereof. 5. 3,4,5-Trimethoxybenzoic acid (12R)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)benzenacyclotetradecaphan-12-yl; 3,4,5-Trimethoxybenzoate (12S)-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 3-Ethoxy-4,5-dimethoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 3-(2-amino-2-oxoethyl)-4,5-dimethoxybenzoic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 3,4,5-Trimethoxybenzoic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 4-Chloro-3-methoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 4-Fluoro-3-methoxybenzoic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 1-(3,4,5-trimethoxybenzyl)-1H-indazole-6-carboxylic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 2,6-Dimethylisonicotinic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 3,5-Dichloro-4-methoxybenzoic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 2-Benzyl-4-chloro-2H-indazole-6-carboxylic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 4-Chloro-1-methyl-1H-indazole-6-carboxylic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 1-Benzyl-4-chloro-1H-indazole-6-carboxylic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 3,4,5-Trifluorobenzoic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 3-Carbamoyl-4,5-dimethoxybenzoic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 3-(Benzyloxy)-4,5-dimethoxybenzoic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 7-Methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 1-Methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 6-Cyanonicotinic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 4-Acetylbenzoic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 4-(Trifluoromethyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 6-(Trifluoromethyl)nicotinic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 6-Methylnicotinic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 3,4-Dichlorobenzoic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 4-Chloro-3-fluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 4-Chlorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 3-Chloro-4-fluorobenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 4-Fluorobenzoic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 4-Morpholinobenzoic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 4-(Trifluoromethoxy)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 2-Chloro-3,4-dimethoxybenzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 4-(Methylsulfonyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 2,3-Dihydrobenzo[b][1,4]dioxine-6-carboxylic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 1-Methyl-1H-indazole-6-carboxylic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 1-Benzyl-1H-indazole-6-carboxylic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; Benzo[d]thiazole-6-carboxylic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-12-yl; [1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 2-(Trifluoromethyl)isonicotinic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 5,6-Dichloronicotinic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 6-Chloro-5-fluoronicotinic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 2-Aminopyrimidine-5-carboxylic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 5-Chloronicotinic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 4-Methoxybenzoic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 4-Methoxy-3-(trifluoromethyl)benzoate 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 3-Chloro-4-methoxybenzoic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl ester 3,4-Dimethoxybenzoic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 6-Methoxynicotinic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 5-Methoxynicotinic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 2-Methoxypyrimidine-5-carboxylic acid 74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 3,4,5-Trimethoxybenzoic acid 16-fluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; 3,4,5-Trimethoxybenzoic acid 16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl; N-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-12-yl)-3,4,5-trimethoxybenzamide; N-(74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-12-yl)-3,4,5-trimethoxy-N-methylbenzamide; N-(16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-12-yl)-3,4,5-trimethoxybenzamide; N-(16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-12-yl)-3,4,5-trimethoxy-N-methylbenzamide; N-((12R)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)benzenacyclotetradecaphan-12-yl)-3,4,5-trimethoxybenzamide; N-((12R)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)benzenacyclotetradecaphan-12-yl)-3,4,5-trimethoxy-N-methylbenzamide; N-((12S)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-12-yl)-3,4,5-trimethoxybenzamide; N-((12S)-16,16-difluoro-74,75-dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-12-yl)-3,4,5-trimethoxy-N-methylbenzamide, and pharmaceutically acceptable salts or solvates thereof The compound of any one of enumerated embodiments 2-4 is selected from the group consisting of: 6. The compound of any one of the preceding enumerated embodiments, wherein said compound contains only one chiral center. 7. The compound of enumerated embodiment 6, wherein the compound is a racemic mixture containing "R" and "S" isomers. 8. The compound of enumerated embodiment 6, wherein said compound is an "R" isomer. 9. The compound of enumerated embodiment 6, wherein said compound is the "S" isomer. 10. The compound of any one of enumerated embodiments 1-5, wherein the compound contains more than one chiral center. 11. The compound of enumerated embodiment 10, wherein said chiral centers independently comprise the "R" or "S" configuration. 12. The compound according to enumerated embodiment 10, wherein said chiral centers comprise the same configuration. 13. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments and at least one pharmaceutically acceptable excipient. 14. The pharmaceutical composition of enumerated embodiment 13, further comprising an adenosine receptor antagonist. 15. The pharmaceutical composition of enumerated embodiment 14, wherein the adenosine receptor antagonist is an A2A or A2B receptor antagonist. 16. The adenosine receptor antagonist is 5-Bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile; 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine; and 4-Hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide The pharmaceutical composition of enumerated embodiment 14, selected from: 17. The adenosine receptor antagonist is a compound of formula (III): [ka] [During the ceremony, R 1 = a 5- or 6-membered heteroaryl, or a 5- or 6-membered aryl, wherein said heteroaryl or aryl group is optionally substituted with one or more substituents selected from C1-C6 alkyl and halo; R 2 = 6-membered aryl or 6-membered heteroaryl, the heteroaryl or aryl group is optionally substituted with one or more substituents selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, and alkylsulfonalkyl; The substituents may be oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl optionally substituted with one or more substituents selected from alkylsulfonyl and alkylsulfonealkyl; Alternatively, said heteroaryl or aryl group is optionally substituted with two substituents, said two substituents together with the atoms to which they are attached being selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, and forming a 5- or 6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl ring, or a 5- or 6-membered heterocyclyl ring optionally substituted with one or more substituents selected from alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl. or a pharmaceutically acceptable salt or solvate thereof. 18. A method for inhibiting ENT1 in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of the enumerated embodiments 1 to 12. 19. A method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of the enumerated embodiments 1-12. 20. A method of treating cancer in a patient in need thereof, comprising administering to the patient a combination of a compound according to any one of enumerated embodiments 1-12 and an adenosine receptor antagonist. 21. The method of enumerated embodiment 20, wherein a compound of any one of enumerated embodiments 1-12 is administered prior to, concomitantly with, or following administration of the adenosine receptor antagonist. 22. The method of any one of enumerated embodiments 20-21, wherein the adenosine receptor antagonist is an A2A or A2B receptor antagonist. 23. The adenosine receptor antagonist is 5-Bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile; 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine; and 4-Hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide 21. The method of enumerated embodiment 20, selected from: 24. The adenosine receptor antagonist is a compound of formula (III): [ka] [During the ceremony, R 1 = a 5- or 6-membered heteroaryl, or a 5- or 6-membered aryl, wherein said heteroaryl or aryl group is optionally substituted with one or more substituents selected from C1-C6 alkyl and halo; R 2 = 6-membered aryl or 6-membered heteroaryl, the heteroaryl or aryl group is optionally substituted with one or more substituents selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, and alkylsulfonalkyl; The substituents may be oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl optionally substituted with one or more substituents selected from alkylsulfonyl and alkylsulfonealkyl; Alternatively, said heteroaryl or aryl group is optionally substituted with two substituents, said two substituents together with the atoms to which they are attached being selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, and forming a 5- or 6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl ring, or a 5- or 6-membered heterocyclyl ring optionally substituted with one or more substituents selected from alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl. 21. The method of recited embodiment 20, wherein the compound is CI 11149, or a pharmaceutically acceptable salt or solvate thereof. 25. A parts kit comprising: (a) a first portion comprising an effective amount of a compound according to any one of the recited embodiments 1-12; (b) a second portion comprising an effective amount of an adenosine receptor antagonist; The kit of parts. 26. The kit-of-parts according to enumerated embodiment 25, wherein the adenosine receptor antagonist is an A2A or A2B receptor antagonist. 27. The adenosine receptor antagonist is 5-Bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile; 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine; and 4-Hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide 26. The kit of parts of enumerated embodiment 25, selected from: 28. The adenosine receptor antagonist is a compound of formula (III): [ka] [During the ceremony, R 1 = a 5- or 6-membered heteroaryl, or a 5- or 6-membered aryl, wherein said heteroaryl or aryl group is optionally substituted with one or more substituents selected from C1-C6 alkyl and halo; R 2 = 6-membered aryl or 6-membered heteroaryl, the heteroaryl or aryl group is optionally substituted with one or more substituents selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, and alkylsulfonalkyl; The substituents may be oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl optionally substituted with one or more substituents selected from alkylsulfonyl and alkylsulfonealkyl; Alternatively, said heteroaryl or aryl group is optionally substituted with two substituents, said two substituents together with the atoms to which they are attached being selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, and forming a 5- or 6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl ring, or a 5- or 6-membered heterocyclyl ring optionally substituted with one or more substituents selected from alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl. 26. The kit of parts according to enumerated embodiment 25, wherein the compound is a compound selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 2 [Example]

[0481] The present invention will be better understood by reference to the following examples, which are intended to represent specific embodiments of the invention and are not intended to limit the scope of the invention. The following abbreviations are used: THF: tetrahydrofuran; DCM: dichloromethane; EtOAC: ethyl acetate; ACN: acetonitrile; TEA: triethylamine; DIPEA: N,N-diisopropylethylamine; EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; HAUT: (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; DPPF: 1,1'-bis(diphenylphosphino)ferrocene HOBt: 1-hydroxybenzotriazole; DTAD: di-tert-butyl azodicarboxylate; EDC.HCl: N'-Ethylcarbodiimide hydrochloride N2: nitrogen gas; min:minutes; hr: time; Na2SO4: sodium sulfate; TLC: thin layer chromatography; prep-HPLC: preparative high-pressure liquid chromatography; HPLC: high pressure liquid chromatography; SiO2: Silica gel; K2CO3: Potassium carbonate; LiOH: lithium hydroxide. DCC: N,N'-dicyclohexylcarbodiimide DMAP: 4-dimethylaminopyridine DEAD: Diethyl azodicarboxylate PPh3: Triphenylphosphine TBAF: tetra-n-butylammonium fluoride TFA: Trifluoroacetic acid

[0482] I. Chemical Examples The MS data provided in the Examples described below were obtained as follows: LCMS were recorded using an Agilent 6130 or 6130B multimode (ESI+APCI).

[0483] LCMS method Method A This method was used for LCMS analysis of intermediates. The column used for chromatography was a ZORBAX Eclipse XDB-C18 2.1 x 30 mm (3.5 µm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100–1000. Mobile phase A was water containing 0.037% trifluoroacetic acid, and mobile phase B was HPLC-grade acetonitrile containing 0.018% trifluoroacetic acid. The gradient was 5–95% B in 2.20 min, 5% B in 0.01 min, 5–95% B (0.01–1.00 min), 95–100% B (1.00–1.80 min), 5% B in 1.81 min, and held at 5% B for 0.39 min. The flow rate was 1.0 mL / min.

[0484] Method B This method was used for LCMS analysis of compounds. The column used for chromatography was a Kinetex C18 50 x 2.1 mm column (5 μm particles). The detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection with positive electrospray ionization. The MS range was 100–1000. The gradient was 5% B at 0.40 min, 5–95% B from 0.40–3.00 min, held at 95% B for 1.00 min, then 95–5% B at 0.01 min, with a flow rate of 1.0 mL / min. Mobile phase A was water with 0.037% trifluoroacetic acid, and mobile phase B was acetonitrile with 0.018% trifluoroacetic acid.

[0485] Preparative basic LCMS Method for purification by prep-HPLC: Equipment: Gilson 281 semi-preparative HPLC system Mobile phase: A: H2O containing 10 mM NH4HCO3; B: ACN Column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm Flow rate: 25mL / min Monitor wavelength: 220nm and 254nm [Table 3] Preparative acidic LCMS Equipment: Gilson 281 semi-preparative HPLC system Mobile phase: A: HCl / H2O=0.1% v / v; B: ACN Column: Phenomenex Luna C18 100 x 30 mm x 5 μm Flow rate: 25mL / min Monitor wavelength: 220nm and 254nm [Table 4] Chiral SFC Method A: Column: Chiralcel OD-3 50 x 4.6mm inner diameter, 3um Mobile phase: Phase A is CO2, Phase B is MeOH (0.05% DEA); Gradient elution: 40% MeOH (0.05% DEA) in CO Flow rate: 3 mL / min; Detector: PDA Column temperature: 35°C; Back pressure: 100 Bar Chiral SFC Method B: Column: Chiralpak IC-3 50 x 4.6mm inner diameter, 3um Mobile phase: A2 = heptane; B2 = 80% EtOH (0.05% DEA) Flow rate: 1mL / min Wavelength: 220nm Column temperature: 35C Chiral HPLC: CHIRAL-HPLC (Column: SB 100 × 4.6 mm 3.0 um; Mobile phase: A: (60% DCM + 20 mM NH); B: MeOH; Flow rate: 3 mL / min; Concentration of pump B: 10% to 50.0% in 3.7 min; Detection: 254 nm). NMR analysis The NMR data provided in the examples described below was obtained as follows: 1H-NMR: Bruker DPX 400MHz. The abbreviations for multiplexes in NMR spectra are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad line). Unless otherwise noted, solvents, reagents and starting materials were purchased from commercial suppliers and used as received.

[0486] Example I.1. Synthesis of intermediate compounds Intermediate compound 1: [ka] To a solution of methyl 3-hydroxy-4,5-dimethoxybenzoate (0.5 g, 2.35 mmol) in tetrahydrofuran (9 mL) and methanol (3 mL) was added LiOH.HO (495 mg, 11.75 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 16 h. The solvent was removed and the residue was dissolved in water (5 mL). The aqueous phase was acidified with HCl (3 N) to pH = 4. The aqueous phase was extracted with ethyl acetate (4 × 5 mL). The combined organic phase was washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give intermediate compound 1 (480 mg, crude) as a white solid. 1H NMR (400MHz, CDCl3-d) δ12.71(s,1H),9.52(s,1H),7.08(s,1H),7.02(s,1H),3.77(s,3H),3.70(s,3H).

[0487] Intermediate compound 2: [ka] To a solution of intermediate compound 1 (480 mg, 2.4 mmol) in toluene (8 mL), 1,1-di-tert-butoxy-N,N-dimethylmethanamine (1.97 g, 9.6 mmol) was added at 20 °C. The mixture was stirred at 85 °C for 1 hour. At room temperature, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic phases were washed with brine (10 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 90 / 10) to give intermediate compound 2 (300 mg, 63% yield) as a white solid. 1H NMR(CDCl3-d)δ7.26(d,J=1.8Hz,1H),7.19-7.16(m,1H),5.84-5.80(m,1H),3.98-3.94(m,3H),3.93-3.89(m,3H),1.60-1.57(m,9H)

[0488] Intermediate compound 3: [ka] The Grignard reagent was prepared by the following procedure: To a mixture of Mg (1.41 g, 58.1 mmol) and I2 (80.2 mg, 315.8 mmol) in tetrahydrofuran (40 mL) was added a solution of ((3-bromopropoxy)methyl)benzene (11.1 g, 48.4 mmol) in tetrahydrofuran (30 mL). The reaction mixture was stirred at 25 °C for 1 h. The internal temperature rose from 25 °C to 65 °C. Most of the Mg was consumed, and the internal temperature cooled from 65 °C to 25 °C. The remaining Mg was filtered off to give a yellow tetrahydrofuran solution, which was used directly in the next step. To a solution of intermediate compound 63 (11.0 g, 58.4 mmol) in tetrahydrofuran (50 mL), Grignard reagent (70 mL tetrahydrofuran solution) was added at 0 °C. The reaction mixture was then warmed to 25 °C and stirred for 16 h. The reaction mixture was poured into an aqueous solution of NH4Cl (200 mL). The mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic phase was washed with brine (50 mL), dried over NaSO, and the suspension was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:0 to 90:10) to give intermediate compound 3 (4.24 g, 26% yield) as a colorless oil. 1H NMR (400MHz CDCl3-d) δppm 7.26-7.18(m,5H),4.44(s,2H),3.83-3.79(m,3H),3.43(s,3H),1.64-1.47(m,6H),0.82(s,9H),0.00(s,6H).

[0489] Intermediate compound 4: [ka] To a solution of intermediate compound 3 (4.94 g, 14.6 mmol) and intermediate compound 2 (3.72 g, 17.5 mmol) in tetrahydrofuran (100 mL) was added DCC (4.52 g, 21.9 mmol) and DMAP (2.67 g, 21.9 mmol) at 20 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 90 / 10) to give intermediate compound 4 (4.9 g, 63% yield) as a colorless oil. 1H NMR(400MHz,CDCl3-d)δ=7.36-7.25(m,7H),5.31-5.17(m,1H),4.50-4.44(m,2H),3.92-3.85(m,8H ),3.73-3.65(m,2H),3.52-3.43(m,2H),2.01-1.61(m,6H),0.90-0.81(m,10H),0.09-0.03(m,6H).

[0490] Intermediate compound 5: [ka] To a solution of Pd / C (150 mg, 10% purity) in methanol (20 mL) was added intermediate compound 4 (1.4 g, 2.63 mmol) at 20° C. The mixture was purged and degassed with H three times and stirred under H (15 psi) at 20° C. for 3 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give intermediate compound 5 (800 mg, 61% yield) as a colorless oil. 1H NMR (400MHz, CDCl3-d) δppm 7.28-7.25(m,2H),5.30-5.20(m,1H),3.91-3.86(m,9H),3.73-3.62(m,4H),2.03-1.84(m,2H), 1.84-1.74(m,2H),1.68-1.59(m,2H),1.45-1.37(m,1H),0.86-0.84(m,9H),0.03--0.02(m,6H)

[0491] Intermediate compound 6: [ka] To a solution of intermediate compound 5 (700 mg, 1.58 mmol) and intermediate 2 (442.36 mg, 1.74 mmol) in toluene (8 mL), triphenylphosphine (705.18 mg, 2.69 mmol, 1.7 equiv.) was added. Then, DEAD (479.7 mg, 2.37 mmol) was added at 0° C. After the addition, the mixture was stirred at 115° C. for 6 h. The solvent was removed, and the crude product was purified by prep-TLC (eluting with petroleum ether / ethyl acetate = 2 / 1) to give intermediate compound 6 (603 mg, 56% yield) as a colorless oil. 1H NMR(CDCl3-d 400MHz)δppm 7.26-7.22(m,4H),7.21-7.17(m,2H),7.16-7.13(m,1H),5.34-5.28(m,1H),4.07-4.00(m,2H),3.96-3.91(m,4H),3 .91-3.83(m,18H),3.74-3.65(m,2H),2.04-1.78(m,6H),1.58-1.54(m,20H),0.94-0.78(m,9H),0.04--0.04(m,6H)

[0492] Intermediate compound 7: [ka] To a solution of intermediate compound 6 (440 mg, 648.13 μmol, 1 equiv.) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (972.19 μL, 1 M, 1.5 equiv.) at 25° C. The mixture was stirred at 25° C. for 3 h. The reaction was slowly quenched with water (20 mL) at 0° C. and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to give intermediate compound 7 (250 mg, 68% yield) as a colorless oil. LCMS (ESI position ion) m / z: 587.2 (M+Na)+ (calculated: 564.2)

[0493] Intermediate compound 8: [ka] To a mixture of intermediate compound 7 (250 mg, 442.78 μmol) in dichloromethane (3 mL) was added triethylamine (89.61 mg, 885.55 μmol) and methanesulfonyl chloride (76.08 mg, 664.16 μmol) at 0° C. The mixture was then stirred at 0° C. for 2 h. The reaction mixture was slowly quenched with water (10 mL) at 0° C. and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO, petroleum ether / ethyl acetate=1 / 1) to give intermediate compound 8 (210 mg, 74% yield) as a colorless oil. LCMS (ESI position ion) m / z: 665.2 (M+Na)+ (calculated: 642.2). 1H NMR(400MHz,CDCl3-d)δppm 7.22(s,2H),7.16(d,J=1.8Hz,1H),7.15-7.13(m,1H),5.31(br t,J=5.9Hz,1H),4.32-4.20(m,2H),4.01(br d,J=6.5Hz,2H),3.84(s,9H),3.82(s,3H),3.81-3.79(s,3H),2.93-2.90(s,3H),2.17-2.10(m,2H),1.93-1.80(m,4H),1.51(s,9H).

[0494] Intermediate compound 9: [ka] To a solution of intermediate compound 8 (210 mg, 326.74 μmol) in acetonitrile (2 mL) were added tert-butyl 1,4-diazepane-1-carboxylate (65.44 mg, 326.74 μmol), potassium iodide (54.24 mg, 326.74 μmol), and K2CO3 (225.79 mg, 1.63 mmol) at 20 °C. The mixture was stirred at 60 °C for 12 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 1 / 1) to give intermediate compound 9 (220 mg, 90% yield) as a colorless oil. LCMS (ESI position ion) m / z: 747.4 (M+H)+ (calculated: 746.4)

[0495] Intermediate compound 10: [ka] To a mixture of intermediate compound 9 (220 mg, 294.56 μmol) in ethyl acetate (3 mL) was added HCl / EtOAc (5 mL, 4 M) at 20° C. The mixture was stirred at 20° C. for 2 hours. The solvent was removed under reduced pressure to give crude intermediate compound 10 (220 mg, crude, HCl salt) as a white solid, which was used directly in the next step without any further purification. LCMS (ESI position ion) m / z: 647.4 (M+H)+ (calculated: 646.3)

[0496] Intermediate compound 11: [ka] To a mixture of intermediate compound 10 (220 mg, 340.15 μmol) in acetonitrile (2 mL) was added KCO (141.03 mg, 1.02 mmol) and (3-bromopropoxy)(tert-butyl)dimethylsilane (103.37 mg, 408.18 μmol) at 25° C. The reaction mixture was stirred at 25° C. for 12 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give crude intermediate compound 11 (200 mg, 72% yield) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI position ion) m / z: 819.5 (M+H)+ (calculated: 818.4)

[0497] Intermediate compound 12: [ka] To a solution of intermediate compound 11 (50 mg, 61.04 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL) at 20° C. The reaction mixture was stirred at 20° C. for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure to give crude intermediate compound 12 (50 mg, crude) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI position ion) m / z: 649.4 (M+H)+ (calculated: 648.3).

[0498] Intermediate compound 13: [ka] NaOH (2 M, 200 mL) was added to a solution of methyl 3-hydroxy-4,5-dimethoxybenzoate (25.0 g, 118 mmol, 1.0 equiv) in MeOH (200 mL), and the resulting mixture was stirred at 60 °C under N for 16 h. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The mixture was acidified with 6 M HCl to pH = 2-3. The precipitate was collected by filtration and washed with water (3 × 50 mL) to give 3-hydroxy-4,5-dimethoxybenzoic acid (20 g, 86%) as an off-white solid. LC-MS(ES+) m / z: 199 (M+H)+ (calculated: 198.0).

[0499] To a stirred mixture of 3-hydroxy-4,5-dimethoxybenzoic acid (20.0 g, 101 mmol, 1.0 equiv.) and 3-bromopropanol (56.1 g, 404 mmol, 4.0 equiv.) was added H2SO4 (0.99 g, 10.1 mmol, 0.1 equiv.). The resulting mixture was stirred at 120 °C for 10–20 min and then at 100 °C for 4 h. The mixture was allowed to cool to room temperature, then diluted with EtOAc (300 mL), washed sequentially with HO (100 mL), saturated NH4CO3 (2 × 100 mL), and brine (100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), gradient from 30% to 70% in 10 min; detector, UV 254 nm) to give intermediate compound 13 (21 g, 65% yield) as a pale yellow solid. LC-MS(ES+) m / z: 319 (M+H)+ (calculated: 318.0). 1H NMR(300MHz,DMSO-d6)δppm 9.62(br,1H),7.16(s,1H),7.06(s,1H),4.36-4.31(m,2H),3.80(s,3H),3.72(s,3H),3.68-3.63(m,2H),2.28-2.22(m,2H).

