Semi-saturated bicyclic derivatives and related uses

Abstract

This disclosure relates to compounds of the following formula (I): This invention relates to TIFF2026515712000685.tif18128, as well as their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods of preparation thereof. The compounds disclosed herein are useful for modulating DNA polymerase Θ activity and may be used in the treatment of disorders involving DNA polymerase Θ activity, such as cancer.

Description

[Technical Field]

[0001] Related applications This application claims priority and benefits of U.S. Provisional Patent Application No. 63 / 457,353, filed on April 5, 2023, and U.S. Provisional Patent Application No. 63 / 542,486, filed on October 4, 2023, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background This disclosure relates to a small molecule antagonist of DNA polymerase Θ, designed for the treatment of cancer.

[0003] Proper repair of DNA double-strand breaks (DSBs) is essential for maintaining genomic integrity. Incorrect repair of DSBs can lead to mutations in critical coding or regulatory regions, while the accumulation of unrepaired DNA damage introduces mitotic stress, which can lead to genomic alterations or cell death. In normal cells, DSBs are repaired primarily through two key mechanisms. DNA lesions occurring during DNA replication (S phase) are typically repaired by homologous recombination (HR), which uses replicated "sister chromatids" as templates for error-free repair. In contrast, non-homologous end joining (NHEJ) is the primary DSB repair process when no DNA template is available for template repair. A third DSB repair pathway, called Alt-EJ, microhomology-mediated end joining (MMEJ), or theta-mediated end joining (TMEJ), is performed by polymerase theta (POLΘ). In contrast to NHEJ and HR, TMEJ is thought to play a limited role in healthy cells under normal conditions.

[0004] Some tumors carry inactivating mutations in homologous repair genes, frequently impairing the function of BRCA1 or BRCA2. As a result, these tumors are inherently sensitive to DNA damaging agents, as well as inhibitors of specific DNA repair proteins. Therefore, DNA crosslinking agents, such as platinum-based chemotherapy agents, are more effective in BRCA-mutated tumors than in tumors with intact BRCA function. Similarly, the small molecule inhibitor PARP1 / 2 is effective in BRCA1 / 2-deficient tumors, as this inhibitor relies on the PARP enzyme to repair single-strand DNA breaks and prevent their conversion to toxic DSBs, which overwhelm the repair capacity of HR-deficient cells.

[0005] Another approach to therapeutically targeting HR-deficient tumors involves inhibiting backup repair pathways such as TMEJ via POLΘ. Consistent with its role as a backup DNA repair enzyme, cleavage of the POLΘ locus is well-tolerated in mouse models, inducing only a mild phenotype characterized by micronuclei in reticulocytes and leading to increased cellular (not biotic) sensitivity to DNA crosslinkers. In contrast, POLΘ DNA repair activity has been shown to be essential for cell survival when NHEJ or HR is inactivated, which involves POLΘ as a potential target for cancer therapy in specific mutational environments.

[0006] POLΘ, unique to the human genome, contains both an N-terminal SF2 DNA helicase domain and a C-terminal DNA polymerase domain. In the environment of chromosomal double-slash bridges (DSBs), these domains work together to repair DSBs containing long 3' single-stranded DNA overhangs. Specifically, the helicase domain is thought to remove the RPA protein complex from the overhang and facilitate annealing to the opposite DNA end via a region of DNA microhomology. The annealed DNA then acts as a primer for the POLΘ polymerase domain, which extends the annealed DNA to fill the gap in the single-stranded DNA. Given the role of POLΘ catalytic activity in the DNA repair process, which is crucial in HR-deficient tumors, POLΘ represents an attractive target for chemotherapeutic inhibitors of which are being developed to exploit its newly discovered functional dependence.

[0007] This disclosure arises from a need to provide compounds for modulating DNA polymerase Θ activity with improved therapeutic capacity, particularly compounds having improved physicochemical, pharmacological, and / or pharmaceutical properties. [Overview of the project]

[0008] overview In some embodiments, this disclosure relates to compounds of the following formula (I): This provides TIFF2026515712000002.tif24128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein, X 1 is CH, S, or N, X 2 is N, S, or O, R 1 and R 2 They, together with the atoms they bond to, form a C5-C 10 Forms cycloalkyl or 5-10 member heterocycloalkyl groups, C5-C 10 Cycloalkyl or 5-10 member heterocycloalkyl groups include one or more R amay be replaced with, each R a is independently oxo, halo, cyano, -OR a1 , -N(R a1 )2, -C(O)R a1 , -C(O)N(R a1 )2, -C(O)OR a1 , -S(O)2N(R a1 )2, -S(O)2(R a1 ), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl may be substituted with one or more R a1 s, each R a1 is independently H, oxo, halo, cyano, -OH, -NH2, -C(O)(C1-C6 alkyl), -C(O)(C3-C 10 cycloalkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl, and -C(O)(C3-C 10 cycloalkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl may be substituted with one or more R a2 s, each R a2These are independently C1-C6 alkyl, C3-C alkyl, and C3-C alkyl groups which may be substituted with oxo, halo, cyano, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, or -OH. 10 These are cycloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl, which may be substituted with oxo. R 3 C6-C 10 It is an aryl or 5-10 member heteroaryl, C6-C 10 Aryl or 5-10 member heteroaryls are one or more R 3a It has been replaced with, Each R 3a These are independently halo, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 It is an aryl or 5-10 member heteroaryl, and is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 An aryl, or a 5-10 member heteroaryl, is one or more R 3a1 It may also be replaced with Each R 3a1 These are independently oxo, halo, cyano, -OH, -C(O)(C1-C6 alkyl), -C(O)(O-(C1-C6 alkyl)), and C3-C 10 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, -O(C1-C6 haloalkyl), C3-C 10 Cycloalkyl, C6-C 10 They are aryl or 5- to 10-membered heteroaryl compounds.

[0009] In some embodiments, the Disclosure provides compounds that can be obtained by methods for preparing the compounds described herein (for example, methods comprising one or more steps described in Schemes 1 to 7), or compounds obtained by such methods.

[0010] In some embodiments, the Disclosure provides a pharmaceutical composition comprising a compound of the Disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0011] In some embodiments, the Disclosure provides intermediates described herein that are suitable for use in methods for preparing the compounds described herein (for example, the intermediates are selected from the intermediates described in Examples 1 to 753).

[0012] In some embodiments, the Disclosure provides a method for modulating DNA polymerase Θ activity (e.g., in vitro or in vivo), the method comprising contacting cells with an effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0013] In certain embodiments, the Disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject where such treatment is necessary, the method comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject.

[0014] In certain embodiments, the Disclosure provides a method for treating a disease or disorder disclosed herein in a subject where such treatment is necessary, the method comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject.

[0015] In some embodiments, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in modulating DNA polymerase Θ activity (e.g., in vitro or in vivo).

[0016] In certain embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of diseases or disorders disclosed herein.

[0017] In certain embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment of diseases or disorders disclosed herein.

[0018] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for modulating DNA polymerase Θ activity (e.g., in vitro or in vivo).

[0019] In certain embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder disclosed herein.

[0020] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of a disease or disorder disclosed herein. In some embodiments, regulation is inhibition.

[0021] In some embodiments, the Disclosure provides a method for preparing the compounds of the Disclosure.

[0022] In some embodiments, the Disclosure provides a method for preparing a compound, comprising one or more steps described herein.

[0023] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which this disclosure pertains. In this specification, singular forms also include plural forms unless the context explicitly indicates otherwise. Methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this disclosure, but preferred methods and materials are described below. All publications, patent applications, patents, and other references referenced herein are incorporated by reference. References cited herein are not considered prior art to the inventions described in the claims. In case of any conflict, this specification, including definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative and not intended to limit the scope. In case of any conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0024] Other features and advantages of this disclosure will be apparent from the following detailed description and claims. [Modes for carrying out the invention]

[0025] Detailed explanation This disclosure relates to semi-saturated bicyclic derivatives, prodrugs, and pharmaceutically acceptable salts thereof that can modulate DNA polymerase Θ activity and are therefore useful in methods of treating the human or animal body. This disclosure also relates to processes for the preparation of these compounds, pharmaceutical compositions comprising them, and their use in the treatment of DNA polymerase Θ-related disorders such as cancer.

[0026] definition Unless otherwise stated, the following terms used in this specification and in the claims have the meanings set forth below.

[0027] While various options for the variable portion are described herein and are not intended to limit you, it is understood that this disclosure is intended to encompass operable embodiments having combinations of options. This disclosure may be interpreted as excluding non-operable embodiments resulting from certain combinations of options. For example, variable portion X 1 , X 2 , R 1 , R 2 , R a , R a1 , R a2 , R 3 , R 3a , and R 3a1 Various options are described herein, but this disclosure is limited to the variable part X 1 , X 2 , R 1 , R 2 , R a , R a1 , R a2 , R 3 , R 3a , and R 3a1 This can be interpreted as excluding the structure of an unmanipulable compound resulting from a specific combination of these elements.

[0028] As used herein, “alkyl,” “C1, C2, C3, C4, C5, or C6 alkyl,” or “C1-C6 alkyl” is intended to include a C1, C2, C3, C4, C5, or C6 linear saturated aliphatic hydrocarbon group and a C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon group. For example, C1-C6 alkyl includes C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl, and include moieties having one to six carbon atoms. In some embodiments, the linear or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for linear, C3-C6 for branched), and in other embodiments, the linear or branched alkyl has four or fewer carbon atoms.

[0029] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl having a specified substituent that substitutes one or more hydrogen atoms on one or more carbons of a hydrocarbon skeleton. These substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0030] As used herein, the term “alkenyl” includes unsaturated aliphatic groups that are similar in length, may be substituted for the alkyl groups described above, but contain at least one double bond. For example, the term “alkenyl” includes linear alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, linear or branched alkenyl groups have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

[0031] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl having a specified substituent that substitutes one or more hydrogen atoms on one or more carbon atoms of a hydrocarbon skeleton. These substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0032] As used herein, the term “alkynyl” includes unsaturated aliphatic groups that are similar in length, may be substituted for the alkyls described above, but contain at least one triple bond. For example, “alkynyl” includes linear alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, noninyl, desynyl) and branched alkynyl groups. In certain embodiments, linear or branched alkynyl groups have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3-C6” includes alkynyl groups containing three to six carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to contain a divalent unsaturated aliphatic hydrocarbon group in a C2, C3, C4, C5, or C6 chain (straight or branched). For example, a C2-C6 alkenylene linker is intended to contain C2, C3, C4, C5, and C6 alkenylene linker groups.

[0033] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl having a specified substituent that substitutes one or more hydrogen atoms on one or more carbon atoms of a hydrocarbon skeleton. These substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0034] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moieties) include both unsubstituted moieties and moieties having one or more of the specified substituents. For example, substituted heterocycloalkyls include those substituted with one or more alkyl groups such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0035] As used herein, the term "cycloalkyl" refers to a group of 3 to 30 carbon atoms (e.g., C3-C3-C3). 12 , C3-C 10This refers to monocyclic or polycyclic (e.g., condensed, cross-linked, or spirocyclic) saturated or partially unsaturated hydrocarbon systems having C3-C8 rings. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyls, only one of the rings within the cycloalkyl must be non-aromatic.

[0036] As used herein, the term "heterocycloalkyl" means one or more heteroatoms (such as O, N, S, P, or Se), for example, one or one to two or one to three or one to four or one to five or one to six heteroatoms, or a saturated or partially unsaturated 3- to 8-membered monocyclic, 7- to 12-membered bicyclic (condensed, bridged, or spiro-ring), or 11- to 14-membered tricyclic (condensed, bridged, or spiro-ring) ring system having, for example, one, two, three, four, five, or six heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur, for example, unless otherwise specified.Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxyranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, and 1,4-diazepa Nyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]yl, 7'H -Spiro[cyclohexane-1,5'-flo[3,4-b]pyridine]-yl, 3'H-Spiro[cyclohexane-1,1'-flo[3,4-c]pyridine]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexane-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8- Examples include tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxazaspiro[3.4]octanyl, 2-oxazaspiro[3.4]octan-6-yl, and 5,6-dihydro-4H-cyclopenta[b]thiophenyl.In the case of polycyclic heterocycloalkyls, only one of the rings in the heterocycloalkyl must be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0037] If a variable part has two bonds to the rest of the compound's formula, it is understood that these two bonds can be on the same atom or different atoms of the variable part. For example, if the variable part (e.g., variable part X) is a cycloalkyl or heterocycloalkyl and has two bonds to the rest of the compound's formula, these two bonds can be on the same atom or different atoms of the cycloalkyl or heterocycloalkyl.

[0038] As used herein, the term “aryl” includes aromatic groups, which include conjugated or polycyclic systems having one or more aromatic rings and containing no heteroatoms within the ring structure. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl.

[0039] As used herein, the term "heteroaryl" is intended to include stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocycles, consisting of a carbon atom and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., one or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., one, two, three, four, five, or six heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another defined substituent). The nitrogen and sulfur heteroatoms may be oxidized as desired (i.e., N → O and S(O) p(wherein p=1 or 2). Note that the total number of S and O atoms in the aromatic heterocyclic ring is 1 or less. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl groups can also be condensed or bridged with non-aromatic alicyclic or heterocyclic rings to form polycyclic systems (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0040] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, such as tricyclic and bicyclic aryl groups, and examples include naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphtholidine, indole, benzofuran, purine, benzofuran, deazapurine, and indoridine.

[0041] The ring is represented by a circle, and all ring members are carbon atoms (for example, If the ring is TIFF2026515712000003.tif11128), then the ring is an aryl ring. If the ring is represented by a circle, then heteroatoms (e.g., A ring is a heteroaryl ring if it contains at least one ring member that is a TIFF2026515712000004.tif11128). A polycyclic aryl group or heteroaryl group is a ring containing two or more circles (for example, This can be shown in TIFF2026515712000005.tif17128.

[0042] Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings are heteroatoms such as ring-forming carbons or N at one or more ring positions. Salts, phosphonatos, phosphinatos, aminos (including alkylaminos, dialkylaminos, arylaminos, diarylaminos, and alkylarylaminos), acylaminos (including alkylcarbonylaminos, arylcarbonylaminos, carbamoyls, and ureidos), amidinos, iminos, sulfhydryls, alkylthios, arylthios, thiocarboxylates, sulfates, alkylsulfinyls, sulfonates, sulfamoyls, sulfonamides, nitros, trifluoromethyls, cyanos, azides, heterocyclyls, alkylaryls, or aromatic or heteroaromatic moieties may be substituted with the above substituents. Aryl and heteroaryl groups may also be condensed or crosslinked with non-aromatic alicyclic or heterocyclic rings to form polycyclic systems (e.g., tetralins, methylenedioxyphenyls such as benzo[d][1,3]dioxol-5-yl).

[0043] As used herein, the term “approximately” refers to an enumerated quantity, value, or duration within ±10% of the enumerated quantity, value, or duration. In some embodiments, “approximately” refers to an enumerated quantity, value, or duration within ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5%. In other embodiments, “approximately” refers to an enumerated quantity, value, or duration within ±10%, ±8%, ±6%, ±5%, ±4%, or ±2%. In other embodiments, “approximately” refers to an enumerated quantity, value, or duration within ±5%. In some embodiments, “approximately” refers to an enumerated quantity, value, or duration within ±2% or ±1%. For example, in some embodiments, when the term “approximately” is used when enumerating temperatures or temperature ranges, these terms refer to the enumerated temperature or temperature range within ±5°C, ±2°C, or ±1°C. In other embodiments, the term “approximately” refers to the enumerated temperature or temperature range within ±2°C.

[0044] As used herein, the term “substitution” means that one or more hydrogen atoms on a given atom are substituted with a group selected from the given group, provided that the substitution does not exceed the normal valence of the given atom and the substitution results in a stable compound. When the substituent is oxo or keto (i.e., =O), two hydrogen atoms on the atom are substituted. Keto substituents are not present on aromatic moieties. A double bond in a ring, as used herein, is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). “Stable compound” and “stable structure” mean a compound that remains after isolation from a reaction mixture to a useful purity and is robust enough to be formulated into an effective therapeutic agent.

[0045] If a bond to a substituent is shown to intersect with a bond connecting two atoms in the ring, then such substituent may be bonded to any atom in the ring. If substituents are enumerated without indicating the atom to which such substituent is bonded to the rest of the compound in a given formula, then such substituent may be bonded to any atom in such formula. Combinations of substituents and / or variable parts are permitted, but only if such combinations result in a stable compound.

[0046] If any variable part (e.g., R) occurs multiple times in any component or formula of a compound, its definition in each occurrence is independent of its definition in all other occurrences. Therefore, for example, if a group is shown to be substituted with 0 to 2 R parts, that group may optionally be substituted with up to 2 R parts, and in each occurrence, R is selected independently of the definition of R. Furthermore, combinations of substituents and / or variable parts are permitted, but only if such combinations result in a stable compound.

[0047] As used herein, the terms "hydroxy" or "hydroxyl" refer to -OH or -O - It contains a group having a group.

[0048] As used herein, the terms "halo" or "halogen" refer to fluoro, chloro, bromo, and iodine.

[0049] The terms "haloalkyl" or "haloalkoxyl" refer to alkyl or alkoxyl molecules substituted with one or more halogen atoms.

[0050] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl having specified substituents that substitute one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. These substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0051] As used herein, the terms “alkoxy” or “alkoxyl” include substituted and unsubstituted alkyl groups, alkenyl groups, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy group may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0052] As used herein, expressions such as “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C,” and “selected from A, B, and C” are used interchangeably and all refer to a selection from the group consisting of A, B, and / or C, i.e., one or more A's, one or more B's, one or more C's, or any combination thereof, unless otherwise indicated.

[0053] It should be understood that this disclosure provides methods for the synthesis of any compound of the formulas described herein. This disclosure also provides detailed methods for the synthesis of various disclosed compounds of this disclosure by the schemes shown below, as well as by the schemes shown in the examples.

[0054] Throughout the specification, where a composition is described as having, including, or containing certain components, it should be understood that the composition is also intended to be essentially composed of or consisting of the listed components. Similarly, where a method or process is described as having, including, or containing certain process steps, the process is also intended to be essentially composed of or consisting of the listed processing steps. Furthermore, naturally, the order of the steps for performing a particular action is not important, as long as the invention remains operable. Moreover, two or more steps or actions can be performed simultaneously.

[0055] It should be understood that the synthesis process of this disclosure can accommodate a wide variety of functional groups, and therefore a variety of substituted starting materials can be used. The process generally provides the desired final compound at or near the end of the entire process, but in certain examples, it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0056] It should be understood that the compounds of this disclosure can be prepared in various ways using commercially available starting materials, compounds known in the literature, or readily prepared intermediates by employing either standard synthetic methods and procedures known to those skilled in the art or evident to those skilled in the art from the perspective of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules, as well as the transformation and manipulation of functional groups, can be obtained from relevant scientific literature or standard textbooks in the art. Not limited to any one or more sources, but including Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition, John Wiley & Sons: New York, 2001, Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd Traditional texts such as John Wiley & Sons, New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) are incorporated herein by reference and are useful and recognized textbooks of organic synthesis known to those skilled in the art.

[0057] Those skilled in the art will understand that the order of certain steps, such as the introduction and removal of protecting groups, in the reaction sequences and synthetic schemes described herein is modifiable. Those skilled in the art will recognize that certain groups may require protection from reaction conditions through the use of protecting groups. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups, as well as methods for introducing and removing these groups, can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3. rd This can be seen in edition, John Wiley & Sons: New York, 1999.

[0058] Unless otherwise stated, any description of a treatment or preventive method should be understood to include the use of a compound that provides such treatment or preventive action as described herein. Unless otherwise stated, any description of a treatment or preventive method should be further understood to include the use of a compound that prepares a medicament for treating or preventing such condition. Treatment or preventive action includes treatment or preventive action in humans or non-human animals, including rodents and other disease models.

[0059] Unless otherwise stated, any description of a treatment method should be understood to include the use of a compound that provides such treatment as described herein. Unless otherwise stated, any description of a treatment method should be further understood to include the use of a compound that prepares a medicament for treating such condition. Treatments include treatment of humans or non-human animals, including rodents and other disease models.

[0060] As used herein, the term “subject” includes cell lines, cell cultures, tissues, and organs, in addition to humans and non-human animals. In some embodiments, the subject is a mammal. Mammals may be, for example, humans or primates, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. The subject may also be a bird or poultry. In some embodiments, the subject is a human.

[0061] As used herein, the term “subject in need” refers to a subject who has a disease or is at high risk of developing a disease. A subject in need may be a subject who has been previously diagnosed or identified as having one of the diseases or disorders disclosed herein. A subject in need may also be a subject suffering from one of the diseases or disorders disclosed herein. Alternatively, a subject in need may be a subject at high risk of developing such a disease or disorder compared to the general population (i.e., a subject who is more likely to develop such a disorder compared to the general population). A subject in need may be refractory or resistant to one of the diseases or disorders disclosed herein (i.e., a subject who is not responding to treatment or has not yet responded to treatment). A subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, a subject in need has received and failed all known effective therapies for one of the diseases or disorders disclosed herein. In some embodiments, a subject in need has received at least one prior therapy.

[0062] As used herein, the terms “to treat” or “to treat” describe the management and care of a patient for the purpose of combating a disease, condition, or disorder, and include the administration of the compounds of the Disclosure, or pharmaceutically acceptable salts, polymorphs, or solvates thereof, to alleviate the symptoms or complications of a disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The terms “to treat” may also include treating cells in vitro or in animal models. Naturally, references to “to treat” or “to treat” include the alleviation of established symptoms of a condition. Therefore, “treating” a condition, disorder or symptom, and “treating” such a condition, disorder or symptom, includes: (1) preventing or delaying the onset of clinical signs of a condition, disorder or symptom in a person who is predisposed to suffering from or being susceptible to the condition, disorder or symptom but has not yet experienced or exhibited any clinical or subclinical signs of the condition, disorder or symptom; (2) inhibiting a condition, disorder or symptom, i.e., stopping, reducing or delaying the onset of the disease or its relapse (in the case of maintenance treatment) or at least one clinical or subclinical sign thereof; or (3) alleviating or reducing the disease, i.e., regressing at least one of the condition, disorder or symptom or its clinical or subclinical signs.

[0063] It should be understood that the compounds of this disclosure, or any pharmaceutically acceptable salts, polymorphs, or solvates thereof, can be used or may be used to prevent related diseases, conditions, or disorders, or can be used or may be used to identify suitable candidates for such purposes.

[0064] As used herein, the terms “prevent,” “prevent,” or “protect from” describe reducing or eliminating the onset of signs or complications of such disease, condition, or disorder.

[0065] Those skilled in the art should understand that they can refer to general standard texts for a detailed description of the known art or equivalent art discussed herein. These texts include Ausubel et al., *Current Protocols in Molecular Biology*, John Wiley and Sons, Inc. (2005), and Sambrook et al., *Molecular Cloning*, A Laboratory Manual (3 rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000), Colligan et al., Current Protocols in Immunology, John Wiley & Sons, NY, Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY, Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing. Co.,Easton,PA,18 th The edition (1990) is one example. These texts can, of course, be referenced when performing or using the manner of this disclosure.

[0066] It should be understood that this disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0067] As used herein, the term “pharmaceutical composition” means a formulation containing the compound of the Disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition may be a bulk or a unit dosage form. A unit dosage form may be any of various forms, including, for example, capsules, IV bags, tablets, a single pump on an aerosol inhaler, or a vial. The amount of the active ingredient (e.g., a formulation of the disclosed compound or a salt, hydrate, solvate, or isomer) in a unit dose of the composition is an effective amount and will vary according to the specific treatment being addressed. Those skilled in the art will understand that it may be necessary to make routine adjustments to the dosage depending on the patient’s age and condition. The dosage will also depend on the route of administration. Various routes are intended, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, subarachnoid, and intranasal. Dosage forms for topical or transdermal administration of the compounds of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

[0068] As used herein, the term “pharmaceutically acceptable” means those compounds, anions, cations, substances, compositions, carriers and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, in proportion to a reasonable benefit-risk ratio, within the bounds of sound medical judgment.

[0069] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is generally safe, non-toxic, not biologically or otherwise undesirable, and useful in the preparation of a pharmaceutical composition containing an excipient that is acceptable for veterinary and human pharmaceutical use. As used herein and in the claims, “pharmaceutically acceptable excipient” includes both one and more such excipients.

[0070] It should be understood that the pharmaceutical compositions of this disclosure are formulated to be suitable for their intended route of administration. Examples of routes of administration include parenteral administration, e.g., intravenous, intradermal, subcutaneous, oral (e.g., oral ingestion), inhalation, transdermal (topical), and transmucosal administration. Liquids or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: sterile diluents such as water for injection, physiological saline, fixative oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and agents for adjusting tonicity such as sodium chloride or dextrose. pH can be adjusted with an acid or base such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be sealed in ampoules, disposable syringes, or multi-dose vials of glass or plastic.

[0071] It should be understood that the compounds or pharmaceutical compositions of this disclosure may be administered to subjects in many of the well-known methods currently used in chemotherapy. For example, the compounds of this disclosure may be injected into the bloodstream or body cavities, or ingested orally, or applied through the skin using a patch. The selected dose should be sufficient to constitute an effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., the disease or disorder disclosed herein) and the patient's health should preferably be closely monitored for a reasonable period during and after treatment.

[0072] As used herein, the term “therapeutic effective dose” refers to the amount of a drug used to treat, improve, and / or prevent a specific disease or condition, or to produce a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective dose for a given subject will depend on the subject's weight, size, and health, the nature and severity of the condition, and the therapeutic agent or combination of therapeutic agents selected for administration. A therapeutic effective dose for a given situation can be determined by conventional experimentation, which is within the skill and judgment of the clinician.

[0073] It should be understood that for any compound, the therapeutically effective dose can first be estimated, for example, by cell culture assays in neoplastic cells or by animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models may be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED. 50 (Therapeutic dose effective in 50% of the population) and LD 50 This can be determined by the dose that is lethal to 50% of the population. The dose-to-toxicity ratio is the therapeutic index, or ratio LD50. 50 / ED 50 It can be expressed as follows. Pharmaceutical compositions exhibiting a large therapeutic index are preferred. The dosage may vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0074] Dosage and administration are adjusted to provide a sufficient level of activator or to maintain the desired effect. Factors to consider include the severity of the disease state, the subject's overall health, age, weight and sex, diet, timing and frequency of administration, drug combinations, sensitivity to response, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3-4 days, weekly, or every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0075] Pharmaceutical compositions containing the active compounds of this disclosure can be manufactured in generally known ways, for example, by conventional mixing, dissolution, granulation, sugar-coated tablet manufacturing, levigating, emulsification, encapsulation, encapsulation, or lyophilization processes. The pharmaceutical compositions can be formulated in conventional ways using one or more pharmaceutically acceptable carriers containing excipients and / or auxiliaries that facilitate the processing of the active compounds into pharmaceutically usable preparations. Naturally, the appropriate formulation depends on the chosen route of administration.

[0076] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (if water-soluble) or dispersants, and sterile powders for the immediate preparation of sterile injectable solutions or dispersants. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophore EL® (BASF, Parsippany, New Jersey), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid enough to pass easily through an injection needle. It must be stable under manufacturing and storage conditions and protected against microbial contamination such as bacteria and fungi. Carriers may be solvents or dispersion media containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), cyclodextrin, and suitable mixtures thereof. Adequate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersants, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents in the composition, such as sugars, polyalcohols like mannitol and sorbitol, and sodium chloride. Sustained absorption of the injectable composition can be achieved by including absorption-delaying agents in the composition, such as aluminum monostearate and gelatin.

[0077] Sterile injectable solutions can be prepared by incorporating the required amount of the active compound into a suitable solvent having one or a combination of the components listed above, as needed, followed by filtration sterilization. Generally, dispersants are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and other necessary components from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation method is vacuum drying and freeze-drying, which yield the active ingredient powder from a pre-sterilized filtered solution to any additional desired components.

[0078] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable food-grade carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, lozenges, capsules, or pouches. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, where the compound in the fluid carrier is applied orally, rinsed in the mouth, spat out, or swallowed. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or sterote; flow enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0079] When administered by inhalation, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant, such as a gas like carbon dioxide, or from a nebulizer.

[0080] Systemic administration may also be by mucosal or percutaneous means. In the case of mucosal or percutaneous administration, a suitable penetrating agent is used in the formulation for the barrier to which the agent is to be penetrated. Such penetrating agents are generally known in the art and include, for example, mucosal agents, surfactants, bile salts, and fusidic acid derivatives. Mucosal administration can be achieved through the use of nasal sprays, powders, or suppositories. In the case of percutaneous administration, the active compound is formulated into ointments, salves, gels, or creams, which are generally known in the art.

[0081] The active compound can be prepared with a pharmaceutically acceptable carrier that protects the compound from rapid elimination from the body, such as controlled-release formulations including implants and microencapsulation delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyacid anhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. The methods for preparing such formulations will be apparent to those skilled in the art. The materials can also be commercially obtained from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes that target infected cells having monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared by methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0082] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions into unit dosage forms. As used herein, a unit dosage form refers to a physically distinct unit suitable as a unit dose to the target to be treated, each unit containing a predetermined amount of the active compound calculated to produce the desired therapeutic effect in relation to the required pharmaceutical carrier. The specifications of the unit dosage forms in this disclosure are determined by and directly depend on the inherent characteristics of the active compound and the specific therapeutic effect to be achieved.

[0083] For therapeutic use, the dosage of a pharmaceutical composition used in accordance with this disclosure will vary depending on the drug, the age, weight and clinical condition of the recipient patient, and other factors that influence the selected dosage, in particular, the experience and judgment of the clinician or physician administering the therapy. Generally, the dosage should be sufficient to delay, preferably regress, the symptoms of the disease or disorder disclosed herein, and preferably to completely regress the disease or disorder. The dosage may range from about 0.01 mg / kg per day to about 5000 mg / kg per day. An effective dose of the drug is one that results in an objectively identifiable improvement, as described by a clinician or other qualified observer. Improvement in survival and proliferation indicates regression. As used herein, the term “effective dose mode” refers to the amount of the active compound that produces the desired biological effect in the subject or cells.

[0084] It should be understood that pharmaceutical compositions may be contained in a container, pack, or dispenser along with a package insert for administration.

[0085] In the case of the compounds of this disclosure that can further form salts, it should be understood that all of these forms are intended to be within the scope of the disclosure as described in the claims.

[0086] As used herein, the term “pharmaceutically acceptable salt” refers to a derivative of a compound of the disclosed herein, which is modified by forming a salt of the parent compound with its acid or base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic salts of organic acids of basic residues such as amines, and alkali organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic organic acids. Examples of such conventional non-toxic salts include, but are not limited to, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolyarsanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, and hydroxynaphth Examples include those derived from toeic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and inorganic and organic acids selected from commonly present amine acids, such as glycine, alanine, phenylalanine, and arginine.

[0087] In some embodiments, pharmaceutically acceptable salts include sodium salts, potassium salts, calcium salts, magnesium salts, diethylamine salts, choline salts, meglumine salts, benzathine salts, trometamic acid salts, ammonia salts, arginine salts, or lysine salts.

[0088] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvate, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-octa-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, and muconic acid. The disclosure also includes salts formed when an acidic proton present in the parent compound is substituted with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, or N-methylglucamine. In salt form, it is understood that the ratio of the compound to the cation or anion of the salt may be 1:1, or any other ratio, such as 3:1, 2:1, 1:2, or 1:3.

[0089] All references to pharmaceutically acceptable salts should be understood to include the solubilized form (solvate) or crystalline form (polymorph) of the same salt as defined herein.

[0090] The compound or a pharmaceutically acceptable salt thereof may be administered orally, nasally, percutaneously, pulmonaryly, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, subarachnoidally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of specific routes of administration.

[0091] Dosage regimens utilizing compounds are selected according to various factors, including the patient's type, breed, age, weight, sex, and medical condition, the severity of the condition being treated, the route of administration, the patient's renal and hepatic function, and the specific compound or salt used. A physician or veterinarian skilled in the art can easily determine and prescribe the effective dose of drug necessary to prevent, counteract, or halt the progression of the condition.

[0092] The formulation and administration techniques of the compounds disclosed in this disclosure are described in Remington: The Science and Practice of Pharmacy, 19 th This can be seen in edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical preparation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions. The compounds are present in such pharmaceutical composition in an amount sufficient to provide a desired dose within the range described herein.

[0093] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of this disclosure are evident from various examples. The provided examples illustrate different components and methods useful for carrying out this disclosure. The examples do not limit the disclosure described in the claims. Based on this disclosure, those skilled in the art can identify and adopt other components and methods useful for carrying out this disclosure.

[0094] In the synthetic schemes described herein, compounds may be represented in a single specific configuration for simplification. Such a specific configuration should not be interpreted as limiting this disclosure to one or another isomer, tautomer, regioisomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer, or stereoisomer.

[0095] All publications and patent documents referenced herein are incorporated herein by reference in such a manner as it is specifically and individually indicated that each publication or document is incorporated herein by reference. The references to publications and patent documents are not intended to acknowledge any of them as relevant prior art and do not constitute any endorsement of their content or date. While the present invention has been described herein in specification, those skilled in the art will recognize that the invention can be carried out in various embodiments, and that the foregoing description and the following examples are for illustrative purposes only and do not limit the scope of the subsequent claims.

[0096] As used herein, the phrase "compounds of the disclosure" refers both generally and specifically to the compounds disclosed herein.

[0097] Compounds of the Disclosure In some embodiments, this disclosure relates to compounds of the following formula (I): This provides TIFF2026515712000006.tif24128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein, X 1 is CH, S, or N, X 2 is N, S, or O, R 1 and R 2 They, together with the atoms they bond to, form a C5-C10 forms a cycloalkyl or 5- to 10-member heterocycloalkyl, C5-C 10 The cycloalkyl or 5- to 10-member heterocycloalkyl may be substituted with one or more R a and each R a is independently oxo, halo, cyano, -OR a1 , -N(R a1 )2, -C(O)R a1 , -C(O)N(R a1 )2, -C(O)OR a1 , -S(O)2N(R a1 )2, -S(O)2(R a1 ), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-member heteroaryl, or 3- to 10-member heterocycloalkyl, and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-member heteroaryl, or 3- to 10-member heterocycloalkyl may be substituted with one or more R a1 and each R a1 is independently H, oxo, halo, cyano, -OH, -NH2, -C(O)(C1-C6 alkyl), -C(O)(C3-C 10 cycloalkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, 3- to 10-member heterocycloalkyl, C6-C 10 aryl, or 5- to 10-member heteroaryl, and -C(O)(C3-C 10 cycloalkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, 3- to 10-member heterocycloalkyl, C6-C 10An aryl, or a 5-10 member heteroaryl, is one or more R a2 It may also be replaced with Each R a2 These are independently C1-C6 alkyl, C3-C alkyl, and C3-C alkyl groups which may be substituted with oxo, halo, cyano, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, or -OH. 10 These are cycloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl, which may be substituted with oxo. R 3 C6-C 10 It is an aryl or 5-10 member heteroaryl, C6-C 10 Aryl or 5-10 member heteroaryls are one or more R 3a It has been replaced with, Each R 3a These are independently halo, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 It is an aryl or 5-10 member heteroaryl, and is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 An aryl, or a 5-10 member heteroaryl, is one or more R 3a1 It may also be replaced with Each R 3a1 These are independently oxo, halo, cyano, -OH, -C(O)(C1-C6 alkyl), -C(O)(O-(C1-C6 alkyl)), and C3-C 10 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, -O(C1-C6 haloalkyl), C3-C 10 Cycloalkyl, C6-C 10They are aryl or 5- to 10-membered heteroaryl compounds.

[0098] In some embodiments, this disclosure relates to compounds of the following formula (I): This provides TIFF2026515712000007.tif23128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein, X 1 is CH, S, or N, X 2 is N, S, or O, R 1 and R 2 They, together with the atoms they bond to, form a C5-C 10 Forms cycloalkyl or 5-10 member heterocycloalkyl groups, C5-C 10 Cycloalkyl or 5-10 member heterocycloalkyl groups include one or more R a It may also be replaced with Each R a These are independently oxo, halo, cyano, -OR a1 , -N(R a1 )2, -C(O)R a1 ,-C(O)N(R a1 )2, -C(O)OR a1 -S(O)2N(R a1 )2, -S(O)2(R a1 ), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 5-10 member heteroaryl, or 3-10 member heterocycloalkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, or 3-10 member heterocycloalkyl is one or more R a1 It may also be replaced with Each R a1These are independently H, oxo, halo, cyano, -OH, -NH2, -C(O)(C1-C6 alkyl), and -C(O)(C3-C 10 Cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 It is an aryl or 5-10 member heteroaryl, and -C(O)(C3-C 10 Cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 An aryl, or a 5-10 member heteroaryl, is one or more R a2 It may also be replaced with Each R a2 These are independently C1-C6 alkyl, C3-C alkyl, and C3-C alkyl groups which may be substituted with oxo, halo, cyano, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, or -OH. 10 These are cycloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl, which may be substituted with oxo. R 3 C6-C 10 It is an aryl or 5-10 member heteroaryl, C6-C 10 Aryl or 5-10 member heteroaryls are one or more R 3a It has been replaced with, Each R 3a These are independently halo, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10It is an aryl or 5-10 member heteroaryl, and is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 An aryl, or a 5-10 member heteroaryl, is one or more R 3a1 It may also be replaced with Each R 3a1 These are independently oxo, halo, cyano, -C(O)(C1-C6 alkyl), -C(O)(O-(C1-C6 alkyl)), and C3-C 10 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O(C1-C6 haloalkyl), C3-C (which may be substituted with cycloalkyl groups) 10 Cycloalkyl, C6-C 10 They are aryl or 5- to 10-membered heteroaryl compounds.

[0099] Regarding the compounds disclosed herein, the variable portion X 1 , X 2 , R 1 , R 2 , R a , R a1 , R a2 , R 3 , R 3a , and R 3a1 Each of these may be selected from the bases described herein, where applicable, and variable part X 1 , X 2 , R 1 , R 2 , R a , R a1 , R a2 , R 3 , R 3a , and R 3a1 Any base described herein for any of the variable parts X 1 , X 2 , R 1 , R 2 , R a , R a1 , R a2 , R 3 , R 3a, and R 3a1 It is understood that one or more of the remaining parts can be combined with any of the bases described herein.

[0100] In some embodiments, X 1 It is either CH or S.

[0101] In some embodiments, X 1 It is either CH or N.

[0102] In some embodiments, X 1 It is either S or N.

[0103] In some embodiments, X 1 is CH. In some embodiments, X 1 is S. In some embodiments, X 1 It is N.

[0104] In some embodiments, X 2 It is either N or S.

[0105] In some embodiments, X 2 It is either N or O.

[0106] In some embodiments, X 2 It is either O or S.

[0107] In some embodiments, X 2 In some embodiments, X 2 is S. In some embodiments, X 2 It is O.

[0108] In some embodiments, R 1 and R 2 These atoms, together with the atoms to which they are bonded, form C5-C6 cycloalkyl or 5-6 membered heterocycloalkyl groups.

[0109] In some embodiments, R 1 and R 2These atoms, together with the atoms to which they are bonded, form a C5-C6 cycloalkyl or 5-6 member heterocycloalkyl, and the C5-C6 cycloalkyl or 5-6 member heterocycloalkyl has one or more R a It may be replaced with .

[0110] In some embodiments, R 1 and R 2 These atoms, together with the atoms to which they are bonded, form a C5-C6 cycloalkyl or 5-6 member heterocycloalkyl, and the C5-C6 cycloalkyl or 5-6 member heterocycloalkyl has one or more R a It has been replaced with.

[0111] In some embodiments, R 1 and R 2 Together with the atoms to which they are bonded, C5-C 10 It forms a cycloalkyl group.

[0112] In some embodiments, R 1 and R 2 These, together with the atoms they bond to, form one or more R a C5-C may be replaced with 10 It forms a cycloalkyl group.

[0113] In some embodiments, R 1 and R 2 Together with the atoms to which they are bonded, one or more R a C5-C replaced by 10 It forms a cycloalkyl group.

[0114] In some embodiments, R 1 and R 2 These atoms, together with the atoms to which they are bonded, form a C6 cycloalkyl group.

[0115] In some embodiments, R 1 and R 2 Together with the atoms to which they are bonded, one or more R aIt forms a C6 cycloalkyl group which may be substituted with a different compound.

[0116] In some embodiments, R 1 and R 2 Together with the atoms to which they are bonded, one or more R a It forms a C6 cycloalkyl group substituted with [the specified compound].

[0117] In some embodiments, R 1 and R 2 These atoms, together with the atoms to which they are bonded, form 5-10 membered heterocycloalkyl groups.

[0118] In some embodiments, R 1 and R 2 Together with the atoms to which they are bonded, one or more R a It forms a 5-10 member heterocycloalkyl group which may be substituted with other molecules.

[0119] In some embodiments, R 1 and R 2 Together with the atoms to which they are bonded, one or more R a It forms a 5-10 member heterocycloalkyl group substituted with the other members.

[0120] In some embodiments, R 1 and R 2 These atoms, together with the atoms to which they are bonded, form a 5-7 membered heterocycloalkyl group.

[0121] In some embodiments, R 1 and R 2 Together with the atoms to which they are bonded, one or more R a It forms a 5- to 7-membered heterocycloalkyl group, which may be substituted with other molecules.

[0122] In some embodiments, R 1 and R 2 Together with the atoms to which they are bonded, one or more R aIt forms a 5-7 member heterocycloalkyl group substituted with [the specified element].

[0123] In some embodiments, R 1 and R 2 These atoms, together with the atoms to which they are bonded, form a five-membered heterocycloalkyl group.

[0124] In some embodiments, R 1 and R 2 Together with the atoms to which they are bonded, one or more R a It forms a 5-membered heterocycloalkyl group which may be substituted with [another compound].

[0125] In some embodiments, R 1 and R 2 Together with the atoms to which they are bonded, one or more R a It forms a 5-membered heterocycloalkyl group substituted with [the specified compound].

[0126] In some embodiments, R 1 and R 2 These atoms, together with the atoms to which they are bonded, form a six-membered heterocycloalkyl group.

[0127] In some embodiments, R 1 and R 2 Together with the atoms to which they are bonded, one or more R a It forms a 6-membered heterocycloalkyl group which may be substituted with [another compound].

[0128] In some embodiments, R 1 and R 2 Together with the atoms to which they are bonded, one or more R a It forms a 6-membered heterocycloalkyl group substituted with [the specified compound].

[0129] Some implementation methods, each R a These are independently oxo, -OR a1 , -N(R a1 )2, -C(O)R a1 ,-C(O)N(Ra1 )2, -C(O)OR a1 -S(O)2N(R a1 )2, -S(O)2(R a1 ), C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 They are aryl, 5-10 member heteroaryl, or 3-10 member heterocycloalkyl.

[0130] Some implementation methods, each R a These are independently oxo, -OR a1 , -N(R a1 )2, -C(O)R a1 ,-C(O)N(R a1 )2, -C(O)OR a1 -S(O)2N(R a1 )2, -S(O)2(R a1 ), C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl, 5-10 membered heteroaryl, or 3-10 membered heterocycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, or 3-10 member heterocycloalkyl is one or more R a1 It may be replaced with .

[0131] Some implementation methods, each R a These are independently oxo, -OR a1 , -N(R a1 )2, -C(O)R a1 ,-C(O)N(R a1 )2, -C(O)OR a1 -S(O)2N(R a1 )2, -S(O)2(R a1 ), C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl, 5-10 membered heteroaryl, or 3-10 membered heterocycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10Aryl, 5-10 member heteroaryl, or 3-10 member heterocycloalkyl is one or more R a1 It has been replaced with.

[0132] Some implementation methods, each R a It is an independent oxo.

[0133] Some implementation methods, each R a It is a separate entity, a halo.

[0134] Some implementation methods, each R a R is independently F, Cl, Br, or I. In some embodiments, each R a R is independently F, Cl, or Br. In some embodiments, each R a These are independently either F or Cl.

[0135] Some implementation methods, each R a Independently, F. In some embodiments, each R a Independently, each R is Cl. In some embodiments, each R a Independently, each R is Br. In some embodiments, each R a Independently, it is I.

[0136] Some implementation methods, each R a It is independently cyano.

[0137] Some implementation methods, each R a These are independent, -OR a1 That is the case.

[0138] Some implementation methods, each R a These are independent of -N(R a1 )2.

[0139] Some implementation methods, each R a -C(O)R a1 That is the case.

[0140] Some implementation methods, each R a-C(O)N(R) a1 )2.

[0141] Some implementation methods, each R a -C(O)OR a1 That is the case.

[0142] Some implementation methods, each R a Independently, -S(O)2N(R a1 )2.

[0143] Some implementation methods, each R a Independently, -S(O)2(R a1 )

[0144] Some implementation methods, each R a These are independently C1-C6 alkyl groups.

[0145] Some implementation methods, each R a Each is independent of one or more R a1 It is a C1-C6 alkyl group which may be substituted with [another molecule].

[0146] Some implementation methods, each R a Each is independent of one or more R a1 It is a C1-C6 alkyl group that is substituted with [a specific compound].

[0147] Some implementation methods, each R a R is independently methyl. In some embodiments, each R a Independently, each R is ethyl. In some embodiments, each R a In some embodiments, each R is independently propyl. a R is independently butyl. In some embodiments, each R a In some embodiments, each R is independently a pentill. a In some embodiments, each R is independently hexyl. a Independently, each R is isopropyl. In some embodiments, each R a Independently, each R is isobutyl. In some embodiments, each R aIndependently, each R is isopentyl. In some embodiments, each R a is independently isohexyl. In some embodiments, each R a Independently, each R is secbutyl. In some embodiments, each R a Independently, each R is secpentyl. In some embodiments, each R a In some embodiments, each R is independently sec hexyl. a It is independently tertbutyl.

[0148] Some implementation methods, each R a These are independently C2-C6 alkenyls.

[0149] Some implementation methods, each R a Each is independent of one or more R a1 It is a C2-C6 alkenyl that may be substituted with [another compound].

[0150] Some implementation methods, each R a Each is independent of one or more R a1 It is a C2-C6 alkenyl that is substituted with [a specific compound].

[0151] Some implementation methods, each R a These are independently C2-C6 alkynyl compounds.

[0152] Some implementation methods, each R a Each is independent of one or more R a1 It is a C2-C6 alkynyl that may be substituted with [another compound].

[0153] Some implementation methods, each R a Each is independent of one or more R a1 It is a C2-C6 alkynyl that is substituted with [a specific compound].

[0154] Some implementation methods, each R a These are independently C1-C6 haloalkyl groups.

[0155] Some implementation methods, each R aEach is independent of one or more R a1 It is a C1-C6 haloalkyl which may be substituted with [another compound].

[0156] Some implementation methods, each R a Independently, each R is a halomethyl. In some embodiments, each R a Independently, each R is a haloethyl. In some embodiments, each R a Independently, each R is a halopropyl. In some embodiments, each R a Independently, each R is a halobutyl. In some embodiments, each R a Independently, each R is halopentyl. In some embodiments, each R a It is independently a halohexyl.

[0157] Some implementation methods, each R a It is independent, C3-C 10 It is a cycloalkyl group.

[0158] Some implementation methods, each R a Each is independent of one or more R a1 C3-C may be replaced with 10 It is a cycloalkyl group.

[0159] Some implementation methods, each R a Each is independent of one or more R a1 C3-C is replaced by 10 It is a cycloalkyl group.

[0160] Some implementation methods, each R a These are independently C3-C7 cycloalkyl groups.

[0161] Some implementation methods, each R a Each is independent of one or more R a1 It is a C3-C7 cycloalkyl that may be substituted with a different compound.

[0162] Some implementation methods, each R a Each is independent of one or more R a1 It is a C3-C7 cycloalkyl group that is substituted with [a specific compound].

[0163] Some implementation methods, each R a It is independent, C6-C 10 It is Ariel.

[0164] Some implementation methods, each R a Each is independent of one or more R a1 C6-C may be replaced with 10 It is Ariel.

[0165] Some implementation methods, each R a Each is independent of one or more R a1 C6-C is replaced by 10 It is Ariel.

[0166] Some implementation methods, each R a It is independently a C6 aryl.