[0500] Intermediate compound 14: [ka] To a solution of intermediate compound 8 (3.4 g, 5.29 mmol) in ACN (50 mL) were added tert-butyl 6,6-difluoro-1,4-diazepane-1-carboxylate (1.50 g, 6.35 mmol, 1.2 equiv.), KCO (3.66 g, 26.45 mmol, 5 equiv.), and KI (878.17 mg, 5.29 mmol, 1 equiv.). The mixture was stirred at 60 °C for 60 h. The reaction mixture was diluted with EtOAc (100 mL) and stirred at 20 °C for 30 min. The mixture was then filtered. The filter cake was washed with EtOAc (30 mL × 3). The filtrate was concentrated, and the residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 6 / 1 to 3 / 1) to give intermediate compound 14 (1.93 g, 47% yield) as a colorless oil. LCMS (ESI position ion) m / z: 783.4 (M+H)+ (calculated: 782.4) 1H NMR:(400MHz,CDCl3)δ=7.29(s,2H),7.24-7.21(m,2H),5.35(br s,1H),4.10-4.03(m,2H),3.91(s,9H),3.89(s,3H),3.87(s,3H),3.52-3.48(m,4H),2.99-2.95(m,4H),2.78-2.65(m,4H),1.92(br s,4H),1.59(s,9H),1.45(s,9H)

[0501] Intermediate compound 15: [ka] To a solution of intermediate compound 14 (1100 mg, 1.41 mmol, 1 equiv.) in ACN (22 mL) was added water (66 mL) and 40% H3PO4 in water (64.67 g, 659.98 mmol, 38.50 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with water and extracted with DCM (100 mL × 3). The organic layer was washed with saturated aqueous NaHCO3 and brine and dried over Na2SO4. The solution was concentrated, and the residue was purified by silica gel chromatography eluting with petroleum ether:ethyl acetate (5 / 1 to 0 / 1) to give intermediate compound 15 (290 mg, 30% yield) as a colorless oil. LCMS (ESI position ion) m / z: 683.3 (M+H)+ (calculated: 682.3)

[0502] Intermediate compound 16: [ka] To a solution of intermediate compound 15 (330 mg, 483.34 μmol, 1 equiv.) in ACN (6 mL) was added KI (80.23 mg, 483.34 μmol, 1 equiv.), K2CO3 (200.41 mg, 1.45 mmol, 3 equiv.), and (3-bromopropoxy)(tert-butyl)dimethylsilane (979.25 mg, 3.87 mmol, 8 equiv.). The mixture was stirred at 70 °C for 12 h. The reaction mixture was diluted with DCM (30 mL) and stirred at 20 °C for 30 min. The mixture was then filtered. The filter cake was washed with DCM (10 mL × 3). The filtrate was concentrated and purified by preparative TLC (SiO2, petroleum ether / EtOAc = 3 / 1, Rf = 0.29) to give intermediate compound 16 (405 mg, 98% yield) as a colorless oil. LCMS (ESI position ion) m / z: 855.4 (M+H)+ (calculated: 854.5) 1H NMR:(400MHz,CDCl3)δ=7.30(s,2H),7.23(q,J=1.8Hz,2H),5.31(br s,1H),4.08(br s,2H),3.93-3.87(m,15H),3.65(t,J=6.2Hz,2H),3.08-2.89(m,4H),2.75-2.57(m,8 H),2.01-1.79(m,6H),1.68-1.61(m,2H),1.59(s,9H),0.91-0.86(m,9H),0.05(s,6H)

[0503] Intermediate compound 17: [ka] A solution of intermediate compound 16 (400 mg, 467.79 μmol, 1 equiv) in HCl / dioxane (4 M, 40.00 mL, 342.03 equiv) was stirred at 20° C. for 2 h. The reaction mixture was concentrated and purified by reverse-phase HPLC (column: Phenomenex Synergi C18 150 × 25 × 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 38%–68%, 9 min) to give intermediate compound 17 (285 mg, 89% yield) as an off-white solid. LCMS (ESI position ion) m / z: 685.3 (M+H)+ (calculated: 684.3) 1H NMR:(400MHz,CDCl3)δ=7.21(d,J=6.9Hz,4H),5.25(br s,1H),4.05(br s,2H),3.84(s,15H),3.77(t,J=5.4Hz,2H),3.02-2.89(m,4H),2.73-2.58(m,8H),1.89-1.72(m,6H),1.65(quartet,J=5.6Hz,2H)

[0504] Intermediate compound 18: [ka] To a solution of intermediate compound 6 (500 mg, 610.42 μmol, 1 equiv) in THF (8 mL), MeOH (8 mL), and HO (8 mL) was added NaOH (244.15 mg, 6.10 mmol) at 0° C. under N. The reaction mixture was stirred at 15° C. for 1 h. The reaction was concentrated in vacuo, and the solution was extracted with ethyl acetate (3×20 mL). The organic layers were combined, washed with water (20 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by preparative HPLC to give intermediate 18 (65 mg, 11.5% yield) as a yellow oil.

[0505] Intermediate compound 19: [ka] To a solution of intermediate compound 18 (96 mg, 153.63 μmol) in DCM (5 mL) was added TEA (46.62 mg, 406.86 μmol) and mesyl chloride (26.4 mg, 230.43 μmol) at 0° C. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with ice water (10 mL) and extracted with dichloromethane (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo to give crude intermediate compound 19 (80 mg) as a yellow oil, which was used without further purification.

[0506] Intermediate compound 20: [ka] To a solution of intermediate compound 19 (80 mg, 113.76 μmol, 1 equiv) in ethanol (1 mL) was added NH4OH (0.3 mL, 30% purity) at 20° C., and the mixture was stirred at 60° C. for 12 h. The reaction was concentrated under reduced pressure to give crude intermediate compound 20 (70 mg) as a yellow oil, which was used without further purification.

[0507] Intermediate compound 21: [ka] To a solution of intermediate compound 1 (28.56 mg, 113.76 μmol, 1.1 equiv) in DCM (1 mL) was added TEA (68.11 mg, 673.12 μmol), EDCI (53.76 mg, 280.49 μmol), and HOAt (30.52 mg, 224.35 μmol) at 0° C. The mixture was stirred at 0° C. for 5 minutes. Then, intermediate compound 20 (70 mg, 112.21 μmol, 1 equiv) was added. The mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated in vacuo to give crude intermediate 21 (160 mg, crude) as a yellow oil, which was used without further purification. Intermediate compound 22: [ka] To a solution of intermediate compound 21 (100 mg, 122.2 μmol) in DCM (5 mL) was added TFA (1.5 mL, 20.3 mmol) at 0° C. The mixture was stirred at 20° C. for 5 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give intermediate compound 22 (41.0 mg, 48% yield) as a yellow oil. LCMS (ESI position ion) m / z: 648.3 (M+H)+ (calculated: 647.3)

[0508] Intermediate compound 23: [ka] To a solution of benzyl 1,4-diazepane-1-carboxylate (2000 mg, 8.54 mmol, 1.77 mL) in ACN (30 mL), tert-butyl (3-bromopropyl)carbamate (2.03 g, 8.54 mmol), KI (283.41 mg, 1.71 mmol), and DIPEA (2.21 g, 17.07 mmol, 2.97 mL) were added and stirred at 100 °C for 12 h, still resulting in a white suspension. The mixture was concentrated directly and poured into HO (30 mL). It was then extracted with DCM (40 mL × 2), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica column chromatography (from EtOAc to 10:1 EtOAc / MeOH) to give intermediate compound 23 (2.7 g, 81% yield) as a yellow oil. LCMS (ESI position ion) m / z: 392.3 (M+H)+ (calculated: 391.2) Intermediate compound 24: [ka] To a mixture of intermediate compound 23 (1.5 g, 3.83 mmol, 1 equiv.) in MeOH (10 mL) was added Pd / C (2 g, 3.83 mmol, 10% purity, 1 equiv.) under 20 psi H atmosphere and stirred at 25° C. for 12 h. The mixture was directly filtered through Celite, and the filtrate was concentrated in vacuo to give crude intermediate compound 24 (750 mg, 76% yield) as a yellow oil. 1H NMR(400MHz,CD3OD-d4)δ3.08(t,J=6.8Hz,2H),2.97-2.90(m,4H),2.75-2.69 (m,4H),2.58-2.52(m,2H),1.86-1.79(m,2H),1.70-1.61(m,2H),1.43(s,9H)

[0509] Intermediate compound 25: [ka] To a solution of intermediate compound 8 (1.7 g, 2.65 mmol, 1 equiv.) and intermediate compound 24 (748.84 mg, 2.91 mmol, 1.1 equiv.) in MeCN (20 mL) was added KI (439.08 mg, 2.65 mmol, 1 equiv.) and K2CO3 (1.83 g, 13.23 mmol, 5 equiv.). The mixture was stirred at 60 °C for 12 h. The reaction mixture was diluted with HO (100 mL) and then extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with petroleum ether / EtOAc (1 / 1) to DCM / MeOH (10 / 1) to give intermediate compound 25 (2 g, 94% yield) as a yellow oil. LCMS (ESI position ion) m / z: 804.3 (M+H)+ (calculated: 803.5) 1H NMR(400MHz,CDCl3-d)δ7.31(s,2H),7.22(s,2H),5.38-5.27(m,1H),4.12-4.09(m,2H),3.89-3.85(m,9H),3.84(d,J=4.4Hz,6H), 3.09(t,J=6.7Hz,2H),2.91-2.76(m,8H),2.73-2.61(m,4H),2.02-1.82(m,8H),1.70(quartet,J=7.1Hz,2H),1.59(s,9H),1.44(s,9H).

[0510] Intermediate compound 26: [ka] To a solution of intermediate compound 25 (500 mg, 621.91 umol, 1 equiv.) was added HCl / dioxane (4 M, 155.48 uL, 1 equiv.). The reaction was stirred at 25° C. for 12 hours. The reaction mixture was concentrated in vacuo to give crude intermediate compound 26 (380 mg, 94% yield) as a yellow solid. LCMS (ESI position ion) m / z: 648.2 (M+H)+ (calculated: 647.3) 1H NMR(400MHz,CD3OD-d4)δ7.19(s,2H),7.18-7.16(m,2H),5.25-5.15(m,1H),4.05-3.99(m,2 H),3.77-3.75(m,9H),3.72(d,J=2.9Hz,10H),3.52-3.40(m,4H),3.31-3.24(m,2H),3.23(br s,1H),3.19(br s,1H),2.93(t,J=7.6Hz,2H),2.25(br s,2H),2.20-2.12(m,2H),2.08-1.98(m,2H),1.96-1.91(m,2H),1.89-1.81(m,2H).

[0511] Intermediate compound 27: [ka] To a solution of tert-butyl N-(3-hydroxypropyl)-N-methyl-carbamate (2 g, 10.57 mmol, 1 equiv.) in DCM (20 mL) was added triphenylphosphine (4.16 g, 15.85 mmol, 1.5 equiv.) at 0 °C, followed by tetrabromomethane (5.26 g, 15.85 mmol, 1.5 equiv.) and stirring for 30 min. The mixture was concentrated in vacuo. The residue was purified by silica column chromatography (petroleum ether / EtOAc = 10 / 1 to 5 / 1) to give intermediate compound 27 (2 g, 75% yield) as a yellow liquid. LCMS (ESI position ion) m / z: 195.7 (M+H-56)+ (calculated: 251.05) 1H NMR (400MHz, chloroform-d) δ 3.41-3.37 (m, 2H), 3.36-3.31 (m, 2H), 2.86 (s, 3H), 2.11-2.03 (m, 2H), 1.45 (s, 9H)

[0512] Intermediate compound 28: [ka] To a solution of intermediate compound 27 (753.34 mg, 2.99 mmol, 1.4 equiv.) and benzyl 1,4-diazepane-1-carboxylate (500 mg, 2.13 mmol, 1 equiv.) in MeCN (30 mL) was added KI (70.85 mg, 426.82 mmol, 0.2 equiv.) and DIPEA (551.63 mg, 4.27 mmol, 2 equiv.), and the reaction mixture was stirred at 100 °C for 12 h. The mixture was concentrated in vacuo and poured into HO (30 mL). It was then extracted with EtOAc (30 mL × 3) and concentrated in vacuo. The residue was purified by silica column chromatography (from EtOAc to DCM / MeOH = 20 / 1) to give intermediate compound 28 (800 mg, 92% yield) as a brown liquid. LCMS (ESI position ion) m / z: 406.1 (M+H)+ (calculated: 405.3) 1H NMR (400MHz, methanol-d4) δ7.41-7.27(m,5H),5.16-5.09(m,2H),3.60-3.51(m,4H),3.27-3.21(m,2H),2.84(br s,3H),2.81-2.65(m,4H),2.61-2.45(m,2H),1.91-1.82(m,2H),1.79-1.67(m,2H),1.45(d,J=1.8Hz,9H)

[0513] Intermediate compound 29: [ka] To a mixture of intermediate compound 28 (800 mg, 1.97 mmol, 1 equiv) in MeOH (15 mL) was added Pd / C (800 mg, 1.97 mmol, 10% purity, 1.00 equiv) under H (25 psi) and stirred at 30° C. for 12 h. The mixture was filtered and concentrated in vacuo to give intermediate compound 29 (500 mg, 93% yield) as a brown liquid. 1H NMR(400MHz,MeOD-d4)δ3.31-3.26(m,2H),2.97-2.92(m,4H),2.98-2.91(m,3 H),2.96-2.91(m,4H),2.56-2.49(m,2H),1.89-1.72(m,4H),1.49-1.45(m,9H)

[0514] Intermediate compound 30: [ka] To a mixture of intermediate compound 8 (900 mg, 1.40 mmol, 1 equiv.) and intermediate compound 29 (500 mg, 1.84 mmol, 1.32 equiv.) in MeCN (30 mL) was added KI (232.46 mg, 1.40 mmol, 1 equiv.) and KCO (967.66 mg, 7.00 mmol, 5 equiv.), and the reaction mixture was stirred at 60 °C for 12 h. The mixture was poured into HO (30 mL) and extracted with EtOAc (30 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica column chromatography (DCM / MeOH = 10 / 1) to give intermediate compound 30 (1 g, 87% yield) as a yellow liquid. LCMS (ESI position ion) m / z: 818.5 (M+H)+ (calculated: 817.5) 1H NMR (400MHz, methanol-d4)δ=7.29(s,2H),7.20(s,2H),5.31-5.25(m,1H),4.12-4.06(m,2H), 3.87-3.84(m,9H),3.82(d,J=4.0Hz,6H),3.23(t,J=7.1Hz,2H),2.87-2.81(m,3H),2.74(br s,8H),2.62(br t,J=7.2Hz,2H),2.54-2.43(m,2H),2.05-1.86(m,6H),1.85-1.77(m,2H),1.75-1.66(m,2H),1.57(s,9H),1.45(s,9H)

[0515] Intermediate compound 31: [ka] A solution of intermediate compound 30 (950 mg, 1.16 mmol, 1 equiv) in HCl / dioxane (4 M, 10 mL, 34.44 equiv) was stirred for 2 h at 25° C. The reaction was concentrated in vacuo to give intermediate compound 31 (700 mg, 91% yield) as a yellow solid. LCMS (ESI position ion) m / z: 662.3 (M+H)+ (calculated: 661.4) 1H NMR(400MHz,MeOD-d4)δ7.29(s,2H),7.20(s,2H),5.31-5.25(m,1H),4.12-4.06(m,2H),3 .87-3.84(m,9H),3.82(d,J=4.0Hz,6H),3.23(t,J=7.1Hz,2H),2.87-2.81(m,3H),2.74(br s,8H),2.62(br t,J=7.2Hz,2H),2.54-2.43(m,2H),2.05-1.86(m,6H),1.85-1.77(m,2H),1.75-1.66(m,2H)

[0516] Intermediate compound 32: [ka] To a stirred solution of (2R,3S)-2-(hydroxymethyl)-5-methoxytetrahydrofuran-3-ol (19 g, 128.24 mmol, 1 equiv.) in anhydrous THF (650 mL) at 25 °C, triphenylphosphine (50.45 g, 192.36 mmol, 1.5 equiv.) was added, followed by imidazole (17.46 g, 256.49 mmol, 2 equiv.), and the resulting mixture was stirred at 80 °C for 0.5 h. After cooling to 25 °C, a solution of I2 (48.82 g, 192.36 mmol, 1.5 equiv.) in anhydrous THF (190 mL) was slowly added, and the resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered. The filter cake was washed with EtOAc (500 mL), and the combined filtrates were concentrated in vacuo to remove the solvent. The residue was purified by column chromatography on silica gel eluted with (petroleum ether / ethyl acetate=10 / 1 to 3 / 1) to give intermediate compound 32 (23.2 g, 56% yield) as a pale yellow oil. 1H NMR(400MHz,DMSO-d6)δ5.26-5.15(m,1H),5.06-4.92(m,1H),4.17-4.10(m,0.5H),3.85- 3.77(m,1H),3.56(dt,J=3.8,5.8Hz,0.5H),3.51-3.45(m,0.5H),3.34-3.28(m,1H),3.26 (d,J=3.0Hz,3H),3.21(dd,J=7.3,10.3Hz,0.5H),2.40(ddd,J=5.8,8.3,13.8Hz,0.5H),2 .16-2.07(m,0.5H),1.95(td,J=5.6,13.4Hz,0.5H),1.69(ddd,J=2.6,5.3,13.6Hz,0.5H).

[0517] Intermediate compound 33: [ka] To a stirred solution of intermediate compound 32 (23.19 g, 89.88 mmol) in EtOH (350 mL) at 25 °C, Zn (49.07 g, 750.42 mmol), tert-butyl 1,4-diazepane-1-carboxylate (15 g, 74.90 mmol, 14.71 mL, 1 equiv.) in EtOH (90 mL), NaBHCN (11.77 g, 187.24 mmol), and AcOH (5.40 g, 89.88 mmol, 5.14 mL) were added sequentially, and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated aqueous NaHCO (1000 mL) and stirred for 30 min. After dilution with EtOAc (500 mL), the mixture was filtered through Celite, and the cake was washed with EtOAc (200 mL). The aqueous layer was extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give crude intermediate compound 33 (27 g) as a pale yellow oil. 1H NMR(400MHz,CDCl3-d)δ5.89(ddd,J=5.0,10.5,17.1Hz,1H),5.36-5.27(m,1H),5.13(td,J=1.6,10.5Hz,1H),4.38( dtd,J=1.7,3.3,8.0Hz,1H),3.57-3.43(m,4H),2.86-2.61(m,6H),1.97-1.83(m,2H),1.80-1.59(m,2H),1.48(s,9H)

[0518] Intermediate compound 34: [ka] A mixture of intermediate compound 33 (5 g, 17.58 mmol, 1 equiv) in HCl / MeOH (4 M, 4.40 mL, 1 equiv) was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo to give crude intermediate compound 34 (4.50 g) as a yellow oil. LCMS (ESI position ion) m / z: 185.1 (M+H)+ (calculated: 184.2) 1H NMR(400MHz,MeOD-d4)δ5.93(ddd,J=5.6,10.6,17.2Hz,1H),5.37-5.31(m,1H),5.18(td,J=1.3,10.5Hz,1 H),4.27(qd,J=4.2,5.5Hz,1H),4.13-3.55(m,6H),3.51-3.38(m,4H),2.42-2.30(m,2H),2.13-1.92(m,2H)

[0519] Intermediate compound 35: [ka] To a solution of methyl 3-hydroxy-4,5-dimethoxybenzoate (4 g, 18.85 mmol, 1 equiv.) and pyridine (2.98 g, 37.70 mmol, 2 equiv.) in DCM (50 mL) was added trifluoromethanesulfonic anhydride (7.98 g, 28.28 mmol, 1.5 equiv.) dropwise at 0 °C under a N atmosphere. The reaction was then warmed to 25 °C and stirred for 12 h. The reaction mixture was diluted with water (100 mL) and then extracted with DCM (2 × 40 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether / EtOAc = 93 / 7) to give intermediate compound 35 (6.36 g, 98% yield) as a yellow oil. LCMS (ESI position ion) m / z: 345.2 (M+H)+ (calculated: 344.0)

[0520] Intermediate compound 36: [ka] To a solution of intermediate compound 35 (100 mg, 290.48 μmol, 1 equiv.) and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (244.06 mg, 1.45 mmol, 5 equiv.) in dioxane (4 mL) and HO (1.3 mL) was added Pd(dppf)Cl.CHCl (23.72 mg, 29.05 μmol, 0.1 equiv.) and KPO (308.29 mg, 1.45 mmol, 5 equiv.). The mixture was degassed with N three times and then stirred at 80 °C for 2 h under a N atmosphere. The reaction mixture was filtered, and the filter cake was washed with EtOAc (50 mL). The filtrate was diluted with water (100 mL) and then extracted with ethyl acetate (40 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified on silica gel eluted with (petroleum ether / Et0Ac=95 / 5) to give intermediate compound 36 (2.3 g) as a pale yellow oil. LCMS (ESI position ion) m / z: 237.2 (M+H)+ (calculated: 236.1) 1H NMR(400MHz,CDCl3-d)δ7.44(d,J=2.0Hz,1H),7.40(d,J=1.9Hz,1H),5.95-5.83(m,1H),5.01(m ,1H),4.98(qd,J=1.5,7.4Hz,1H),3.83(s,3H),3.82(s,3H),3.79(s,3H),3.35(d,J=6.6Hz,2H).

[0521] Intermediate compound 37: [ka] To a solution of intermediate compound 36 (1.1 g, 4.66 mmol) in THF (9 mL) and HO (3 mL) was added NaOH (372.44 mg, 18.62 mmol, 4 equiv.). The reaction was stirred at 25 °C for 12 h. The reaction solution was diluted with HO (50 mL) and extracted with EtOAc (20 mL). The organic layer was discarded. The aqueous phase was acidified to pH = 2 with 1 M aqueous HCl and then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo to give intermediate compound 37 (440 mg, 42% yield) as a brown solid. LCMS (ESI position ion) m / z: 223.0 (M+H)+ (calculated: 222.1) 1H NMR (400MHz, CD3OD-d4) δ7.54-7.50(m,2H),6.03-5.92(m,1H),5.08-5.02(m,2H),3.91(s,3H),3.86(s,3H),3.42(d,J=6.5Hz,2H).

[0522] Intermediate compound 38: [ka] To a solution of tert-butyl N-(3-bromopropyl)carbamate (4.17 g, 17.50 mmol, 1 equiv.) and intermediate compound 34 (4.5 g, 17.50 mmol, 1 equiv., 2HCl) in ACN (45 mL), TEA (17.70 g, 174.96 mmol, 24.35 mL, 10 equiv.) was added and stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified on silica gel (DCM / methanol = 10 / 1 to 5 / 1, Rf = 0.5) to give intermediate compound 38 (3.2 g, 54% yield) as a brown oil. 1H NMR(400MHz,MeOD-d4)δ=5.89(ddd,J=5.8,10.5,17.2Hz,1H),5.26(td,J=1.6,17.3Hz,1H),5.11(td,J=1.5,10.5Hz,1H),4.22-4.1 6(m,1H),3.09(t,J=6.8Hz,2H),2.87-2.72(m,10H),2.60-2.55(m,2H),1.88(td,J=5.9,11.7Hz,2H),1.76-1.64(m,4H),1.45(s,9H)

[0523] Intermediate compound 39: [ka] A mixture of intermediate compound 38 (3.2 g, 9.37 mmol, 1 equiv) in HCl / MeOH (4 M, 106.66 mL, 45.53 equiv) was stirred for 1 h at 25° C. The reaction was concentrated in vacuo to give intermediate 39 (2.7 g, 82% yield) as an off-white solid. 1H NMR (400MHz, methanol-d4)δ=1.87-2.11(m,2H) 2.17-2.29(m,2H) 2.32-2.53(m,2H) 3.05-3.16(m,2H) 3.37-3.55(m,5H) 3.61-4.06(m,6H) 4.22-4.32(m,1H) 5.19-5.25(m,1H) 5.29-5.40(m,1H) 5.87-5.99(m,1H)

[0524] Intermediate compound 40: [ka] To a mixture of intermediate compound 39 (473.49 mg, 1.35 mmol, 1.2 equiv, 3HCl), intermediate compound 37 (250 mg, 1.12 mmol, 1 equiv), and DIPEA (581.56 mg, 4.50 mmol, 4 equiv) in DMF (7.5 mL) was added HATU (641.60 mg, 1.69 mmol, 1.5 equiv). The reaction was stirred at 25 °C for 10 min. The reaction mixture was concentrated in vacuo. The residue was purified by reverse-phase chromatography to give intermediate compound 40 (580 mg, 93% yield) as an off-white solid. LCMS (ESI position ion) m / z: 446.4 (M+H)+ (calculated: 445.3) 1H NMR(400MHz,MeOD-d4)δ7.44(d,J=2.1Hz,1H),7.37-7.35(m,1H),6.08-5.84(m,2H),5.40-5.29(m,1H),5.24-5.15(m,1H),5.12 -5.01(m,2H),4.31-4.24(m,1H),4.08-3.71(m,15H),3.59-3.37(m,9H),2.89-2.80(m,5H),2.48-2.34(m,2H),2.19-1.90(m,5H)

[0525] Intermediate compound 41: [ka] To a solution of intermediate compound 40 (480 mg, 1.08 mmol, 1 equiv.) in DCM (270 mL) was added [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium (135.00 mg, 215.44 μmol, 0.2 equiv.). The reaction mixture was degassed with N2 three times and then stirred at 25 °C for 48 h under a N2 atmosphere. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (Column: Waters Xbridge 150 × 25 mm × 5 μm; Mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 12%–42%, 9 min) to give intermediate compound 41 (12 mg, 3% yield) as an off-white solid. LCMS (ESI position ion) m / z: 418.2 (M+H)+ (calculated: 417.3) 1H NMR(400MHz,MeOD-d4)δ7.39-7.35(m,1H),7.27-7.23(m,1H),5.90-5.79(m,1H),5.52-5.40(m,1H),4 .16-4.06(m,1H),3.93(s,3H),3.88(s,3H),3.60-3.38(m,5H),2.88-2.30(m,10H),1.86-1.66(m,7H)

[0526] Intermediate compound 42: [ka] To a solution of intermediate compound 41 (10 mg, 23.95 μmol, 1 equiv.) in MeOH (1 mL) was added aqueous Pd / C (23.95 μmol, 10% purity) under a H balloon (15 psi). The reaction was stirred at 25° C. for 0.5 h under a H balloon (15 psi). The mixture was filtered, and the filtrate was concentrated in vacuo to give crude intermediate compound 42 (10 mg) as an off-white solid. LCMS (ESI position ion) m / z: 420.2 (M+H)+ (calculated: 419.3)

[0527] Intermediate compound 43: [ka] A mixture of 6-bromo-4-chloro-1H-indazole (4.5 g, 19.44 mmol, 1 equiv.), Pd(dppf)Cl.CHCl (1.59 g, 1.94 mmol, 0.1 equiv.), and TEA (3.93 g, 38.88 mmol, 5.41 mL, 2 equiv.) in MeOH (100 mL) was stirred at 80 °C for 12 h under 50 psi of CO (194.40 mmol, 10 equiv.). The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica (petroleum ether / ethyl acetate = 5 / 1) to give intermediate compound 43 (3.3 g, 80% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ13.74-13.95(m,1H) 8.28(s,1H) 8.15(s,1H) 7.67(s,1H) 3.91(s,3H)

[0528] Intermediate compound 44: [ka] A mixture of intermediate compound 43 (3.3 g, 15.67 mmol, 1 equiv.) and LiOH (1.13 g, 47.00 mmol, 3 equiv.) in MeOH (30 mL) and HO (6 mL) was stirred at 50° C. for 12 h. The reaction mixture was acidified to pH 5 with 1 N HCl, and then the mixture was concentrated in vacuo to give a yellow solid. The yellow solid was triturated with water (100 mL), filtered, and the filter cake was dried in vacuo to give intermediate compound 44 (3 g, 97% yield) as a white solid. LCMS (ESI position ion) m / z: 195.0 (M+H)+ (calculated: 196.0)

[0529] Intermediate compound 45: [ka] A mixture of intermediate compound 44 (3 g, 15.26 mmol, 1 equiv.) and tert-butyl (E)-N,N'-diisopropylcarbamate (12.23 g, 61.04 mmol, 4 equiv.) in toluene (50 mL) was stirred at 80 °C for 48 h under a N atmosphere. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (3 × 30 mL), and the combined organic phases were concentrated to dryness in vacuo. The residue was purified by column chromatography on silica (petroleum ether / ethyl acetate = 5 / 1) to give intermediate compound 45 (1.3 g, 34% yield) as a yellow solid. 1H NMR(400MHz,CDCl3-d)δ10.35-10.49(m,1H) 8.21(s,1H) 8.11(s,1H) 7.78(s,1H) 1.64(s,9H)

[0530] Intermediate compound 46: [ka] To a mixture of intermediate compound 5 (4 g, 9.04 mmol, 1 equiv.), TEA (1.83 g, 18.07 mmol, 2.52 mL, 2 equiv.), and DMAP (220.81 mg, 1.81 mmol, 0.2 equiv.) in DCM (50 mL) was added 4-toluenesulfonyl chloride (2.58 g, 13.56 mmol, 1.5 equiv.), and the reaction mixture was stirred at 30 °C for 12 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 30 mL), and the combined organic phases were concentrated to dryness under vacuum. The residue was purified by column chromatography on silica (petroleum ether / ethyl acetate = 3 / 1) to give intermediate compound 46 (3.7 g, 67% yield) as a yellow oil. LCMS (ESI position ion) m / z: 597.3 (M+H)+ (calculated: 596.2) 1H NMR(400MHz,CDCl3-d)δ7.77(d,J=8.31Hz,2H) 7.33(d,J=7.95Hz,2H) 7.26(s,2H) 5.15-5.26(m,1H) 4.03-4.07(m,2H) 3.92(s,3H) 3.64-3.72(m,2H) 2.42-2.46(m,3H) 1.81-1.99(m,2H) 1.70-1.80(m,4H) 0.87(s,9H) 0.01(s,6H)

[0531] Intermediate Compound 47 and Intermediate Compound 48: [ka] A mixture of intermediate compound 45 (1.3 g, 5.14 mmol, 1 equiv.), intermediate compound 46 (3.7 g, 6.20 mmol, 1.21 equiv.), KI (1.71 g, 10.29 mmol, 2 equiv.), and KCO (2.13 g, 15.43 mmol, 3 equiv.) in MeCN (20 mL) was stirred at 60 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography on silica (petroleum ether / ethyl acetate = 5 / 1) to give intermediate compound 47 (2 g, 2.95 mmol, 57% yield) as a yellow oil and intermediate compound 48 (1.3 g, 37% yield) as a yellow oil. Intermediate compound 47: 1H NMR(400MHz,CDCl3-d)δ8.08(s,1H) 8.03(s,1H) 7.71(s,1H) 5.24-5.34(m,1H) 4.47(t,J=6.94Hz,2H) 3.87-3.93(m,9H) 3.67(t,J=6.19Hz,2H) 2.02-2.10(m,2H) 1.82-1.97(m,2H) 1.71-1.79(m,2H) 1.64(s,9H) 0.85(s,9H)-0.01(s,6H) Intermediate compound 48: LCMS (ESI position ion) m / z: 677.6 (M+H)+ (calculated: 596.2) 1H NMR(400MHz,CDCl3-d)δ8.32(s,1H) 8.00(s,1H) 7.65(d,J=0.75Hz,1H) 5.28-5.36(m,1H) 4.50(t,J=6.94Hz,2H) 3.86-3.94(m,9H) 3.63-3.71(m,2H) 2.06-2.24(m,2H) 1.82-1.97(m,2H) 1.76(br d,J=6.88Hz,2H) 1.61(s,9H) 0.85(s,9H)-0.01(s,6H)

[0532] Intermediate compound 49: [ka] Intermediate compound 47 (1.9 g, 2.81 mmol, 1 equiv) and NHF (1.04 g, 28.05 mmol, 10 equiv) in MeOH (30 mL) were stirred at 80 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL), filtered, and the filtrate was concentrated in vacuo to give crude intermediate compound 49 (1.57 g, 99% yield) as a yellow oil. LCMS (ESI position ion) m / z: 563.2 (M+H)+ (calculated: 562.2)

[0533] Intermediate compound 50: [ka] To a solution of intermediate compound 49 (1.65 g, 2.93 mmol, 1 equiv.) and TEA (889.61 mg, 8.79 mmol, 1.22 mL, 3 equiv.) in DCM (30 mL) was slowly added methanesulfonyl chloride (671.39 mg, 5.86 mmol, 453.64 μL, 2 equiv.) at 0° C., and the reaction mixture was then stirred at 20° C. for 2 h. The reaction mixture was poured into a saturated aqueous solution of NaHCO (20 mL) at 0° C. and extracted with dichloromethane (3×20 mL). The combined organic phases were concentrated to dryness in vacuo to give crude intermediate compound 50 (1.4 g, 74% yield) as a brown oil, which was used without further purification.

[0534] Intermediate compound 51: [ka] A mixture of intermediate compound 50 (500 mg, 779.88 μmol, 1 equiv.), intermediate compound 24 (301.08 mg, 1.17 mmol, 1.5 equiv.), KCO (323.35 mg, 2.34 mmol, 3 equiv.), and KI (258.92 mg, 1.56 mmol, 2 equiv.) in MeCN (10 mL) was stirred at 60 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 × 25 × 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 38%–68%, 9 min) to give intermediate compound 51 (200 mg, 32% yield) as a brown oil. LCMS (ESI position ion) m / z: 802.3 (M+H)+ (calculated: 801.4)

[0535] Intermediate compound 52: [ka] A mixture of intermediate compound 51 (200 mg, 249.25 μmol, 1 equiv) in HCl / dioxane (4 M, 5 mL, 80.24 equiv) was stirred for 1 h at 30° C. The reaction mixture was concentrated in vacuo to give crude intermediate compound 51 (130 mg, 76% yield, HCl) as a brown solid, which was used without further purification. LCMS (ESI position ion) m / z: 646.5 (M+H)+ (calculated: 645.3)

[0536] Intermediate compound 53: [ka] Intermediate compound 48 (1.2 g, 1.77 mmol, 1 equiv) and NHF (656.20 mg, 17.72 mmol, 10 equiv) in MeOH (20 mL) were stirred at 80 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was dissolved in ethyl acetate (30 mL), filtered, and the filtrate was concentrated in vacuo to give crude intermediate compound 53 (970 mg, 99% yield) as a yellow oil. LCMS (ESI position ion) m / z: 563.2 (M+H)+ (calculated: 662.2)

[0537] Intermediate compound 54: [ka] To a solution of intermediate compound 53 (1.05 g, 1.91 mmol, 1 equiv.) and TEA (580.59 mg, 5.74 mmol, 798.61 uL, 3 equiv.) in DCM (30 mL) was slowly added methanesulfonyl chloride (438.16 mg, 3.83 mmol, 296.05 uL, 2 equiv.) at 0 °C, and the reaction mixture was then stirred at 20 °C for 2 h. The reaction mixture was poured into a saturated aqueous solution of NaHCO (20 mL) at 0 °C and extracted with DCM (20 mL × 3). The combined organic phases were dried over NaSO and concentrated in vacuo to give intermediate compound 54 (1.2 g, 98% yield) as a brown oil, which was used without further purification. LCMS (ESI position ion) m / z: 541.5 (M+H-100)+ (calculated: 640.2) Intermediate compound 55: [ka] A mixture of intermediate compound 54 (500.00 mg, 779.88 μmol, 1 equiv.), intermediate compound 24 (301.08 mg, 1.17 mmol, 1.5 equiv.), KCO (323.35 mg, 2.34 mmol, 3 equiv.), and KI (258.92 mg, 1.56 mmol, 2 equiv.) in MeCN (10 mL) was stirred at 60° C. for 12 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (water (0.225% FA)-MeCN, 50%) to give intermediate compound 55 (300 mg, 48% yield) as a brown oil. LCMS (ESI position ion) m / z: 802.3 (M+H)+ (calculated: 801.4)

[0538] Intermediate compound 56: [ka] A mixture of intermediate compound 55 (300.00 mg, 373.88 umol, 1 equiv) in HCl / dioxane (4 M, 5.00 mL, 53.49 equiv) was stirred for 6 h at 30° C. The reaction mixture was concentrated in vacuo to give intermediate compound 56 (250 mg, 98% yield, HCl) as a brown solid, which was used without further purification. LCMS (ESI position ion) m / z: 646.2 (M+H)+ (calculated: 645.3)

[0539] Intermediate compound 57: [ka] To a solution of compound 3-hydroxybenzoic acid (0.2 g, 1.45 mmol, 1 equiv.) in toluene (2 mL), 1,1-ditert-butoxy-N,N-dimethyl-methanamine (294.41 mg, 1.45 mmol, 347.18 μL, 1 equiv.) was added, and the mixture was then stirred at 105 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 100 / 1 to 3 / 1) to give intermediate compound 57 (0.1 g, 35% yield) as a colorless oil. 1H NMR(400MHz,CDCl3-d)δ=7.66-7.52(m,2H),7.33(s,1H),7.10-7.01(m,1H),6.27-5.79(m,1H),1.66-1.58(m,9H)

[0540] Intermediate compound 58: [ka] To a solution of intermediate compound 5 (0.7 g, 1.58 mmol, 1 equiv.), intermediate compound 57 (307.17 mg, 1.58 mmol, 1 equiv.), and triphenylphosphine (746.65 mg, 2.85 mmol, 1.8 equiv.) in toluene (30 mL) was added DEAD (413.14 mg, 2.37 mmol, 431.25 μL, 1.5 equiv.) at 0° C. The mixture was stirred at 115° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 100 / 1 to 10 / 1) to give intermediate compound 58 (0.4 g, 41% yield) as a colorless oil. LCMS (ESI position ion) m / z: 641.2 (M+Na+)+ (calculated: 618.3)

[0541] Intermediate compound 59: [ka] To a solution of intermediate compound 58 (430 mg, 694.86 μmol, 1 equiv.) in MeOH (1 mL) was added NHF (514.71 mg, 13.90 mmol, 20 equiv.), and the mixture was then stirred at 75° C. for 2 h. The residue was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 10 / 1 to 3 / 1) to give intermediate compound 59 (450 mg) as a colorless oil. LCMS (ESI position ion) m / z: 627.1 (M+Na+)+ (calculated: 504.2)

[0542] Intermediate compound 60: [ka] To a solution of intermediate compound 59 (450 mg, 891.85 μmol, 1 equiv) and TEA (360.98 mg, 3.57 mmol, 496.54 μL, 4 equiv) in DCM (5 mL) was added methanesulfonyl chloride (306.49 mg, 2.68 mmol, 207.09 μL, 3 equiv) dropwise at 0° C. The mixture was stirred at 0° C. for 2 h. The mixture was slowly quenched with ice water (30 mL) and then extracted with DCM (40 mL × 3). The combined organic phase was washed with brine (60 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo to give crude intermediate compound 60 (500 mg) as a yellow oil. LCMS (ESI position ion) m / z: 605.1 (M+Na+)+ (calculated: 582.2)

[0543] Intermediate compound 61: [ka] To a solution of compound 60 (500 mg, 858.14 μmol, 1 equiv.) and 3-(1,4-diazepan-1-yl)propan-1-ol (167.08 mg, 858.14 μmol, 1 equiv., HCl) in CHCN (15 mL) was added KCO (355.80 mg, 2.57 mmol, 3 equiv.) and KI (142.45 mg, 858.14 μmol, 1 equiv.), and the mixture was then stirred at 65° C. for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give crude intermediate compound 61 (500 mg, crude) as a yellow oil. LCMS (ESI position ion) m / z: 645.3 (M+Na+)+ (calculated: 644.3)

[0544] Intermediate compound 62: [ka] A solution of compound 61 (400 mg, 620.35 μmol, 1 equiv.) in HCl / dioxane (4 M, 40.00 mL, 257.92 equiv.) was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column: Phenomenex Synergi C18 150 × 25 × 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 38% to 68%, 9 min) to give intermediate compound 62 (350 mg) as a red solid. LCMS (ESI position ion) m / z: 589.2 (M+H+)+ (calculated: 588.3)

[0545] Intermediate compound 63: [ka] To a solution of 3-((tert-butyldimethylsilyl)oxy)propan-1-ol (10 g, 52.53 mmol, 1 equiv.) in CHCN (200 mL), 2-iodoxybenzoic acid (IBX) (14.71 g, 52.53 mmol, 1 equiv.) was added, and the mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (petroleum ether / EtOAc = 100 / 1 to 20 / 1) to give intermediate compound 63 (7 g, 71% yield) as a colorless oil. 1H NMR(400MHz,CDCl3-d)δ7.90(s,1H),3.98(t,J=6.0Hz,2H),2.60-2.56(m,2H),0.87(s,9H),0.05(s,6H)

[0546] Intermediate compound 64: [ka] Allylmagnesium bromide (1 M, 63.72 mL, 1.2 equiv.) was added dropwise to a solution of intermediate compound 63 (10 g, 53.10 mmol, 1 equiv.) in THF (60 mL) at 0 °C. The mixture was allowed to warm to 20 °C and stirred for 16 h. The reaction mixture was diluted with a saturated aqueous solution of NH4Cl (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (300 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (petroleum ether / EtOAC = 100 / 1 to 20 / 1) to give intermediate compound 64 (10 g, 82% yield) as a colorless oil. 1H NMR(400MHz,CDCl3-d)δ5.88-5.67(m,1H),5.09-4.96(m,2H),3.86-3.68(m,3H),3.27(d, J=2.0Hz,1H),2.23-2.11(m,2H),1.64-1.55(m,2H),0.84-0.81(m,9H),0.04-0.02(m,6H)

[0547] Intermediate compound 65: [ka] To a solution of intermediate compound 64 (1.20 g, 5.21 mmol, 1 equiv.) and benzoic acid (763.20 mg, 6.25 mmol, 1.2 equiv.) in THF (12 mL), DCC (1.61 g, 7.81 mmol, 1.5 equiv.) and DMAP (954.36 mg, 7.81 mmol, 1.5 equiv.) were added, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 5 / 1) to give intermediate compound 65 (1.46 g) as a colorless oil. LCMS (ESI position ion) m / z: 335.3 (M+H)+ (calculated: 334.2) 1H NMR(400MHz,CDCl3-d)δ8.04(dd,J=1.0,8.1Hz,2H),7.59-7.54(m,1H),7.47-7.41(m,2H),5.89-5.78(m,1H),5.34-5.27( m,1H),5.15-5.05(m,2H),3.76-3.70(m,2H),2.55-2.46(m,2H),1.99-1.89(m,2H),0.89-0.87(m,12H),0.03-0.01(m,6H).

[0548] Intermediate compound 66: [ka] To a solution of intermediate compound 65 (3 g, 8.97 mmol, 1 equiv.) in THF (50 mL) was slowly added BH THF (1 M, 35.87 mL, 4 equiv.) at 25 °C under a N atmosphere, and the reaction mixture was then stirred at 70 °C for 12 h. The reaction mixture was quenched with 2 N NaOH (20 mL, aq.) at 10 °C, and then HO (5.08 g, 44.84 mmol, 4.31 mL, 30% purity, 5 equiv.) was slowly added to the reaction mixture at 0 °C, and the resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with a saturated aqueous solution of NaSO (100 mL), extracted with EtOAc (3 × 50 mL), and the combined organic phases were concentrated to dryness in vacuo. The residue was purified by column chromatography on silica (SiO2, petroleum ether / EtOAc = 2 / 1) to give intermediate compound 66 (1.5 g, 47% yield) as a yellow oil. 1H NMR(400MHz,MeOD-d4)δppm 8.02(d,J=7.34Hz,2H) 7.55-7.65(m,1H) 7.42-7.52(m,2H) 5.22-5.40(m,1H) 3.68-3.80(m,2H) 3.54-3.60(m,2H) 1.89-1.97(m,2H) 1.76-1.84(m,2H) 1.58-1.67(m,2H) 0.87(s,9H) 0.00(d,J=4.77Hz,6H)

[0549] Intermediate compound 67: [ka] To a solution of intermediate compound 66 (500 mg, 1.42 mmol, 1 equiv.), intermediate compound 57 (287.14 mg, 1.48 mmol, 1.04 equiv.), and triphenylphosphine (503.81 mg, 1.92 mmol, 1.35 equiv.) in toluene (5 mL) was added DEAD (295.24 mg, 1.70 mmol, 308.18 μL, 1.20 equiv.) at 0 °C. The resulting mixture was stirred at 115 °C for 12 h under a N atmosphere. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica (SiO, petroleum ether / EtOAc = 20 / 1) to give intermediate compound 67 (259 mg) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ7.99(d,J=7.9Hz,2H),7.71-7.66(m,1H),7.55(t,J=7.5Hz,2H ),7.51-7.47(m,1H),7.44-7.38(m,2H),7.20-7.16(m,1H),5.33-5.22(m,1H),4.07(br t,J=5.4Hz,2H),3.74-3.69(m,2H),1.96-1.85(m,6H),1.57(s,9H),0.85(s,9H),0.01(d,J=5.1Hz,6H)

[0550] Intermediate compound 68: [ka] A solution of intermediate compound 67 (212 mg, 400.95 μmol, 1 equiv) and NHF (148.50 mg, 4.01 mmol, 10 equiv) in MeOH (4.2 mL) was stirred at 80° C. for 2 h. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate (10 mL) and filtered. The filtrate was concentrated under reduced pressure to give crude intermediate compound 68 (227 mg) as a colorless oil. LCMS (ESI position ion) m / z: 437.1 (M+Na+)+ (calculated: 414.2)

[0551] Intermediate compound 69: [ka] To a mixture of intermediate compound 68 (1.9 g, 4.58 mmol, 1 equiv.) and TEA (1.39 g, 13.75 mmol, 1.91 mL, 3 equiv.) in DCM (20 mL) at 0 °C, methanesulfonyl chloride (1.05 g, 9.17 mmol, 709.59 μL, 2 equiv.) was slowly added. The reaction mixture was then stirred at 20 °C for 2 h. The reaction mixture was poured into a saturated aqueous solution of NaHCO (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were concentrated to dryness in vacuo to give crude intermediate compound 69 (2.2 g) as a yellow oil, which was used without further purification.