[0167] Some implementation methods, each R a Each is independent of one or more R a1 It is a C6 aryl that may be substituted with [another C6 aryl

[0168] Some implementation methods, each R a Each is independent of one or more R a1 It is a C6 aryl that has been substituted.

[0169] Some implementation methods, each R a These are independently 5- to 10-membered heteroaryl compounds.

[0170] Some implementation methods, each R a Each is independent of one or more R a1 It is a 5- to 10-membered heteroaryl that may be substituted with [another compound].

[0171] Some implementation methods, each R a Each is independent of one or more R a1 It is a 5- to 10-membered heteroaryl that is substituted with [a specific compound].

[0172] Some implementation methods, each R a These are independently 5-6 member heteroaryl compounds.

[0173] Some implementation methods, each R a Each is independent of one or more R a1 It is a 5-6 member heteroaryl that may be substituted with [another compound].

[0174] Some implementation methods, each R a Each is independent of one or more R a1 It is a 5-6 member heteroaryl that is substituted with [a specific compound].

[0175] Some implementation methods, each R a These are independently 3- to 10-membered heterocycloalkyl groups.

[0176] Some implementation methods, each R a Each is independent of one or more R a1 It is a 3- to 10-membered heterocycloalkyl that may be substituted with [a specific compound].

[0177] Some implementation methods, each R a Each is independent of one or more R a1 It is a 3- to 10-membered heterocycloalkyl group that is substituted with [a specific compound].

[0178] Some implementation methods, each R a These are independently 3- to 7-membered heterocycloalkyl groups.

[0179] Some implementation methods, each R a Each is independent of one or more R a1 It is a 3- to 7-membered heterocycloalkyl group which may be substituted with a different compound.

[0180] Some implementation methods, each R a Each is independent of one or more R a1 It is a 3- to 7-membered heterocycloalkyl group that is substituted with [a specific compound].

[0181] Some implementation methods, each R a Independently, the following are: TIFF2026515712000008.tif177147TIFF2026515712000009.tif224147TIFF2026515712000010.tif206147 TIFF2026515712000011.tif210147TIFF2026515712000012.tif207147TIFF2026515712000013.tif33147.

[0182] Some implementation methods, each R a These are independently selected from the following: TIFF2026515712000014.tif152147TIFF2026515712000015.tif224147TIFF2026515712000016.tif210147TIFF20265157120 00017.tif207147TIFF2026515712000018.tif215147TIFF2026515712000019.tif219147TIFF2026515712000020.tif62147.

[0183] Some implementation methods, each R a These are independently selected from the following: TIFF2026515712000021.tif153148TIFF2026515712000022.tif217147TIFF2026515712000023.tif224147TIFF2026515712000024.tif185147 TIFF2026515712000025.tif204147TIFF2026515712000026.tif198147TIFF2026515712000027.tif223147TIFF2026515712000028.tif194147 TIFF2026515712000029.tif197147TIFF2026515712000030.tif206147TIFF2026515712000031.tif222147TIFF2026515712000032.tif213147 TIFF2026515712000033.tif210147TIFF2026515712000034.tif196147TIFF2026515712000035.tif220147TIFF2026515712000036.tif198147.

[0184] Some implementation methods, each R a1 These are independently H, halo, cyano, -C(O)(C1-C6 alkyl), and -C(O)(C3-C 10 Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 They are aryl or 5- to 10-membered heteroaryl compounds.

[0185] Some implementation methods, each R a1 These are independently H, halo, cyano, -C(O)(C1-C6 alkyl), and -C(O)(C3-C 10 Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 It is an aryl or 5-10 member heteroaryl, and -C(O)(C3-C 10 Cycloalkyl, C1-C6 alkyl, C3-C 10Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 An aryl, or a 5-10 member heteroaryl, is one or more R a2 It may be replaced with .

[0186] Some implementation methods, each R a1 These are independently H, halo, cyano, -C(O)(C1-C6 alkyl), and -C(O)(C3-C 10 Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 It is an aryl or 5-10 member heteroaryl, and -C(O)(C3-C 10 Cycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 An aryl, or a 5-10 member heteroaryl, is one or more R a2 It has been replaced with.

[0187] Some implementation methods, each R a1 H is independent of H.

[0188] Some implementation methods, each R a1 It is an independent oxo.

[0189] Some implementation methods, each R a1 It is a separate entity, a halo.

[0190] Some implementation methods, each R a1 R is independently F, Cl, Br, or I. In some embodiments, each R a1 R is independently F, Cl, or Br. In some embodiments, each R a1 These are independently either F or Cl.

[0191] Some implementation methods, each R a1 Independently, F. In some embodiments, each R a1 Independently, each R is Cl. In some embodiments, each R a1Independently, each R is Br. In some embodiments, each R a1 Independently, it is I.

[0192] Some implementation methods, each R a1 It is independently cyano.

[0193] Some implementation methods, each R a1 It is independently -OH.

[0194] Some implementation methods, each R a1 It is independently -NH2.

[0195] Some implementation methods, each R a1 These are independently -C(O)(C1-C6 alkyl).

[0196] Some implementation methods, each R a1 These are independent of -C(O)(C3-C 10 It is a cycloalkyl group.

[0197] Some implementation methods, each R a1 Each is independent of one or more R a2 Even if it is substituted with -C(O)(C3-C 10 It is a cycloalkyl group.

[0198] Some implementation methods, each R a1 Each is independent of one or more R a2 -C(O)(C3-C) is substituted. 10 It is a cycloalkyl group.

[0199] Some implementation methods, each R a1 These are independently C1-C6 alkyl groups.

[0200] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a C1-C6 alkyl group which may be substituted with [another molecule].

[0201] Some implementation methods, each R a1Each is independent of one or more R a2 It is a C1-C6 alkyl group that is substituted with [a specific compound].

[0202] Some implementation methods, each R a1 R is independently methyl. In some embodiments, each R a1 Independently, each R is ethyl. In some embodiments, each R a1 In some embodiments, each R is independently propyl. a1 R is independently butyl. In some embodiments, each R a1 In some embodiments, each R is independently a pentill. a1 In some embodiments, each R is independently hexyl. a1 Independently, each R is isopropyl. In some embodiments, each R a1 Independently, each R is isobutyl. In some embodiments, each R a1 Independently, each R is isopentyl. In some embodiments, each R a1 is independently isohexyl. In some embodiments, each R a1 Independently, each R is secbutyl. In some embodiments, each R a1 Independently, each R is secpentyl. In some embodiments, each R a1 In some embodiments, each R is independently sec hexyl. a1 It is independently tertbutyl.

[0203] Some implementation methods, each R a1 These are independently C2-C6 alkenyls.

[0204] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a C2-C6 alkenyl that may be substituted with [another compound].

[0205] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a C2-C6 alkenyl that is substituted with [a specific compound].

[0206] Some implementation methods, each R a1 These are independently C2-C6 alkynyl compounds.

[0207] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a C2-C6 alkynyl that may be substituted with [another compound].

[0208] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a C2-C6 alkynyl that is substituted with [a specific compound].

[0209] Some implementation methods, each R a1 These are independently C1-C6 haloalkyl groups.

[0210] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a C1-C6 haloalkyl which may be substituted with [another compound].

[0211] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a C1-C6 haloalkyl that is substituted with [a specific compound].

[0212] Some implementation methods, each R a1 Independently, each R is a halomethyl. In some embodiments, each R a1 Independently, each R is a haloethyl. In some embodiments, each R a1 Independently, each R is a halopropyl. In some embodiments, each R a1 Independently, each R is a halobutyl. In some embodiments, each R a1 Independently, each R is halopentyl. In some embodiments, each R a1 It is independently a halohexyl.

[0213] Some implementation methods, each R a1 These are independently C1-C6 alkoxy compounds.

[0214] Some implementation methods, each Ra1 Each is independent of one or more R a2 It is a C1-C6 alkoxy that may be substituted with [another compound].

[0215] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a C1-C6 alkoxy that is substituted with [a specific compound].

[0216] Some implementation methods, each R a1 It is independent, C3-C 10 It is a cycloalkyl group.

[0217] Some implementation methods, each R a1 Each is independent of one or more R a2 C3-C may be replaced with 10 It is a cycloalkyl group.

[0218] Some implementation methods, each R a1 Each is independent of one or more R a2 C3-C is replaced by 10 It is a cycloalkyl group.

[0219] Some implementation methods, each R a1 These are independently C3-C7 cycloalkyl groups.

[0220] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a C3-C7 cycloalkyl that may be substituted with a different compound.

[0221] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a C3-C7 cycloalkyl group that is substituted with [a specific compound].

[0222] Some implementation methods, each R a1 These are independently 3- to 10-membered heterocycloalkyl groups.

[0223] Some implementation methods, each R a1Each is independent of one or more R a2 It is a 3- to 10-membered heterocycloalkyl that may be substituted with [a specific compound].

[0224] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a 3- to 10-membered heterocycloalkyl group that is substituted with [a specific compound].

[0225] Some implementation methods, each R a1 These are independently 3- to 7-membered heterocycloalkyl groups.

[0226] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a 3- to 7-membered heterocycloalkyl group which may be substituted with a different compound.

[0227] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a 3- to 7-membered heterocycloalkyl group that is substituted with [a specific compound].

[0228] Some implementation methods, each R a1 It is independent, C6-C 10 It is Ariel.

[0229] Some implementation methods, each R a1 Each is independent of one or more R a2 C6-C may be replaced with 10 It is Ariel.

[0230] Some implementation methods, each R a1 Each is independent of one or more R a2 C6-C replaced by 10 It is Ariel.

[0231] Some implementation methods, each R a1 It is independently a C6 aryl.

[0232] Some implementation methods, each R a1 Each is independent of one or more R a2It is a C6 aryl that may be substituted with [another C6 aryl

[0233] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a C6 aryl that has been substituted.

[0234] Some implementation methods, each R a1 These are independently 5- to 10-membered heteroaryl compounds.

[0235] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a 5- to 10-membered heteroaryl that may be substituted with [another compound].

[0236] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a 5- to 10-membered heteroaryl that is substituted with [a specific compound].

[0237] Some implementation methods, each R a1 These are independently 5-6 member heteroaryl compounds.

[0238] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a 5-6 member heteroaryl that may be substituted with [another compound].

[0239] Some implementation methods, each R a1 Each is independent of one or more R a2 It is a 5-6 member heteroaryl that is substituted with [a specific compound].

[0240] Some implementation methods, each R a1 Independently, the following are: H, -OH, -CH3, TIFF2026515712000037.tif46148TIFF2026515712000038.tif209147TIFF202651571200 0039.tif201147TIFF2026515712000040.tif210147TIFF2026515712000041.tif103147.

[0241] Some implementation methods, each R a2 These are independently oxo, cyano, -OH, -N(C1-C6 alkyl)2, C1-C6 alkyl, and C3-C 10 The compounds are cycloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, which may be substituted with oxo.

[0242] Some implementation methods, each R a2 These are independently C1-C6 alkyl, C3-C alkyl, and C3-C alkyl groups which may be substituted with oxo, cyano, -OH, -N(C1-C6 alkyl)2, C1-C6 alkoxy, or -OH. 10 The compounds are cycloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, which may be substituted with oxo.

[0243] Some implementation methods, each R a2 These are independently oxo, cyano, -OH, -N(C1-C6 alkyl)2, C1-C6 alkoxy or -OH-substituted C1-C6 alkyl, C3-C 10 The compounds are cycloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, which may be substituted with oxo.

[0244] Some implementation methods, each R a2 It is an independent oxo.

[0245] Some implementation methods, each R a2It is a separate entity, a halo.

[0246] Some implementation methods, each R a2 R is independently F, Cl, Br, or I. In some embodiments, each R a2 R is independently F, Cl, or Br. In some embodiments, each R a2 These are independently either F or Cl.

[0247] Some implementation methods, each R a2 Independently, F. In some embodiments, each R a2 Independently, each R is Cl. In some embodiments, each R a2 Independently, each R is Br. In some embodiments, each R a2 Independently, it is I.

[0248] Some implementation methods, each R a2 It is independently cyano.

[0249] Some implementation methods, each R a2 It is independently -OH.

[0250] Some implementation methods, each R a2 It is independently -NH2.

[0251] Some implementation methods, each R a2 These are independently -NH(C1-C6 alkyl).

[0252] Some implementation methods, each R a2 These are independently -N(C1-C6 alkyl)2.

[0253] Some implementation methods, each R a2 These are independently C1-C6 alkyl groups.

[0254] Some implementation methods, each R a2 These are independently C1-C6 alkoxy or C1-C6 alkyl groups which may be substituted with -OH groups.

[0255] Some implementation methods, each R a2 These are independently C1-C6 alkoxy or C1-C6 alkyl groups substituted with -OH.

[0256] Some implementation methods, each R a2 This is independently a C1-C6 alkyl which may be substituted with a C1-C6 alkoxy.

[0257] Some implementation methods, each R a2 These are independently C1-C6 alkyl groups substituted with C1-C6 alkoxy groups.

[0258] Some implementation methods, each R a2 These are independently C1-C6 alkyl groups that may be substituted with -OH groups.

[0259] Some implementation methods, each R a2 These are independently C1-C6 alkyl groups substituted with -OH.

[0260] Some implementation methods, each R a2 R is independently methyl. In some embodiments, each R a2 Independently, each R is ethyl. In some embodiments, each R a2 In some embodiments, each R is independently propyl. a2 R is independently butyl. In some embodiments, each R a2 In some embodiments, each R is independently a pentill. a2 In some embodiments, each R is independently hexyl. a2 Independently, each R is isopropyl. In some embodiments, each R a2 Independently, each R is isobutyl. In some embodiments, each R a2 Independently, each R is isopentyl. In some embodiments, each R a2 is independently isohexyl. In some embodiments, each R a2 Independently, each R is secbutyl. In some embodiments, each R a2Independently, each R is secpentyl. In some embodiments, each R a2 In some embodiments, each R is independently sec hexyl. a2 It is independently tertbutyl.

[0261] Some implementation methods, each R a2 It is independent, C3-C 10 It is a cycloalkyl group.

[0262] Some implementation methods, each R a2 These are independently C3-C7 cycloalkyl groups.

[0263] Some implementation methods, each R a2 These are independently C1-C6 haloalkoxy compounds.

[0264] Some implementation methods, each R a2 These are independently C1-C6 haloalkyl groups.

[0265] Some implementation methods, each R a2 These are independently C1-C6 alkoxy compounds.

[0266] Some implementation methods, each R a2 These are independently 3- to 10-membered heterocycloalkyl groups.

[0267] Some implementation methods, each R a2 These are independently 3- to 10-membered heterocycloalkyl groups, which may be substituted with oxo groups.

[0268] Some implementation methods, each R a2 These are independently oxo-substituted 3- to 10-membered heterocycloalkyl groups.

[0269] Some implementation methods, each R a2 These are independently 3- to 7-membered heterocycloalkyl groups.

[0270] Some implementation methods, each R a2These are independently 3- to 7-membered heterocycloalkyl groups, which may be substituted with an oxo molecule.

[0271] Some implementation methods, each R a2 These are independently oxo-substituted 3- to 7-membered heterocycloalkyl groups.

[0272] Some implementation methods, each R a2 These are independently 5- to 10-membered heteroaryl compounds.

[0273] Some implementation methods, each R a2 These are independently 5-6 member heteroaryl compounds.

[0274] Some implementation methods, each R a2 These are independently oxo, -CH3, -CH2CH3, -CH(CH3)2, -Cl, -F, -CN, -CHF2, -OCH3, -CF3, -OCHF2, -OH, -CH2CHF2, -CH2CF3, -CH2OH, -CH2OCH3, -OCF3, -N(CH3)2, -OCH(CH3)2, The filename is TIFF2026515712000042.tif15128.

[0275] In some embodiments, R 3 C6-C 10 It is Ariel.

[0276] In some embodiments, R 3 is one or more R 3a C6-C may be replaced with 10 It is Ariel.

[0277] In some embodiments, R 3 is one or more R 3a C6-C is replaced by 10 It is Ariel.

[0278] In some embodiments, R 3 This is a C6 aryl compound.

[0279] In some embodiments, R3 is one or more R 3a It is a C6 aryl that may be substituted with [another C6 aryl

[0280] In some embodiments, R 3 is one or more R 3a It is a C6 aryl that has been substituted.

[0281] In some embodiments, R 3 These are 5-10 member heteroaryl compounds.

[0282] In some embodiments, R 3 is one or more R 3a It is a 5- to 10-membered heteroaryl that may be substituted with [another compound].

[0283] In some embodiments, R 3 is one or more R 3a It is a 5- to 10-membered heteroaryl that is substituted with [a specific compound].

[0284] In some embodiments, R 3 is one R 3a It is a 5- to 10-membered heteroaryl that may be substituted with [another compound].

[0285] In some embodiments, R 3 is one R 3a It is a 5- to 10-membered heteroaryl that is substituted with [a specific compound].

[0286] In some embodiments, R 3 It is a 5-6 member heteroaryl compound.

[0287] In some embodiments, R 3 is one or more R 3a It is a 5-6 member heteroaryl that may be substituted with [another compound].

[0288] In some embodiments, R 3 is one or more R 3a It is a 5-6 member heteroaryl that is substituted with [a specific compound].

[0289] In some embodiments, R 3 is one R 3a It is a 5-6 member heteroaryl that may be substituted with [another compound].

[0290] In some embodiments, R 3 is one R 3a It is a 5-6 member heteroaryl that is substituted with [a specific compound].

[0291] In some embodiments, R 3 The following is true: TIFF2026515712000043.tif77147TIFF2026515712000044.tif130154.

[0292] In some embodiments, R 3 The following is true: TIFF2026515712000045.tif58148.

[0293] In some embodiments, R 3 The following is true: TIFF2026515712000046.tif29128.

[0294] Some implementation methods, each R 3a It is a separate entity, a halo.

[0295] Some implementation methods, each R 3a R is independently F, Cl, Br, or I. In some embodiments, each R 3a R is independently F, Cl, or Br. In some embodiments, each R 3a These are independently either F or Cl.

[0296] Some implementation methods, each R 3a Independently, F. In some embodiments, each R 3a Independently, each R is Cl. In some embodiments, each R 3a Independently, each R is Br. In some embodiments, each R 3a Independently, it is I.

[0297] Some implementation methods, each R 3a It is independently cyano.

[0298] Some implementation methods, each R 3a R is independent of 3a It is -OH.

[0299] Some implementation methods, each R 3a It is independently -NH2.

[0300] Some implementation methods, each R 3a These are independently C1-C6 alkyl groups.

[0301] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a C1-C6 alkyl group which may be substituted with [another molecule].

[0302] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a C1-C6 alkyl group that is substituted with [a specific compound].

[0303] Some implementation methods, each R 3a R is independently methyl. In some embodiments, each R 3a Independently, each R is ethyl. In some embodiments, each R 3a In some embodiments, each R is independently propyl. 3a R is independently butyl. In some embodiments, each R 3a In some embodiments, each R is independently a pentill. 3a In some embodiments, each R is independently hexyl. 3a Independently, each R is isopropyl. In some embodiments, each R 3a Independently, each R is isobutyl. In some embodiments, each R 3a Independently, each R is isopentyl. In some embodiments, each R 3a is independently isohexyl. In some embodiments, each R 3aIndependently, each R is secbutyl. In some embodiments, each R 3a Independently, each R is secpentyl. In some embodiments, each R 3a In some embodiments, each R is independently sec hexyl. 3a It is independently tertbutyl.

[0304] Some implementation methods, each R 3a These are independently C2-C6 alkenyls.

[0305] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a C2-C6 alkenyl that may be substituted with [another compound].

[0306] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a C2-C6 alkenyl that is substituted with [a specific compound].

[0307] Some implementation methods, each R 3a These are independently C2-C6 alkynyl compounds.

[0308] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a C2-C6 alkynyl that may be substituted with [another compound].

[0309] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a C2-C6 alkynyl that is substituted with [a specific compound].

[0310] Some implementation methods, each R 3a These are independently C1-C6 haloalkyl groups.

[0311] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a C1-C6 haloalkyl which may be substituted with [another compound].

[0312] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a C1-C6 haloalkyl that is substituted with [a specific compound].

[0313] Some implementation methods, each R 3a Independently, each R is a halomethyl. In some embodiments, each R 3a Independently, each R is a haloethyl. In some embodiments, each R 3a Independently, each R is a halopropyl. In some embodiments, each R 3a Independently, each R is a halobutyl. In some embodiments, each R 3a Independently, each R is halopentyl. In some embodiments, each R 3a It is independently a halohexyl.

[0314] Some implementation methods, each R 3a It is independent, C3-C 10 It is a cycloalkyl group.

[0315] Some implementation methods, each R 3a Each is independent of one or more R 3a1 C3-C may be replaced with 10 It is a cycloalkyl group.

[0316] Some implementation methods, each R 3a Each is independent of one or more R 3a1 C3-C is replaced by 10 It is a cycloalkyl group.

[0317] Some implementation methods, each R 3a These are independently C3-C7 cycloalkyl groups.

[0318] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a C3-C7 cycloalkyl that may be substituted with a different compound.

[0319] Some implementation methods, each R 3a Each is independent of one or more R 3a1It is a C3-C7 cycloalkyl group that is substituted with [a specific compound].

[0320] Some implementation methods, each R 3a These are independently 3- to 10-membered heterocycloalkyl groups.

[0321] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a 3- to 10-membered heterocycloalkyl that may be substituted with [a specific compound].

[0322] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a 3- to 10-membered heterocycloalkyl group that is substituted with [a specific compound].

[0323] Some implementation methods, each R 3a These are independently 3- to 7-membered heterocycloalkyl groups.

[0324] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a 3- to 7-membered heterocycloalkyl group which may be substituted with a different compound.

[0325] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a 3- to 7-membered heterocycloalkyl group that is substituted with [a specific compound].

[0326] Some implementation methods, each R 3a It is independent, C6-C 10 It is Ariel.

[0327] Some implementation methods, each R 3a Each is independent of one or more R 3a1 C6-C may be replaced with 10 It is Ariel.

[0328] Some implementation methods, each R 3a Each is independent of one or more R 3a1 C6-C is replaced by 10It is Ariel.

[0329] Some implementation methods, each R 3a It is independently a C6 aryl.

[0330] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a C6 aryl that may be substituted with [another C6 aryl

[0331] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a C6 aryl that has been substituted.

[0332] In some embodiments, R 3a C6-C 10 It is Ariel.

[0333] In some embodiments, R 3a is one or more R 3a1 C6-C may be replaced with 10 It is Ariel.

[0334] In some embodiments, R 3a is one or more R 3a1 C6-C is replaced by 10 It is Ariel.

[0335] In some embodiments, R 3a This is a C6 aryl compound.

[0336] In some embodiments, R 3a is one or more R 3a1 It is a C6 aryl that may be substituted with [another C6 aryl

[0337] In some embodiments, R 3a is one or more R 3a1 It is a C6 aryl that has been substituted.

[0338] Some implementation methods, each R 3a These are independently 5- to 10-membered heteroaryl compounds.

[0339] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a 5- to 10-membered heteroaryl that may be substituted with [another compound].

[0340] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a 5- to 10-membered heteroaryl that is substituted with [a specific compound].

[0341] Some implementation methods, each R 3a These are independently 5-6 member heteroaryl compounds.

[0342] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a 5-6 member heteroaryl that may be substituted with [another compound].

[0343] Some implementation methods, each R 3a Each is independent of one or more R 3a1 It is a 5-6 member heteroaryl that is substituted with [a specific compound].

[0344] Some implementation methods, each R 3a -CH3, cyclopropyl, The filename is TIFF2026515712000047.tif131149.

[0345] Some implementation methods, each R 3a -CH3, The filename is TIFF2026515712000048.tif58148.

[0346] Some implementation methods, each R 3a -CH3, The filename is TIFF2026515712000049.tif17128.

[0347] Some implementation methods, each R 3a1 It is an independent oxo.

[0348] Some implementation methods, each R 3a1 It is a separate entity, a halo.

[0349] Some implementation methods, each R 3a1 R is independently F, Cl, Br, or I. In some embodiments, each R 3a1 R is independently F, Cl, or Br. In some embodiments, each R 3a1 These are independently either F or Cl.