[0552] Intermediate compound 70: [ka] To a solution of intermediate compound 69 (250 mg, 507.53 μmol, 1 equiv.) and intermediate compound 24 (391.87 mg, 1.52 mmol, 3 equiv.) in CH3CN (5 mL), K2CO3 (280.58 mg, 2.03 mmol, 4 equiv.) and KI (168.50 mg, 1.02 mmol, 2 equiv.) were added, and the mixture was then stirred at 60 °C for 12 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 × 25 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (water (0.225% FA) / MeCN, 40%–50%) to give intermediate compound 70 (134 mg, 40% yield) as a yellow oil. LCMS (ESI position ion) m / z: 654.6 (M+H)+ (calculated: 653.4)

[0553] Intermediate compound 71: [ka] A mixture of intermediate compound 70 (134 mg, 204.94 μmol, 1 equiv) in HCl / dioxane (4 M, 1.54 mL, 30 equiv) was stirred at 20° C. for 2 h. The mixture was concentrated in vacuo to give crude intermediate compound 71 (82 mg, 75% yield, HCl) as a yellow oil. LCMS (ESI position ion) m / z: 498.4 (M+H)+ (calculated: 497.3)

[0554] Intermediate compound 72: [ka] A solution of methyl 4-chloro-3-methoxy-5-nitrobenzoate (15 g, 61.07 mmol, 1 equiv.), iron (13.64 g, 244.28 mmol, 4 equiv.), and NH4Cl (26.13 g, 488.57 mmol, 8 equiv.) in EtOH (225 mL) and HO (75 mL) was stirred at 70 °C for 2 h. After cooling to ambient temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with HO (300 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give crude intermediate compound 72 (14.38 g) as a pale yellow solid. 1H NMR (400MHz, DMSO-d6) δ7.11 (s, 1H), 6.86-6.71 (m, 1H), 5.74-5.60 (m, 2H), 3.82 (s, 6H).

[0555] Intermediate compound 73: [ka] A suspension of CuCl (4.49 g, 33.39 mmol, 1.2 equiv) and tert-butyl nitrite (4.30 g, 41.74 mmol, 4.96 mL, 1.5 equiv) in CHCN (60 mL) was heated to 50 °C. A solution of intermediate compound 72 (6 g, 27.83 mmol, 1 equiv) in CHCN (60 mL) was added dropwise at 50 °C. The reaction mixture was stirred at 80 °C for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was suspended in water (300 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure to give crude intermediate compound 73 (5.38 g) as a pale yellow solid. 1H NMR (400MHz, DMSO-d6) δ7.70 (d, J = 1.75 Hz, 1H), 7.55 (d, J = 1.63 Hz, 1H), 3.97 (s, 3H), 3.88 (s, 3H).

[0556] Intermediate compound 74: [ka] To a solution of intermediate compound 73 (5.38 g, 22.89 mmol, 1 equiv.) in DCM (200 mL) was added boron tribromide (11.47 g, 45.77 mmol, 4.41 mL, 2 equiv.) at 0 °C. The mixture was stirred at 30 °C for 12 h. The reaction mixture was added dropwise to a saturated aqueous solution of Na2CO3 (200 mL). A large amount of white precipitate formed and dissolved by the addition of ethyl acetate (100 mL). The organic layer was washed with saturated aqueous Na2CO3 (100 mL). The combined aqueous layers were washed with ethyl acetate (200 mL). The organic layer was discarded, and the aqueous layer was acidified to pH = 4 with HCl (12 M) and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (40 mL) and HO (10 mL). To the above reaction mixture was added NaOH (2 g, 50 mmol, 2.2 equiv.). The reaction mixture was stirred at 50° C. for 12 h. After cooling to room temperature, the reaction mixture was diluted with HO (100 mL) and acidified to pH 2 with HCl (12 M). The mixture was extracted with EtOAc (100 mL×2). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to give crude intermediate compound 74 (4.57 g, 96% yield) as a pale yellow solid. 1H NMR (400MHz, DMSO-d6) δ 14.12-12.37 (m, 1H), 11.76-10.96 (m, 1H), 7.51 (s, 2H).

[0557] Intermediate compound 75: [ka] To a solution of intermediate compound 74 (1 g, 4.83 mmol, 1 equiv.) in toluene (20 mL) was added 1,1-di-tert-butoxy-N,N-dimethylmethanamine (3.92 g, 19.32 mmol, 4.64 mL, 4 equiv.). The mixture was stirred at 85 °C for 12 h. The reaction was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc 100 / 1 to 25 / 1) to give intermediate compound 75 (540 mg, 42% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 11.15 (s, 1H), 7.47 (s, 2H), 1.53 (s, 9H).

[0558] Intermediate compound 76: [ka] To a solution of intermediate compound 75 (540 mg, 2.05 mmol, 1 equiv.), intermediate compound 5 (908.39 mg, 2.05 mmol, 1 equiv.), and PPh3 (968.94 mg, 3.69 mmol, 1.8 equiv.) in toluene (12 mL) was added DEAD (536.15 mg, 3.08 mmol, 559.65 μL, 1.5 equiv.) at 0 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc 100 / 1 to 20 / 1) to give intermediate compound 76 (1.2 g, 84% yield) as a pink oil. 1H NMR(400MHz,DMSO-d6)δ7.54(d,J=1.59Hz,1H),7.41-7.43(m,1H),7.15-7.18(m,2H),5.21-5.28(m,1H),4.19(br s,2H),3.79(s,6H),3.72(s,3H),3.65-3.70(m,2H),1.96(br dd,J=13.57,5.62Hz,2H),1.78-1.88(m,4H),1.54(s,9H),-0.03(d,J=4.52Hz,6H).

[0559] Intermediate compound 77: [ka] To a solution of intermediate compound 76 (500 mg, 727.04 μmol, 1 equiv) in MeOH (10 mL) was added NHF (269.27 mg, 7.27 mmol, 10 equiv). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give crude intermediate compound 77 (440 mg) as a pale pink oil. LCMS (ESI position ion) m / z: 573.1 (M+H)+ (calculated: 572.1) 1H NMR(400MHz,DMSO-d6)δ7.54(d,J=1.63Hz,1H),7.42(d,J=1.63Hz,1H),7.17-7.16(m,2H),5.27-5.20(m,1 H),4.22-4.16(m,2H),3.79(s,6H),3.72(s,3H),3.49(s,2H),1.99(s,1H),1.91-1.79(m,6H),1.54(s,9H).

[0560] Intermediate compound 78: [ka] To a solution of intermediate compound 77 (1 g, 1.74 mmol, 1 equiv.) and TEA (529.36 mg, 5.23 mmol, 728.15 uL, 3 equiv.) in DCM (10 mL) at 0 °C, methanesulfonyl chloride (399.51 mg, 3.49 mmol, 269.94 uL, 2 equiv.) was slowly added, and the reaction mixture was then stirred at 20 °C for 2 h. The reaction mixture was poured into a saturated aqueous solution of NaHCO (10 mL) at 0 °C and extracted with DCM (3 × 20 mL). The combined organic layers were concentrated to dryness in vacuo to give crude intermediate compound 78 (1.1 g, 96% yield) as a brown oil, which was used without further purification. 1H NMR(400MHz,CDCl3-d)δ=7.65(d,J=1.63Hz,1H) 7.41(d,J=1.63Hz,1H) 7.28(s,2H) 5.35-5.45(m,1H) 4.27-4.41(m,2H) 4.09-4.13(m,2H) 3.92(s,9H) 3.15(s,1H) 2.99(s,3H) 2.22(q,J=6.30Hz,2H) 1.92-2.03(m,4H) 1.59(s,9H)

[0561] Intermediate compound 79: [ka] To a suspension of intermediate compound 78 (500 mg, 767.40 μmol, 1 equiv) in CHCN (10 mL) was added 3-(1,4-diazepan-1-yl)propan-1-ol (182.15 mg, 1.15 mmol, 1.5 equiv), KCO (318.18 mg, 2.30 mmol, 3 equiv), and KI (254.78 mg, 1.53 mmol, 2 equiv). The reaction mixture was stirred at 60° C. for 12 h. The reaction was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150 × 25 × 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 38%–68%, 9 min) to give intermediate compound 79 (470 mg, 84% yield) as a brown oil. 1H NMR(400MHz,DMSO-d6)δ7.56-7.54(m,1H),7.45-7.41(m,1H),7.27-7.21(m,2H),5.19(br d,J=5.00Hz,1H),4.12-4.18(m,2H),3.80(s,6H),3.72(s,3H),2.84-2.78(m,4H),2.72-2.65(m,6H),2.57(br t,J=7.07Hz,3H),2.30(s,2H),1.99-1.79(m,7H),1.78-1.71(m,2H),1.64-1.58(m,2H),1.54(s,9H).

[0562] Intermediate compound 80: [ka] A solution of intermediate compound 79 (470 mg, 658.55 umol, 1 equiv) in HCl / dioxane (10 mL) was stirred for 12 hours at 30° C. The mixture was concentrated under reduced pressure to give crude intermediate compound 80 (350 mg, 81% yield) as a yellow solid. LCMS (ESI position ion) m / z: 657.1 (M+H)+ (calculated: 656.2)

[0563] Intermediate compound 81: [ka] A suspension of CuBr2 (4.41 g, 19.76 mmol, 925.04 uL, 1.2 equiv) and tert-butyl nitrite (2.55 g, 24.69 mmol, 2.94 mL, 1.5 equiv) in CH3CN (35 mL) was warmed to 50 °C. A solution of intermediate compound 72 (3.55 g, 16.46 mmol, 1 equiv) in CH3CN (35 mL) was added dropwise at 50 °C. The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in HO (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with HO (2 × 100 mL). The organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc 100 / 1 to 50 / 1) to give intermediate compound 81 (2.64 g, 57% yield) as a pale yellow solid. 1H NMR (400MHz, DMSO-d6) δ7.84(d,J=1.75Hz,1H),7.58(d,J=1.88Hz,1H),3.97(s,3H),3.89(s,3H).

[0564] Intermediate compound 82: [ka] To a solution of intermediate compound 81 (2.64 g, 9.44 mmol, 1 equiv) in DCM (100 mL) was added boron tribromide (4.73 g, 18.89 mmol, 1.82 mL, 2 equiv) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into a saturated aqueous solution of Na2CO3 (200 mL). A large amount of white precipitate formed and dissolved by the addition of EtOAc (100 mL). The organic layer was washed with a saturated aqueous solution of Na2CO3 (100 mL). The combined aqueous layers were extracted with EtOAc (200 mL). The aqueous layer was acidified to pH = 3 with hydrochloric acid (12 M) and extracted with EtOAc (2 × 150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude intermediate compound 82 (5.38 g) as a pale yellow solid. 1H NMR (400MHz, DMSO-d6) δ7.70 (d, J = 1.75 Hz, 1H), 7.55 (d, J = 1.63 Hz, 1H), 3.97 (s, 3H), 3.88 (s, 3H).

[0565] Intermediate compound 83: [ka] To a solution of intermediate compound 82 (500 mg, 1.99 mmol, 1 equiv.) in toluene (10 mL), 1,1-di-tert-butoxy-N,N-dimethylmethanamine (808.56 mg, 3.98 mmol, 953.49 μL, 2 equiv.) was added. The mixture was stirred at 85° C. for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc 100 / 1 to 20 / 1) to give intermediate compound 83 (170 mg, 28% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ11.13 (s, 1H), 7.60 (d, J = 1.88 Hz, 1H), 7.50 (d, J = 1.88 Hz, 1H), 1.53 (s, 9H).

[0566] Intermediate compound 84: [ka] To a solution of intermediate compound 83 (210 mg, 682.78 μmol, 1 equiv.), intermediate compound 5 (302.21 mg, 682.78 μmol, 1 equiv.), and triphenylphosphine (322.35 mg, 1.23 mmol, 1.8 equiv.) in toluene (4 mL) was added DEAD (178.36 mg, 1.02 mmol, 186.18 μL, 1.5 equiv.) at 0° C. The reaction mixture was stirred at 110° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether / EtOAc = 5 / 1) to give intermediate compound 84 (390 mg, 73% yield) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ7.66(d,J=1.63Hz,1H),7.44(d,J=1.50Hz,1H),7.14-7.18(m,2H),5.24(br d,J=3.38Hz,1H),4.15-4.21(m,2H),3.79(s,6H),3.72(s,3H),3.64-3.70(m,2H),1. 90-2.02(m,2H),1.79-1.89(m,4H),1.54(s,9H),0.81(s,9H),-0.03(d,J=4.63Hz,6H)

[0567] Intermediate compound 85: [ka] A suspension of intermediate compound 84 (70 mg, 95.61 μmol, 1 equiv.), Pd(OAc) (2.15 mg, 9.56 μmol, 0.1 equiv.), and DPPF (10.60 mg, 19.12 μmol, 0.2 equiv.) in NH / MeOH (7 M, 10 mL) was stirred at 80 °C for 12 h under a CO (50 psi) atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether / EtOAc = 1 / 1) to give intermediate compound 85 (20 mg, 30% yield) as a white solid. LCMS (ESI position ion) m / z: 696.2 (M+H)+ (calculated: 695.3)

[0568] Intermediate compound 86: [ka] To a solution of intermediate compound 85 (40 mg, 57.45 umol, 1 equiv) in MeOH (3 mL) was added NHF (21.28 mg, 574.47 umol, 10 equiv). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was suspended in EtOAc (30 mL) and stirred at 15° C. for 0.5 h. The suspension was filtered, and the filtrate was concentrated under reduced pressure to give crude intermediate compound 86 (38 mg) as a colorless oil. LCMS (ESI position ion) m / z: 582.1 (M+H)+ (calculated: 581.2)

[0569] Intermediate compound 87: [ka] To a mixture of intermediate compound 86 (38 mg, 65.29 μmol, 1 equiv) and TEA (13.21 mg, 130.58 μmol, 18.17 μL, 2 equiv) in DCM (3 mL) was added methanesulfonyl chloride (15 mg, 130.95 μmol, 10.14 μL, 2.01 equiv) at 0° C. The mixture was stirred at 25° C. for 2 h. The mixture was poured into water (20 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with brine (2×30 mL), dried over NaSO, filtered, and concentrated in vacuo to give crude intermediate compound 87 (45 mg) as a colorless oil.

[0570] Intermediate compound 88: [ka] A mixture of intermediate compound 87 (45 mg, 68.17 μmol, 1 equiv.), 3-(1,4-diazepan-1-yl)propan-1-ol (16.18 mg, 102.25 μmol, 1.5 equiv.), KCO (28.26 mg, 204.51 μmol, 3 equiv.), and KI (22.63 mg, 136.34 μmol, 2 equiv.) in MeCN (4 mL) was stirred at 60° C. for 16 h. The mixture was filtered and washed with MeCN (5 × 10 mL). The combined filtrate was concentrated in vacuo. The residue was purified by reverse phase (column: spherical C18 20-35 mm 100A 80 g; mobile phase: [water (0.5% FA)-ACN]; B%: 25%-34%, 15 min) to give intermediate compound 88 (31 mg, 62% yield) as a colorless oil. LCMS (ESI position ion) m / z: 722.2 (M+H)+ (calculated: 721.3)

[0571] Intermediate compound 89: [ka] A mixture of intermediate compound 88 (31 mg, 42.49 μmol, 99% purity, 1 equiv) in HCl / dioxane (4 M, 531.14 μL, 50 equiv) and DCM (0.5 mL) was stirred for 12 h at 30° C. The mixture was concentrated in vacuo to give crude intermediate compound 89 (33 mg) as a yellow oil. LCMS (ESI position ion) m / z: 666.1 (M+H)+ (calculated: 665.3)

[0572] Intermediate compound 90: [ka] To a solution of methyl 4-amino-3-methoxybenzoate (20 g, 110.38 mmol, 1 equiv.) in CH3CN (200 mL) was added N-chlorosuccinimide (16.21 g, 121.42 mmol, 1.1 equiv.), and the mixture was then stirred at 20 °C for 12 h. The reaction mixture was diluted with water (800 mL) and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (3 × 400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAC = 100 / 1 to 5 / 1) to give intermediate compound 90 (18 g, 76% yield) as an off-white solid. 1H NMR (400MHz, CDCl3-d) δ7.67(d,J=1.6Hz,1H),7.37(d,J=1.6Hz,1H),4.73-4.32(m,2H),3.92(s,3H),3.88(s,3H)

[0573] Intermediate compound 91: [ka] To a solution of tert-butyl nitrite (11.48 g, 111.30 mmol, 13.24 mL, 1.5 equiv) and CuBr (19.89 g, 89.04 mmol, 4.17 mL, 1.2 equiv) in CHCN (160 mL) was slowly added intermediate compound 90 (16 g, 74.20 mmol, 1 equiv) in CHCN (50 mL) at 50 °C, and the mixture was then stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (1000 mL) and washed with water (3 × 600 mL). The combined organic layers were washed with brine (3 × 500 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 100 / 1 to 5 / 1) to give intermediate compound 91 (16 g, 77% yield) as a white solid. 1H NMR (400MHz, CDCl3-d) δ7.76(d,J=1.7Hz,1H),7.44(d,J=1.7Hz,1H),3.96(d,J=13.1Hz,6H)

[0574] Intermediate compound 92: [ka] To a solution of intermediate compound 91 (6 g, 21.47 mmol, 1 equiv.) in DCM (110 mL) was added boron tribromide (21.51 g, 85.86 mmol, 8.27 mL, 4 equiv.) at 0° C., and the mixture was then stirred at 25° C. for 12 h. The reaction mixture was quenched by addition to water (600 mL), then diluted with DCM (500 mL), and extracted with water (3×400 mL). The combined organic layers were washed with brine (3×400 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was triturated with water (500 mL) at 25° C. for 30 min to give intermediate compound 92 (5 g) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ11.70-10.71(m,1H),7.54-7.42(m,2H)

[0575] Intermediate compound 93: [ka] To a solution of intermediate compound 92 (0.75 g, 2.98 mmol, 1 equiv.) in toluene (20 mL), 1,1-di-tert-butoxy-N,N-dimethylmethanamine (2.43 g, 11.93 mmol, 2.86 mL, 4 equiv.) was added, and the mixture was then stirred at 105 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 100 / 1 to 5 / 1) to give intermediate compound 93 (0.3 g, 33% yield) as a white solid. 1H NMR (400MHz, CDCl3-d) δ7.65(d,J=2.0Hz,1H),7.53(d,J=1.8Hz,1H),5.79(s,1H),1.59(s,9H)

[0576] Intermediate compound 94: [ka] To a solution of intermediate compound 5 (1.3 g, 2.94 mmol, 1 equiv.) and intermediate compound 93 (903.35 mg, 2.94 mmol, 1 equiv.) in toluene (13 mL) was added triphenylphosphine (1.39 g, 5.29 mmol, 1.8 equiv.), followed by DEAD (767.26 mg, 4.41 mmol, 800.90 μL, 1.5 equiv.) at 0°C. The mixture was stirred at 0-110°C for 12 h. The reaction mixture was diluted with EtOAc (800 mL) and extracted with water (3 × 500 mL). The combined organic layers were washed with brine (3 × 400 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 100 / 1 to 10 / 1) to give intermediate compound 94 (1.5 g, 70% yield) as a colorless oil.

[0577] Intermediate compound 95: [ka] A suspension of intermediate compound 94 (1.5 g, 2.05 mmol, 1 equiv.), Pd(OAc) (46.00 mg, 204.87 µmol, 0.1 equiv.), and DPPF (227.15 mg, 409.74 µmol, 0.2 equiv.) in NH (7 M, 80 mL, 273.34 equiv.) (MeOH) was stirred at 80 °C for 72 h under a CO (50 psi) atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 10 / 1 to 3 / 1) to give intermediate compound 95 (350 mg, 24% yield) as a colorless oil. LCMS (ESI position ion) m / z: 696.2 (M+H)+ (calculated: 695.3)

[0578] Intermediate compound 96: [ka] To a solution of intermediate compound 95 (300 mg, 430.85 μmol, 1 equiv.) in MeOH (5 mL), NHF (319.15 mg, 8.62 mmol, 20 equiv.) was added. The mixture was stirred at 75 °C for 3 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 52% to 72%, 7 min) to give intermediate compound 96 (250 mg) as a colorless oil. LCMS (ESI position ion) m / z: 582.2 (M+H)+ (calculated: 581.2) 1H NMR(400MHz,CDCl3-d)δ7.52(d,J=1.0Hz,1H),7.37(d,J=0.8Hz,1H),7.24(s,2H),6.50(br s,1H),6.24(br s,1H),5.36(br d,J=3.4Hz,1H),4.20-4.02(m,3H),3.89(s,8H),3.75-3.50(m,2H),1.99-1.72(m,6H),1.57(s,9H)

[0579] Intermediate compound 97: [ka] To a solution of intermediate compound 96 (120 mg, 206.17 μmol, 1 equiv) and EtN (52.16 mg, 515.43 μmol, 71.74 μL, 2.5 equiv) in DCM (3 mL) was added methanesulfonyl chloride (0.25 g, 2.18 mmol, 168.92 μL, 10.59 equiv) dropwise at 0° C. The mixture was stirred at 0° C. for 2 h. The mixture was slowly quenched with ice water (30 mL) and then extracted with DCM (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give crude intermediate compound 97 (120 mg) as a yellow oil. LCMS (ESI position ion) m / z: 660.1 (M+H)+ (calculated: 659.2)

[0580] Intermediate compound 98: [ka] To a solution of intermediate compound 97 (120 mg, 181.78 μmol, 1 equiv.) in CH3CN (3 mL) was added intermediate compound 24 (56.14 mg, 218.14 μmol, 1.2 equiv.), K2CO3 (125.62 mg, 908.91 μmol, 5 equiv.), and KI (30.18 mg, 181.78 μmol, 1 equiv.). The mixture was stirred at 60 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 18% to 48%, 7 min) to give intermediate compound 98 (50 mg) as an off-white solid. LCMS (ESI position ion) m / z: 821.3 (M+H)+ (calculated: 820.4)

[0581] Intermediate compound 99: [ka] A solution of intermediate compound 98 (30 mg, 36.52 μmol, 1 equiv.) in HCl / dioxane (4 M, 1 mL, 109.52 equiv.) was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 1% to 30%, 8 min) to give intermediate compound 99 (30 mg) as a colorless oil. LCMS (ESI position ion) m / z: 665.2 (M+H)+ (calculated: 664.3)

[0582] Intermediate compound 100: [ka] To a solution of intermediate compound 94 (1.2 g, 1.64 mmol, 1 equiv.) in MeOH (15 mL) was added NHF (1.21 g, 32.78 mmol, 20 equiv.). The mixture was stirred at 75 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 10 / 1 to 1 / 1) to give intermediate compound 100 (0.5 g) as a colorless oil. 1H NMR:(400MHz,CDCl3)δ7.64(d,J=1.3Hz,1H),7.34(d,J=1.1Hz,1H),7.30-7.27(m,2H),5.39(br d,J=5.3Hz,1H),4.15-4.08(m,2H),3.90(s,9H),3.71(br d,J=5.6Hz,2H),2.51(br s,1H),2.03-1.82(m,6H),1.58(s,9H)

[0583] Intermediate compound 101: [ka] To a solution of intermediate compound 100 (360 mg, 582.61 μmol, 1 equiv) and TEA (235.82 mg, 2.33 mmol, 324.37 μL, 4 equiv) in DCM (10 mL) was added methanesulfonic anhydride (304.46 mg, 1.75 mmol, 3 equiv) dropwise at 0° C. The mixture was stirred at 0° C. for 2 h, and the mixture was slowly quenched with ice water (200 mL) and then extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×150 mL), dried over NaSO, filtered, and concentrated in vacuo to give crude intermediate compound 101 (400 mg) as a yellow oil, which was used without further purification.

[0584] Intermediate compound 102: [ka] To a solution of intermediate compound 101 (360 mg, 517.24 μmol, 1 equiv.) in CH3CN (6 mL), intermediate compound 24 (159.75 mg, 620.69 μmol, 1.2 equiv.), K2CO3 (357.44 mg, 2.59 mmol, 5 equiv.), and KI (85.86 mg, 517.24 μmol, 1 equiv.) were added. The mixture was stirred at 60 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 40 mm × 15 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 25%–55%, 10 min) to give intermediate compound 102 (400 mg, 80% yield) as a colorless oil. 1H NMR:(400MHz,CDCl3)δ7.65(br d,J=1.8Hz,1H),7.35(s,1H),7.29-7.27(m,2H),5.31(br s,1H),4.12(br s,2H),3.92(s,9H),3.19(br s 2H),3.01(br s,4H),2.94-2.89(m,2H),2.83(br d,J=7.1Hz,4H),2.79-2.64(m,4H),2.07-1.77(m,10H),1.59(s,9H),1.43(s,9H)

[0585] Intermediate compound 103: [ka] A solution of intermediate compound 102 (300 mg, 349.95 μmol, 1 equiv.) in HCl / dioxane (4 M, 12.27 mL, 140.21 equiv.) was added and stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: Waters Xbridge 150 × 25 mm × 5 μm; Mobile phase: [water (0.05% v / v ammonia hydroxide)-ACN]; B%: 21% to 51%, 8 min) to give intermediate compound 103 (52 mg, 52% yield) as a white solid. 1H NMR:(400MHz,MeOD)δ7.66(d,J=1.6Hz,1H),7.51(s,1H),7.30(s,2H),5.30(br d,J=3.7Hz,1H),4.21(br s,2H),3.92-3.79(m,9H),3.13(br d,J=1.3Hz,4H),3.07-2.70(m,10H),2.17-1.81(m,10H)

[0586] Intermediate compound 104: [ka] Intermediate 104 was isolated as a minor compound during the preparation of intermediate compound 98. LCMS (ESI position ion) m / z: 803.5 (M+H)+ (calculated: 802.4)

[0587] Intermediate compound 105: [ka] A mixture of intermediate compound 104 (50 mg, 62.24 μmol, 1 equiv) in HCl / dioxane (4 M, 1.70 mL, 109.52 equiv) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: Waters Xbridge 150 × 25 mm × 5 μm; Mobile phase: [water (0.05% v / v ammonia hydroxide)-ACN]; B%: 16%–46%, 8 min) to give intermediate compound 105 (18 mg, 45% yield) as a white solid. LCMS (ESI position ion) m / z: 647.3 (M+H)+ (calculated: 646.3)

[0588] Intermediate compound 106: [ka] To a stirred solution of 4-penten-1-ol (100 g, 1161 mmol, 1.0 equiv) and imidazole (118.6 g, 1741 mmol, 1.5 equiv) in DCM (800 mL) was added tert-butyldimethylsilyl chloride (192.5 g, 1277 mmol, 1.1 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The resulting mixture was washed with 0.5 M aqueous HCl (3 × 500 mL). The organic layer was concentrated under reduced pressure to give intermediate compound 106 (190 g, 82% yield) as a colorless oil. LC-MS(ES+) m / z: 201 (M+H)+ (calculated value: 200.1)

[0589] Intermediate compound 107: [ka] A solution of intermediate compound 106 (95 g, 474 mmol, 1.0 equiv.), Grubbs' second-generation catalyst (20.1 g, 23.7 mmol, 0.05 equiv.), and crotonaldehyde (56.5 g, 806 mmol, 1.7 equiv.) in DCM (8075 mL) was stirred at 37 °C overnight. The mixture was then allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO, EtOAc / petroleum ether = 1 / 100 to 1 / 10) to give intermediate compound 107 (70 g, 65% yield) as a yellow oil. LC-MS(ES+) m / z: 229 (M+H)+ (calculated: 228.1)

[0590] Intermediate compound 108: [ka] To a stirred solution of (2S)-2-[bis[3,5-bis(trifluoromethyl)phenyl][(trimethylsilyl)oxy]methyl]pyrrolidine (261 mg, 0.43 mmol, 0.1 equiv) and benzoic acid (54 mg, 0.43 mmol, 0.1 equiv) in toluene (2.2 mL) at 0 °C, intermediate compound 107 (1.0 g, 4.4 mmol, 1.0 equiv) was added, followed by E-benzaldoxime (1.6 g, 13.1 mmol, 3.0 equiv), and the solution was stirred at 0 °C for 4 h. The reaction mixture was diluted with DCM (15 mL), followed by the addition of tert-butyl 1,4-diazepane-1-carboxylate (1.4 g, 7.0 mmol, 1.6 equiv), and the reaction mixture was stirred at room temperature for an additional 1 h. Sodium borohydride (324 mg, 8.8 mmol, 2.0 equiv.) was added, and the reaction mixture was stirred at room temperature for an additional 1 h. The reaction mixture was diluted with saturated aqueous NH4Cl and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over MgSO4, and evaporated under reduced pressure. The crude oil was purified by preparative HPLC (column (C18-I, 20–40 μm); mobile phase (MeOH / HO = 40%–100% in 6 min; 100% in 5 min; detectors (254 nm and 220 nm)) to give intermediate compound 108 (650 mg, 28% yield) as a colorless oil. Note: The compound was found to be racemic. LC-MS(ES+) m / z: 534 (M+H)+ (calculated value: 533.4)

[0591] Intermediate compound 109: [ka] To a solution of intermediate compound 108 (5.6 g, 10.5 mmol, 1.0 equiv.) and DIEA (5.4 g, 42 mmol, 4.0 equiv.) in DCM (100 mL) was added trimethylsilyl trifluoromethanesulfonate (7.0 g, 31.5 mmol, 3.0 equiv.) at 0 °C. The resulting solution was stirred at room temperature for 2 h and then quenched by the addition of 20 mL of water. The organic phase was washed with 20 mL of water and brine (2 × 30 mL). The organic layer was dried over NaSO and concentrated. The residue was purified by preparative HPLC (column (C18-I, 20-40 μm); mobile phase (MeOH / HO = 20% to 100% in 7 min; 100% in 3 min; detectors (254 nm and 220 nm)) to give intermediate compound 9 (4 g, 75% yield) as a light brown oil. LC-MS(ES+) m / z: 434 (M+H)+ (calculated value: 433.3) 1H NMR(300MHz,DMSO-d6)δ7.21(s,1H),7.10(s,1H),4.30-4.26(m,2H),3.84-3.74(m,6H) ),2.80-2.71(m,4H),2.65-2.57(m,6H),1.84-1.60(m,4H),0.99(s,9H),0.16(s,6H).

[0592] Intermediate compound 110: [ka] A solution of intermediate compound 109 (3.4 g, 7.8 mmol, 1.0 equiv.), intermediate compound 13 (2.6 g, 8.2 mmol, 1.05 equiv.), and KCO (1.2 g, 8.6 mmol, 1.1 equiv.) in CHCN (53 mL) was stirred at 50 °C for 16 h. The reaction mixture was then poured into 150 mL of water / ice. The resulting solution was extracted with EtOAc (3 × 100 mL), and the combined organic layers were dried over NaSO and concentrated. The residue was purified by preparative HPLC (C18-I, 20-40 μm column; mobile phase (MeOH / HO = 40% to 100% in 7 min; 100% in 5 min; detectors (254 nm and 220 nm)) to give intermediate compound 110 (4.1 g, 78% yield) as a light brown oil. LC-MS(ES+) m / z: 672 (M+H)+ (calculated value: 671.4)

[0593] Intermediate compound 111: [ka] To a solution of intermediate compound 110 (4.1 g, 6.1 mmol, 1.0 equiv.) in DCM (50 mL) was added 3 M HCl (120 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h, and then the DCM layer was discarded. The pH value of the aqueous layer was adjusted to 7–8 with a saturated solution of NaHCO3. The resulting solution was extracted with DCM (3 × 100 mL), and the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC (column (C18-I, 20–40 μm); mobile phase (MeOH / HO = 20%–95%: 8 min; detectors (254 nm and 220 nm)) to give intermediate compound 111 (2.7 g, 79% yield) as a colorless oil. LC-MS(ES+) m / z: 558 (M+H)+ (calculated value: 557.3) 1H NMR(300MHz,CDCl3)δ8.07(s,1H),7.58-7.56(m,2H),7.38-7.28(m,5H),7.19(s,1H),4.49-4.31(m,3H) ,3.96(s,3H),3.91(s,3H),3.78-3.69(m,2H),2.80-2.66(m,12H),1.93-1.88(m,6H),1.74-1.71(m,4H).

[0594] Intermediate compound 112: [ka] To a mixture of 3-hydroxy-4,5-dimethoxybenzoic acid (20.0 g, 101 mmol, 1.0 equiv.) and 3-bromopropan-1-amine (16.7 g, 121 mmol, 1.2 equiv.) in DMF (400 mL) was added dropwise DIEA (39.1 g, 303 mmol, 3.0 equiv.) and propylphosphonic anhydride solution (77.0 g, 121 mmol, 1.2 equiv.) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (1.2 L) at room temperature. The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (1 × 500 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 5 / 1 to 1 / 1) to give intermediate compound 112 (15 g, 47% yield) as an off-white solid. LC-MS(ES+) m / z: 318 (M+H)+ (calculated value: 317.0)

[0595] Intermediate compound 113: [ka] To a stirred solution of intermediate compound 109 (10.0 g, 23.1 mmol, 1.0 equiv.) and KCO (7.97 g, 57.7 mmol, 2.5 equiv.) in CHCN (250 mL) under a nitrogen atmosphere, intermediate compound 112 (11.0 g, 34.6 mmol, 1.5 equiv.) was added portionwise at room temperature. The reaction mixture was stirred at 50 °C overnight and allowed to cool to room temperature. The resulting suspension was filtered, the precipitate was washed with acetonitrile (1 × 100 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (column, C18 silica gel; mobile phase, MeOH in water, 80% to 95% gradient in 8 min and 95% to 100% gradient in 9 min; detector, UV 254 nm and 220 nm) to give intermediate compound 113 (5 g, 32% yield) as a pale yellow oil. LC-MS (ES+) m / z: 671 (M+H)+ (calculated: 670.4)

[0596] Intermediate compound 114: [ka] To a stirred solution of intermediate compound 113 (5.0 g, 7.6 mmol, 1.0 equiv) in DCM (50 mL) under a nitrogen atmosphere was added HCl (2 M in water, 50 mL) at 0 °C. The resulting mixture was stirred at room temperature for another 2 h. The aqueous layer was extracted with DCM (1 × 50 mL). The pH of the aqueous layer was adjusted to pH = 7 with a saturated aqueous solution of NaHCO and extracted with THF (3 × 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give crude intermediate compound 114 (3.6 g, 87% yield) as a pale yellow oil. The crude product was used in the next step without further purification. LC-MS (ES+) m / z: 557 (M+H)+ (calculated value: 556.3)

[0597] Intermediate compound 115: [ka] AcO (7.65 g, 75 mmol, 1.5 equiv) was added dropwise to a solution of 3-hydroxy-4,5-dimethoxybenzoic acid (9.90 g, 50 mmol, 1.00 equiv) in pyridine (100 mL) at 0° C. The resulting solution was stirred at 0° C. for 3 h and then concentrated. The crude intermediate compound 115 (10 g) was used directly in the next step without further purification. LC-MS(ES+) m / z: 241 (M+H)+ (calculated: 240.1).

[0598] Intermediate compound 116: [ka] A solution of intermediate compound 115 (10 g, 41.7 mmol, 1.0 equiv.), tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (12.15 g, 50 mmol, 1.2 equiv.), EDCI (11.98 g, 62.5 mmol, 1.5 equiv.), and DMAP (7.62 g, 62.5 mmol, 1.5 equiv.) in DCM (100 mL) was stirred at room temperature for 12 h. The reaction mixture was then quenched with 100 mL of HO and extracted with DCM (3 × 100 mL). The combined organic layers were concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 3 / 1) to give intermediate compound 116 (7 g, 30% yield over two steps) as a colorless oil. LC-MS(ES+) m / z: 466 (M+H)+ (calculated: 465.2).

[0599] Intermediate compound 117: [ka] A solution of intermediate compound 116 (6.50 g, 14.0 mmol, 1.0 equiv) and potassium carbonate (3.85 g, 28.0 mmol, 2.0 equiv) in MeOH (65 mL) was stirred at room temperature for 2 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude intermediate compound 117 (5.8 g) was used directly in the next step without further purification. LC-MS(ES+) m / z: 424 (M+H)+ (calculated: 423.2).

[0600] Intermediate compound 118: [ka] A solution of intermediate compound 117 (5.8 g) and TFA (7.8 g) in DCM (110 mL) was stirred at room temperature for 2 hours. The mixture was then basified to pH = 7 with a saturated solution of NaHCO3 and filtered. The precipitate was washed with DCM (2 × 20 mL), and the filtrate was concentrated under reduced pressure. Crude intermediate compound 118 (4.02 g) was used directly as a yellow oil in the next step without further purification. LC-MS(ES+) m / z: 324 (M+H)+ (calculated: 323.2).

[0601] Intermediate compound 119: [ka] To a stirred solution of (2S)-2-[bis[3,5-bis(trifluoromethyl)phenyl][(trimethylsilyl)oxy]methyl]pyrrolidine (261 mg, 0.43 mmol, 0.1 equiv) and benzoic acid (54 mg, 0.43 mmol, 0.1 equiv) in toluene (2.2 mL) at 0 °C, intermediate compound 107 (1.0 g, 4.4 mmol, 1.0 equiv) was added, followed by E-benzaldoxime (1.6 g, 13.1 mmol, 3.0 equiv), and the solution was stirred at 0 °C for 4 h. The reaction mixture was diluted with DCM (15 mL), followed by the addition of intermediate compound 118 (2.25 g, 7.0 mmol, 1.6 equiv), and the reaction mixture was stirred at room temperature for another hour. Sodium borohydride (324 mg, 8.8 mmol, 2.0 equiv) was then added, and the reaction mixture was stirred at room temperature for another hour. The reaction mixture was quenched with saturated NH4Cl and extracted with DCM (3 × 20 mL). The combined organic components were dried over MgSO4 and evaporated to dryness. The resulting oil was purified by preparative HPLC (column (C18-I, 20-40 μm); mobile phase (MeOH / HO = 50%-100%: 6 min; 100%: 5 min); detector (220 nm)) to give intermediate compound 119 (750 mg, 16% yield) as a colorless oil. LC-MS(ES+) m / z: 657 (M+H)+ (calculated: 656.4).

[0602] Intermediate compound 120: [ka] A solution of intermediate compound 119 (670 mg, 1.0 mmol, 1.0 equiv) in 2 M HCl in EtO (10 mL) was stirred at room temperature for 2 h. EtO was removed, and the pH of the residue was adjusted to pH 7–8 with a saturated solution of NaHCO. The resulting solution was extracted with DCM (3 × 10 mL), and the combined organic layers were dried over NaSO and concentrated. The crude product was purified by preparative HPLC (column (C18-I, 20–40 μm); mobile phase (MeOH / HO = 30%–80%: 8 min; detectors (254 nm and 220 nm)) to give intermediate compound 120 (300 mg, 54% yield) as a yellow oil. LC-MS(ES+) m / z: 543 (M+H)+ (calculated: 542.3).

[0603] Intermediate compound 121: [ka] A solution of ADDP (0.19 g, 0.75 mmol, 1.5 equiv) and n-Bu3P (0.15 g, 0.75 mmol, 1.5 equiv) in anhydrous THF (2.0 mL) was stirred under N2 for 15 min, after which a solution of intermediate compound 120 (271 mg, 0.5 mmol, 1.0 equiv) in THF (3 mL) was added. The mixture was stirred at 45 °C for 1 h. The reaction was then quenched by the addition of HO (5 mL), and the resulting solution was extracted with EtOAc (2 × 5 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by preparative HPLC (column (C18-I, 20-40 μm); mobile phase (MeOH / HO = 30% to 100% in 7 min; 100% in 3 min; detectors (254 nm and 220 nm)) to give intermediate compound 121 (55 mg, 21% yield) as an off-white solid. LC-MS(ES+) m / z: 525 (M+H)+ (calculated: 524.3).

[0604] Intermediate compound 122: [ka] A mixture of intermediate compound 121 (55 mg, 0.1 mmol, 1.0 equiv) and Pd / C (5 mg) in MeOH (5 mL) was stirred under H (3 atm) for 2 h at room temperature. The resulting mixture was then filtered, the solid was washed with MeOH (5 mL), and the filtrate was concentrated under reduced pressure. The crude intermediate compound 122 (43 mg) was used directly in the next step without further purification. LC-MS(ES+) m / z: 422 (M+H)+ (calculated: 421.4).

[0605] Intermediate compound 123: [ka] To a stirred solution of (2S)-2-{bis[3,5-bis(trifluoromethyl)phenyl][(trimethylsilyl)oxy]methyl}pyrrolidine (0.26 g, 0.44 mmol, 0.1 equiv) and benzoic acid (0.05 g, 0.44 mmol, 0.1 equiv) in toluene (2.3 mL) was added intermediate compound 107 (1.0 g, 4.4 mmol, 1.0 equiv) followed by benzaldoxime (1.6 g, 13.1 mmol, 3.0 equiv) at 0° C. The resulting mixture was stirred at 0° C. for 4 h and then diluted with DCM (15.3 mL). Then, tert-butyl 1,4-diazepane-1-carboxylate (1.23 g, 6.1 mmol, 1.4 equiv.) was added, and the resulting mixture was stirred at room temperature for 1 h, followed by the addition of NaBHCN (0.55 g, 8.8 mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 1 h, then quenched with saturated NH4Cl (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / THF: 8 / 2 to 0 / 10) to give intermediate compound 123 (600 mg, 26% yield) as a yellow oil. LC-MS(ES+) m / z: 522 (M+H)+ (calculated: 521.4).

[0606] Intermediate compound 124: [ka] Intermediate compound 124 (2.1 g, 47% yield), a pale yellow oil, was synthesized from tert-butyl N-(2-aminoethyl)-N-methylcarbamate (2.14 g, 12.3 mmol, 1.4 equiv.) using the protocol described for intermediate compound 123. LC-MS(ES+) m / z: 508 (M+H)+ (calculated: 507.3).

[0607] Intermediate compound 125: [ka] To a stirred mixture of intermediate compound 124 (2.1 g, 4.1 mmol, 1.0 equiv) in MeOH (40 mL) was added (CHO)n (0.91 g) in several portions at room temperature. The resulting mixture was stirred at room temperature for 2 h under N2. Then, NaBH3CN (0.78 g, 12.4 mmol, 3.0 equiv) was added in several portions, and the resulting mixture was stirred at room temperature for another 2 h. The reaction was quenched with 50 mL of saturated NH4Cl and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / THF: 5 / 1 to 1 / 1) to give intermediate compound 125 (2.1 g, 97% yield) as a pale yellow oil. LC-MS(ES+) m / z: 522 (M+H)+ (calculated: 521.4).

[0608] Intermediate compounds 126 and 127: [ka] To a stirred solution of intermediate compound 123 (500 mg, 0.96 mmol, 1.0 equiv) and DIEA (619 mg, 4.8 mmol, 5.0 equiv) in DCM (10 mL) was added TMSOTf (639 mg, 2.9 mmol, 3.0 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 h, then quenched with 10 mL of NH4Cl and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to give intermediate compound 126 (450 mg, 89% yield) as a yellow oil. LC-MS(ES+) m / z: 422 (M+H)+ (calculated: 421.3). Using the same protocol, intermediate compound 127 (850 mg, 50% yield) was synthesized as a yellow oil from intermediate compound 125 (2.1 g, 4.0 mmol, 1.0 equiv). LC-MS(ES+) m / z: 422 (M+H)+ (calculated: 421.3).

[0609] Intermediate compounds 128 and 129: [ka] To a stirred solution of intermediate compound 126 (450 mg, 1.1 mmol, 1.0 equiv.) and intermediate compound 13 (375 mg, 1.2 mmol, 1.1 equiv.) in MeCN (10 mL) was added KCO (221 mg, 1.6 mmol, 1.5 equiv.) at room temperature. The resulting mixture was stirred at 50 °C for 16 h, then allowed to cool to room temperature and filtered. The solid was washed with MeCN (3 × 10 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / THF 10 / 1 / to 3 / 1) to give intermediate compound 128 (500 mg, 71% yield) as a brown oil. LC-MS(ES+) m / z: 660 (M+H)+ (calculated: 659.4). Using the same protocol, intermediate compound 129 (1.4 g, 84% yield) was synthesized as a brown oil from intermediate compound 127 (850 mg, 2.0 mmol, 1.0 equiv). LC-MS(ES+) m / z: 660 (M+H)+ (calculated: 659.4).

[0610] Intermediate Compounds 130 and 131: [ka] To a stirred solution of intermediate compound 128 (600 mg, 0.9 mmol, 1.0 equiv) in DCM (10 mL) was added HCl (2 M, 10 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h, after which the organic layer was separated. The aqueous layer was basified to pH = 8 with saturated NaHCO3 and extracted with DCM (3 × 50 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (column, C18 silica gel; mobile phase, CH3CN and 0.05% TFA, 20% to 60% gradient in 10 min; detector, UV 254 nm) to give intermediate compound 130 (200 mg, 40% yield) as a colorless oil. LC-MS(ES+) m / z: 546 (M+H)+ (calculated: 545.3). Using the same protocol, intermediate compound 131 (500 mg, 43% yield) was synthesized as a yellow oil from intermediate compound 129 (1.4 g, 2.1 mmol, 1.0 equiv). LC-MS(ES+) m / z: 546 (M+H)+ (calculated: 545.3).

[0611] Intermediate compounds 132 and 133: [ka] To a stirred solution of intermediate compound 130 (160 mg, 0.3 mmol, 1.0 equiv.) and triphenylphosphine (231 mg, 0.9 mmol, 3.0 equiv.) in THF (5 mL) was added ADDP (222 mg, 0.9 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature under N for 1 h and then quenched with saturated NH4Cl (10 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (column, C18 silica gel; mobile phase, CH3CN and 0.05% TFA, 30% to 70% gradient in 10 min; detector, UV 254 nm) to give intermediate compound 132 (56 mg, 36% yield) as a pale yellow oil. LC-MS(ES+) m / z: 528 (M+H)+ (calculated: 527.3). Using the same protocol, intermediate compound 133 (300 mg, 62% yield) was synthesized as a pale yellow oil from intermediate compound 131 (500 mg, 0.9 mmol, 1.0 equiv). LC-MS(ES+) m / z: 528 (M+H)+ (calculated: 527.3).