[0350] Some implementation methods, each R 3a1 Independently, F. In some embodiments, each R 3a1 Independently, each R is Cl. In some embodiments, each R 3a1 Independently, each R is Br. In some embodiments, each R 3a1 Independently, it is I.

[0351] Some implementation methods, each R 3a1 It is independently cyano.

[0352] Some implementation methods, each R 3a1 It is independently -OH.

[0353] Some implementation methods, each R 3a1 These are independently -C(O)(C1-C6 alkyl).

[0354] Some implementation methods, each R 3a1 These are independently -C(O)(O-(C1-C6 alkyl)).

[0355] Some implementation methods, each R 3a1 These are independently C1-C6 alkyl groups.

[0356] Some implementation methods, each R 3a1 It is independent, C3-C 10 It is a C1-C6 alkyl group that may be substituted with a cycloalkyl group.

[0357] Some implementation methods, each R3a1 It is independent, C3-C 10 These are C1-C6 alkyl groups substituted with cycloalkyl groups.

[0358] Some implementation methods, each R 3a1 R is independently methyl. In some embodiments, each R 3a1 Independently, each R is ethyl. In some embodiments, each R 3a1 In some embodiments, each R is independently propyl. 3a1 R is independently butyl. In some embodiments, each R 3a1 In some embodiments, each R is independently a pentill. 3a1 In some embodiments, each R is independently hexyl. 3a1 Independently, each R is isopropyl. In some embodiments, each R 3a1 Independently, each R is isobutyl. In some embodiments, each R 3a1 Independently, each R is isopentyl. In some embodiments, each R 3a1 is independently isohexyl. In some embodiments, each R 3a1 Independently, each R is secbutyl. In some embodiments, each R 3a1 Independently, each R is secpentyl. In some embodiments, each R 3a1 In some embodiments, each R is independently sec hexyl. 3a1 It is independently tertbutyl.

[0359] Some implementation methods, each R 3a1 These are independently C2-C6 alkenyls.

[0360] Some implementation methods, each R 3a1 These are independently C2-C6 alkynyl compounds.

[0361] Some implementation methods, each R 3a1 These are independently C1-C6 haloalkyl groups.

[0362] Some implementation methods, each R 3a1Independently, each R is a halomethyl. In some embodiments, each R 3a1 Independently, each R is a haloethyl. In some embodiments, each R 3a1 Independently, each R is a halopropyl. In some embodiments, each R 3a1 Independently, each R is a halobutyl. In some embodiments, each R 3a1 Independently, each R is halopentyl. In some embodiments, each R 3a1 It is independently a halohexyl.

[0363] Some implementation methods, each R 3a1 These are independently C1-C6 haloalkoxy compounds.

[0364] Some implementation methods, each R 3a1 These are independently C1-C6 alkoxy compounds.

[0365] Some implementation methods, each R 3a1 These are independently -O(C1-C6 haloalkyl).

[0366] Some implementation methods, each R 3a1 It is independent, C3-C 10 It is a cycloalkyl group.

[0367] Some implementation methods, each R 3a1 These are independently C3-C7 cycloalkyl groups.

[0368] Some implementation methods, each R 3a1 It is independent, C6-C 10 It is Ariel.

[0369] Some implementation methods, each R 3a1 It is independently a C6 aryl.

[0370] Some implementation methods, each R 3a1 These are independently 5- to 10-membered heteroaryl compounds.

[0371] Some implementation methods, each R 3a1These are independently 5-6 member heteroaryl compounds.

[0372] Some implementation methods, each R 3a1 These are independently cyano or C1-C6 alkoxy compounds.

[0373] Some implementation methods, each R 3a1 These are independently methyl, cyano, -Cl, or -OCH3.

[0374] Some implementation methods, each R 3a1 These are independently oxo, methyl, -CF2H, cyano, -F, -Cl, -OH, -OCF2H, or -OCH3.

[0375] In some embodiments, the compound is a compound of formula (I), where, X 1 is CH, S, or N, X 2 is N, S, or O, R 1 and R 2 They, together with the atoms they bond to, form a C5-C 10 Forms cycloalkyl or 5-10 member heterocycloalkyl groups, C5-C 10 Cycloalkyl or 5-10 member heterocycloalkyl groups include one or more R a It may also be replaced with Each R a These are independently oxo, halo, cyano, -OR a1 , -N(R a1 )2, -C(O)R a1 ,-C(O)N(R a1 )2, -C(O)OR a1 -S(O)2N(R a1 )2, -S(O)2(R a1 ), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, C6-C 10These are aryl, 5-10 member heteroaryl, or 3-10 member heterocycloalkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, or 3-10 member heterocycloalkyl is one or more R a1 It may also be replaced with Each R a1 These are independently H, oxo, halo, cyano, -OH, -NH2, -C(O)(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 It is an aryl or 5-10 member heteroaryl, and is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 An aryl, or a 5-10 member heteroaryl, is one or more R a2 It may also be replaced with Each R a2 These are independently a C1-C6 alkyl, C1-C6 haloalkoxy, or 3-10 member heterocycloalkyl, or 5-10 member heteroaryl, which may be substituted with oxo, halo, cyano, -OH, -NH2, C1-C6 alkoxy, or oxo. R 3 C6-C 10 It is an aryl or 5-10 member heteroaryl, C6-C 10 Aryl or 5-10 member heteroaryls are one or more R 3a It has been replaced with, Each R 3a These are independently halo, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C10 It is an aryl or 5-10 member heteroaryl, and is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 An aryl, or a 5-10 member heteroaryl, is one or more R 3a1 It may also be replaced with Each R 3a1 These are independently oxo, halo, cyano, -C(O)(C1-C6 alkyl), -C(O)(O-(C1-C6 alkyl)), and C3-C 10 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O(C1-C6 haloalkyl), C3-C (which may be substituted with cycloalkyl groups) 10 Cycloalkyl, C6-C 10 They are aryl or 5- to 10-membered heteroaryl compounds.

[0376] In some embodiments, the compound is a compound of formula (I), where, X 1 is either S or N, X 2 is N or S, R 1 and R 2 These atoms, together with the atoms to which they are bonded, form a C5-C6 cycloalkyl or 5-6 member heterocycloalkyl, and the C5-C6 cycloalkyl or 5-6 member heterocycloalkyl has one or more R a It may also be replaced with Each R a These are independently oxo, -OR a1 , -N(R a1 )2, -C(O)R a1 ,-C(O)N(R a1 )2, -C(O)OR a1 -S(O)2N(R a1 )2, -S(O)2(R a1 ), C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10The aryl, 5-10 membered heteroaryl, or 3-10 membered heterocycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, or 3-10 member heterocycloalkyl is one or more R a1 It may also be replaced with Each R a1 These are independently H, halo, cyano, -C(O)(C1-C6 alkyl), and -C(O)(C3-C 10 Cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 It is an aryl or 5-10 member heteroaryl, and -C(O)(C3-C 10 Cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 An aryl, or a 5-10 member heteroaryl, is one or more R a2 It may also be replaced with Each R a2 These are independently C1-C6 alkyl, C3-C alkyl, and C3-C alkyl groups which may be substituted with oxo, cyano, -OH, -N(C1-C6 alkyl)2, C1-C6 alkoxy, or -OH. 10 These are cycloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl, which may be substituted with oxo. R 3 is one R 3a It is a 5-10 member heteroaryl that is substituted with R 3a is one or more R 3a1 C6-C may be replaced with 10 It is Ariel, Each R 3a1 These are independently cyano or C1-C6 alkoxy compounds.

[0377] In some embodiments, the compound is a compound of the following formula (IA): TIFF2026515712000050.tif19128, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, or tautomers.

[0378] In some embodiments, the compound is a compound of the following formulas: (IB), (IC), (ID), or (IE): TIFF2026515712000051.tif45128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, where m is 0 to 6, n is 0 to 8, and p is 0 to 6.

[0379] In some embodiments, the compound is a compound of the following formula (IF): TIFF2026515712000052.tif19128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, where p is between 0 and 4.

[0380] In some embodiments, the compound is a compound of the following formula (I-Fa): TIFF2026515712000053.tif17128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, where p is between 0 and 4.

[0381] In some embodiments, the compound is a compound of the following formula (I-Fb): TIFF2026515712000054.tif21128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, where p is between 0 and 4.

[0382] In some embodiments, the compound is a compound of the following formula (I-Fb'): TIFF2026515712000055.tif19128, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, or tautomers.

[0383] In some embodiments, the compound is a compound of the following formula (I-Fc): TIFF2026515712000056.tif19128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, where p is 0 to 4 and q is 1 to 4.

[0384] In some embodiments, the compound is the compound of formula (I-Fc'): TIFF2026515712000057.tif21128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, where q is 1 to 4.

[0385] In some embodiments, the compound is a compound of the following formula (I-Fd): TIFF2026515712000058.tif21128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, where p is between 0 and 4.

[0386] In some embodiments, the compound is a compound of the following formula (I-Fd'): TIFF2026515712000059.tif21128, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, or tautomers.

[0387] In some embodiments, the compound is a compound of the following formula (IG): TIFF2026515712000060.tif19128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, where q is 1 to 4.

[0388] In some embodiments, the compound is a compound of the following formula (I-Ga): TIFF2026515712000061.tif19128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, where q is 1 to 4.

[0389] In some embodiments, the compound is a compound of the following formula (I-Ga'): TIFF2026515712000062.tif21128, or its pharmaceutically acceptable salts, solvates, clathrates, hydrates, stereoisomers, or tautomers.

[0390] In some embodiments, the compound is one of the compounds listed in Table 1, or a prodrug or pharmaceutically acceptable salt thereof.

[0391] In some embodiments, the compound is one of the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0392] In some embodiments, the compound is a prodrug of the compound listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0393] In some embodiments, the compound is one of the compounds listed in Table 1.

[0394] In some embodiments, the compound is one of the compounds listed in Table 2, or a prodrug or pharmaceutically acceptable salt thereof.

[0395] In some embodiments, the compound is one of the compounds listed in Table 2, or a pharmaceutically acceptable salt thereof.

[0396] In some embodiments, the compound is a prodrug of the compounds listed in Table 2, or a pharmaceutically acceptable salt thereof.

[0397] In some embodiments, the compound is one of the compounds listed in Table 2.

[0398] In some embodiments, the compound is one of the compounds listed in Table 3, or a prodrug or pharmaceutically acceptable salt thereof.

[0399] In some embodiments, the compound is one of the compounds listed in Table 3, or a pharmaceutically acceptable salt thereof.

[0400] In some embodiments, the compound is a prodrug of the compound listed in Table 3, or a pharmaceutically acceptable salt thereof.

[0401] In some embodiments, the compound is one of the compounds listed in Table 3.

[0402] Each compound in Tables 1-3 is assigned a compound number, with any other compound number indicated in parentheses. For compounds with two compound numbers, both numbers may be used interchangeably to refer to the same compound.

[0403] (Table 1) TIFF2026515712000063.tif238167TIFF2026515712000064.tif244167TIFF2026515712000065.tif249167TIFF2026515712000066.tif255167TIFF2026515712000067.tif255167TIFF2026515712000068.tif255167TIFF2026515712000069.tif233167TIFF2026515712000070.tif254167TIFF2026515712000071.tif244167TIFF2026515712000072.tif254167TIFF2026515712000073.tif254167TIFF2026515712000074.tif255167TIFF2026515712000075.tif254167TIFF2026515712000076.tif254167TIFF2026515712000077.tif254167TIFF2026515712000078.tif244167TIFF2026515712000079.tif254167TIFF2026515712000080.tif245167TIFF2026515712000081.tif248167TIFF2026515712000082.tif249167TIFF2026515712000083.tif243167TIFF2026515712000084.tif254167TIFF2026515712000085.tif255167TIFF2026515712000086.tif254167TIFF2026515712000087.tif249167TIFF2026515712000088.tif254167TIFF2026515712000089.tif254167TIFF2026515712000090.tif255167TIFF2026515712000091.tif254167TIFF2026515712000092.tif254167TIFF2026515712000093.tif255167TIFF2026515712000094.tif239167TIFF2026515712000095.tif244167TIFF2026515712000096.tif234167TIFF2026515712000097.tif254167TIFF2026515712000098.tif255167TIFF2026515712000099.tif249167TIFF2026515712000100.tif244167TIFF2026515712000101.tif249167TIFF2026515712000102.tif255167TIFF2026515712000103.tif254167TIFF2026515712000104.tif234167TIFF2026515712000105.tif255167TIFF2026515712000106.tif254167TIFF2026515712000107.tif244167TIFF2026515712000108.tif254167TIFF2026515712000109.tif255167TIFF2026515712000110.tif239167TIFF2026515712000111.tif249167TIFF2026515712000112.tif238167TIFF2026515712000113.tif247167TIFF2026515712000114.tif230167TIFF2026515712000115.tif221167TIFF2026515712000116.tif255167TIFF2026515712000117.tif228167TIFF2026515712000118.tif241167TIFF2026515712000119.tif224167TIFF2026515712000120.tif232167TIFF2026515712000121.tif254167TIFF2026515712000122.tif238167TIFF2026515712000123.tif255166TIFF2026515712000124.tif249167TIFF2026515712000125.tif255167TIFF2026515712000126.tif251167TIFF2026515712000127.tif245167TIFF2026515712000128.tif244167TIFF2026515712000129.tif249167TIFF2026515712000130.tif247167TIFF2026515712000131.tif238167TIFF2026515712000132.tif240167TIFF2026515712000133.tif237167TIFF2026515712000134.tif255167TIFF2026515712000135.tif249167TIFF2026515712000136.tif239167TIFF2026515712000137.tif249167TIFF2026515712000138.tif244167TIFF2026515712000139.tif249167TIFF2026515712000140.tif224167TIFF2026515712000141.tif244167TIFF2026515712000142.tif234167TIFF2026515712000143.tif242167TIFF2026515712000144.tif252167TIFF2026515712000145.tif255167TIFF2026515712000146.tif251167TIFF2026515712000147.tif226167TIFF2026515712000148.tif255167TIFF2026515712000149.tif119167.

[0404] <s (Table 2) TIFF2026515712000150.tif228167TIFF2026515712000151.tif238167TIFF2026515712000152.tif230167TIFF2026515712000153.tif227167TIFF2026515712000154.tif255167TIFF2026515712000155.tif249167TIFF2026515712000156.tif127167

[0405] (Table 3) TIFF2026515712000157.tif237167TIFF2026515712000158.tif237167TIFF2026515712000159.tif237167TIFF2026515 712000160.tif252167TIFF2026515712000161.tif242167TIFF2026515712000162.tif252167TIFF2026515712000163.t if240167TIFF2026515712000164.tif247167TIFF2026515712000165.tif238167TIFF2026515712000166.tif237167TIF F2026515712000167.tif247167TIFF2026515712000168.tif238167TIFF2026515712000169.tif237167TIFF20265157120 00170.tif235167TIFF2026515712000171.tif237167TIFF2026515712000172.tif252167TIFF2026515712000173.tif23 8167TIFF2026515712000174.tif235167TIFF2026515712000175.tif238167TIFF2026515712000176.tif220167TIFF202 6515712000177.tif247167TIFF2026515712000178.tif255167TIFF2026515712000179.tif214167TIFF20265157120001 80.tif247167TIFF2026515712000181.tif247167TIFF2026515712000182.tif221167TIFF2026515712000183.tif162167

[0406] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 1.

[0407] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 2.

[0408] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 3.

[0409] In some embodiments, the Disclosure provides compounds that are isotopic derivatives (e.g., isotope-labeled compounds) of any one of the compounds of the formulas disclosed herein.

[0410] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1, or a prodrug or pharmaceutically acceptable salt thereof.

[0411] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0412] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0413] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1.

[0414] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 2, or a prodrug or pharmaceutically acceptable salt thereof.

[0415] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 2, or a pharmaceutically acceptable salt thereof.

[0416] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 2, or a pharmaceutically acceptable salt thereof.

[0417] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 2.

[0418] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 3, or a prodrug or pharmaceutically acceptable salt thereof.

[0419] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 3, or a pharmaceutically acceptable salt thereof.

[0420] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 3, or a pharmaceutically acceptable salt thereof.

[0421] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 3.

[0422] In some embodiments, the compound is selected from compound numbers 7, 9, 10, 15, 18, 379, 387, 389, 400, 404, 415, 425, 450, 508, 548, 584, 585, 586, 592, and 594, or their prodrugs or pharmaceutically acceptable salts.

[0423] In some embodiments, the compound is selected from compound numbers 7, 9, 10, 15, 18, 379, 387, 389, 400, 404, 415, 425, 450, 508, 548, 584, 585, 586, 592, and 594, or their pharmaceutically acceptable salts.

[0424] In some embodiments, the compound is selected from compound numbers 7, 9, 10, 15, 18, 379, 387, 389, 400, 404, 415, 425, 450, 508, 548, 584, 585, 586, 592, and 594.

[0425] In some embodiments, the compound is selected from compound numbers 2, 5, 14, 49, 146, 652, 653, 655, 691, 793, 820, 828, 908, 922, 951, 952, 964, 980, 987, 990, 996, 1003, 1005, 1010, 1013, 1014, 1016, 1019, 1023, 1029, 1032, 1039, 1041, and 1046, or their prodrugs or pharmaceutically acceptable salts.

[0426] In some embodiments, the compound is selected from compound numbers 2, 5, 14, 49, 146, 652, 653, 655, 691, 793, 820, 828, 908, 922, 951, 952, 964, 980, 987, 990, 996, 1003, 1005, 1010, 1013, 1014, 1016, 1019, 1023, 1029, 1032, 1039, 1041, and 1046, or pharmaceutically acceptable salts thereof.

[0427] In some embodiments, the compound is selected from compound numbers 2, 5, 14, 49, 146, 652, 653, 655, 691, 793, 820, 828, 908, 922, 951, 952, 964, 980, 987, 990, 996, 1003, 1005, 1010, 1013, 1014, 1016, 1019, 1023, 1029, 1032, 1039, 1041, and 1046.

[0428] In some embodiments, the compound is selected from compound numbers 7, 9, 10, 15, 18, 379, 387, 389, 400, 404, 415, 425, 450, 508, 548, 584, 585, 586, 592, 594, 2, 5, 14, 49, 146, 652, 653, 655, 691, 793, 820, 828, 908, 922, 951, 952, 964, 980, 987, 990, 996, 1003, 1005, 1010, 1013, 1014, 1016, 1019, 1023, 1029, 1032, 1039, 1041, and 1046, or their prodrugs or pharmaceutically acceptable salts.

[0429] In some embodiments, the compound is selected from compound numbers 7, 9, 10, 15, 18, 379, 387, 389, 400, 404, 415, 425, 450, 508, 548, 584, 585, 586, 592, 594, 2, 5, 14, 49, 146, 652, 653, 655, 691, 793, 820, 828, 908, 922, 951, 952, 964, 980, 987, 990, 996, 1003, 1005, 1010, 1013, 1014, 1016, 1019, 1023, 1029, 1032, 1039, 1041, and 1046, or pharmaceutically acceptable salts thereof.

[0430] In some embodiments, the compound is selected from compound numbers 7, 9, 10, 15, 18, 379, 387, 389, 400, 404, 415, 425, 450, 508, 548, 584, 585, 586, 592, 594, 2, 5, 14, 49, 146, 652, 653, 655, 691, 793, 820, 828, 908, 922, 951, 952, 964, 980, 987, 990, 996, 1003, 1005, 1010, 1013, 1014, 1016, 1019, 1023, 1029, 1032, 1039, 1041, and 1046.

[0431] In some embodiments, the compound is a compound obtainable by or acquired by the method described herein, and optionally, the method comprises one or more steps described in schemes 1 to 7.

[0432] It is understood that isotopic derivatives can be prepared using any of the various techniques recognized in the art. For example, isotopic derivatives can generally be prepared by replacing an isotopic labeling reagent with a non-isotopic labeling reagent by performing the procedures disclosed in the schemes and / or examples described herein.

[0433] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0434] In some embodiments, the isotope derivative is a deuterium-labeled compound of any one of the compounds of the formulas disclosed herein.

[0435] As used herein, the term "isotope derivative" refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotope derivative of a compound of formula (I) is isotopically enriched or labeled with respect to one or more isotopes as compared to the corresponding compound of formula (I). In some embodiments, the isotope derivative is 2 H, 13 C, 14 C, 15 N, 18 O, 29 Si, 31 P, and [[ID=ig]] 34 S, enriched or labeled with respect to one or more atoms selected from. In some embodiments, the isotope derivative is a deuterium-labeled compound (i.e., 2 H is enriched in one or more of its atoms). In some embodiments, the compound is 18 an F-labeled compound. In some embodiments, the compound is 123 an I-labeled compound, 124 an I-labeled compound, 125 an I-labeled compound, 129 an I-labeled compound, 131 an I-labeled compound, 135 an I-labeled compound, or any combination thereof. In some embodiments, the compound is 33 an S-labeled compound, 34 an S-labeled compound, 35 an S-labeled compound, 36 an S-labeled compound, or any combination thereof.

[0436] 18 F, 123 I, [[ID=Si]]<o000905>I, 125 I, 129 I, 131 I, 135 I, <000091o>S, 34 S, 35 S, and / or36 It is understood that S-labeled compounds can be prepared using any of the various techniques recognized in the art. For example, deuterium-labeled compounds are generally prepared using 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 It can be prepared by replacing the S-labeled reagent with a non-isotope-labeled reagent and performing the procedures disclosed in the schemes and / or examples described herein.

[0437] As mentioned above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and 36 Compounds of the present invention containing one or more atoms of S, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present invention. Furthermore, isotopes (e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 Substitution with S) may result in certain therapeutic benefits stemming from greater metabolic stability, such as an increased half-life in vivo or a reduction in the required dose.

[0438] To avoid any ambiguity, it should be understood that, in this specification, when a group satisfies the requirement of being “described herein,” that group encompasses not only the broadest definition that first arose, but also each and all of the specific definitions applied to that group.

[0439] The various functional groups and substituents constituting the compound of formula (I) are typically selected so that the molecular weight of the compound does not exceed 1000 daltons. More commonly, the molecular weight of the compound is less than 900 daltons, e.g., less than 800 daltons, or less than 750 daltons, or less than 700 daltons, or less than 650 daltons. More conveniently, the molecular weight is less than 600 daltons, e.g., 550 daltons or less.

[0440] Suitable pharmaceutically acceptable salts of the compounds of this disclosure are, for example, acid addition salts of the compounds of this disclosure that are sufficiently basic, such as acid addition salts of inorganic organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, methane sulfonate citrate, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of this disclosure that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts having an organic base that yields a pharmaceutically acceptable cation, such as methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0441] Any compound of any of the formulas disclosed herein and any pharmaceutically acceptable salt thereof will be understood to include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomers of the compound.

[0442] It will be understood that the compounds disclosed herein may be presented in a particular configuration. Such a particular configuration should not be construed as limiting this disclosure to one or more isomers, tautomers, regioisomers, or stereoisomers, nor does it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers. In some embodiments, the presentation of a compound herein in a particular configuration is intended to encompass and refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof, but this presentation is further intended to refer to a particular configuration of the compound.

[0443] It will be understood that the compounds disclosed herein may be presented without a specific configuration (e.g., without a specific stereochemistry). Such presentations are intended to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, presentations of compounds herein without a specific configuration are intended to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0444] As used herein, the term “isomer” means a compound having the same molecular formula but differing in the arrangement of its atoms or the spatial configuration of its atoms. Isomers that differ in the spatial configuration of their atoms are called “stereoisomers.” Stereoiomers that are not mirror images of each other are called “diastereoisomers,” and stereoisomers that are mirror images of each other but cannot be superimposed are called “enantiomers,” or sometimes called optical isomers. A mixture containing equal amounts of individual enantiomer forms with opposite chiralities is called a “racemic mixture.”

[0445] As used herein, the term “chiral center” refers to a carbon atom to which four non-identical substituents are bonded.

[0446] As used herein, the term “chiral isomer” means a compound having at least one chiral center. Compounds with multiple chiral centers may exist either as individual diastereomers or as a mixture of diastereomers, called a “diastereomer mixture.” Where a single chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are ranked according to the sequence rules of Kahn, Ingold, and Prelog. (Cahn et al.,Angew.Chem.Inter.Edit.1966,5,385;errata 511, Cahn et al.,Angew.Chem.1966,78,413;Cahn and Ingold,J.Chem.Soc.1951(London),612, Cahn et al.,Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0447] As used herein, the term “geometric isomer” means a diastereomer resulting from the presence of a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl) that opposes rotation. These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, which indicate whether the group is on the same side or opposite side of the double bond in the molecule according to the Kahn-Ingold-Prelogue rule.

[0448] It should be understood that the compounds of this disclosure may be represented as different chiral or geometric isomers. Where a compound has chiral or geometric isomeric forms, all isomers are intended to be included within the scope of this disclosure, and the nomenclature of the compounds does not exclude any isomers, and naturally, not all isomers may have the same level of activity.

[0449] It should be understood that the structures and other compounds discussed in this disclosure include all of their atropic isomers. Naturally, not all atropic isomers may possess the same level of activity.

[0450] As used herein, the term “atropic isomer” refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers exist due to rotational limitations caused by the obstruction of rotation of the larger group around a central bond. Such atropic isomers typically exist as a mixture, but as a result of recent advances in chromatography techniques, in selected cases it is possible to separate a mixture of two atropic isomers.

[0451] As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomer to another. This conversion results in a formal migration of hydrogen atoms, involving the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of sets of tautomers in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is called tautomerism. Of the various possible types of tautomerism, two are commonly observed. Keto-enol tautomerism involves a simultaneous shift of electrons and hydrogen atoms. Ring chain tautomerism arises as a result of an aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxyl groups (-OH) in the same molecule, giving rise to the cyclic (ring-shaped) form exhibited by glucose.

[0452] It should be understood that the compounds of this disclosure may be represented as different tautomers. Where a compound has tautomer forms, all tautomer forms are intended to be included within the scope of this disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have higher levels of activity than others.

[0453] Compounds that have the same molecular formula but differ in the nature or arrangement of their atomic bonds, or in the arrangement of their atoms in space, are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers." If a compound has a chiral center, for example, if it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by the R and S arrangement rules of Kahn and Prelogue, or by the rotation of the plane of polarization of the molecule, which is then named dextrorotatory or levorotatory (i.e., (+) isomer or (-) isomer, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0454] The compounds of this disclosure may have one or more asymmetric centers, and therefore such compounds may be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, descriptions or nomenclasments of specific compounds in this specification and claims are intended to include both individual enantiomers and mixtures thereof, racemates, or otherwise. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by separation of racemates (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of this disclosure may have geometric isomer centers (E and Z isomers). It should be understood that this disclosure encompasses all optical isomers, diastereoisomers, and geometric isomers, and mixtures thereof, that have polymerase Θ inhibitory activity.

[0455] This disclosure also includes compounds of the disclosure as defined herein, which include one or more isotopic substitutions.

[0456] It should be understood that any compound of any formula described herein includes, where applicable, the compound itself, as well as its salts and solvates. Salts may be formed, for example, between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chlorides, bromides, iodides, sulfates, bisulfates, sulfamates, nitrates, phosphates, citrates, methanesulfons, trifluoroacetates, glutamates, glucurons, glutarates, malates, maleates, succinates, fumarates, tartrates, tosylates, salicylates, lactates, naphthalenesulfons, and acetates (e.g., trifluoroacetates).

[0457] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts may also be formed between a cation and a negatively charged group (e.g., a carboxylate) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, and calcium ions, and ammonium cations such as tetramethylammonium or diethylamine ions. The substituted compounds disclosed herein also include salts thereof containing a quaternary nitrogen atom.

[0458] It should be understood that the compounds of this disclosure, for example, salts of these compounds, may exist in either a hydrated or unhydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates and dihydrates. Non-limiting examples of solvates include ethanol solvate and acetone solvate.

[0459] As used herein, the term “solvate” means a solvation form containing either stoichiometric or nonstoichiometric amounts of solvent. Some compounds tend to capture a fixed molar ratio of solvent molecules in their crystalline solid state, thereby forming solvates. When the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by a combination of one or more water molecules and one molecule of a substance in which water retains its molecular state as H2O.

[0460] As used herein, the term “analog” refers to a compound that is structurally similar to another compound but differs slightly in composition (for example, by one atom being substituted by an atom of a different element, or by the presence of a particular functional group, or by one functional group being substituted by another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance, but whose structural origins are not similar or equivalent to those of the reference compound.

[0461] As used herein, the term “derivative” refers to a compound having a common core structure and being substituted with one of the various groups described herein.

[0462] As used herein, the term “biological equivalent” refers to a compound resulting from the exchange of one atom or group of atoms with another broadly similar atom or group of atoms. The purpose of biological equivalent substitution is to create a novel compound having similar biological properties to the parent compound. Biological equivalent substitution may be based on physicochemical or morphological factors. Examples of biological equivalents of carboxylic acids include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 31473176, 1996.

[0463] It should be understood that any particular compound among the formulas disclosed herein may exist not only in solvated form but also in non-solvated form, such as in hydrated form. Preferred pharmaceutically acceptable solvates are hydrates such as hemihydrate, monohydrate, dihydrate, or trihydrate. It should be understood that this disclosure encompasses all such solvated forms having polymerase Θ inhibitory activity.

[0464] It should be understood that any one particular compound among the formulas disclosed herein may exhibit crystalline polymorphism, and that this disclosure encompasses all such forms or mixtures thereof that have polymerase Θ inhibitory activity. In general, crystalline materials are known to be analyzeable using conventional techniques such as X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and nuclear magnetic resonance spectroscopy in solution and / or solid state. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0465] Any one of the compounds of the formulas disclosed herein may exist in many different tautomer forms, and a reference to a compound of formula (I) includes all such forms. To avoid doubt, if a compound may exist in one of several tautomer forms and only one is specifically described or shown, nevertheless all other compounds are encompassed by formula (I). Examples of tautomer forms include, for example, the keto, enol, and enolate forms, such as those in the following tautomer pairs: keto / enol (exemplified below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enthiol, and nitro / acinitro. TIFF2026515712000184.tif19128

[0466] Any compound of any of the formulas disclosed herein that contains an amine functional group may also form an N-oxide. References herein to compounds of formula (I) containing an amine functional group also include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are those of nitrogen atoms in tertiary amines or nitrogen-containing heterocycles. N-oxides may be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid); see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience. More specifically, N-oxides may be prepared by the procedure of LWDeady (Syn.Comm.1977,7,509~514), where the amine compound reacts with metachloroperbenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0467] Any compound of any of the formulas disclosed herein may be administered in the form of a prodrug that is modified in the body of a human or animal in order to release the compound of the disclosure. Prodrugs can be used to alter the physical and / or pharmacokinetic properties of the compound of the disclosure. Prodrugs can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be bonded. Examples of prodrugs include derivatives of any of the formulas disclosed herein that contain an alkyl or acyl substituent on the ester or amide group that is cleavable in vivo. In some embodiments, the prodrug of the disclosure is compound 21a of scheme 4. In some embodiments, the prodrug of the disclosure is compound 21a of scheme 4, where R is a C1-C6 alkyl which may be substituted with a C1-C6 alkoxy, and the C1-C6 alkoxy may be substituted with one or more oxo or -COOH groups. In some embodiments, the prodrug of the Disclosure is the compound of Example 780A or 780B. In some embodiments, the prodrug of the Disclosure is the compound of Table AK. In some embodiments, the prodrug of the Disclosure is (Z)-4-((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-(5-(difluoromethyl)picolinoyl)-5,6-dihydro-2H-pyrrolo[3,4-d]thiazole-3(4H)-yl)methoxy)-4-oxobutanoic acid. In some embodiments, the prodrug of the present disclosure is 4-((2'-chloro-N-(5-(5-(difluoromethyl)picolinoyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide)methoxy)-4-oxobutanoic acid.

[0468] Accordingly, this disclosure includes any one of the formulas disclosed herein as defined above, when made available by organic synthesis and when made available in the body of a human or animal by cleavage of its prodrug. Accordingly, this disclosure also includes any one of the formulas disclosed herein produced by organic synthesis means, and also such compounds produced in the body of a human or animal by metabolism of precursor compounds, i.e., any one of the formulas disclosed herein may be a compound produced by synthesis or a compound produced metabolically.

[0469] A suitable pharmaceutically acceptable prodrug of any one of the formulas disclosed herein is based on reasonable medical judgment that it is suitable for administration to the human or animal body without undesirable pharmacological activity and without excessive toxicity. Various forms of prodrugs have been described in the following publications, for example: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985), b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985), c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard pp. 113-191 (1991), d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992), e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988), f) N. Kakeya, et al. al., Chem. Pharm. Bull., 32, 692 (1984), g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACS Symposium Series, Volume 14, and H) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0470] A suitable pharmaceutically acceptable prodrug of any one of the formulas disclosed herein having a hydroxyl group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of any one of the formulas disclosed herein containing a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in the body of a human or animal to produce the parent hydroxyl compound. Suitable groups for forming pharmaceutically acceptable esters with a hydroxyl group include inorganic esters such as phosphate esters (including phosphoramidocyclic esters). Even more suitable groups for forming pharmaceutically acceptable esters with a hydroxyl group include, for example, acetyl groups, benzoyl groups, phenylacetyl groups, and C1-C groups such as substituted benzoyl and phenylacetyl groups. 10 C1-C groups such as alkanoyl groups, ethoxycarbonyl groups, N,N-(C1-C6 alkyl)2-carbamoyl groups, 2-dialkylaminoacetyl groups, and 2-carboxyacetyl groups. 10 Examples of alkoxycarbonyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxyl group include acetoxymethyl and α-acyloxyalkyl groups such as pivaloyloxymethyl.

[0471] A suitable pharmaceutically acceptable prodrug of any one of the formulas disclosed herein having a carboxyl group is, for example, an in vivo cleavable amide, such as an amine such as ammonia, such as a methylamine. 1-4The amides include alkylamines, such as (C1-C4 alkyl)2 amines like dimethylamine, N-ethyl-N-methylamine, or diethylamine; C1-C4 alkoxy-C2-C4 alkylamines like 2-methoxyethylamine; phenyl-C1-C4 alkylamines like benzylamine; and amino acids or their esters such as glycine. A suitable pharmaceutically acceptable prodrug of any one of the compounds of the formulas disclosed herein having an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example, acetyl, benzoyl, phenylacetyl, and C1-C such as substituted benzoyl and phenylacetyl groups. 10 Examples of amides formed by alkanoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl.

[0472] The in vivo effect of any one of the compounds of the formulas disclosed herein may be partially exerted by one or more metabolites formed in the human or animal body after administration of any one of the compounds of the formulas disclosed herein. As mentioned above, the in vivo effect of any one of the compounds of the formulas disclosed herein may also be exerted by the metabolism (prodrug) of the precursor compound.

[0473] This disclosure is appropriate to exclude any individual compounds that do not possess the biological activity defined herein.

[0474] Synthesis method In some embodiments, the Disclosure provides a method for preparing the compounds of the Disclosure.

[0475] In some embodiments, the Disclosure provides a method for compounding a compound comprising one or more steps described herein.

[0476] In some embodiments, the Disclosure provides compounds that are obtainable by, or obtained by, or directly obtained by, methods for preparing the compounds described herein.

[0477] In some embodiments, the Disclosure provides intermediates described herein that are suitable for use in methods for preparing the compounds described herein.

[0478] The compounds of this disclosure can be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further described in the attached examples.

[0479] It should be understood that in the descriptions of the synthesis methods described herein, and in any standard of synthesis methods used to prepare the starting materials, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and work-up procedure, can be selected by those skilled in the art.

[0480] Those skilled in organic synthesis understand that the functionalities present in various parts of a molecule must be compatible with the reagents and reaction conditions used.

[0481] It will be understood that during the synthesis of the compounds of this disclosure in the processes specified herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent undesirable reactions. An experienced chemist will understand when such protection is necessary and how such protecting groups can be placed in place and subsequently removed. For examples of protecting groups, see one of the many general texts on the subject, e.g., 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any simple method known to those skilled in the art, where described in the literature or appropriate for the removal of the protecting group of interest, and such method is selected to result in the removal of the protecting group with minimal interference to other groups in the molecule. Thus, when reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect these groups in some of the reactions referred to herein.

[0482] As an example, suitable protecting groups for amino groups or alkylamino groups include, for example, acyl groups, such as alkanoyl groups like acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; or aroyl groups, such as benzoyl. The deprotection conditions for the above protecting groups inevitably vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl or alkoxycarbonyl groups, or aroyl groups, can be removed by hydrolysis using a suitable base such as an alkali metal hydroxide, such as lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as tert-butoxycarbonyl groups can be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed by hydrogenation with a catalyst such as palladium carbon, or by treatment with a Lewis acid, such as boron tris(trifluoroacetate). Suitable alternative protecting groups for primary amino groups include phthaloyl groups, which can be removed by treatment with alkylamines, such as dimethylaminopropylamine, or hydrazine.

[0483] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, alkanoyl groups such as acetyl, alloyl groups such as benzoyl, or arylmethyl groups such as benzyl. The deprotection conditions for the above protecting groups will inevitably vary depending on the choice of protecting group. For example, acyl groups such as alkanoyl groups and alloyl groups can be removed by hydrolysis using suitable bases such as alkali metal hydroxides such as lithium hydroxide and sodium hydroxide, or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation with a catalyst such as palladium-carbon.

[0484] Suitable protecting groups for the carboxyl group include, for example, esterifying groups such as methyl or ethyl groups that can be removed by hydrolysis with a base such as sodium hydroxide, or for example, tert-butyl groups that can be removed by treatment with an acid such as an organic acid such as trifluoroacetic acid, or for example, benzyl groups that can be removed by hydrogenation with a catalyst such as palladium carbon.

[0485] Once a compound of formula (I) has been synthesized by any of the processes specified herein, the process may further include the additional steps of (i) removing any protecting groups present, (ii) converting compound formula (I) to another compound of formula (I), (iii) forming a pharmaceutically acceptable salt, hydrate, or solvate thereof, and / or (iv) forming a prodrug thereof.

[0486] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0487] Conveniently, the reaction of the compounds takes place in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), or dioxane; and ethylene glycosides. Examples of such solvents include, but are not limited to, glycol ethers such as monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglym); ketones such as acetone, methyl isobutyl ketone (MIBK), or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF), or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate; or mixtures of such solvents or mixtures with water.

[0488] The reaction temperature is appropriately between approximately -100°C and 300°C, depending on the reaction steps and the conditions used.

[0489] The reaction time generally ranges from less than a minute to several days, depending on the reactivity of each compound and the respective reaction conditions. A suitable reaction time can be easily determined by methods known in the art, such as monitoring the reaction. Based on the reaction temperature mentioned above, a suitable reaction time generally ranges from 10 minutes to 48 hours.

[0490] Furthermore, additional compounds of this disclosure can be readily prepared by utilizing the procedures described herein, in addition to ordinary skill in the art. Those skilled in the art will readily understand that these compounds can be prepared using known variations of the conditions and processes of the following preparation procedures.

[0491] As will be understood by those skilled in the art of organic synthesis, the compounds of this disclosure are readily accessible through a variety of synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will readily recognize what reagents and reaction conditions are used to obtain the compounds of this disclosure, how they are applied, and how they can be adapted in any particular case whenever necessary or useful. Furthermore, some of the compounds of this disclosure can be readily synthesized under preferred conditions by reacting them with other compounds of this disclosure, for example, by converting a particular functional group present in a compound of this disclosure, or a preferred precursor molecule thereof, to another by applying standard synthetic methods such as reduction, oxidation, addition, or substitution reactions, and these methods are well known to those skilled in the art. Similarly, those skilled in the art will readily apply synthetic protecting (or protecting) groups whenever necessary or useful, and preferred protecting groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis, and are described in more detail, for example, PGMWuts, TW Greene, “Greene's Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).

[0492] The general route for preparing the compounds of this application is described in schemes 1 to 7 of this specification.

[0493] The present invention is described in conjunction with the specific examples described below, but many substitutions, modifications, and variations therein will be apparent to those skilled in the art. In some cases, the order in which the steps of the reaction scheme are carried out may be varied to facilitate the reaction or to avoid undesirable reaction products. Starting materials and intermediates are purchased from commercial sources, prepared from known procedures, or otherwise illustrated.

[0494] Several methods for preparing the compounds of the present invention are described in the following scheme and examples. Unless otherwise indicated, all variable parts are as previously defined.

[0495] Scheme 1 In scheme 1 of TIFF2026515712000185.tif32131, ester 3 is obtained by Suzuki coupling of boronic acid or boronic acid ester 2 with halopyridine 1. This ester can be hydrolyzed under basic conditions (for example, using NaOH) to obtain carboxylic acid 4.

[0496] Scheme 2 In scheme 2 of TIFF2026515712000186.tif26128, amide 7 may be formed via amide coupling between carboxylic acid 5 and amine 6, via amide coupling using a coupling reagent (e.g., HATU, or other common amide coupling reagents) and a base (e.g., DIPEA).

[0497] Scheme 3 In Scheme 3 of TIFF2026515712000187.tif96150, if the amide 7 described in Scheme 2 is characterized by a protected ketone, e.g., a ketal intermediate 8, exemplary compounds can be obtained using the following synthesis scheme. Ketone 9 can be prepared via ketal 8 under acidic conditions. This ketone can be converted to amine 11 via reductive amination with amine 10. Alternatively, ketone 9 can be reduced to alcohol 12 and converted to ether 14 via the Mitsunobu reaction with alcohol 13. Another approach is to mesylate alcohol 12, and S N Amine 17 can be formed by adding an amine via two reactions.

[0498] Scheme 4 In Scheme 4 of TIFF2026515712000188.tif90166, if amide 7 described in Scheme 2 is characterized by a protected amine intermediate 18, exemplary compounds can be obtained using the following synthetic scheme. Deprotection of amine 18 yields amine 19 (e.g., the Boc group is removed by the use of an acid). Amine 19 can be used in a number of reactions. Reductive amination with an aldehyde or ketone yields amine 19a. Amide coupling with carboxylic acid 20 (e.g., using T3P) yields amide 21. Alternatively, acylation with an acid chloride also yields amide 21. Amine 19 can also be reacted with a sulfonyl chloride to obtain sulfonamide or sulfamide 22. Chan-Lam coupling of amine 19 with a boronic acid or ester and copper yields amine 23. Alternatively, S between amine 19 and an aryl fluoride... N Amine 23 can also be obtained using Ar chemistry. Compound 21a can be obtained by reacting compound 21 with an alkyl halide in the presence of an inorganic base, where R is a metabolizable group (for example, compound 21a can be metabolized in vivo to release the compound of formula (I)).

[0499] Scheme 5 In Scheme 5 of TIFF2026515712000189.tif19132, if the amide 7 described in Scheme 2 is characterized by an ester intermediate 24, exemplary compounds can be obtained using the following synthesis scheme. The amide 26 can be formed in two steps via hydrolysis of the ester 24 and amide coupling with the carboxylic acid 25 (e.g., by using T3P).

[0500] Scheme 6 In Scheme 6 of TIFF2026515712000190.tif21139, if the amide 7 described in Scheme 2 is characterized by a protected amine 27, exemplary compounds can be obtained using the following synthesis scheme. Amide 29 can be formed in two steps via deprotection of compound 27 (e.g., the Boc group will be removed by the use of an acid). Amide 29 is obtained by amide coupling with amine 28 (e.g., using T3P).

[0501] Scheme 7 In Scheme 7 of TIFF2026515712000191.tif78130, if the amide 7 described in Scheme 2 is characterized by a protected amine intermediate 30, exemplary compounds can be obtained using the following synthetic scheme. Deprotection of 30 yields amine 31 (for example, the Boc group will be removed by the use of an acid). Amine 30 can be used in a variety of reactions. Reductive amination with a ketone or aldehyde 32 yields amine 33. Alternatively, Chan-Lam coupling with a boronic acid or ester yields amine 34. Acylation of 31 with an acid chloride yields amide 35, while reaction with a sulfonyl chloride yields sulfonamide or sulfamide 36.

[0502] Bioassay Compounds designed, selected, and / or optimized by the methods described above, once generated, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds are biologically active. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they have the expected activity, binding activity, and / or binding specificity.

[0503] Furthermore, high-throughput screening can be used to expedite analysis using such assays. As a result, it may be possible to rapidly screen for the activity of the molecules described herein using techniques known in the art. Conventional methodologies for performing high-throughput screening are described, for example, Devlin (1998) High Throughput Screening, Marcel Dekker, and U.S. Patent No. 5,763,263. High-throughput assays may be one or more different assay techniques, including but not limited to those described below.

[0504] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds disclosed herein. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0505] In some embodiments, biological assays are described in the examples herein.

[0506] In some embodiments, the biological assay is an ATPase assay.

[0507] In some embodiments, the compounds of this disclosure, the ATPase assay, are combined with biotinylated Avi-POLθ[2-894], 50-nucleotide polythymine repeat single-stranded DNA, and ATP in a buffer. In some embodiments, this mixture is incubated, an ADP-Glo ​​reagent is added, and a subsequent incubation is carried out. In some embodiments, a kinase detection reagent may be added, and a third incubation may be carried out.

[0508] In some embodiments, the activity is measured via an emission signal (for example, measured with an EnVision multimode plate reader).

[0509] Pharmaceutical composition In some embodiments, the Disclosure provides pharmaceutical compositions comprising the compounds of the Disclosure as active ingredients. In some embodiments, the Disclosure provides pharmaceutical compositions comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the Disclosure provides pharmaceutical compositions comprising the compounds listed in Table 1. In some embodiments, the Disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1. In some embodiments, the Disclosure provides pharmaceutical compositions comprising a compound described in any one of the prior claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0510] As used herein, the term “composition” is intended to encompass products containing a specified amount of a particular component, as well as any products resulting directly or indirectly from a specified amount of a specified combination of components.

[0511] The compounds of this disclosure can be formulated for oral administration in the form of tablets, capsules (each including sustained-release or prolonged-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of this disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all by using forms well known to those skilled in the art of medicine.

[0512] The formulations of this disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonic agents, viscosity / suspensioning agents, buffering agents, and pH adjusters, as well as mixtures thereof.

[0513] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins, such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, and 2-hydro These include xi-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof, selected from the group.

[0514] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, tetrasodium edetate, and mixtures thereof.

[0515] Any suitable preservative can be used. Examples of preservatives include quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, methylthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid and mixtures thereof, selected from the group.

[0516] The aqueous vehicle may also contain an isotonic agent to adjust its tonicity (osmotic pressure). The isotonic agent may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, and triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0517] Aqueous vehicles may also contain viscous / suspensioning agents. Suitable viscous / suspensioning agents include those selected from the group consisting of cellulose derivatives, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and crosslinked acrylic acid polymers (carbomers) such as polyalkenyl ethers or divinyl glycols (Carbopol - Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0518] To adjust the formulation to an acceptable pH (typically within the ranges of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain pH adjusters. The pH adjusters are typically selected from the group consisting of potassium hydroxide, sodium hydroxide, hydrochloric acid, and mixtures thereof, and are mineral acids or metal hydroxide bases, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to the desired acceptable pH range. Therefore, it may not be necessary to use both an acid and a base, and this depends on the formulation, as the addition of either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0519] Aqueous vehicles may also contain buffers to stabilize the pH. When used, buffers are selected from the group consisting of phosphate buffers (e.g., sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (e.g., boric acid, or its salts including disodium tetraborate), citrate buffers (e.g., citric acid, or its salts including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0520] The formulation may further contain a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylene-sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0521] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable food-grade carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound is incorporated with excipients and can be used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, where the compound in the fluid carrier is applied orally, rinsed in the mouth, spat out, or swallowed. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or sterote; flow enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0522] In a further aspect of the present disclosure, a pharmaceutical composition is provided comprising, in connection with a pharmaceutically acceptable diluent or carrier, one of the compounds of the present disclosure as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0523] The compositions of this disclosure may be in forms suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., creams, ointments, gels, or aqueous or oily liquids or suspensions), administration by inhalation (e.g., as finely divided powders or liquid aerosols), administration by air (e.g., as finely divided powders), or parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or suppositories for rectal administration).

[0524] The compositions of this disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Accordingly, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0525] An effective amount of the compounds of this disclosure for use in therapy is sufficient to treat or prevent, slow the progression of, and / or reduce the symptoms associated with the polymerase Θ-related conditions referred to herein.