[0612] Intermediate compounds 134 and 135: [ka] A mixture of intermediate compound 132 (46 mg, 0.09 mmol, 1.0 equiv) and Pd / C (20 mg) in MeOH (5 mL) was stirred under H (3 atm) for 2 h at room temperature. The resulting mixture was then filtered, the solid was washed with MeOH (5 mL), and the filtrate was concentrated under reduced pressure to give intermediate compound 134 (27 mg, 73% yield) as a pale yellow oil. LC-MS(ES+) m / z: 425 (M+H)+ (calculated: 424.3). 1H NMR(300MHz,DMSO-d6)δppm 8.22(s,1H),7.32(s,1H),7.22(s,1H),4.27-3.99(m,4H),3.83(s,3H),3.8 0-3.76 (m, 4H), 2.92-2.87 (m, 1H), 2.75-2.46 (m, 11H), 1.97-1.88 (m, 10H). Using the same protocol, intermediate compound 135 (200 mg, 74% yield) was synthesized as a pale yellow oil from intermediate compound 133 (300 mg, 0.57 mmol, 1.0 equiv). LC-MS(ES+) m / z: 425 (M+H)+ (calculated: 424.3).

[0613] Intermediate compound 136: [ka] A solution of compound 38 (300 mg, 0.69 mmol, 1.0 equiv.) and SOCl2 (409 mg, 3.4 mmol, 5.0 equiv.) in DCM (10 mL) was stirred at room temperature for 3 h. The resulting mixture was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: C18-I, 20-40 μm; mobile phase A: water: 0.05% TFA; mobile phase B: ACN; flow rate: 80 mL / min; gradient: 10% B to 60% B in 7 min, 55% B; detectors at 254 nm and 220 nm) to give intermediate compound 136 (230 mg, 74% yield) as a colorless oil. LC-MS(ES+) m / z: 455 (M+H)+ (calculated: 454.2). 1HNMR(300MHz,CDCl3)δppm 7.33(s,1H),7.21(s,1H),4.44-4.42(m,2H),4.20-40.9(m,3H),3.94-3.84(m,7H),3.74-3.13(m,11H),2.32-1.98(m,10H).

[0614] Intermediate compound 137: [ka] To a stirred solution of compound 38 (100 mg, 0.23 mmol, 1.0 equiv) and TEA (35 mg, 0.34 mmol, 1.5 equiv) in DCM (3 mL) at 0 °C under nitrogen was added MsCl (32 mg, 0.28 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 1 h, then diluted with DCM (5 mL) and washed with water (3 × 2 mL). The organic layer was dried over NaSO and evaporated under reduced pressure. The crude intermediate 137 (110 mg, 93% yield) was used without purification. LC-MS(ES+) m / z: 515 (M+H)+ (calculated: 514.2).

[0615] Example I.2. Synthesis of Final Compounds Compound 1: [ka] Compound 1 was separated from compound 5 by preparative SFC according to the conditions of chiral SFC method A. LCMS (ESI position ion) m / z: 631.5 (M+H)+ (calculated: 630.3) SFC: retention time = 1.392 min, ee = 97.46% 1H NMR(400MHz,MeOD)δ7.42(d,J=1.7Hz,1H),7.36-7.30(m,3H),5.58(br d,J=5.0Hz,1H),4.45-4.33(m,2H),4.31-4.23(m,1H),4.10-3.98(m,1H),3.90-3.84(m,9H),3.82(d,J=2 .7Hz,6H),3.14-3.03(m,1H),2.96-2.77(m,4H),2.74-2.66(m,3H),2.66-2.51(m,4H),2.10-1.76(m,10H)

[0616] Compound 2: Compound 2 was separated from compound 5 by preparative SFC according to the conditions of chiral SFC method A. LCMS (ESI position ion) m / z: 631.4 (M+H)+ (calculated: 630.3) SFC: retention time = 0.576 min, ee = 100% 1H NMR(400MHz,MeOD)δ7.41(d,J=1.7Hz,1H),7.32(s,3H),5.64-5.51(m,1H),4.42-4.32(m,2H),4.31-4.22(m,1H),4.08-3.98(m,1H),3. 90-3.84(m,9H),3.82(d,J=2.6Hz,6H),3.14-3.03(m,1H),2.96-2.76(m,4H),2.75-2.66(m,3H),2.65-2.49(m,4H),2.09-1.76(m,10H)

[0617] Compound 3: [ka] To a solution of intermediate compound 22 (40 mg, 61.76 μmol, 1 equiv.) in DCM (2 mL) was added EDCI (35.52 mg, 185.24 μmol) and DMAP (22.64 mg, 185.24 μmol) at 20° C. The resulting mixture was stirred at 20° C. for 12 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 3 (11.8 mg, 30% yield) as a pale yellow solid. LCMS (ESI position ion) m / z: 630.3 (M+H)+ (calculated: 629.3) 1H NMR(400MHz,CDOD3)δppm 7.29-7.43(m,2H),7.22(s,2H),4.59-4.76(m,1H),4.04-4.56(m,5H),3.36-4.03(m,23H),1.60-2.64(m,10H).

[0618] Compound 4: [ka] To a solution of intermediate compound 17 (50 mg, 73.02 μmol, 1 equiv) in toluene (12.5 mL) was added EtN (44.33 mg, 438.14 μmol, 60.98 μL, 6 equiv) and 2,4,6-trichlorobenzoyl chloride (89.05 mg, 365.11 μmol, 57.08 μL, 5 equiv). The mixture was stirred at 20° C. for 1 h. The mixture was diluted with toluene (25 mL), and a solution of DMAP (103.48 mg, 847.06 μmol, 11.6 equiv) in toluene (12.5 mL) was added. The mixture was stirred at 90° C. for 12 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (SiO, petroleum ether / EtOAc = 1 / 5, Rf = 0.55) to give compound 4 (25 mg, 51% yield) as a white solid. LCMS (ESI position ion) m / z: 667.3 (M+H)+ (calculated: 666.3) 1H NMR:(400MHz,MeOD)δ7.47(d,J=1.8Hz,1H),7.36(s,1H),7.32(s,2H),5.60(br s,1H),4.52-4.31(m,3H),4.13(br s,1H),3.91-3.87(m,9H),3.84(d,J=1.0Hz,6H),3.14-2.58(m,11H),2.17-1.71(m,9H)

[0619] Compound 5: [ka] To a solution of intermediate compound 12 (50 mg, 77.07 μmol) in dichloromethane (3 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (44.32 mg, 231.22 μmol) and dimethylaminopyridine (28.25 mg, 231.22 μmol) at 20° C. The reaction mixture was stirred at 25° C. for 6 h. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give compound 1 (6.2 mg, 12% yield) as a white solid. LCMS (ESI position ion) m / z: 631.3 (M+H)+ (calculated: 631.3). 1H NMR(400MHz,CD3OD-d4)1.76-2.13(m,11H),2.53-2.67(m,4H),2.67-3.02(m,7H),3.82(d,J=2. 69Hz,6H),3.84-3.90(m,9H),4.02-4.10(m,1H),4.25-4.33(m,1H),4.34-4.44(m,2H),5.59(br s,1H),7.33(s,3H),7.44(s,1H)

[0620] Compound 6: Compound 6 was separated from compound 4 by preparative SFC according to the conditions of chiral SFC method A. LCMS (ESI position ion) m / z: 667.3 (M+H)+ (calculated: 666.3) SFC: retention time = 1.727 min, ee = 98.95% 1H NMR(400MHz,MeOD)δ7.45(d,J=1.8Hz,1H),7.34(d,J=1.7Hz,1H),7.30(s,2H),5.56(br d,J=5.5Hz,1H),4.45-4.29(m,3H),4.16-4.06(m,1H),3.96-3.84(m,9H),3.82(d,J=1.2Hz,6H),3.24(br t,J=13.9Hz,2H),3.10-2.87(m,6H),2.87-2.79(m,1H),2.79-2.59(m,3H),2.09-1.75(m,8H)

[0621] Compound 8: [ka] To a solution of intermediate compound 26 (380 mg, 586.64 umol, 1 equiv) in DCM (120 mL) was added EDCI (337.38 mg, 1.76 mmol, 3 equiv) and DMAP (286.68 mg, 2.35 mmol, 4 equiv). The reaction was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was diluted with HO (60 mL) and then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was dissolved in DMF (5 mL) and then purified by Prep-HPLC (Column: Phenomenex Synergi C18 150 × 25 mm × 10 μm; Mobile phase: [water (0.225% FA)-ACN]; B%: 8%-38%, 10 min) to give compound 8 (150 mg, 41% yield) as a white solid. LCMS (ESI position ion) m / z: 630.3 (M+H)+ (calculated: 629.3) 1H NMR(400MHz,CD3OD-d4)δ7.34(s,2H),7.22(d,J=2.0Hz,1H),7.13(d,J=2.0Hz,1H),5.52(br d,J=6.2Hz,1H),4.38-4.28(m,1H),4.25-4.16(m,1H),3.92-3.87(m,9H),3.85(s,3H),3.83(s,3H) ),3.68-3.58(m,1H),3.51-3.41(m,1H),3.04-2.95(m,1H),2.89-2.54(m,11H),2.01-1.73(m,10H)

[0622] Compound 9: [ka] Compound 9 was separated from compound 8 by preparative SFC according to the conditions of chiral SFC method B. LCMS (ESI position ion) m / z: 630.6 (M+H)+ (calculated: 629.3) SFC: retention time = 4.099 min, ee = 95.48% 1H NMR(400MHz,MeOD)δ7.36-7.30(m,3H),7.21(d,J=1.8Hz,1H),5.43(br d,J=3.9Hz,1H),4.42-4.31(m,1H),4.27-4.16(m,1H),3.89(s,3H),3.85(s,6H),3.8 1(d,J=6.1Hz,6H),3.72-3.61(m,1H),3.53-3.44(m,1H),3.14-2.97(m,4H),2.94(br t,J=6.4Hz,2H),2.90-2.78(m,4H),2.74(br t,J=6.7Hz,2H),2.16-2.04(m,1H),2.00-1.89(m,9H)

[0623] Compound 10: Compound 10 was separated from compound 8 by preparative SFC according to the conditions of chiral SFC method B. LCMS (ESI position ion) m / z: 630.6 (M+H)+ (calculated: 629.3) SFC: retention time = 6.989 min, ee = 95.48% 1H NMR(400MHz,MeOD)δ7.32(s,2H),7.20(d,J=1.7Hz,1H),7.16(d,J=1.6Hz,1H),5.48(br d,J=5.7Hz,1H),4.36-4.27(m,1H),4.23-4.14(m,1H),3.90-3.85(m,9H),3.82(d ,J=7.2Hz,6H),3.67-3.58(m,1H),3.49-3.40(m,1H),3.03-2.95(m,1H),2.89(br t,J=5.2Hz,2H),2.86-2.77(m,3H),2.76-2.63(m,4H),2.59(br t,J=6.5Hz,2H),2.01-1.87(m,5H),1.87-1.72(m,5H)

[0624] Compound 11: [ka] To a solution of intermediate compound 31 (700 mg, 1.06 mmol, 1 equiv.) in DCM (200 mL) was added EDCI (608.31 mg, 3.17 mmol, 3 equiv.) and DMAP (516.90 mg, 4.23 mmol, 4 equiv.). The reaction was stirred at 25 °C for 12 h. The mixture was then concentrated in vacuo to give an oil. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150 × 50 mm × 10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 37%-67%, min) to give compound 11 (220 mg, 32% yield) as a white solid. LCMS (ESI position ion) m / z: 644.6 (M+H)+ (calculated: 643.3) 1H NMR (400MHz, methanol-d4) δ7.32(s,2H),6.79-6.69(m,2H),5.54-5.46(m,1H),4.33-4.24(m,1H),4.19-4.10(m,1H),3.87(d,J=9 .4Hz,9H),3.84-3.79(m,6H),3.55-3.44(m,1H),3.40-3.32(m,1H),3.12-3.02(m,3H),2.74-2.39(m,12H),2.06-1.49(m,10H)

[0625] Compound 12: [ka] Compound 12 was separated from compound 11 by preparative SFC according to the conditions of chiral SFC method A. LCMS (ESI position ion) m / z: 644.6 (M+H)+ (calculated: 643.3) SFC: retention time = 2.653 min, ee = 100% 1H NMR(400MHz,MeOD-d4)δ7.32(s,2H),6.79-6.69(m,2H),5.59-5.43(m,1H),4.33-4.11(m,2H),3.87(d,J=9.3Hz,9H) ,3.85-3.78(m,6H),3.55-3.45(m,1H),3.40-3.34(m,1H),3.15-3.03(m,3H),2.78-2.41(m,12H),2.07-1.49(m,10H)

[0626] Compound 13: Compound 13 was separated from compound 11 by preparative SFC according to the conditions of chiral SFC method A. LCMS (ESI position ion) m / z: 644.6 (M+H)+ (calculated: 643.3) SFC: retention time = 3.358 min, ee = 99.12% 1H NMR(400MHz,MeOD-d4)δ7.32(s,2H),6.79-6.69(m,2H),5.59-5.43(m,1H),4.33-4.11(m,2H),3.87(d,J=9.3Hz,9H) ,3.85-3.78(m,6H),3.55-3.45(m,1H),3.40-3.34(m,1H),3.15-3.03(m,3H),2.78-2.41(m,12H),2.07-1.49(m,10H)

[0627] Compound 14: [ka] To a solution of intermediate compound 42 (6 mg, 14.30 μmol, 1 equiv) in DCM (1 mL) was added 3,4,5-trimethoxybenzoyl chloride (16.49 mg, 71.50 μmol, 5 equiv) and EtN (10.13 mg, 100.11 μmol, 13.93 μL, 7 equiv). The mixture was stirred at 25 °C for 12 h under N. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (Column: Waters Atlantis T3 150 × 30 mm × 5 μm; Mobile phase: [water (0.225% FA)-ACN]; B%: 10% to 40%, 10 min) to give compound 14 (2.2 mg, 25% yield) as an off-white solid. LCMS (ESI position ion) m / z: 614.4 (M+H)+ (calculated: 613.3) 1H NMR(400MHz,MeOD-d4)δ7.50-7.44(m,1H),7.41-7.37(m,1H),7.33-7.28(m,2H),5.34-5.20(m,2H),3.91-3.86(m,3H),3.86-3.82(m,6H),3.74- 3.63(m,1H),3.54-3.38(m,2H),3.29-3.17(m,5H),3.12-2.99(m,1H),2. 86-2.76(m,6H),2.59-2.41(m,2H),2.08-1.82(m,7H),1.78-1.54(m,4H)

[0628] Compound 15 and Compound 16: [ka] A mixture of intermediate compound 52 (120 mg, 175.79 μmol, 1 equiv., HCl), EDCI (101.10 mg, 527.37 μmol, 3 equiv.), and DMAP (85.90 mg, 703.16 μmol, 4 equiv.) in DCM (10 mL) was stirred for 1 h at 30° C. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane (2×10 mL). The combined organic phases were concentrated to dryness in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B%: 50%–80%, 9 min), followed by chiral separation by SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O MEOH]; B%: 45%–45%, 6.1 min; 45 min) to give compound 15 (21.7 mg, 19% yield) and compound 16 (16 mg, 15% yield) as colorless oils. Compound 15: LCMS (ESI position ion) m / z: 628.2 (M+H)+ (calculated: 627.3) SFC: retention time = 1.106 min, ee = 100% 1H NMR(400MHz,MeOD-d4)δ8.17(s,1H) 8.13(s,1H) 7.63(s,1H) 7.28(s,2H) 5.33-5.44(m,1H) 4.52-4.68(m,2H) 4.30(br s,1H) 4.10-4.26(m,1H) 3.86(s,6H) 3.82(s,3H) 3.67-3.73(m,1H) 3.49-3.58(m,1H) 2.94(br s,2H) 2.91(br d,J=5.25Hz,5H) 2.69(br d,J=4.50Hz,1H) 2.62(br dd,J=10.76,5.25Hz,1H) 2.47(br d,J=6.63Hz,2H) 2.16(dt,J=13.98,6.96Hz,1H) 1.92(br s,3H) 1.78-1.86(m,3H) 1.67-1.74(m,1H) 1.53-1.63(m,1H) Compound 16: LCMS (ESI position ion) m / z: 628.2 (M+H) + (calculated value: 627.3) SFC: Holding time = 1.796 minutes, ee = 98.75% 1H NMR(400MHz,MeOD-d4)δ8.12(d,J=5.38Hz,2H) 7.63(s,1H) 7.27(s,2H) 5.26-5.37(m,1H) 4.52-4.68(m,2H) 3.86(s,6H) 3.82(s,3H) 3.64-3.73(m,1H) 3.40-3.49(m,1H) 2.68-2.81(m,6H) 2.59(br t,J=5.19Hz,2H) 2.48-2.55(m,2H) 2.29-2.39(m,2H) 2.09-2.23(m,1H) 1.92-2.04(m,1H) 1.75-1.89(m,4H) 1.64-1.75(m,3H) 1.53-1.62(m,1H)

[0629] Compound 17 and compound 18:

change

[0630] Compound 19 and Compound 20: [ka] A mixture of intermediate compound 71 (70 mg, 131.07 μmol, 1 equiv., HCl), DMAP (64.05 mg, 524.26 μmol, 4 equiv.), and EDCI (75.38 mg, 393.20 μmol, 3 equiv.) in DCM (50 mL) was stirred at 30 °C for 12 h. The reaction mixture was washed with water (20 mL), and the organic phase was concentrated to dryness under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 38%–68%, 8 min) to give the racemic compound as a yellow solid. The racemate was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O MeOH]; B%: 50% to 50%, 5.3; 15 min) to give compound 19 (4.3 mg, 7% yield) as a colorless oil and compound 20 (5.8 mg, 9% yield) as a colorless oil. Compound 19: LCMS (ESI position ion) m / z: 480.3 (M+H)+ (calculated: 479.3) SFC: retention time = 1.221 min, ee = 100% 1H NMR(400MHz,MeOD-d4)δ7.98-8.03(m,2H) 7.58-7.64(m,1H) 7.45-7.51(m,2H) 7.37-7.44(m,2H) 7.35(d,J=1.63Hz,1H) 7.11(dt,J=7.75,1.94Hz,1H) 5.41(quartet,J=5.94Hz,1H) 4.13-4.26(m,2H) 3.54-3.62(m,1H) 3.45-3.53(m,1H) 2.88-2.97(m,1H) 2.71-2.83(m,7H) 2.57-2.68(m,4H) 1.86-2.04(m,6H) 1.80(dt,J=11.69,5.78Hz,2H) 1.69-1.76(m,2H) Compound 20: LCMS (ESI position ion) m / z: 480.3 (M+H)+ (calculated: 479.3) SFC: retention time = 1.684 min, ee = 99% 1H NMR(400MHz,MeOD-d4)δ8.01(d,J=7.13Hz,2H) 7.58-7.64(m,1H) 7.45-7.51(m,2H) 7.36-7.44(m,2H) 7.35(s,1H) 7.11(dt,J=7.75,1.88Hz,1H) 5.41(br t,J=5.88Hz,1H) 4.12-4.26(m,2H) 3.54-3.62(m,1H) 3.45-3.53(m,1H) 2.88-2.98(m,1H) 2.72-2.83(m,7H) 2.58-2.68(m,4H) 1.87-2.04(m,6H) 1.78-1.85(m,2H) 1.69-1.76(m,2H)

[0631] Compound 21: [ka] A suspension of intermediate compound 80 (50 mg, 76.04 μmol, 1 equiv.), DMAP (37.16 mg, 304.15 μmol, 4 equiv.), and EDCI (43.73 mg, 228.11 μmol, 3 equiv.) in DCM (50 mL) was stirred at 30° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM / MeOH (10 / 1, 20 mL) and washed with HO (30 mL). The aqueous layer was extracted with DCM / MeOH (10 / 1, 2×20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 26%-56%, 10 min) to give compound 21 (1.5 mg, 2% yield) as a white solid. LCMS (ESI position ion) m / z: 639.2 (M+H)+ (calculated: 638.2) 1H NMR(400MHz,MeOD-d4)δ8.60-8.49(m,1H),7.74(d,J=1.5Hz,1H),7.71-7.67(m,1H),7.33-7.31(m,2H),5.61- 5.52(m,1H),4.59-4.51(m,1H),4.48-4.32(m,2H),4.22-4.13(m,1H),3.87(s,6H),3.83-3.82(m,3H),3.23(br s,4H),3.02-2.92(m,1H),2.88-2.82(m,1H),2.79-2.71(m,1H),2.65- 2.59(m,4H),2.27-2.13(m,2H),2.06-1.97(m,3H),1.93-1.86(m,6H).

[0632] Compound 22 and Compound 23: [ka] The enantiomers of compound 21 were separated by chiral SFC (column: DAICEL CHIRALPAK AD-H (250 mm × 30 mm, 5 μm); mobile phase: [0.1% NH₃H₂O ETOH]; B%: 35% to 35%, 3.6; 40 min) to give compound 22 (11.4 mg, 4% yield) as a pale yellow solid and compound 23 (11.1 mg, 4% yield) as a pale yellow solid. Compound 22: LCMS (ESI position ion) m / z: 639.2 (M+H)+ (calculated: 638.2) SFC: retention time = 1.507 min, ee = 86.7% 1H NMR(400MHz,MeOD-d4)δ7.71-7.68(m,1H),7.65-7.62(m,1H),7.32(s,2H),5.61-5.52(m,1H),4.56-4.48(m,1H),4.4 5-4.38(m,1H),4.38-4.31(m,1H),4.13(dt,J=4.4,9.0Hz,1H),3.86(s,6H),3.82(s,3H),3.25-3.08(m,4H),2.95(br t,J=9.3Hz,1H),2.89-2.81(m,1H),2.80-2.71(m,1H),2.65-2.57(m,4H),2.25-2.12(m,2H),2.02-1.81(m,9H). Compound 23: LCMS (ESI position ion) m / z: 639.2 (M+H)+ (calculated: 638.2) SFC: retention time = 2.089 min, ee = 96.2% 1H NMR(400MHz,MeOD-d4)δ7.71-7.67(m,1H),7.62-7.59(m,1H),7.31(s,2H),5.61-5 .52(m,1H),4.53-4.43(m,1H),4.43-4.34(m,1H),4.33-4.24(m,1H),4.12-4.03(m ,1H),3.86(s,6H),3.82(s,3H),3.11-3.01(m,1H),2.95-2.76(m,4H),2.71-2.66( m, 1H), 2.72-2.66 (m, 2H), 2.58-2.48 (m, 3H), 2.06-1.85 (m, 8H), 1.84-1.76 (m, 3H).