[0526] An effective amount of the compounds of this disclosure for use in therapy is sufficient to treat, slow the progression of, and / or reduce the symptoms associated with the polymerase Θ-related conditions referred to herein.

[0527] The size of the dose of the compound of formula (I) for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of medicine.

[0528] How to use In some embodiments, the Disclosure provides a method for modulating DNA polymerase Θ activity, the method comprising contacting cells with a compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0529] In some embodiments, the Disclosure provides a method for modulating DNA polymerase Θ activity (e.g., in vitro or in vivo), the method comprising contacting cells with an effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0530] In some embodiments, the Disclosure provides a method for modulating DNA polymerase Θ activity (e.g., in vitro or in vivo), the method comprising contacting cells with a compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0531] In some embodiments, the Disclosure provides a method for modulating DNA polymerase Θ activity (e.g., in vitro or in vivo), the method comprising contacting cells with an effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0532] In some embodiments, the Disclosure provides a method for modulating DNA polymerase Θ activity (e.g., in vitro or in vivo), the method comprising contacting cells with a compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0533] In certain embodiments, the Disclosure provides a method for treating or preventing a disease or disorder in a subject where such treatment is needed, the method comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof to a subject.

[0534] In certain embodiments, the Disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject where such treatment is necessary, the method comprising administering a therapeutically effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof to the subject.

[0535] In certain embodiments, the Disclosure provides a method for treating a disease or disorder disclosed herein in a subject where such treatment is necessary, the method comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject.

[0536] In certain embodiments, the Disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject where such treatment is necessary, the method comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof to a subject.

[0537] In certain embodiments, the Disclosure provides a method for treating a disease or disorder disclosed herein in a subject where such treatment is necessary, the method comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0538] In some embodiments, the Disclosure provides a method for inhibiting DNA repair by DNA polymerase Θ in cancer cells, the method comprising contacting cells with an effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure. In some embodiments, the cancer is HR-deficient cancer.

[0539] In certain embodiments, the Disclosure provides a method for treating and / or preventing cancer in a patient, in which case the cancer is characterized by reduced or absent BRCA gene expression, absence of the BRCA gene, or reduced function of the BRCA protein, and the method comprises administering to a subject a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure.

[0540] In some embodiments, the disease or disorder is associated with the DNA polymerase Θ activity involved. In some embodiments, the disease or disorder is a disease or disorder in which DNA polymerase Θ activity is involved.

[0541] In some embodiments, the disease or disorder is associated with the DNA polymerase Θ activity involved. In some embodiments, the disease or disorder is a disease or disorder in which DNA polymerase Θ activity is involved.

[0542] In some embodiments, the disease or disorder is cancer.

[0543] In certain embodiments, the Disclosure provides a method for treating or preventing cancer in a subject where such treatment is needed, the method comprising administering a therapeutically effective amount of the Compounds of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0544] In certain embodiments, the Disclosure provides a method for treating cancer in a subject where such treatment is needed, the method comprising administering a therapeutically effective amount of the Compounds of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0545] In certain embodiments, the Disclosure provides a method for treating or preventing cancer in a subject where such treatment is needed, the method comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0546] In certain embodiments, the Disclosure provides a method for treating cancer in a subject where such treatment is necessary, the method comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0547] In certain embodiments, the Disclosure provides a compound of the Disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure for use in modulating DNA polymerase Θ activity.

[0548] In some embodiments, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in modulating DNA polymerase Θ activity (e.g., in vitro or in vivo).

[0549] In some embodiments, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in modulating DNA polymerase Θ activity (e.g., in vitro or in vivo).

[0550] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for inhibiting DNA repair by DNA polymerase Θ in cells. In some embodiments, the cells are HR-deficient cells.

[0551] In certain embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment and / or prevention of a patient's disease characterized by overexpression of DNA polymerase Θ.

[0552] In certain embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment and / or prevention of cancer in a patient, in which case the cancer is characterized by reduced or absent BRCA gene expression, absence of the BRCA gene, or reduced function of the BRCA protein.

[0553] In some embodiments, BRCA is BRCA1. In some embodiments, BRCA is BRCA2.

[0554] In certain embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment and / or prevention of HR-deficient cancer in patients.

[0555] In certain embodiments, the Disclosure provides a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of a disease or disorder.

[0556] In certain embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of diseases or disorders disclosed herein.

[0557] In certain embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment of diseases or disorders disclosed herein.

[0558] In certain embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of cancer in subjects where such treatment is needed.

[0559] In certain embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment of cancer in subjects where such treatment is necessary.

[0560] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for modulating DNA polymerase Θ activity.

[0561] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for modulating DNA polymerase Θ activity (e.g., in vitro or in vivo).

[0562] In certain embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder disclosed herein.

[0563] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of a disease or disorder disclosed herein.

[0564] In certain embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating or preventing cancer in a subject where such treatment is necessary.

[0565] In certain embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a pharmaceutical product for treating cancer in a subject where such treatment is necessary.

[0566] This disclosure provides compounds that function as regulators of DNA polymerase Θ activity.

[0567] In some embodiments, the compounds of this disclosure are antagonists of the DNA polymerase Θ receptor.

[0568] In some embodiments, the regulation of the DNA polymerase Θ receptor is achieved by activating the DNA polymerase Θ receptor.

[0569] In some embodiments, regulation is inhibition.

[0570] The efficacy of the compounds disclosed herein can be determined by industry-accepted assays / disease models in accordance with standard practices that reveal the same efficacy as those described in the Art, and can also be found in the ordinary knowledge of the present time.

[0571] This disclosure also provides a method for treating a disease or disorder involving DNA polymerase Θ activity in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound specified herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0572] In some embodiments, cancers include lymphoma, soft tissue cancer, rhabdoid cancer, multiple myeloma, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, prostate cancer, breast cancer, ovarian cancer, uterine cancer, lung cancer, fibroblast cancer, central nervous system cancer, urinary tract cancer, upper respiratory tract and gastrointestinal cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer (data from large-scale dropout screening of cancer cell lines indicate that some cell lines of the above cancers are polymerase Θ-dependent for proliferation; see https: / / depmap.org / portal / ).

[0573] In some embodiments, HR-deficient cancer is breast cancer. Breast cancers include, but are not limited to, lobular carcinoma in situ, ductal carcinoma in situ, invasive ductal carcinoma, triple-negative breast cancer, HER-positive breast cancer, estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, HER and estrogen receptor-positive breast cancer, HER and estrogen and progesterone receptor-positive breast cancer, inflammatory breast cancer, papillary Paget's disease, phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic breast carcinoma, micropapillary carcinoma, and mixed carcinoma. In a second embodiment, HR-deficient cancer is ovarian cancer. Ovarian cancer includes, but is not limited to, epithelial ovarian cancer, mature teratomas, undifferentiated germ cell tumors, endodermal sinus tumors, granulosa-theca tumors, Sertoli-Leydig cell tumors, and primary peritoneal carcinomas. In some cases, ovarian cancer originates from cells in the fallopian tubes.

[0574] In some embodiments, the cancer is selected from ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, or uterine cancer.

[0575] In some embodiments, the cancer is resistant to treatment with at least one PARP inhibitor.

[0576] In some embodiments, the cancer is resistant to treatment with a single PARP inhibitor.

[0577] In some embodiments, the subjects have received prior treatment with PARP inhibitors, and their cancer is recurrent or refractory.

[0578] In some embodiments, the PARP inhibitor is a selective PARP inhibitor.

[0579] In some embodiments, the PARP inhibitor is a non-selective PARP inhibitor.

[0580] In some embodiments, the PARP inhibitor is olaparib.

[0581] In some embodiments, cancer has a defect in the DNA damage repair process.

[0582] In some embodiments, cancer is sensitive to POLΘ inhibition.

[0583] In some embodiments, cancer has evidence of increased POLΘ activity.

[0584] In some embodiments, cancer has elevated expression of POLΘ mRNA or protein.

[0585] In some embodiments, cancer is associated with increased expression of POLΘ mRNA.

[0586] In some embodiments, cancer exhibits increased expression of the POLΘ protein.

[0587] In some embodiments, cancers are classified by genotype.

[0588] In some embodiments, the genotype has a regulated function.

[0589] In some embodiments, the regulated function is an inactivating mutation, deletion, or other genomic modification.

[0590] In some embodiments, the genotype lacks mRNA or protein expression.

[0591] In some embodiments, cancer is caused by the regulation of the function of at least one gene.

[0592] In some embodiments, the gene is selected from ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.

[0593] In some embodiments, the cancer is homologous recombination deficiency (HRD) cancer.

[0594] In some embodiments, cancer is classified as HRD cancer because its tumor is unable to accurately repair double-strand breaks in DNA through homologous recombination.

[0595] In some embodiments, the mutation is in a gene that, in the case of deletion, causes HRD.

[0596] In some embodiments, cancer involves impaired homologous recombination (HR) or non-homologous DNA end joining (NHEJ) repair pathways.

[0597] In some embodiments, cancer with impaired HR is dependent on PolΘ activity.

[0598] In some embodiments, cancer with impaired NHEJ is dependent on PolΘ activity.

[0599] In some embodiments, cancer is a tumor. In some embodiments, cancer is a solid tumor.

[0600] Route of administration The compounds of this disclosure, or pharmaceutically acceptable salts thereof, may be administered alone as monotherapy, or in addition to one or more other substances and / or treatments. Such combination therapies may be achieved by the simultaneous, sequential, or separate administration of the individual components of the treatment.

[0601] For example, therapeutic effects can be enhanced by the administration of an adjuvant (i.e., an adjuvant alone may have only minimal therapeutic benefit, but when combined with another therapeutic agent, it enhances the overall therapeutic benefit to the individual). Alternatively, and only as an illustration, the benefits experienced by an individual can be increased by administering a compound of formula (I) together with another therapeutic agent (including a therapeutic regimen) that also has therapeutic benefits.

[0602] In cases where the compounds of this disclosure are administered in combination with other therapeutic agents, the compounds of this disclosure do not need to be administered via the same route as the other therapeutic agents, and may be administered via different routes due to their different physical and chemical characteristics. For example, the compounds of this disclosure may be administered orally to generate and maintain their good blood levels, while the other therapeutic agents may be administered intravenously. The initial dose may be administered according to established protocols known in the art, and the dose, method of administration, and timing of administration may then be modified by an experienced clinician based on the observed effects.

[0603] The specific selection of other therapeutic agents will depend on the diagnosis of the participating physicians, their judgment of the individual's condition, and the appropriate treatment protocol. According to this aspect of the Disclosure, a combination is provided for use in the treatment of diseases involving DNA polymerase Θ activity, the combination comprising the compounds of the Disclosure as defined above herein, or pharmaceutically acceptable salts thereof, and other suitable agents.

[0604] A further aspect of the present disclosure provides a pharmaceutical composition comprising one or more excipients, carriers, diluents, and / or binders (e.g., pharmaceutically acceptable excipients, carriers, diluents, and / or binders) in combination with the compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0605] In addition to its use in therapeutic medicine, compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of in vitro and in vivo testing systems for evaluating the effects of DNA polymerase Θ activity regulators in experimental animals such as dogs, rabbits, monkeys, miniature pigs, rats, and mice, as part of the search for novel therapeutic agents.

[0606] Any of the above-described features of the pharmaceutical compositions, processes, methods, uses, pharmaceuticals, and manufacturing of this disclosure may also apply to any of the alternative embodiments of the macromolecules of this disclosure described herein.

[0607] The compounds of this disclosure or pharmaceutical compositions containing these compounds may be administered to a subject by any convenient route of administration, whether systemic / peripheral or topical (i.e., at the desired site of action).

[0608] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (e.g., by patches, ointments, etc.); transmucosal (e.g., by patches, ointments, etc.); intranasal (e.g., by nasal spray or powder); ocular (e.g., by eye drops); lung (e.g., by inhalation or insufflation therapy, e.g., via aerosol from the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral administration, including, for example, by injection, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal; and, for example, by implantation of subcutaneous or intramuscular depots or reservoirs.

[0609] Exemplary Embodiments Exemplary Embodiment 1. Compounds of the following formula (I): TIFF2026515712000192.tif24128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein in the formula, X 1 is CH, S, or N, X 2 is N, S, or O, R 1 and R 2 They, together with the atoms they bond to, form a C5-C 10 Forms cycloalkyl or 5-10 member heterocycloalkyl groups, C5-C10 The cycloalkyl or 5- to 10-membered heterocycloalkyl may be substituted with one or more R a and may be optionally substituted, each R a is independently oxo, halo, cyano, -OR a1 , -N(R a1 )2, -C(O)R a1 , -C(O)N(R a1 )2, -C(O)OR a1 , -S(O)2N(R a1 )2, -S(O)2(R a1 ), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl may be substituted with one or more R a1 and may be optionally substituted, each R a1 is independently H, oxo, halo, cyano, -OH, -NH2, -C(O)(C1-C6 alkyl), -C(O)(C3-C 10 cycloalkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl, and -C(O)(C3-C 10 cycloalkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 1​​​​a2 These are independently C1-C6 alkyl, C3-C alkyl, and C3-C alkyl groups which may be substituted with oxo, halo, cyano, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, or -OH. 10 These are cycloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl, which may be substituted with oxo. R 3 C6-C 10 It is an aryl or 5-10 member heteroaryl, C6-C 10 Aryl or 5-10 member heteroaryls are one or more R 3a It has been replaced with, Each R 3a These are independently halo, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 It is an aryl or 5-10 member heteroaryl, and is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 An aryl, or a 5-10 member heteroaryl, is one or more R 3a1 It may also be replaced with Each R 3a1 These are independently oxo, halo, cyano, -OH, -C(O)(C1-C6 alkyl), -C(O)(O-(C1-C6 alkyl)), and C3-C 10 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, -O(C1-C6 haloalkyl), C3-C 10 Cycloalkyl, C6-C 10 It is an aryl or a 5-10 member heteroaryl. The aforementioned compound, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0610] Exemplary Embodiment 2. Compounds of the following formula (I): TIFF2026515712000193.tif24128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein in the formula, X 1 is CH, S, or N, X 2 is N, S, or O, R 1 and R 2 They, together with the atoms they bond to, form a C5-C 10 Forms cycloalkyl or 5-10 member heterocycloalkyl groups, C5-C 10 Cycloalkyl or 5-10 member heterocycloalkyl groups include one or more R a It may also be replaced with Each R a These are independently oxo, halo, cyano, -OR a1 , -N(R a1 )2, -C(O)R a1 ,-C(O)N(R a1 )2, -C(O)OR a1 -S(O)2N(R a1 )2, -S(O)2(R a1 ), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, C6-C 10 These are aryl, 5-10 member heteroaryl, or 3-10 member heterocycloalkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, or 3-10 member heterocycloalkyl is one or more R a1 It may also be replaced with Each R a1These are independently H, oxo, halo, cyano, -OH, -NH2, -C(O)(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 It is an aryl or 5-10 member heteroaryl, and is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 An aryl, or a 5-10 member heteroaryl, is one or more R a2 It may also be replaced with Each R a2 These are independently a C1-C6 alkyl, C1-C6 haloalkoxy, or 3-10 member heterocycloalkyl, or 5-10 member heteroaryl, which may be substituted with oxo, halo, cyano, -OH, -NH2, C1-C6 alkoxy, or oxo. R 3 C6-C 10 It is an aryl or 5-10 member heteroaryl, C6-C 10 Aryl or 5-10 member heteroaryls are one or more R 3a It has been replaced with, Each R 3a These are independently halo, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, and C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 It is an aryl or 5-10 member heteroaryl, and is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 An aryl, or a 5-10 member heteroaryl, is one or more R 3a1 It may also be replaced with Each R 3a1These are independently oxo, halo, cyano, -OH, -C(O)(C1-C6 alkyl), -C(O)(O-(C1-C6 alkyl)), and C3-C 10 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, -O(C1-C6 haloalkyl), C3-C 10 Cycloalkyl, C6-C 10 It is an aryl or a 5-10 member heteroaryl. The aforementioned compound, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0611] Exemplary Embodiment 3. X 1 is either S or N, X 2 is N or S, R 1 and R 2 These atoms, together with the atoms to which they are bonded, form a C5-C6 cycloalkyl or 5-6 member heterocycloalkyl, and the C5-C6 cycloalkyl or 5-6 member heterocycloalkyl has one or more R a It may also be replaced with Each R a These are independently oxo, -OR a1 , -N(R a1 )2, -C(O)R a1 ,-C(O)N(R a1 )2, -C(O)OR a1 -S(O)2N(R a1 )2, -S(O)2(R a1 ), C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl, 5-10 membered heteroaryl, or 3-10 membered heterocycloalkyl, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, or 3-10 member heterocycloalkyl is one or more R a1 It may also be replaced with Each R a1 These are independently H, halo, cyano, -C(O)(C1-C6 alkyl), and -C(O)(C3-C 10 Cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 It is an aryl or 5-10 member heteroaryl, and -C(O)(C3-C 10 Cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3-10 member heterocycloalkyl, C6-C 10 An aryl, or a 5-10 member heteroaryl, is one or more R a2 It may also be replaced with Each R a2 These are independently C1-C6 alkyl, C3-C alkyl, and C3-C alkyl groups which may be substituted with oxo, cyano, -OH, -N(C1-C6 alkyl)2, C1-C6 alkoxy, or -OH. 10 These are cycloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, 3-10 member heterocycloalkyl, or 5-10 member heteroaryl, which may be substituted with oxo. R 3 is one R 3a It is a 5-10 member heteroaryl that is substituted with R 3a is one or more R 3a1 C6-C may be replaced with 10 It is Ariel, Each R 3a1 These are independently cyano or C1-C6 alkoxy compounds. The compound described in Exemplary Embodiment 1 or Exemplary Embodiment 2.

[0612] Exemplary Embodiment 4. R 1 and R 2 The compounds according to Exemplary Embodiment 1 or Exemplary Embodiment 2, wherein they, together with the atoms to which they are bonded, form a 5-membered heterocycloalkyl or C6-cycloalkyl group.

[0613] Exemplary Embodiment 5. Each R a They are independent, TIFF2026515712000194.tif124148TIFF2026515712000195.tif220147TIFF2026515712000196.tif217147TIFF2026515712000197.tif218147TIFF202 6515712000198.tif202147TIFF2026515712000199.tif197147TIFF2026515 712000200.tif220147TIFF2026515712000201.tif222147TIFF20265157120 The compound described in any one of the preceding exemplary embodiments, which is 00202.tif193147TIFF2026515712000203.tif204147TIFF2026515712000204.tif222147TIFF2026515712000205.tif213147TIFF2026515712000206.tif206147TIFF2026515712000207.tif225147TIFF2026515712000208.tif218147TIFF2026515712000209.tif198147.

[0614] Exemplary embodiment 6. Each R a1 They are independent, H, -OH, -CH3, The compound described in any one of the preceding exemplary embodiments, which is TIFF2026515712000210.tif213148TIFF2026515712000211.tif224147TIFF2026515712000212.tif224147TIFF2026515712000213.tif110147.

[0615] Exemplary Embodiment 7. Each R a2These are independently oxo, -CH3,-CH2CH3,-CH(CH3)2,-Cl,-F,-CN,-CHF2,-OCH3,-CF3,-OCHF2,-OH,-CH2CHF2,-CH2CF3,-CH2OH,-CH2OCH3,-OCF3,-N(CH3)2,-OCH(CH3)2, A compound described in any one of the prior exemplary embodiments, TIFF2026515712000214.tif17128.

[0616] Exemplary Embodiment 8. R 3 teeth, A compound described in any one of the prior exemplary embodiments, TIFF2026515712000215.tif209153.

[0617] Exemplary Embodiment 9. R 3a -CH3, cyclopropyl, A compound described in any one of the prior exemplary embodiments, which is TIFF2026515712000216.tif130148.

[0618] Exemplary embodiment 10. Each R 3a1 The compound according to any one of the preceding exemplary embodiments, wherein is independently oxo, methyl, -CF2H, cyano, -F, -Cl, -OH, -OCF2H, or -OCH3.

[0619] Exemplary embodiment 11. Compounds of the following formula (IA): A compound according to any one of the exemplary embodiments 1 to 4, which is TIFF2026515712000217.tif22128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0620] Exemplary embodiment 12. Compounds of the following formulas: (IB), (IC), (ID), or (IE): A compound according to any one of the exemplary embodiments 1 to 4, which is TIFF2026515712000218.tif46128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0 to 6, n is 0 to 8, and p is 0 to 6.

[0621] Exemplary Embodiment 13. Compounds of the following formulas (IF) or (I-Fa): A compound according to any one of the exemplary embodiments 1 to 4, which is TIFF2026515712000219.tif19128, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein p is 0 to 4.

[0622] Exemplary Embodiment 14. Compounds of the following formulas: (I-Fb), (I-Fb'), (I-Fc), (I-Fc'), (I-Fd), or (I-Fd'): TIFF2026515712000220.tif98140, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein p is 0 to 4 and q is 0 to 4, as described in any one of Exemplary Embodiments 1 to 4.

[0623] Exemplary embodiment 15. Compounds of the following formulas (IG), (I-Ga), or (I-Ga'): A compound according to any one of Exemplary Embodiments 1 to 4, which is TIFF2026515712000221.tif48133, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein q is 1 to 4.

[0624] Exemplary embodiment 16. Compounds described in any one of the preceding exemplary embodiments, selected from compound numbers 7, 9, 10, 15, 18, 379, 387, 389, 400, 404, 415, 425, 450, 508, 548, 584, 585, 586, 592, 594, 2, 5, 14, 49, 146, 652, 653, 655, 691, 793, 820, 828, 908, 922, 951, 952, 964, 980, 987, 990, 996, 1003, 1005, 1010, 1013, 1014, 1016, 1019, 1023, 1029, 1032, 1039, 1041, and 1046, or pharmaceutically acceptable salts thereof.

[0625] Exemplary Embodiment 17. A compound selected from the compounds listed in Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt thereof, as described in any one of the preceding exemplary embodiments.

[0626] Exemplary Embodiment 18. Compounds obtainable by or acquired by the methods described herein, wherein the method optionally comprises one or more steps described in Schemes 1 to 7.

[0627] Exemplary embodiment 19. A pharmaceutical composition comprising one of the compounds of the preceding exemplary embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0628] Exemplary embodiment 20. The pharmaceutical composition according to exemplary embodiment 19, wherein the compound is selected from the compounds listed in Table 1, Table 2, or Table 3.

[0629] Exemplary embodiment 21. A method for regulating DNA polymerase Θ activity, comprising contacting a cell with one of the compounds of the preceding exemplary embodiments.

[0630] Exemplary embodiment 22. A method for treating or preventing a disease or disorder in a subject to which such treatment is needed, comprising administering to the subject a compound described in any one of Exemplary Embodiments 1 to 18, or a pharmaceutical composition described in Exemplary Embodiment 19 or Exemplary Embodiment 20.

[0631] Exemplary Embodiment 23. A compound from any one of Exemplary Embodiments 1 to 18, or a pharmaceutical composition of Exemplary Embodiment 19 or Exemplary Embodiment 20, for use in regulating DNA polymerase Θ activity.

[0632] Exemplary Embodiment 24. A compound according to any one of Exemplary Embodiments 1 to 18, or a pharmaceutical composition according to Exemplary Embodiment 19 or Exemplary Embodiment 20, for use in the treatment or prevention of a disease or disorder.

[0633] Exemplary embodiment 25. Use of any one of the compounds described in Exemplary Embodiments 1 to 18 in the manufacture of a pharmaceutical product for modulating DNA polymerase Θ activity.

[0634] Exemplary embodiment 26. Use of any one of the exemplary embodiments 1 to 18 of a compound in the manufacture of a pharmaceutical product for the treatment or prevention of a disease or disorder.

[0635] Exemplary Embodiment 27. A disease or disorder related to the DNA polymerase Θ activity involved, as described by any one of the exemplary embodiments 21-26, a compound, pharmaceutical composition, or use.