[0633] Compounds 24, 27, 29, 30, 110, 111, and Compounds 41 to 106: [ka] Compounds 24, 27, 29, 30, 110, 111, 41 to 54 to 106, summarized in the table below, were synthesized according to the following general procedure: To a solution of compound 38 (30 mg, 0.068 mmol, 1.0 equiv.) in DCM (2 mL) was added DMAP (12.4 mg, 0.10 mmol, 1.5 equiv.), EDC.HCl (19.5 mg, 0.10 mmol, 1.5 equiv.), and the required carboxylic acid (24.1 mg, 0.10 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 16 h, then quenched with water and extracted with DCM. The organic layer was concentrated in vacuo. The residue was purified by preparative HPLC to give the desired compound. In the case of Compound 41 and Compound 55, the benzyl protected compounds obtained from the above general procedure were isolated after benzyl deprotection according to the following general procedure: To a solution of the benzyl ether (20 mg, 0.03 mmol, 1.0 equiv.) in ethanol (10 mL) was added Pd / C (2 mg). The reaction mixture was stirred at room temperature for 30 minutes under 1 atm of H2. After the reaction was complete, the mixture was filtered to remove the catalyst, and the resulting solution was concentrated in vacuo. The crude product was then purified by preparative HPLC to give the desired compound. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Table 5-12]

[0634] Compound 25 and Compound 26: [ka] A mixture of intermediate compound 56 (220 mg, 322.28 μmol, 1 equiv., HCl), EDCI (185.34 mg, 966.84 μmol, 3 equiv.), and DMAP (157.49 mg, 1.29 mmol, 4 equiv.) in DCM (100 mL) was stirred at 30 °C for 3 h. The reaction mixture was poured into water (100 mL), extracted with DCM (100 mL), and the combined organic phase was concentrated to dryness under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 47%–77%, 9 min). The enantiomers were separated by SFC (Column: REGIS(s,s)WHELK-O1 (250 mm × 50 mm, 10 μm); Mobile phase: [0.1% NH3HO MeOH]; B%: 50% to 50%, 6 min; 75 min) to give compound 25 (10.6 mg, 5% yield) as a white solid and compound 26 (15.3 mg, 7% yield) as a white solid. Compound 25: LCMS (ESI position ion) m / z: 628.3 (M+H)+ (calculated: 627.3) SFC: retention time = 0.855 min, ee = 98.6% 1H NMR(400MHz,MeOD-d4)δ=8.46(s,1H) 8.00(s,1H) 7.47(s,1H) 7.28(d,J=0.75Hz,2H) 4.96(quadruple line,J=5.47Hz,1H) 4.60(br t,J=5.32Hz,2H) 3.86(d,J=0.88Hz,6H) 3.82(d,J=1.00Hz,3H) 3.59(br t,J=5.13Hz,2H) 2.71-2.80(m,6H) 2.64(br d,J=4.13Hz,2H) 2.46(br d,J=5.50Hz,2H) 2.24-2.36(m,1H) 2.08-2.20(m,1H) 2.00-2.07(m,1H) 1.92-1.99(m,1H) 1.72-1.85(m,6H) 1.40(br d,J=7.25Hz,2H) Compound 26: LCMS (ESI position ion) m / z: 628.3 (M+H) + (calculated value: 627.3) SFC: Holding time = 1.158 minutes, ee = 97.9% 1H NMR(400MHz,MeOD-d4)δ=8.46(s,1H) 8.00(s,1H) 7.47(d,J=0.88Hz,1H) 7.28(s,2H) 4.96(t,J=5.88Hz,1H) 4.60(t,J=5.57Hz,2H) 3.86(s,6H) 3.82(s,3H) 3.59(t,J=5.38Hz,2H) 2.71-2.79(m,6H) 2.64(br d,J=4.13Hz,2H) 2.46(br d,J=5.38Hz,2H) 2.25-2.35(m,1H) 2.10-2.19(m,1H) 2.00-2.09(m,1H) 1.90-1.98(m,1H) 1.81-1.87(m,2H) 1.76-1.80(m,4H) 1.36-1.44(m,2H)

[0635] Compound 121 and compound 28:

change

[0636] Compound 31: [ka] A mixture of compound 38 (120 mg, 0.28 mmol, 1.0 equiv.), DMAP (50.4 mg, 0.41 mmol, 1.5 equiv.), EDC.HCl (64.0 mg, 0.41 mmol, 1.5 equiv.), and benzoic acid (50.4 mg, 0.41 mmol, 1.5 equiv.) in DCM (3 mL) was stirred at room temperature for 16 h. The reaction was quenched with HO (2 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: Atlantis Prep T3 OBD column, 19 × 150 mm 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 15% B to 35% B in 7 min, 35% B; Wavelength: 220 nm) to give compound 31 (HCOOH salt, 63 mg, 42% yield) as a white solid. LC-MS (ES+) m / z: 541 (M+H)+ (calculated value: 540.3) 1H NMR(300MHz,DMSO-d6)δ8.25(s,1H),7.98-7.95(m,2H),7.68-7.63(m,1H),7.54-7.49(m,2H),7.33(s,1H),7.23(s,1H),5.43( br,1H),4.32-4.25(m,3H),4.19-4.30(m,1H),3.83(s,3H),3.72(s,3H),2.96(br,1H),2.73-2.51(m,11H),1.86-1.74(m,10H).

[0637] Compound 32 and Compound 33: [ka] The enantiomers of compound 31 (50 mg) were separated by Chiral HPLC using the following conditions: Column: CHIRAL ART Cellulose-SB, 3 × 25 cm, 5 μm; Mobile phase: A: Hex (0.1% 2 M NH3-MeOH)-HPLC; B: EtOH-HPLC; Flow rate: 5 mL / min; Gradient: 50% B to 50% B in 18 min; Detection: 220 / 254 nm; RT1 (min): 10; RT2 (min): 13. Chiral separation afforded compound 32 (20 mg, 40% yield) as a white solid and compound 33 (17 mg, 34% yield) as a white solid. Compound 32: LC-MS (ES+) m / z: 541 (M+H)+ (calculated value: 540.3) Chiral HPLC: retention time = 2.67 min, ee = 99.8% 1H NMR(300MHz,DMSO-d6)δppm 7.98-7.95(m,2H),7.68-7.63(m,1H),7.54-7.49(m,2H),7.33(s,1H),7.23(s,1H),5.43(br,1H),4.32-4.25 (m,3H),4.19-4.30(m,1H),3.83(s,3H),3.72(s,3H),2.96(br,1H),2.73-2.51(m,11H),1.86-1.74(m,10H). Compound 33: LC-MS (ES+) m / z: 541 (M+H)+ (calculated value: 540.3) Chiral HPLC: retention time = 3.63 min, ee = 99.8% 1H NMR(300MHz,DMSO-d6)δppm 7.98-7.95(m,2H),7.68-7.63(m,1H),7.54-7.49(m,2H),7.33(s,1H),7.23(s,1H),5.43(br,1H),4.32-4.25 (m,3H),4.19-4.30(m,1H),3.83(s,3H),3.72(s,3H),2.96(br,1H),2.73-2.51(m,11H),1.86-1.74(m,10H).

[0638] Compound 34: [ka] A mixture of intermediate compound 122 (40 mg, 0.10 mmol, 1.0 equiv.), DMAP (17.4 mg, 0.14 mmol, 1.5 equiv.), EDC.HCl (27 mg, 0.14 mmol, 1.5 equiv.), and 3,4,5-trimethoxybenzoic acid (30 mg, 0.14 mmol, 1.5 equiv.) in DCM (1 mL) was stirred at room temperature for 12 h. The reaction was then quenched with HO (1 mL), and the resulting mixture was extracted with DCM (2 × 5 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The crude residue was purified by preparative HPLC (Column: Atlantis Prep T3 OBD column, 19 × 150 mm 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 15% B to 35% B in 7 min, 35% B; Wavelength: 220 nm) to give compound 34 (HCOOH salt, 14 mg, 22% yield) as a white solid. LC-MS(ES+) m / z: 616 (M+H)+ (calculated value: 615.3) 1H NMR(300MHz,DMSO-d6)δppm 8.33(br,1H),7.34-7.24(m,4H),5.32(br,1H),4.32-3.98(m,4H),3.83(s,9H),3.73 (s,6H),2.83-2.77(m,2H),2.55-2.45(m,2H),2.03-1.79(m,8H),1.75-1.23(m,9H).

[0639] Compound 35: [ka] A mixture of intermediate compound 134 (27 mg, 0.06 mmol, 1.0 equiv), benzoic acid (11.7 mg, 0.1 mmol, 1.5 equiv), EDC.HCl (24.4 mg, 0.13 mmol, 2.0 equiv), and DMAP (19.42 mg, 0.16 mmol, 2.50 equiv) in DCM (2 mL) was stirred at room temperature for 2 h. The reaction was then quenched with a saturated solution of NH4Cl (2 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: SunFire Prep C18 OBD 5 um, 19 × 150 mm; mobile phase: CH3CN with 0.05% HCOOH, from 5% to 25% in 7 min; detector UV 254 nm) to give compound 35 (7 mg, 18% yield) as an off-white solid. LC-MS(ES+) m / z: 529 (M+H)+ (calculated value: 528.3) 1H NMR(300MHz,DMSO-d6)δppm 8.21(s,2H),7.97-7.94(m,2H),7.68-7.63(m,1H),7.54-7.49(m,2H),7.30(s,1H),7.25(s,1H),5.18(br,1H),4.32-4. 30(m,2H),4.18-4.16(m,2H),3.64(s,3H),3.61(s,3H),2.68-2.36(m,8H),2.21(s,3H),2.17(s,3H),1.86-1.64(m,8H).

[0640] Compound 36: [ka] A mixture of intermediate compound 135 (100 mg, 0.24 mmol, 1.0 equiv.), benzoic acid (585 mg, 0.47 mmol, 2.0 equiv.), EDC.HCl (68 mg, 0.35 mmol, 1.5 equiv.), and DMAP (58 mg, 0.47 mmol, 2.0 equiv.) in DCM (5 mL) was stirred at room temperature for 2 h. The reaction was then quenched with a saturated solution of NH4Cl (5 mL), and the resulting mixture was extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Column: SunFire Prep C18 OBD 5 μm, 19 × 150 mm, Mobile phase: MeCN with 0.1% NH₃.HO, 7% to 30% in 8 min; Detector: UV 254 nm), followed by preparative chiral HPLC (Column: XA-YMC Cellulose-SC, 4.6 × 100 mm, 3 μm; Mobile phase A: n-hexane:DCM (3:1) / IPA (0.1% DEA) 90 / 10; Flow rate: 1 mL / min; Gradient: 0% B to 0% B; Injection volume: 5 μl) to give compound 36 (40 mg, 32% yield) as an off-white solid. LC-MS(ES+) m / z: 529 (M+H)+ (calculated value: 528.3) CHIRAL-HPLC (Column: YMC Cellulose-SC, 100 x 4.6 mm, 3 um 119IA70110; Mobile phase: A: n-hexane / DCM = 3 / 1; B: isopropanol (0.1% DEA); Flow rate: 1 mL / min; Concentration of pump B: 10%; Detection: 254 nm; RT (min): 3.27; ee: 99.8%. 1H NMR(300MHz,DMSO-d6)δppm 7.96-7.93(m,2H),7.67-7.65(m,1H),7.53-7.51(m,2H),7.29(s,1H),7.24(s,1H),5.17(br,1H),4.31-4.26(m,2 H),4.17-4.15(m,2H),3.83(s,3H),3.73(s,3H),2.73-2.30(m,8H),2.17(s,3H),2.14(s,3H),1.83-1.66(m,8H).

[0641] Compound 37: [ka] A solution of DTAD (0.74 g, 3.0 mmol, 1.5 equiv) and n-butylphosphine (0.60 g, 3.0 mmol, 1.5 equiv) in anhydrous THF (20 mL) was stirred under nitrogen for 15 min, followed by the addition of a solution of intermediate compound 111 (1.1 g, 2.0 mmol, 1.0 equiv) in THF (13 mL). The mixture was stirred at 40 °C for 30 min and then quenched by the addition of HO (50 mL). The resulting solution was extracted with EtOAc (2 × 15 mL). The combined organic layers were dried over NaSO and concentrated. The residue was purified by preparative HPLC (column (C18-I, 20-40 μm); mobile phase (MeOH / HO = 30% to 100% in 7 min; 100% in 3 min; detectors (254 nm and 220 nm)) to give compound 37 (0.48 g, 45% yield) as an off-white solid. LC-MS(ES+) m / z: 540 (M+H)+ (calculated: 539.3). 1H NMR(300MHz,DMSO-d6)δ8.31(s,1H),7.57-7.55(m,2H),7.46-7.35(m,4H),7.32(s,1H),4.51-4.48(m,1H),4.32-4. 20(m,3H),4.11-4.05(m,1H),3.84(s,3H),3.74(s,3H),2.89-2.84(m,1H),2.72-2.54(m,11H),1.97-1.71(m,10H).

[0642] Compound 38: [ka] A suspension of compound 37 (300 mg, 0.56 mmol, 1.0 equiv.) and Pd / C (30 mg) in MeOH (5 mL) was stirred at room temperature under H2 (1 atm) for 2 h. The resulting mixture was then filtered, and the solid residue was washed with MeOH (15 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: Atlantis Prep T3 OBD Column, 19 × 150 mm, 5 μm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow Rate: 20 mL / min; Gradient: 15% B to 35% B in 7 min, 35% B; Wavelength: 220 nm) to give compound 38 (HCOOH salt, 166 mg, 62% yield) as an off-white solid. LC-MS (ES+) m / z: 437 (M+H)+ (calculated value: 436.2) 1H NMR(300MHz,DMSO-d6)δ8.22(s,1H),7.32(s,1H),7.22(s,1H),4.27-3.99(m,4H),3.83 (s,3H),3.80-3.76(m,4H),2.92-2.87(m,1H),2.75-2.46(m,11H),1.97-1.88(m,10H).

[0643] Compound 39: [ka] A solution of compound 119 (100 mg, 0.19 mmol, 1.0 equiv) and Pd / C (10 mg) in MeOH (4 mL) was stirred at room temperature for 2 hours under H2 (1 atm). The resulting mixture was filtered, and the solid was washed with MeOH (10 mL) and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Column: Atlantis Prep T3 OBD Column, 19 × 150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow Rate: 20 mL / min; Gradient: 15% B to 35% B in 7 min, 35% B; Wavelength: 220 nm) to give compound 39 (HCOOH salt, 55 mg, 62% yield) as an off-white solid. LC-MS(ES+) m / z: 437 (M+H)+ (calculated: 436.3). Chiral HPLC: retention time = 3.29 min, ee = 100% 1H NMR(300MHz,DMSO-d6)δppm 8.22(s,1H),7.32(s,1H),7.22(s,1H),4.27-3.99(m,4H),3.83(s,3H),3.8 0-3.76 (m, 4H), 2.92-2.87 (m, 1H), 2.75-2.46 (m, 11H), 1.97-1.88 (m, 10H).

[0644] Compound 40: [ka] Compound 40 (HCOOH salt, 55 mg, 62% yield) was obtained as an off-white solid from compound 120 following the procedure described for compound 39. LC-MS(ES+) m / z: 437 (M+H)+ (calculated: 436.3). Chiral HPLC: retention time = 3.89 min, ee = 99% 1H NMR(300MHz,DMSO-d6)δppm 8.22(s,1H),7.32(s,1H),7.22(s,1H),4.27-3.99(m,4H),3.83(s,3H),3.8 0-3.76 (m, 4H), 2.92-2.87 (m, 1H), 2.75-2.46 (m, 11H), 1.97-1.88 (m, 10H).

[0645] Compound 107 and Compound 118: [ka] To a solution of 1H-tetrazole,5-phenyl- (28 mg, 0.19 mmol, 1.5 equiv) in DMF (1.3 mL) was added KCO (35 mg, 0.25 mmol, 2.0 equiv) and the reaction mixture was stirred at 50° C. for 1 h. The mixture was cooled to room temperature and intermediate compound 137 (65 mg, 0.13 mmol, 1.0 equiv) was added. The resulting mixture was stirred at room temperature for 16 hours, then filtered, and the filtrate was purified by preparative HPLC (Column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm 10 nm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 18 mL / min; Gradient: 15% B to 40% B in 7 min, 40% B; Wavelength: 220 nm) to give Compound 108 (TFA salt, 8.1 mg, 11% yield) as an off-white solid and Compound 118 (TFA salt, 3.3 mg, 5% yield) as an off-white solid. Compound 108: LC-MS(ES+) m / z: 565 (M+H)+ (calculated: 564.3). 1H-NMR(400MHz,DMSO-d6)δppm 9.38(br,1H),8.07-8.05(m,2H),7.57-7.55(m,3H),7.44(s,1H),7.23(s,1H),5.37(br,1H),4.38-4.09(m,5H) ),3.83(s,3H),3.77(s,3H),3.73-3.56(m,6H),3.01(br,2H),2.77(br,1H),2.30-1.89(m,11H),1.51(br,1H). Compound 118: LC-MS(ES+) m / z: 565 (M+H)+ (calculated: 564.3). 1H-NMR(400MHz,DMSO-d6)δppm 9.70(br,1H),8.07-8.05(m,2H),7.57-7.55(m,3H),7.30-7.27(m,1H),7.20(s,1H),4.84-4.75(m,2H),4.27-4.11(m,5H),3.8 3(s,3H),3.73(s,3H),3.55-3.07(m,6H),2.91-2.67(m,3H),2.40(br,1H),2.32(br,1H),2.12-2.03(m,3H),1.84-1.56(m,6H).

[0646] Compound 108: [ka] A mixture of intermediate compound 136 (70 mg, 0.15 mmol, 1.0 equiv), KCO (42.5 mg, 0.31 mmol, 2.0 equiv), and 1H-1,2,3-triazole,4-phenyl- (33.5 mg, 0.23 mmol, 1.5 equiv) in DMF (2 mL) was stirred at 50 °C for 16 h. The reaction was then quenched with water (8 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (8 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Column: Sunfire Prep C18 OBD column, 50 × 250 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 65 mL / min; Gradient: 10% B to 45% B in 12 min, 45% B; Wavelength: 220 nm) to give 15 mg of compound 108 (TFA salt, 15 mg, 17% yield) as an off-white solid. LC-MS(ES+) m / z: 564 (M+H)+ (calculated: 563.3). 1HNMR(300MHz,DMSO-d6)δppm 9.81(br,1H),8.27(s,1H),7.85-7.82(m,2H),7.48-7.21(m,5H),4.69-4.54(m,2H), 4.27-4.18(m,4H),3.83(s,3H),3.73(s,3H),3.63-2.87(m,10H),2.21-1.45(m,11H).

[0647] Compound 110: [ka] Compound 117 (21 mg, 0.048 mmol, 1.0 equiv) was dissolved in DCM (0.4 mL) and DIEA (12.45 mg, 0.096 mmol, 2.0 equiv), DCC (19.91 mg, 0.096 mmol, 2.0 equiv), and benzoic acid (7.06 mg, 0.058 mmol, 1.2 equiv) were added at room temperature. The resulting solution was stirred at room temperature for 1 h. The reaction solution was diluted with HO (1 mL) and extracted with DCM (2 × 5 mL). The organic layer was dried over NaSO and concentrated. The residue was purified by preparative HPLC (Column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm 10 nm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 15% B to 40% B in 7 min, 40% B; Wavelength: 220 nm; RT: 6.9 min) to give 10 mg (32% yield) of compound 110 as an off-white solid. LC-MS (ES+) m / z: 540.4 (M+H)+, (calculated 539.3). 1H-NMR(300MHz,MeOH-d4)δppm1.96-2.35(m,10H),3.32-3.70(m,14H),3.85(s,3H),3.94(s,3H),4.30-4.35( m,2H),5.30-5.36(m,1H),7.28(s,1H),7.45(s,1H),7.49-7.53(m,2H),7.63-7.68(s,1H),8.05-8.08(s,2H).

[0648] Compound 114: [ka] To a stirred mixture of intermediate compound 114 (3.6 g, 6.5 mmol, 1.0 equiv.) and ADDP (3.24 g, 12.9 mmol, 2.0 equiv.) in THF (100 mL) under a nitrogen atmosphere, n-butylphosphine (2.62 g, 12.9 mmol, 2.0 equiv.) was added in several portions at room temperature. The resulting mixture was stirred at 40 °C for another 2 h and then allowed to cool to room temperature. The reaction was quenched with a saturated aqueous solution of NH4Cl (100 mL) at room temperature, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: C18-I, 20–40 μm; mobile phase: MeOH / HO = 30–100%, 7 min; 100%, 3 min; detectors at 254 nm and 220 nm) to give compound 114 (1.5 g, 43% yield) as a yellow oil. LC-MS(ES+) m / z: 539 (M+H)+ (calculated: 538.3). 1H-NMR(300MHz,MeOD-d4)δppm 8.09(s,1H),7.57-7.54(m,2H),7.37-7.33(m,3H),7.18-7.14(m,2H),4.50-4.49(m,1H),4.28-4 .24(m,2H),3.89(s,3H),3.84(s,3H),3.54-3.48(m,2H),2.84-2.54(m,12H),1.96-1.73(m,10H).

[0649] Compound 115 and Compound 116: [ka] The enantiomers of compound 114 (150 mg) were separated by SFC to give compound 115 (50 mg, 34% yield) and compound 116 (43 mg, 28% yield) according to the following conditions: column: CHIRAL ART Cellulose-SC, 5 × 25 cm, 5 μm; mobile phase A: HEX:DCM = 1:1 (0.1% DEA) - HPLC, mobile phase B: IPA (0.2% DEA); flow rate: 100 mL / min; gradient: 50% B to 50% B in 11 min; wavelength: 220 nm; RT1 (min): 10.0; sample solvent: IPA:DCM = 1:1; injection volume: 5 mL; number of runs: 25). Compound 115: LC-MS (ES+) m / z: 539 (M+H)+ (calculated value: 538.3) 1H-NMR(300MHz,MeOD-d4)δppm 8.09(s,1H),7.57-7.54(m,2H),7.37-7.33(m,3H),7.18-7.14(m,2H),4.50-4.49(m,1H),4.28-4 .24(m,2H),3.89(s,3H),3.84(s,3H),3.54-3.48(m,2H),2.84-2.54(m,12H),1.96-1.73(m,10H). Compound 116: LC-MS (ES+) m / z: 539 (M+H)+ (calculated value: 538.3) 1H-NMR(300MHz,MeO-d4)δppm 8.09(s,1H),7.57-7.54(m,2H),7.37-7.33(m,3H),7.18-7.14(m,2H),4.50-4.49(m,1H),4.28-4 .24(m,2H),3.89(s,3H),3.84(s,3H),3.54-3.48(m,2H),2.84-2.54(m,12H),1.96-1.73(m,10H). Compound 117: [ka] A mixture of compound 114 (100 mg, 0.19 mmol, 1.0 equiv) and palladium hydroxide on carbon (20 mg) in MeOH (5 mL) was stirred under an H atmosphere for 2 h at room temperature. The resulting suspension was filtered, the filtrate was concentrated under reduced pressure, and the crude product (100 mg) was purified by preparative HPLC (SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm 10 nm; mobile phase A: water (0.1% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 15% B to 38% B in 7.2 min, 40% B; wavelength: 220 nm; RT: 5.3 min) to give compound 117 (TFA salt, 49 mg, 50% yield) as a pale yellow solid. LC-MS (ES+) m / z: 436 (M+H)+, (calculated 435.3) 1H-NMR(300MHz,MeOD-d4)δppm 7.39(s,1H),7.24(s,1H),4.32-4.26(m,2H),3.91(s,4H),3.82(s,3H),3.67-3.30(m,14H),2.42-2.40(m,2H),2.12-1.69(m,8H).