[0636] Exemplary embodiment 28. The disease or disorder is cancer, as described in any one of the exemplary embodiments 21-27, the compound, pharmaceutical composition, or use thereof. [Examples]

[0637] For illustrative purposes, neutral compounds of formula (I) are synthesized and tested in the examples. It is understood that neutral compounds of formula (I) can be converted to corresponding pharmaceutically acceptable salts of the compounds using techniques commonly used in the art (e.g., by saponifying the ester to a carboxylate salt, or by hydrolyzing the amide to form the corresponding carboxylic acid, and then converting the carboxylic acid to a carboxylate salt).

[0638] Abbreviation: TIFF2026515712000222.tif245159TIFF2026515712000223.tif64159

[0639] Preparative HPLC conditions (unless otherwise specified): SHIMADZU preparative HPLC system including LC-20AP pump, SPD-20A detector, and Labsolutions (version 5.90) ​​software. Column: Agilent 10, Prep-C18, 250 × 21.2 mm. Solvent / Gradient: 5 to 80% acetonitrile in 0.1% HCOOH-containing water. Flow rate: 20 mL / min.

[0640] Synthesis of intermediates Intermediate 1: 4-(2-methoxyphenyl)-6-methylnicotinic acid Step 1: A mixture of 4-hydroxy-6-methylnicotinic acid (10.0 g, 65.0 mmol) and POCl3 (40 mL) was heated under reflux for 2 hours, then concentrated under reduced pressure. The residue was cooled to 0°C, and MeOH (40 mL) was slowly added dropwise. The mixture was allowed to rise naturally to room temperature and stirred overnight. The mixture was adjusted to pH 7 with solid Na2CO3, diluted with water (500 mL), and extracted with DCM (3 × 300 mL). The combined organic layers were washed with water (500 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient: 6.6 to 12.5% ​​petroleum ether in SiO2) to obtain methyl 4-chloro-6-methylnicotinate (10.4 g, 85%) as a colorless oil. LCMS: m / z = 186 [M + H] + , 1 H NMR (400MHz, DMSO-d6) δ 8.84 (s, 1H), 7.57 (s, 1H), 3.87 (s, 3H), 2.52 (s, 3H).

[0641] Step 2: To a solution of methyl 4-chloro-6-methylnicotinate (7.00 g, 37.7 mmol) in dried 1,4-dioxane (80 mL), (2-methoxyphenyl)boronic acid (5.73 g, 37.7 mmol), Pd(PPh3)4 (2.18 g, 1.88 mmol), and Cs2CO3 (36.9 g, 113 mmol) were added, and the mixture was heated overnight at 85°C. The mixture was diluted with water (100 mL), extracted with SiO2 (3 × 300 mL), and the combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient: 6.6 to 25% petroleum ether in SiO2) to obtain methyl 4-(2-methoxyphenyl)-6-methylnicotinate (8.0 g, 82%) as a yellow oil. LCMS: m / z = 258 [M + H] + , 1H NMR(400MHz,DMSO-d6)δ 8.73(s,1H),7.40(td,J=7.8,1.8Hz,1H),7.30~7.24(m,2H),7.05(t,J=8.0Hz,2H),3.65(s,3H),3.62(s,3H),2.55(s,3H).

[0642] Step 3: To a solution of methyl 4-(2-methoxyphenyl)-6-methylnicotinate (8.0 g, 31.0 mmol) in water (40 mL) and MeOH (40 mL), NaOH (3.73 g, 93.0 mmol) was added, and the mixture was heated at 50°C for 2 hours. The mixture was adjusted to pH 5 with 1 M aqueous HCl, extracted with a 10:1 mixture of DCM / MeOH (30 mL x 10), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-(2-methoxyphenyl)-6-methylnicotinic acid (5.5 g, 73%) as a white solid. LCMS: m / z = 244 [M + H] + , 1 H NMR(400MHz,DMSO-d6)δ 8.75(s,1H),7.37(td,J=7.8,1.8Hz,1H),7.26~7.16(m,2H),7.03(d,J=7.6Hz,2H),3.67(s,3H),2.53(s,3H).

[0643] Intermediate 13: (6-methoxyimidazo[1,5-a]pyridine-7-yl)boronic acid A mixture of 7-bromo-6-methoxyimidazo[1,5-a]pyridine (500 mg, 2.20 mmol), KOAc (648 mg, 6.61 mmol), bis(pinacolate)diborone (1.12 g, 4.40 mmol), and Pd(dppf)Cl2 (161 mg, 0.220 mmol) in 10 mL of 1,4-dioxane was heated overnight at 100°C under N2. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (6-methoxyimidazo[1,5-a]pyridine-7-yl)boronic acid (1 g), which was used directly in the next step. LCMS: m / z = 193 [M + H] + .

[0644] Intermediate 2: 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid Step 1: A solution of methyl 4-chloro-6-methylnicotinate (5.2 g, 28 mmol), (5-cyano-2-methoxyphenyl)boronic acid (5.0 g, 28.1 mmol), Pd(dppf)Cl2 (2.0 g, 2.8 mmol), and Na2CO3 (9.0 g, 85 mmol) in 1,4-dioxane (200 mL) and water (40 mL) was heated overnight under reflux. The mixture was diluted with water (200 mL), extracted with SiO2 (2 × 200 mL), and the combined organic layers were washed with brine (2 × 200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / alkyl = 5 / 1, volume / volume) to obtain methyl 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinate (5.0 g, 63%) as a yellow solid. LCMS: m / z = 283 [M + H] + .

[0645] Step 2: To a solution of methyl 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinate (5.0 g, 18 mmol) in MeOH (200 mL) and water (400 mL), NaOH (2.1 g, 53 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was diluted with water (1.0 L), extracted with Depositphotos (2 × 1.5 L), and the combined organic layers were washed with brine (2 × 1.0 L), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / Depositphotos = 1 / 1, volume / volume) to obtain 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid (3.9 g, 83%) as a grayish-white solid. LCMS: m / z = 269 [M + H] + .

[0646] (Table U): The following intermediates were prepared using the same procedure as described for intermediate 2. TIFF2026515712000227.tif127165

[0647] Intermediate 3: 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid Step 1: To a solution of methyl 4-chloro-6-methylnicotinate (6.00 g, 32.1 mmol) and (2-chloro-5-methoxypyridine-4-yl)boronic acid (15.0 g, 80.2 mmol) in 1,4-dioxane (140 mL) and water (14 mL), Pd(dtbpf)Cl2 (2.1 g, 3.2 mmol) and K2CO3 (13.3 g, 96.3 mmol) were added, and the mixture was heated at 80°C for 2 hours. The mixture was diluted with water (200 mL), extracted with siRNA (3 × 200 mL), and the combined organic layers were washed with water (200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (siRNA / petroleum ether = 1 / 1) to obtain methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (7.3 g, 31%) as a yellow solid. LCMS: m / z = 293 [M + H] + , 1 ¹H NMR (400 MHz, chloroform-d) δ 9.05 (s, 1H), 8.04 (s, 1H), 7.17 (s, 1H), 7.08 (s, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 2.67 (s, 3H).

[0648] Step 2: To a solution of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (14.6 g, 50.0 mmol) in MeOH (140 mL) and water (140 mL) at 0°C, NaOH (6.00 g, 150 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 5-6 with 2 M aqueous HCl and concentrated under reduced pressure. The residue was purified by a short silica gel column (DCM / MeOH = 10 / 1, volume / volume) to obtain 14.5 g of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid as a yellow solid, which was used without further purification. LCMS: m / z = 279 [M + H] + , 1 H NMR (400MHz, DMSO-d6) δ 8.75 (s, 1H), 8.09 (s, 1H), 7.16 (s, 1H), 6.95 (s, 1H), 3.74 (s, 3H), 2.45 (s, 3H).

[0649] (Table A): The following intermediates were prepared using the same procedure as described for intermediate 3. TIFF2026515712000229.tif203167

[0650] Intermediate 7: 2-(4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate tert-butyl TIFF2026515712000230.tif23128 A solution of 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid (1.5 g, 5.6 mmol), 2-amino-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate tert-butyl (1.35 g, 5.6 mmol), and TCFH (3.2 g, 8.4 mmol) in ACN (90 mL) was mixed with NMI (2.9 g, 22.4 mmol) and heated at 80 °C for 20 hours. The mixture was diluted with water (500 mL), extracted with siRNA (2 × 500 mL), the combined organic layers were washed with brine (2 × 500 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethylacetate = 3 / 1, volume / volume) to obtain 2-(4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate tert-butyl (1.18 g, 43%) as a red solid. LCMS: m / z = 492 [M + H] + , 1 H NMR(400MHz,DMSO-d6)δ 12.6(s,1H),8.72(s,1H),7.88(dd,J=8.8,2.2Hz,1H),7.84(d,J=2.2Hz,1H),7.39(s,1H),7.18 (d,J=8.8,Hz,1H),4.57~4.49(m,2H),4.43~4.35(m,2H),3.56(s,3H),2.58(s,3H),1.46(s,9H).

[0651] Intermediate 8: 2-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate tert-butyl To a solution of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (1.5 g, 5.4 mmol), 2-amino-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylic acid tert-butyl (1.3 g, 5.4 mmol), and TCFH (2.27 g, 8.07 mmol) in ACN (60 mL), NMI (1.77 g, 21.5 mmol) was added, and the mixture was heated overnight at 80 °C. The mixture was concentrated under reduced pressure, the residue was diluted with water (50 mL), and extracted with siRNA (2 × 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1, volume / volume) to obtain 2-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate tert-butyl (2.03 g, 71%) as a grayish-white solid. LCMS: m / z = 502 [M + H] + , 1 H NMR(400MHz,DMSO-d6)δ 12.8(d,J=10.6Hz,1H),8.78(s,1H),8.17(d,J=2.0Hz,1H),7.54(s,1H),7.43(s, 1H),4.58~4.49(m,2H),4.44~4.36(m,2H),3.60(s,3H),2.59(s,3H),1.45(s,9H).

[0652] (Table B): The following intermediates were prepared using the same procedure as described for intermediate 8. TIFF2026515712000232.tif243165TIFF2026515712000233.tif238165TIFF2026515712000234.tif253165 TIFF2026515712000235.tif253165TIFF2026515712000236.tif255165TIFF2026515712000237.tif137165

[0653] Intermediate 29: 3-Chloro-6-(difluoromethyl)picolinic acid Step 1: To a stirred solution of 2,3-dichloro-6-methylpyridine (4.5 g, 28 mmol) in EtOH (100 mL), Pd(dppf)Cl2 (2.0 g, 2.8 mmol) and TEA (14.1 g, 139 mmol) were added in one step at 25°C. The reaction mixture was packed with carbon monoxide and stirred at 110°C for 4 hours under 40 MPa CO. The resulting mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to obtain ethyl 3-chloro-6-methylpicolinate (3.2 g, yield 58%) as a yellow solid. LCMS: m / z = 200 [M + H] + .

[0654] Step 2: To a stirred solution of ethyl 3-chloro-6-methylpicolinate (2.0 g, 10.0 mmol) in dioxane (40 mL), selenium dioxide (13.3 g, 120.2 mmol) was added all at once at 25°C. The reaction mixture was stirred under a nitrogen atmosphere at 140°C for 48 hours. The resulting mixture was cooled to 25°C and diluted with water (50 mL). The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA(3 / 1) to obtain ethyl 3-chloro-6-formylpyridine-2-carboxylate (1.1 g, yield 51%) as a yellow oil. LCMS: m / z = 214 [M + H] + .

[0655] Step 3: To a stirred solution of ethyl 3-chloro-6-formylpyridine-2-carboxylate (1.0 g, 4.7 mmol) in DCM (20 mL), DAST (1.5 g, 9.4 mmol) was added dropwise at 0°C. The reaction mixture was stirred under a nitrogen atmosphere at 25°C for 2 hours. The resulting mixture was quenched with saturated NaHCO3 solution. The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (5 / 1) to obtain ethyl 3-chloro-6-(difluoromethyl)pyridine-2-carboxylate (520 mg, yield 47%) as a yellow oil. LCMS: m / z = 236 [M + H] + .

[0656] Step 4: To a stirred solution of ethyl 3-chloro-6-(difluoromethyl)pyridine-2-carboxylate (500 mg, 2.1 mmol) in THF (5 mL) and H2O (1 mL), LiOH (178 mg, 4.2 mmol) was added all at once at 25°C. The resulting mixture was stirred at 25°C for 2 hours. The residue was acidified to pH 3 with aqueous HCl (1 N), diluted with H2O (25 mL), and extracted with DCM / MeOH (5 / 1) (3 × 30 mL). The organic layer was dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure to obtain 3-chloro-6-(difluoromethyl)picolinic acid (300 mg, unpurified) as a white solid. LCMS: m / z = 208 [M + H] + .

[0657] Intermediate 30: 4-(difluoromethyl)-5-methoxypyrimidine-2-carboxylic acid Step 1: Zinc(II) difluoromethanesulfinate (6.0 g, 21.0 mmol) and TFA (0.8 g, 7.0 mmol) were sequentially added to a stirred solution of 2-chloro-5-methoxypyrimidine (1.0 g, 7.0 mmol) and 2-hydroperoxy-2-methylpropane (2.0 g, 21.0 mmol) in DCM (10 mL) and water (4 mL). The mixture was packed with N2 three times and stirred at 25°C for 12 hours under an N2 atmosphere. The reaction mixture was quenched with saturated sodium thiosulfate solution and extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by reverse-phase chromatography (10 to 30% ACN in water containing 0.1% formic acid regulator) to obtain 2-chloro-4-(difluoromethyl)-5-methoxypyrimidine (131 mg, 10% yield) as a yellow solid. LCMS: m / z = 195 [M + H] + .

[0658] Step 2: Triethylamine (170 mg, 1.7 mmol) was added to a stirred solution of 2-chloro-4-(difluoromethyl)-5-methoxypyrimidine (131 mg, 0.7 mmol) and Pd(dppf)Cl2 (15 mg, 21 μmol) in EtOH (5 mL). The mixture was packed with CO three times and stirred at 100 °C for 6 hours under a CO atmosphere. The resulting mixture was cooled to 25 °C and concentrated under reduced pressure. The mixture was purified by preparative TLC (DCM / MeOH 10 / 1) to obtain ethyl 4-(difluoromethyl)-5-methoxypyrimidine-2-carboxylate (89 mg, yield 57%) as a brown solid. LCMS: m / z = 233 [M + H] + .

[0659] Step 3: To a stirred solution of ethyl 4-(difluoromethyl)-5-methoxypyrimidine-2-carboxylate (79 mg, 0.3 mmol) in THF (2 mL) and water (2 mL), LiOH (16 mg, 0.7 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was acidified to pH 5 with HCl (1 N) and concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH) to obtain 4-(difluoromethyl)-5-methoxypyrimidine-2-carboxylic acid (65 mg, 94% yield) as a brown solid. LCMS: m / z = 205 [M + H] + .

[0660] Intermediate 31: 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid Step 1: To a solution of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (5 g, 17.1 mmol), Pd(dppf)Cl2 (1.4 g, 1.7 mmol), and potassium vinyltrifluoroborate (4.6 g, 34.2 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL), K2CO3 (4.7 g, 34.2 mmol) was added all at once at 25 °C. The reaction mixture was stirred under a nitrogen atmosphere at 130 °C for 16 hours. The mixture was cooled to 25 °C and filtered. The filter cake was washed with ELISA (3 × 50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA(1 / 1) to obtain methyl 5'-methoxy-6-methyl-2'-vinyl-[4,4'-bipyridine]-3-carboxylate (4.7 g, 97% yield) as a brown solid. LCMS: m / z = 285 [M + H] + .

[0661] Step 2: To a solution of methyl 5'-methoxy-6-methyl-2'-vinyl-[4,4'-bipyridine]-3-carboxylate (4.7 g, 16.5 mmol) and OsO4 (420 mg, 1.7 mmol) in THF (40 mL) and H2O (8 mL), NMO (3.9 g, 33.1 mmol) was added. The mixture was stirred at 25°C for 1 hour. NaIO4 (14.1 g, 66.1 mmol) was added in several batches at 25°C, and the reaction mixture was stirred at 25°C for 16 hours. The mixture was filtered, and the filter cake was washed with MeOH (2 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA(1 / 10) to obtain methyl 2'-formyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (600 mg, yield 12.7%) as a brown solid. LCMS: m / z = 287 [M + H] + .

[0662] Step 3: As described in Step 3 of Intermediate 29: 3-chloro-6-(difluoromethyl)picolinic acid, the process was completed from 2'-formyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate methyl to obtain 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate methyl (500 mg, yield 84%) as a brown solid. LCMS: m / z = 309 [M + H] + .

[0663] Step 4: To a solution of methyl 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (450 mg, 1.5 mmol) in MeOH (6 mL) and H2O (2 mL), NaOH (117 mg, 2.9 mmol) was added at 25 °C. The reaction mixture was stirred at 50 °C for 2 hours. The mixture was cooled to 25 °C and acidified to pH 2 with 1 N aqueous HCl. The precipitated solid was collected by filtration to obtain 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (400 mg, unpurified) as a white solid. LCMS: m / z = 295 [M + H] + .

[0664] (Table V): The following intermediates were prepared using the same procedure as described for intermediate 31. TIFF2026515712000241.tif61165

[0665] Intermediate 34: 3-Methoxy-5-(trifluoromethyl)pyrazine-2-carboxylic acid Step 1: To a solution of methyl 3-hydroxypyrazine-2-carboxylate (3.0 g, 19.5 mmol) in DCM (36 mL) and MeOH (4 mL), (trimethylsilyl) diazomethane solution (14.6 mL, 2 M in hexane) was added dropwise at 0°C. The reaction mixture was packed with N2 three times at 25°C, and the reaction mixture was stirred under a nitrogen atmosphere at 25°C for 2 hours. Acetic acid (5.8 g, 96.6 mmol) was added to the above mixture in several portions at 25°C, and the resulting mixture was stirred for a further 30 minutes at 25°C. The reaction product was quenched with water (100 mL) at 0°C. The resulting mixture was extracted with DCM / MeOH (1 / 5, 3 × 100 mL), and the combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using EA / PE(1 / 10) elution to obtain methyl 3-methoxypyrazine-2-carboxylate (1.2 g, 37% yield) as a pale yellow solid. LCMS: m / z = 169 [M + H] + .

[0666] Step 2: To a solution of methyl 3-methoxypyrazine-2-carboxylate (1.3 g, 7.4 mmol) in DCM (20 mL), urea-hydrogen peroxide (1 / 1) (1.1 g, 11.2 mmol) was added all at once at 25°C. The resulting mixture was cooled to 0°C, and 2,2,2-trifluoroacetic anhydride (2.3 g, 11.2 mmol) was added dropwise under a nitrogen atmosphere. The resulting mixture was stirred under a nitrogen atmosphere at 25°C for 1 hour. The reaction products were quenched with saturated Na2SO3 (aqueous solution) (40 mL) at 25°C. The resulting mixture was extracted with DCM (3 × 60 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EA / PE(1 / 1) to obtain a pale yellow solid mixture of 2-methoxy-3-(methoxycarbonyl)pyrazine 1-oxide and 3-methoxy-2-(methoxycarbonyl)pyrazine 1-oxide (1.1 g, yield 68%). LCMS: m / z = 185 [M + H] + .

[0667] Step 3: To a solution of 2-methoxy-3-(methoxycarbonyl)pyrazine 1-oxide and 3-methoxy-2-(methoxycarbonyl)pyrazine 1-oxide (1.3 g, 6.8 mmol) in toluene (20 mL), POCl3 (2.1 g, 13.6 mmol) and DMF (496 mg, 6.8 mmol) were gradually added at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 65°C for 3 hours. The reaction product was quenched at 0°C with saturated NaHCO3 solution (50 mL). The resulting mixture was extracted with EA (3 × 50 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE (1 / 3) to obtain the crude product as a pale yellow solid. The crude product was purified by preparative HPLC (25-55% MeOH in water [10 mmol / L NH4HCO3 and 0.01% NH3H2O]) to obtain methyl 5-chloro-3-methoxypyrazine-2-carboxylate as a pale yellow solid (130 mg, yield 10%) (LCMS: m / z = 203 [M+H]). +) and methyl 6-chloro-3-methoxypyrazine-2-carboxylate (300 mg, 22% yield) were obtained as a pale yellow solid. LCMS: m / z = 203 [M + H] + .

[0668] Step 4: To a solution of sodium iodide (240 mg, 1.6 mmol) in HI (2 mL, 55 wt%), methyl 5-chloro-3-methoxypyrazine-2-carboxylate (130 mg, 642 μmol) was gradually added at 0°C. The reaction mixture was stirred under a nitrogen atmosphere at 25°C for 16 hours. The mixture was diluted with water (20 mL) and basicized to pH 7 with saturated NaHCO3 solution. The resulting mixture was extracted with Âx (3 × 40 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE (1 / 10) to obtain methyl 5-iodo-3-methoxypyrazine-2-carboxylate (110 mg, yield 58%) as a pale yellow solid. LCMS: m / z = 295 [M + H] + .

[0669] Step 5: To a solution of methyl 5-iodo-3-methoxypyrazine-2-carboxylate (140 mg, 476 μmol) in DMF (2 mL), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (274 mg, 1.4 mmol) and copper(I) iodide (18 mg, 95 μmol) were added in several portions at 25°C. The resulting mixture was stirred under a nitrogen atmosphere at 80°C for 16 hours. The resulting mixture was cooled to 25°C and quenched with water (20 mL). The resulting mixture was extracted with ELISA (3 × 20 mL), and the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 4 / 1) to obtain methyl 3-methoxy-5-(trifluoromethyl)pyrazine-2-carboxylate (70 mg, yield 62%) as a pale yellow solid. LCMS: m / z = 237[M+H] + .

[0670] Step 6: Intermediate 29: As described in Step 4 for 3-chloro-6-(difluoromethyl)picolinic acid, the process was completed from methyl 3-methoxy-5-(trifluoromethyl)pyrazine-2-carboxylate to obtain 3-methoxy-5-(trifluoromethyl)pyrazine-2-carboxylic acid (60 mg, yield 71%) as a pale yellow solid. LCMS: m / z = 221 [MH] - .

[0671] Following steps 4-6 above, 3-methoxy-6-(trifluoromethyl)pyrazine-2-carboxylic acid can be synthesized from methyl 6-chloro-3-methoxypyrazine-2-carboxylate.

[0672] Intermediate 35: 2'-Chloro-6-cyclopropyl-5'-methoxy-[4,4'-bipyridine]-3-carboxylic acid Step 1: To a solution of methyl 4,6-dichloronicotinate (15 g, 73 mmol) in 1,4-dioxane (120 mL) and water (12 mL), cyclopropylboronic acid (7.5 g, 87 mmol), Pd(dppf)Cl2 (2.7 g, 3.6 mmol), and K2CO3 (20 g, 0.2 mmol) were added all at once at 25°C. The reaction mixture was packed with N2 three times and stirred under a nitrogen atmosphere at 100°C for 16 hours. The resulting mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA(3 / 1) to obtain methyl 4-chloro-6-cyclopropylnicotinate (5.6 g, yield 36%) as a white oil. LCMS: m / z = 212[M+H] + .

[0673] Step 2: Intermediate 2: As described in Step 1 for 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid, the process was completed from methyl 4-chloro-6-cyclopropylnicotinate to obtain methyl 2'-chloro-6-cyclopropyl-5'-methoxy-[4,4'-bipyridine]-3-carboxylate as a white solid (1.6 g, 20% yield). LCMS: m / z = 319 [M + H] +.

[0674] Step 3: To a solution of methyl 2'-chloro-6-cyclopropyl-5'-methoxy-[4,4'-bipyridine]-3-carboxylate (1.6 g, 5.0 mmol) in THF (12 mL) and water (4 mL), lithium hydroxide (360 mg, 15.0 mmol) was added all at once at 25 °C. The reaction mixture was stirred at 80 °C for 2 hours. The resulting mixture was acidified to pH 6 with HCl (1 N) and concentrated under reduced pressure. MeOH (10 mL) was added, and the mixture was filtered. The filtrate cake was washed with MeOH (3 × 20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (10 to 50% ACN in water containing 0.1% formic acid regulator) to obtain 2'-chloro-6-cyclopropyl-5'-methoxy-[4,4'-bipyridine]-3-carboxylic acid (880 mg, yield 58%) as a white solid. LCMS: m / z = 305[M+H] + .