[0650] Compound 119: [ka] Compound 119 was separated from compound 4 by preparative SFC according to the conditions of chiral SFC method A. LCMS (ESI position ion) m / z: 667.3 (M+H)+ (calculated: 666.3) SFC: retention time = 1.649 min, ee = 100% 1H NMR(400MHz,MeOD)δ7.46(d,J=1.8Hz,1H),7.34(d,J=1.6Hz,1H),7.30(s,2H),5.56(br d,J=4.4Hz,1H),4.45-4.28(m,3H),4.18-4.06(m,1H),3.93-3.84(m,9H),3.82(d,J=1.2Hz,6H),3.24(br t,J=13.9Hz,2H),3.09-2.87(m,6H),2.87-2.79(m,1H),2.78-2.60(m,3H),2.09-1.74(m,8H)

[0651] Compound 120: [ka] To a solution of intermediate compound 89 (30 mg, 45.03 umol, 1 equiv) in DCM (30 mL) was added DMAP (22.00 mg, 180.12 umol, 4 equiv) and EDCI (25.90 mg, 135.09 umol, 3 equiv). The reaction mixture was stirred at 30 °C for 4 h. MeOH (3 mL) and HO (50 mL) were added to the reaction mixture. The aqueous layer was extracted with DCM / MeOH (10 / 1, 2 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 12% to 42%, 10 min) to give compound 120 (1.7 mg, 5% yield) as a white solid. LCMS (ESI position ion) m / z: 648.3 (M+H)+ (calculated: 647.3) 1H NMR(400MHz,MeOD-d4)δ8.60-8.48(m,1H),7.81(s,1H),7.70(d,J=1.5Hz,1H),7.33(s ,2H),5.61-5.53(m,1H),4.60-4.54(m,1H),4.48-4.37(m,2H),4.20-4.14(m,1H),3.87 (s,6H),3.83(s,3H),3.47-3.40(m,1H),3.28-3.17(m,3H),3.12-3.04(m,1H),2.94-2. 88(m,1H),2.84-2.77(m,1H),2.68-2.58(m,4H),2.30-2.17(m,2H),2.01-1.84(m,9H).

[0652] Compound 122: [ka] To a solution of intermediate compound 103 (25 mg, 35.66 μmol, 1 equiv.) in DCM (10 mL) was added EDCI (20.51 mg, 106.98 μmol, 3 equiv.) and DMAP (17.43 mg, 142.64 μmol, 4 equiv.) at 25°C. The reaction mixture was then stirred at 25°C for 4 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 × 25 mm × 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 16%–46%, 10 min) to give compound 122 (22 mg, 90% yield) as an off-white solid. LCMS (ESI position ion) m / z: 682.3 (M+H)+ (calculated: 681.2) 1H NMR:(400MHz,MeOD)δ7.64-7.53(m,2H),7.34(s,2H),5.44(br d,J=4.2Hz,1H),4.51-4.28(m,2H),3.88-3.79(m,9H),3.71-3.45(m,2H),3.10-2.74(m,12H),2.18-1.88(m,10H)

[0653] Compound 123: [ka] To a solution of intermediate compound 105 (10 mg, 15.45 μmol, 1 equiv.) in DCM (8 mL) was added EDCI (8.89 mg, 46.36 μmol, 3 equiv.) and DMAP (7.55 mg, 61.81 μmol, 4 equiv.) at 25°C. The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 15% to 4%, 5 min) to give compound 123 (5.99 mg, 62% yield) as an off-white solid. LCMS (ESI position ion) m / z: 629.2 (M+H)+ (calculated: 628.3) 1H NMR(400MHz,MeOD-d4)δ8.53(s,1H) 7.70(s,1H),7.61(s,1H),7.33(s,2H),5.45(br s,1H),4.66-4.35(m,2H),3.90-3.76(m,9H),3.70-3.52(m,2H),3.19-2.72(m,12H),2.17-1.83(m,10H)

[0654] Compound 124 and Compound 125: [ka] The enantiomers of compound 37 (480 mg) were separated by Chiral-HPLC under the following conditions (column: CHIRAL ART Cellulose-SB, 3 × 25 cm, 5 μm; mobile phase A: CO , mobile phase B: MeOH:DCM=1:1; flow rate: 80 mL / min; gradient: isocratic 40% B; column temperature (35 °C); back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 2.62; RT2 (min): 4.38) to give compound 119 (130 mg) as a white solid and compound 120 (120 mg) as a white solid. Compound 124: LC-MS(ES+) m / z: 540 (M+H)+ (calculated: 539.3). Chiral HPLC: retention time = 1.78 min, ee = 99.5% 1H NMR(300MHz,DMSO-d6)δppm 8.31(s,1H),7.57-7.55(m,2H),7.46-7.35(m,4H),7.32(s,1H),4.51-4.48(m,1H),4.32-4.20(m,3H),4 .11-4.05(m,1H),3.84(s,3H),3.74(s,3H),2.89-2.84(m,1H),2.72-2.54(m,11H),1.97-1.71(m,10H). Compound 125: LC-MS(ES+) m / z: 540 (M+H)+ (calculated: 539.3). Chiral HPLC: retention time = 2.19 min, ee = 99.5% 1H NMR(300MHz,DMSO-d6)δppm 8.31(s,1H),7.57-7.55(m,2H),7.46-7.35(m,4H),7.32(s,1H),4.51-4.48(m,1H),4.32-4.20(m,3H),4 .11-4.05(m,1H),3.84(s,3H),3.74(s,3H),2.89-2.84(m,1H),2.72-2.54(m,11H),1.97-1.71(m,10H).

[0655] II. Biological Examples Example II.1. Assay for ENT1 Activity Example II.1.a Binding Assay the purpose This assay aims to demonstrate that the compounds of the present invention can bind to human ENT1. The principle of the assay is competition between the compounds of the present invention and the ENT1 inhibitor Sahenta-DY647, which emits fluorescence (excitation = 630 nm, emission = 670 nm). By measuring the fluorescence at the end of the assay, the inventors were able to evaluate the binding potency of the compounds of the present invention. method JAR cells expressing ENT1 were purchased from ATCC (HTB-144™). Cells were cultured at 37°C and 5% CO in RPMI 1640 medium (LONZA, #BE12-702F / U1) supplemented with 10% FBS (GIBCO, #10270-106), 10 mM Hepes (LONZA, #BE17-737E), 1 mM sodium pyruvate (LONZA, #BE13-115E), and 2% penicillin / streptomycin (LONZA, #DE17-603E). Assays were performed in the following buffer: HBSS (LONZA®, #LO-527F) supplemented with 10 mM Hepes (LONZA®, #BE17-737E) and 0.1% BSA (Miltenyi®, #130-091-376) on the day of the assay. JAR cells were resuspended in the indicated buffer. Compounds of the invention and Sahenta-DY647 were diluted 200X in the indicated buffer.

[0656] A total of 50,000 cells were preincubated with the compounds of the present invention for 30 minutes at 4°C, followed by the addition of Sahenta-DY647 (100 nM) at the corresponding IC90 and another 30-minute incubation at 4°C. The total reaction volume was 100 μL (50 μL cells, 25 μL of the compounds of the present invention, and 25 μL of Sahenta-DY647) in a U-bottom 96-well plate (Greiner®, #650-180). The plate was washed twice with the same buffer by centrifugation (4 minutes at 4°C, 400 rcf). The cells were resuspended in 70 μL of buffer, and 50 μL was transferred to a Black 384 Optiplate (PerkinElmer®, #6007279). Fluorescence (excitation = 630 nm, emission = 670 nm) was acquired on a Spectramax i3x (Molecular Devices®).

[0657] result The results obtained from this protocol are summarized in Table 5.

[0658] Example II.1.b Functional Assay: Uridine Transport Inhibition Assay the purpose The purpose of this study was to determine the potency of equilibrative nucleoside transporter 1 (ENT1) inhibitors by measuring ENT1-mediated transport in a cellular uptake assay. The human ENT1 transporter can be stably expressed in Madin-Darby canine kidney II (MDCKII) cells by transduction. Uridine is efficiently transported by ENT1 and is used as a probe in the assay as 3H-uridine. Interaction is detected as modulation of the initial rate of 3H-uridine transport by human ENT1 into MDCKII-ENT1-LV cells stably expressing the ENT1 uptake transporter. result The results obtained from this protocol are summarized in Table 6. [Table 6]

[0659] Example II.1.c Functional Assay: T Cell Proliferation Assay the purpose The objective of this study was to determine the potency of equilibrative nucleoside transporter 1 (ENT1) inhibitors to rescue proliferation by stimulated pri...

Claims

1. Compounds of Formula I: 【Chemistry 1】 [During the ceremony, R 1 teeth, 【Chemistry 2】 selected from the group consisting of: Each R 2 are independently absent, halogen, or —NHR 3 , -OR 3 , -R 3 , -C(O)R 3 , -CO 2 R 3 , C(O)N(R 3 ), 2 , -CH 2 C(O)N(R 3 ), 2 , -S(O) 2 R 3 , and -CN; or two occurrences of R 2 together with the atoms bonded to them form hetero forming a cyclyl or heteroaryl ring; Each R 3 are independently selected from absent, —H, oxo, ALK, phenyl, heterocyclyl, and hexacyclyl. selected from terearyl; R 4 teeth, 【Transformation 3】 selected from the group consisting of: Each U independently represents —C(O)O—, —C(O)N(R 3 )—, and —O—N═C(H)—; Each R x are independently selected from C 1-6 alkylene; V 1 is -C(R 3 )-, and -N-; Each V 2 are independently -C(R 3 ) = , -N(R 3 ) -, -N=, and -O- ； V 3 is selected from -C= and -N-; Z is C or N; ALK is unsubstituted alkyl or substituted alkyl, or two occurrences of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring. or a pharmaceutically acceptable salt or solvate thereof.

2. Compound of Formula II: 【Chemistry 4】 [During the ceremony, R 1 is ALK, cycloalkyl, heterocyclyl, 【Transformation 5】 selected from the group consisting of: Each R 2 are independently absent, halogen, -OR 3 , -R 3 , -CO 2 R 3 , C(O)N(R 3 ) 2 , -CH 2 C(O)N(R 3 ) 2 , -S(O) 2 R 3 -CN; or two occurrences of R 2 together with the atoms bonded to them form hetero forming a cyclyl or heteroaryl ring; Each R 3 is independently selected from absent, —H, ALK, phenyl, and heteroaryl; ； R 4 teeth, 【Transformation 6】 and X is -CH 2 -, -CHF-, and -CF 2 - selected from the group consisting of; Each U independently represents —C(O)O—, —C(O)N(R 3 )—, and —O—N═C(H)—; Each R x is independently selected from C 1-6 alkylene; V 1 is -C(R 3 )-, and -N-; Each V 2 are independently -C(R 3 ) = , -N(R 3 ) -, -N=, and -O- ； V 3 is selected from -C=, and -N-; each Z is independently C or N; n 1 is a number 0 or 1, ALK is unsubstituted alkyl or substituted alkyl, or two occurrences of ALK may be joined together with their intervening atoms to form a cycloalkyl or heterocyclyl ring. or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1, wherein each U is independently selected from the group consisting of —C(O)O— and —C(O)N(R 3 )—.

4. Formula IIa: 【Transformation 7】 wherein X is CH 2 , CHF, or CF 2 is] 4. The compound of claim 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, having the formula:

5. R 1 but 【Transformation 8】 The compound according to any one of claims 1 to 4,

6. R 1 but, 【Chemistry 9】 6. The compound of claim 5, wherein:

7. The compound is a compound of formula (IIb): 【Chemistry 10】 7. The compound according to any one of claims 1 to 6, wherein:

8. The compound of any one of claims 1 to 7, wherein U is -C(O)O-.

9. R 4 teeth, 【Chemistry 11】 and R 4 U in the formula is —C(O)O— or —C(O)NR 3 The compound according to any one of claims 1 to 3 and 5 to 6, wherein

10. Formula IIa1: 【Chemistry 12】 3. The compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the formula:

11. 3,4,5-trimethoxybenzoic acid (12S)-7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecane Kafan-12-il 3,4,5-trimethoxybenzoic acid (12R)-7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid 16,16-difluoro-7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid (12S)-16,16-difluoro-7-methylbenzoate 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid (12R)-16,16-difluoro-7-methylbenzoate 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl N-(7 4 , 7 5 -dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-12-yl)-3,4,5-trimethoxybenzamide 3,4,5-trimethoxybenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid (12S)-7 4 , 7 5 -Dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid (12R)-7 4 , 7 5 -Dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid 7 4 , 7 5 -Dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid (12S)-7 4 , 7 5 -Dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid (12R)-7 4 , 7 5 -Dimethoxy-5-methyl-6-oxo-8-oxa-5-aza-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid (11R)-7 4 , 7 5 -Dimethoxy-6-oxo-5-aza-1(1,4)-diazepan-7(1,3)-benzenacyclotridecaphan-11-yl 3,4,5-Trimethoxybenzoic acid (10S)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphan-10-yl 3,4,5-Trimethoxybenzoic acid (10R)-14-chloro-2-oxo-11H-3-aza-1(6,1)-indazola-7(1,4)-diazepanacyclotridecaphan-10-yl 3,4,5-Trimethoxybenzoic acid (12S)-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-Trimethoxybenzoic acid (12R)-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl (12S)-6-oxo-8-oxa-5-aza-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl benzoate (12R)-6-oxo-8-oxa-5-aza-1(1,4)-diazepanone benzoate -7(1,3)-Benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid 7 4 , 7 5 -Dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid (12S)-7 4 , 7 5 -Dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid (12R)-7 4 , 7 5 -Dichloro-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid 7 5 -carbamoyl-7 4 -chloro-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-Trimethoxybenzoic acid (11Z,16E,10S)-14-chloro-2-oxo-12H-3-aza-1(6,2)-indazola-7(1,4)-diazepanacyclotridecaphan-10-yl (11Z,16E,10R)-14-chloro-2-oxo-12H-3-aza-1(6,2)-indazola-7(1,4)-diazepanacyclotridecaphan-10-yl 3,4,5-trimethoxybenzoate 3,4,5-trimethoxybenzoic acid (12S)-7 4 -carbamoyl-7 5 -chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid (12R)-7 4 -carbamoyl-7 5 -chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid 7 4 -Bromo-7 5 -chloro-6-oxo-8-oxa-5-aza-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-trimethoxybenzoic acid 7 5 -chloro-7 4 -cyano-6-oxo-8-oxa-5-aza-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl Benzoic acid (12R)-7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl Benzoic acid (12R)-7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl Benzoic acid (12S)-7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl (Z)-benzaldehyde O-(7 4 , 7 5 -dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-12-yl)oxime 12-hydroxy-7 4 , 7 5 -Dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-6-one 4-Hydroxybenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-Fluorobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-Isopropoxybenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-(Trifluoromethyl)benzoic acid 7 4 , 7 5 -dimethoxy-6-oxo-5,8-di Oxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-(Methylsulfonyl)benzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-phenoxybenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 2-Fluorobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-Bromo-3-cyanobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-Methyl-5-(trifluoromethyl)benzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 2-Fluoro-4-methoxybenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-Methoxy-2-(trifluoromethoxy)benzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl Picolinic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl Nicotinic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl Pyrazine-2-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 6-hydroxynicotinic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl Quinoline-5-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl Oxazole-4-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 1H-1,2,3-triazole-4-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl Acetic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl Cyclopropanecarboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-Methylbutanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4,4,4-trifluorobutanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl Cyclohexanecarboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 1-Methylpiperidine-4-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane -12-yl 3,3-Dimethylcyclobutane-1-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 2-(oxetan-3-yl)acetic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl (1R,5S,6R)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 5-Oxopyrrolidine-3-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 1-Benzyl-5-oxopyrrolidine-3-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-Methoxycyclohexane-1-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 2,6-Difluorobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-(Trifluoromethoxy)benzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-Cyanobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 2-Oxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-(Difluoromethoxy)benzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,5-Dichlorobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4-Dichlorobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 2,3-Dichlorobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 2-Chloro-6-fluoro-3-methylbenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-Fluoro-5-(trifluoromethyl)benzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-Fluoro-3-(trifluoromethyl)benzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-Cyano-3-fluorobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphane-1 2-Il 4-(Trifluoromethyl)benzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,5-Difluorobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4-Difluorobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-Cyano-4-fluorobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-Cyanobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-Chloro-4-fluorobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 1-Methyl-1H-benzo[d]imidazole-5-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-(Oxazol-5-yl)benzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4,5-Dichloro-2-fluorobenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3,4,5-triethoxybenzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-Methoxypropanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-(1H-pyrazol-1-yl)propanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-cyanopropanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-cyanobutanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-Acetamidobutanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-(1H-tetrazol-1-yl)propanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-(Dimethylamino)-4-oxobutanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-Acetamidopropanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-(methylamino)-4-oxobutanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-(1H-1,2,4-triazol-1-yl)propanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-morpholino-4-oxobutanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-(4-fluorophenoxy)propanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4,4-Difluorocyclohexane-1-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 4-(trifluoromethyl)cyclohexane-1-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-(2,5-dioxopyrrolidin-1-yl)propanoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl 3-Methoxycyclohexane-1-carboxylic acid 7 4 , 7 5 -Dimethoxy-6-oxo-5,8-dioxa-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl Benzoic acid 7 4 , 7 5 -Dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepan-7(1,3)-benzenacyclotetradecaphan-12-yl (E)-benzaldehyde O-(7 4 , 7 5 -dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-12-yl)oxime (E)-Benzaldehyde O-((12R)-7 4 , 7 5 -dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-12-yl)oxime (E)-Benzaldehyde O-((12S)-7 4 , 7 5 -dimethoxy-6-oxo-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-12-yl)oxime 12-hydroxy-7 4 , 7 5 -Dimethoxy-8-oxa-5-aza-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-6-one (12R)-12-hydroxy-7 4 , 7 5 -Dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-6-one (12S)-12-hydroxy-7 4 , 7 5 -Dimethoxy-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-6-one 7 4 , 7 5 -Dimethoxy-12-(5-phenyl-2H-tetrazol-2-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-6-one 7 4 , 7 5 -Dimethoxy-12-(4-phenyl-1H-1,2,3-triazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-6-one 7 4 , 7 5 -dimethoxy-12-(5-phenyl-1H-tetrazol-1-yl)-5,8-dioxa-1(1,4)-diazepana-7(1,3)-benzenacyclotetradecaphan-6-one, and pharmaceutically acceptable salts or solvates thereof A compound selected from the group consisting of:

12. A compound of the formula: 【Chemistry 13】 and pharmaceutically acceptable salts or solvates thereof A compound selected from the group consisting of:

13. The compound of any one of claims 1 to 11, wherein the compound contains only one chiral center.

14. 14. The compound of claim 13, wherein the compound is a racemic mixture containing the "R" and "S" isomers.

15. 14. The compound of claim 13, wherein the compound is the "R" isomer.

16. 14. The compound of claim 13, wherein the compound is the "S" isomer.

17. The compound of any one of claims 1 to 11, wherein the compound contains more than one chiral center.

18. 18. The compound of claim 17, wherein said chiral centers independently comprise an "R" or "S" configuration.

19. 18. The compound of claim 17, wherein said chiral centers comprise the same configuration.

20. A compound according to any one of claims 1 to 19, and at least one pharmaceutically acceptable excipient A pharmaceutical composition comprising:

21. 21. The pharmaceutical composition of claim 20, further comprising an adenosine receptor antagonist.

22. 22. The pharmaceutical composition of claim 21, wherein the adenosine receptor antagonist is an A2A or A2B receptor antagonist.

23. The adenosine receptor antagonist 5-bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidin-5-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile; 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine; and 4-hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide; (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof; (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof: (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof; and (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof 22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition is selected from:

24. The adenosine receptor antagonist is a compound of formula (III): 【Chemistry 14】 [During the ceremony, R 1 is a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl; The heteroaryl or aryl group is C 1 -C 6 optionally substituted with one or more substituents selected from alkyl and halo; R 2 is a 6-membered aryl or 6-membered heteroaryl; The heteroaryl or aryl group may be halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfonyl, or the like. optionally substituted with one or more substituents selected from: hydroxyl, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, and alkylsulfonalkyl; The substituents may be oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl optionally substituted with one or more substituents selected from alkylsulfonyl and alkylsulfonealkyl; Alternatively, the heteroaryl or aryl group is optionally substituted with two substituents, said two substituents together with the atoms to which they are attached being: one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl forming a 5- or 6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl ring, or a 5- or 6-membered heterocyclyl ring optionally substituted with 22. The pharmaceutical composition of claim 21, which is:

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 for use in a method for inhibiting ENT1 in a patient in need thereof, The method comprises administering to the patient an effective amount of a compound according to any one of claims 1 to 19. The pharmaceutical composition comprising:

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 for use in a method for the treatment of cancer in a patient in need thereof, comprising: The method comprises administering to the patient an effective amount of a compound according to any one of claims 1 to 19. The pharmaceutical composition comprising:

27. 20. A pharmaceutical composition comprising a combination of a compound according to any one of claims 1 to 19 and an adenosine receptor antagonist for use in a method for the treatment of cancer in a patient in need thereof, the method comprising: administering to said patient a combination of a compound according to any one of claims 1 to 19 and an adenosine receptor antagonist. The pharmaceutical composition comprising:

28. 28. The pharmaceutical composition of claim 27, wherein the compound of any one of claims 1 to 19 is administered prior to, concomitantly with, or after administration of the adenosine receptor antagonist.

29. 29. The pharmaceutical composition of claim 27 or 28, wherein the adenosine receptor antagonist is an A2A or A2B receptor antagonist.

30. The adenosine receptor antagonist 5-bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile; 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine; 4-hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide; (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof; (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof; (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof; and (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof 28. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition is selected from:

31. The adenosine receptor antagonist is a compound of formula (III): 【Chemistry 15】 [During the ceremony, R 1 is a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl; The heteroaryl or aryl group is C 1 -C 6 optionally substituted with one or more substituents selected from alkyl and halo; R 2 is a 6-membered aryl or 6-membered heteroaryl; the heteroaryl or aryl group is optionally substituted with one or more substituents selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, and alkylsulfonalkyl; The substituents may be oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl optionally substituted with one or more substituents selected from alkylsulfonyl and alkylsulfonealkyl; Alternatively, the heteroaryl or aryl group is optionally substituted with two substituents, said two substituents together with the atoms to which they are attached being: Oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonal. one or more substituents selected from forming a 5- or 6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl ring, or a 5- or 6-membered heterocyclyl ring optionally substituted with 28. The pharmaceutical composition of claim 27, which is:

32. A parts kit, (a) a first portion comprising an effective amount of a compound according to any one of claims 1 to 19; (b) a second portion comprising an effective amount of an adenosine receptor antagonist; The kit of parts.

33. 33. The kit of parts of claim 32, wherein the adenosine receptor antagonist is an A2A or A2B receptor antagonist.

34. The adenosine receptor antagonist 5-bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile; 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine; 4-hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide; (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof; (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof; (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof; and (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof 33. The kit of parts of claim 32, selected from:

35. The adenosine receptor antagonist is a compound of formula (III): 【Chemistry 16】 [During the ceremony, R 1 is a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl; The heteroaryl or aryl group is C 1 -C 6 optionally substituted with one or more substituents selected from alkyl and halo; R 2 is a 6-membered aryl or 6-membered heteroaryl; the heteroaryl or aryl group is optionally substituted with one or more substituents selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, and alkylsulfonalkyl; The substituents may be oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl optionally substituted with one or more substituents selected from alkylsulfonyl and alkylsulfonealkyl; Alternatively, the heteroaryl or aryl group is optionally substituted with two substituents, said two substituents together with the atoms to which they are attached being: one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl forming a 5- or 6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl ring, or a 5- or 6-membered heterocyclyl ring optionally substituted with 33. The kit of parts according to claim 32, wherein the kit is:

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