[0675] Intermediate 36: 4-(6-chloro-3-(difluoromethoxy)pyridazin-4-yl)-6-methylnicotinic acid Step 1: Intermediate 2: As described in Step 1 of 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid, the process was completed from 6-chloro-4-iodo-3-methoxypyridazine to obtain methyl 4-(6-chloro-3-methoxypyridazine-4-yl)-6-methylpyridine-3-carboxylate as a brown solid (800 mg, yield 74%). LCMS: m / z = 294 [M + H] + .

[0676] Step 2: To a solution of 4-(6-chloro-3-methoxypyridazin-4-yl)-6-methylpyridine-3-carboxylate methyl (800 mg, 2.7 mmol) in ACN (10 mL), NaI (106 mg, 4.1 mmol) and TMSCl (444 mg, 4.1 mmol) were added in one step at 25°C. The reaction mixture was stirred under a nitrogen atmosphere at 80°C for 3 hours. The mixture was cooled to 25°C, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1 / 1) to obtain 4-(6-chloro-3-hydroxypyridazin-4-yl)-6-methylpyridine-3-carboxylate methyl (300 mg, yield 39%) as a light brown solid. LCMS: m / z = 280 [M + H] + .

[0677] Step 3: To a solution of methyl 4-(6-chloro-3-hydroxypyridazin-4-yl)-6-methylpyridine-3-carboxylate (300 mg, 1.1 mmol) in DMF (5 mL), sodium chlorodifluoroacetate (245 mg, 1.6 mmol) and K2CO3 (445 mg, 3.2 mmol) were added in one step at 25°C. The reaction mixture was stirred under a nitrogen atmosphere at 50°C for 16 hours. The mixture was cooled to 25°C, filtered, and the filtrate cake was washed with MeOH (2 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (10 to 70% MeCN in water containing 0.1% formic acid regulator) to obtain methyl 4-(6-chloro-3-(difluoromethoxy)pyridazin-4-yl)-6-methylnicotinate (200 mg, yield 57%) as a light brown solid. LCMS: m / z = 330 [M + H] + .

[0678] Step 4: A solution of methyl 4-(6-chloro-3-(difluoromethoxy)pyridazin-4-yl)-6-methylnicotinate (180 mg, 0.5 mmol) and LiOH (39 mg, 1.6 mmol) in THF (15 mL) and H2O (5 mL) was stirred at 25°C for 8 hours. The mixture was acidified to pH 2 with 1 N aqueous HCl. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (10 to 70% MeCN in water containing 0.1% formic acid regulator) to obtain 4-(6-chloro-3-(difluoromethoxy)pyridazin-4-yl)-6-methylnicotinic acid (50 mg, yield 29%) as a grayish-white solid. LCMS: m / z = 316 [M + H] + .

[0679] Intermediate 37: 5-(difluoromethyl)-2-methylpyridine-3-carboxylic acid Step 1: To a stirred solution of ethyl 5-bromo-6-methylpyridine-3-carboxylate (1.0 g, 4.0 mmol) in THF (10 mL), LiAlH4 (155 mg, 4.0 mmol) was added dropwise at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at 0°C under a nitrogen atmosphere for 4 hours. The reaction product was quenched with Na2SO4·10H2O at 0°C, and the mixture was stirred at 0°C for 10 minutes. The resulting mixture was filtered, and the filter cake was washed with Et2O (3 × 10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography (10 to 50% MeCN in water containing 0.1% formic acid regulator) to obtain (5-bromo-6-methylpyridine-3-yl)methanol (580 mg, yield 70%) as a pale yellow oil. LCMS: m / z = 202[M+H] + .

[0680] Step 2: To a stirred solution of (5-bromo-6-methylpyridine-3-yl)methanol (560 mg, 2.7 mmol) in DCM (6 mL), DMP (1410 mg, 3.3 mmol) was sequentially added under a nitrogen atmosphere at 0°C. The reaction mixture was stirred under a nitrogen atmosphere at 0°C for 4 hours. After filtration, the filtrate cake was washed with Et2O (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (10 to 50% MeCN in water containing 0.1% formic acid regulator) to obtain 5-bromo-6-methylpyridine-3-carbaldehyde (320 mg, yield 58%) as a pale yellow oil. LCMS: m / z = 200 [M + H] + .

[0681] Step 3: Intermediate 29: As described in Step 3 for 3-chloro-6-(difluoromethyl)picolinic acid, the process was completed from 5-bromo-6-methylpyridine-3-carbaldehyde to obtain 3-bromo-5-(difluoromethyl)-2-methylpyridine (180 mg, yield 58%) as a pale yellow oil. LCMS: m / z = 222 [M + H] + .

[0682] Step 4: Intermediate 30: 4-(difluoromethyl)-5-methoxypyrimidine-2-carboxylic acid was prepared as described in Step 2 from 3-bromo-5-(difluoromethyl)-2-methylpyridine to obtain ethyl 5-(difluoromethyl)-2-methylpyridine-3-carboxylate (100 mg, yield 64%) as a white solid. LCMS: m / z = 216 [M + H] + .

[0683] Step 5: Intermediate 29: 3-chloro-6-(difluoromethyl)picolinic acid was prepared as described in Step 4 from ethyl 5-(difluoromethyl)-2-methylpyridine-3-carboxylate to obtain 5-(difluoromethyl)-2-methylpyridine-3-carboxylic acid (80 mg, 92% yield) as a yellow solid. LCMS: m / z = 188 [M + H] + .

[0684] Intermediate 38: 2-Methoxy-5-(trifluoromethyl)pyrimidine-4-carboxylic acid Intermediate 39: 4-Methoxy-5-(trifluoromethyl)pyrimidine-2-carboxylic acid Step 1: A solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.00 g, 5.00 mmol) and TEA (0.70 g, 7.00 mmol) in CH3OH (10 mL) was stirred at 25°C for 3 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL), and the aqueous layer was extracted with ELISA (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 4-chloro-2-methoxy-5-(trifluoromethyl)pyrimidine and 2-chloro-4-methoxy-5-(trifluoromethyl)pyrimidine (400 mg, mixture) as a grayish-white solid. The crude product was used directly in the next step without further purification. 1 H NMR (300MHz, DMSO-d6) δ 9.04 (q, J = 0.9 Hz, 1H), 8.87 (q, J = 1.0 Hz, 1H), 4.09 (s, 3H), 4.04 (s, 3H).

[0685] Step 2: Intermediate 30: As described in Step 2 for 4-(difluoromethyl)-5-methoxypyrimidine-2-carboxylic acid, the mixture of 4-chloro-2-methoxy-5-(trifluoromethyl)pyrimidine and 2-chloro-4-methoxy-5-(trifluoromethyl)pyrimidine was completed to obtain methyl 4-methoxy-5-(trifluoromethyl)pyrimidine-2-carboxylate and methyl 2-methoxy-5-(trifluoromethyl)pyrimidine-4-carboxylate (300 mg, mixture) as a grayish-white solid. The crude product was used directly in the next step without further purification. 1 H NMR (300MHz, DMSO-d6) δ 9.23 (s, 1H), 4.04 (s, 3H), 3.96 (s, 3H).

[0686] Step 3: Intermediate 29: As described in Step 4 for 3-chloro-6-(difluoromethyl)picolinic acid, the mixture of methyl 4-methoxy-5-(trifluoromethyl)pyrimidine-2-carboxylate and methyl 2-methoxy-5-(trifluoromethyl)pyrimidine-4-carboxylate was completed to obtain 2-methoxy-5-(trifluoromethyl)pyrimidine-4-carboxylic acid and 4-methoxy-5-(trifluoromethyl)pyrimidine-2-carboxylic acid (40 mg, mixture) as a white solid. The crude product was used directly in the next step without further purification. LCMS: m / z = 223 [M + H] + .

[0687] Intermediate 40: 3,6-dimethyl-4-(trifluoromethyl)picolinic acid Step 1: Intermediate 30: As described in Step 2 of 4-(difluoromethyl)-5-methoxypyrimidine-2-carboxylic acid, the preparation was completed from 2-chloro-3,6-dimethylpyridine to obtain methyl 3,6-dimethylpicolinate (1 g, 40%) as a yellow liquid. LCMS: m / z = 166 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.65(d,J=7.9Hz,1H),7.34(d,J=8.0Hz,1H),3.86(d,J=1.2Hz,3H),2.46(s,3H),2.39(s,3H).

[0688] Step 2: To a solution of methyl 3,6-dimethylpicolinate (1 g, 6 mmol) in CHCl3 (60 mL) and water (20 mL), zinc trifluoromethanesulfonate (4 g, 2.00 equivalents) and tert-butyl hydroperoxide (2 g, 70%, 0.02 mol) were added. The mixture was stirred at 50°C for 16 hours. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution, and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / siRNA (0 to 20% gradient over 30 minutes) to obtain methyl 3,6-dimethyl-4-(trifluoromethyl)picolinate (500 mg, 40%) as a yellow liquid. LCMS: m / z = 234 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.77(s,1H),3.91(s,3H),2.56(s,3H),2.40(s,3H), 19 F NMR(377MHz,DMSO-d6)δ -62.02.

[0689] Step 3: Intermediate 29: As described in Step 4 for 3-chloro-6-(difluoromethyl)picolinic acid, the process was completed from methyl 3,6-dimethyl-4-(trifluoromethyl)picolinic acid to obtain 3,6-dimethyl-4-(trifluoromethyl)picolinic acid (500 mg, unpurified) as a white solid. The crude product was used directly in the next step without further purification. LCMS: m / z = 220 [M + H] + .

[0690] (Table W): The following intermediates were prepared using the same procedure as described for intermediate 40. TIFF2026515712000248.tif84165

[0691] Intermediate 44: 5-cyano-3-methyl-6-(trifluoromethyl)picolinic acid Step 1: To a solution of methyl 6-amino-3-bromopicolinate (6.4 g, 28 mmol) in 1,4-dioxane (60 mL), K2CO3 (11 g, 83 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (50 wt% in THF, 21 g, 83 mmol), and Pd(dppf)Cl2.DCM (2.3 g, 2.8 mmol) were added, and the mixture was heated in a sealed tube under N2 at 115°C for 4 hours. The mixture was diluted with water (50 mL), extracted with SiO2 (5 × 50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / acetate = 10 / 1 to 5 / 1 to 3 / 1 to 1 / 1, volume / volume) to obtain methyl 6-amino-3-methylpicolinate (3.4 g, 70%) as a yellow oily substance. LCMS: m / z = 167 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.32 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 5.98 (s, 2H), 3.77 (s, 3H), 2.21 (s, 3H).

[0692] Step 2: To a solution of methyl 6-amino-3-methylpicolinate (3.4 g, 20 mmol) in CHCl3 (120 mL), a solution of bromine (4.9 g, 31 mmol) in CHCl3 (15 mL) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (150 mL), extracted with DCM (5 × 50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / alkyl = 10 / 1 to 5 / 1 to 3 / 1, volume / volume) to obtain methyl 6-amino-5-bromo-3-methylpicolinate (3.67 g, 70%) as a grayish-white solid. LCMS: m / z = 245 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.76 (s, 1H), 6.30 (s, 2H), 3.79 (s, 3H), 2.24 (s, 3H).

[0693] Step 3: To a solution of methyl 6-amino-5-bromo-3-methylpicolinate (2.0 g, 8.2 mmol) in MeCN (80 mL) at 0°C, CuI (3.1 g, 16 mmol) and isopentyl nitrite (2.1 g, 18 mmol) were added. The mixture was stirred at 0°C for 1 hour, then heated at 60°C for 16 hours. The mixture was diluted with water (50 mL), extracted with Depositphotos (5 × 50 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / Depositphotos = 1 / 0 to 10 / 1 to 5 / 1, volume / volume) to obtain methyl 5-bromo-6-iodo-3-methylpicolinate (606 mg, 20%) as a yellow solid. LCMS: m / z = 356 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.15 (s, 1H), 3.86 (s, 3H), 2.39 (s, 3H).

[0694] Step 4: To a solution of methyl 5-bromo-6-iodo-3-methylpicolinate (600 mg, 1.69 mmol) in NMP (8 mL), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (971 mg, 5.06 mmol) and CuI (64.2 mg, 0.337 mmol) were added, and the mixture was heated at 80°C for 16 hours. The mixture was diluted with water (30 mL), extracted with siRNA (3 × 30 mL), and the combined organic layers were washed with water (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / DCM = 1 / 1, volume / volume) to obtain methyl 5-bromo-3-methyl-6-(trifluoromethyl)picolinate (146 mg, 26%) as a yellow solid. LCMS: m / z = 298 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.51 (s, 1H), 3.90 (s, 3H), 2.54 (s, 3H).

[0695] Step 5: To a solution of methyl 5-bromo-3-methyl-6-(trifluoromethyl)picolinate (43 mg, 0.14 mmol) in DMF (1 mL), zinc (2.4 mg, 0.036 mmol), Zn(CN)2 (10 mg, 0.087 mmol), and Pd(dppf)Cl2 (5.3 mg, 7.2 μmol) were added, and the mixture was heated in a sealed tube under N2 at 120°C for 16 hours. The mixture was diluted with water (10 mL), extracted with RINKAN (3 × 15 mL), and the combined organic layers were washed with water (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / DCM = 1 / 1, volume / volume) to obtain methyl 5-cyano-3-methyl-6-(trifluoromethyl)picolinate (17 mg, 41%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 8.77 (s, 1H), 3.94 (s, 3H), 2.58 (s, 3H).

[0696] Step 6: Intermediate 29: As described in Step 4 for 3-chloro-6-(difluoromethyl)picolinic acid, the process was completed from methyl 5-cyano-3-methyl-6-(trifluoromethyl)picolinic acid to obtain 5-cyano-3-methyl-6-(trifluoromethyl)picolinic acid (18 mg, 84%) as a white solid, which was used directly in the next step. LCMS: m / z = 229 [MH] - . 1 H NMR (400MHz, DMSO-d6) δ 8.29 (s, 1H), 2.33 (s, 3H).

[0697] Intermediate 45: 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid Step 1: To a solution of methyl 4-chloro-6-methylnicotinate (5.00 g, 26.9 mmol), bis(pinacolate)diborone (20.5 g, 80.8 mmol), and KOAc (15.9 g, 162 mmol) in dioxane (100 mL), Pd(dppf)Cl2 (2.96 g, 4.04 mmol) was added, and the mixture was heated under N2 at 100°C for 2 hours. The mixture was diluted with water (25 mL), extracted with DCM (6 × 20 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM to DCM / MeOH = 100 / 1, volume / volume) to obtain methyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (3.00 g, 38%) as a white solid. LCMS: m / z = 196[M-C6H 12 +3H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.93~8.88 (m, 1H), 7.36 (s, 1H), 3.87 (s, 3H), 2.54 (s, 3H), 1.33 (s, 12H).

[0698] Step 2: To a solution of 6-chloro-5-fluoropyridine-3-ol (1.00 g, 6.78 mmol) and K2CO3 (1.87 g, 13.6 mmol) in acetone (10 mL) at 0°C, MeI (1.15 g, 8.13 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (20 mL), extracted with DCM (5 × 20 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether to petroleum ether / siRNA = 10 / 1, volume / volume) to obtain 2-chloro-3-fluoro-5-methoxypyridine (900 mg, 82%) as a colorless oil. LCMS: m / z = 162 [M + H] + . 1H NMR (400MHz, DMSO-d6) δ 8.04 (d, J = 2.6 Hz, 1H), 7.70 (dd, J = 10.4, 2.6 Hz, 1H), 3.86 (s, 3H).

[0699] Step 3: To a solution of 2-chloro-3-fluoro-5-methoxypyridine (4.84 g, 30.0 mmol) in THF (80 mL) under N2 at -78°C, n-butyllithium (2.5 M in hexane, 14.4 mL, 35.9 mmol) was added dropwise, and the mixture was stirred at -78°C for 0.5 hours. Iodine (9.88 g, 38.9 mmol) was added, and stirring continued at -78°C for 2 hours, then at room temperature for 16 hours. The reaction mixture was quenched with saturated sodium thiosulfate aqueous solution, and the mixture was extracted with RINKAN (10 × 80 mL). The combined organic layers were washed with brine (5 × 100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 2-chloro-3-fluoro-4-iodo-5-methoxypyridine (8.1 g, 94%) as a brown solid. LCMS: m / z = 288 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.94 (s, 1H), 3.99 (s, 3H).

[0700] Step 4: Intermediate 2: As described in Step 1 for 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid, the process was completed from 2-chloro-3-fluoro-4-iodo-5-methoxypyridine and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate methyl to obtain 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate methyl (200 mg, 93%) as a yellow oil. LCMS m / z = 311 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 9.04 (s, 1H), 8.23 ​​(s, 1H), 7.44 (s, 1H), 3.83 (s, 3H), 3.70 (s, 3H), 2.59 (s, 3H).

[0701] Step 5: Intermediate 1: As described for 4-(2-methoxyphenyl)-6-methylnicotinic acid, the process was completed from methyl 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate to obtain 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (100 mg, 53%) as a white solid. LCMS: m / z = 297.15 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 9.03 (s, 1H), 8.22 (s, 1H), 7.39 (s, 1H), 3.84 (s, 3H), 2.57 (s, 3H).

[0702] Intermediate 46: (1s,3s)-3-(difluoromethoxy)cyclobutane-1-carboxylic acid Step 1: To a solution of (1s,3s)-3-hydroxycyclobutane-1-carboxylate methyl (800 mg, 6.15 mmol) in MeCN (10 mL), CuI (234 mg, 1.23 mmol) and a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (1.31 g, 7.38 mmol) in MeCN (2 mL) were added, and the mixture was heated at 50°C for 3 hours. The mixture was diluted with water (100 mL), extracted with RINKAN (50 mL x 3), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (1s,3s)-3-(difluoromethoxy)cyclobutane-1-carboxylate methyl (900 mg, 81%), which was used without further purification. 1 H NMR(400MHz,DMSO-d6)δ 6.81~6.41(m,1H),5.27(t,J=7.4Hz,1H),3.62(s,3H),2.86(s,1H),2.36(ddt,J=12.4,7.0,2.2Hz,2H),2.19~2.16(m,2H).

[0703] Step 2: To a solution of (1s,3s)-3-(difluoromethoxy)cyclobutane-1-carboxylate methyl (932 mg, 5.17 mmol) in THF (10 mL) and water (2 mL), LiOH (285 mg, 11.9 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was adjusted to pH 3 with 2 M aqueous HCl and concentrated under reduced pressure. The residue was dissolved in DCM / MeOH (15 / 1), filtered, and the filtrate was concentrated under reduced pressure to obtain (1s,3s)-3-(difluoromethoxy)cyclobutane-1-carboxylic acid (500 mg, 58%), which was used without further purification.

[0704] Intermediate 47: (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid Step 1: To a solution of (1s,3s)-3-hydroxycyclobutane-1-carboxylic acid (200 mg, 1.72 mmol) in DMF (3 mL), NaHCO3 (434 mg, 5.17 mmol) and benzyl bromide (442 mg, 2.58 mmol) were added, and the mixture was stirred overnight at room temperature. The mixture was diluted with water (15 mL), separated with RINKAN (30 mL x 3), and the combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (1s,3s)-3-hydroxycyclobutane-1-carboxylic acid benzyl (308 mg, 86%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 7.35(tdd,J=10.4,6.4,3.8Hz,5H),5.19(d,J=7.0Hz,1H),5.08(s,2H),3.97(td,J=8.4,6.8Hz ,1H),2.61(ddd,J=10.0,7.8,2.2Hz,1H),2.40(tdd,J=7.6,6.0,2.8Hz,2H),2.02~1.92(m,2H).

[0705] Step 2: To a solution of silver trifluoromethanesulfonate (2.24 g, 8.73 mmol), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.16 g, 3.27 mmol), and potassium fluoride (5.08 g, 8.73 mmol) in HCl (10 mL), (1s,3s)-3-hydroxycyclobutane-1-carboxylate benzyl (450 mg, 2.18 mmol), 2-fluoropyridine (847 mg, 8.73 mmol), and (trifluoromethyl)trimethylsilane (775 mg, 5.45 mmol) were added. The mixture was stirred at room temperature in the dark under an N2 atmosphere for 24 hours. The mixture was diluted with water (15 mL), extracted with ethyl acetate (50 mL x 2), and the combined organic layers were washed with water (10 mL) and brine (10 mL). The mixture was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 5 / 1, volume / volume) to obtain (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylate benzyl (320 mg, 27%) as a yellow solid. 1 ¹H NMR (400MHz, chloroform-d) δ 7.41~7.31 (m, 5H), 5.14 (s, 2H), 4.57 (p, J=7.6Hz, 1H), 2.82~2.70 (m, 1H), 2.68~2.58 (m, 2H), 2.58~2.48 (m, 2H).

[0706] Step 3: To a solution of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid benzyl (320 mg, 1.17 mmol) in EtOH (5 mL), 10% Pd / C (320 mg) was added, and the mixture was stirred overnight at room temperature under an H2 atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (190 mg, 88%) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 4.73(p,J=7.4Hz,1H),2.73~2.62(m,1H),2.57(ddd,J=9.6,7.2,2.6Hz,2H),2.26(qd,J=9.6,9.2,2.6Hz,2H).

[0707] (Table X): The following examples were prepared using the same procedure as described for intermediate 17. TIFF2026515712000253.tif61167

[0708] Intermediate 49: 6-(difluoromethoxy)spiro[3,3]heptane-2-carboxylic acid Step 1: To a solution of methyl 6-hydroxyspiro[3,3]heptane-2-carboxylate (50 mg, 0.29 mmol) and KOAc (0.17 g, 1.8 mmol) in DCM / water (1 / 1, 2 mL) at 0 °C, (bromodifluoromethyl)trimethylsilane (0.24 g, 1.2 mmol) was added, and the mixture was stirred at 25 °C for 16 hours. The mixture was diluted with saturated aqueous NaHCO3 (10 mL), extracted with DCM (2 × 20 mL), and the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / alkyl = 1 / 1, volume / volume) to obtain methyl 6-(difluoromethoxy)spiro[3.3]heptane-2-carboxylate (30 mg, 46%) as a yellow oily substance. 1 H NMR(400MHz,DMSO-d6)δ 6.57(t,J=76.0Hz,1H),4.44(p,J=7.4Hz,1H),3.57(s,3H),3.09~2.99(m,1H),2.48~2. 42(m,1H),2.32~2.26(m,1H),2.25~2.14(m,4H),2.10~2.03(m,1H),2.02~1.95(m,1H).

[0709] Step 2: To a solution of methyl 6-(difluoromethoxy)spiro[3.3]heptane-2-carboxylic acid (30 mg, 0.14 mmol) in THF / water (4 / 1, 2 mL), LiOH (9.8 mg, 0.41 mmol) was added, the mixture was stirred at 25°C for 2 hours, and then concentrated under reduced pressure to obtain 6-(difluoromethoxy)spiro[3.3]heptane-2-carboxylic acid (25 mg, Li salt) as a white solid.1 H NMR(400MHz,DMSO-d6)δ 6.78~6.34(m,1H),4.48~4.35(m,1H),2.57~2.52(m,1H),2.42~2.31(m,1H), 2.28~2.17(m,1H),2.11~2.04(m,2H),2.02~1.95(m,2H),1.93~1.87(m,2H).

[0710] Intermediate 50: 5-(difluoromethyl)-3-methoxypyrazine-2-carboxylic acid Step 1: To a solution of 5-bromo-3-methoxypyrazine-2-amine (10.0 g, 49.0 mmol) in 1,4-dioxane (100 mL) and water (25 mL), potassium trifluoro(vinyl)borate (6.57 g, 49.0 mmol), K2CO3 (13.6 g, 98.0 mmol), and Pd(dppf)Cl2 (3.59 g, 4.90 mmol) were added, and the mixture was heated under N2 at 80°C for 6 hours. The mixture was diluted with water (100 mL), extracted with ELISA (3 × 100 mL), and the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / Âxate = 10 / 1 to 5 / 1) to obtain 3-methoxy-5-vinylpyrazine-2-amine (2.58 g, 34%) as a yellow solid. LCMS: m / z = 152 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.46(s,1H),6.64~6.54(m,1H),6.44(s,2H),5.86(dd,J=17.2,2.2Hz,1H),5.10(dd,J=10.6,2.2Hz,1H),3.92(s,3H).

[0711] Step 2: To a solution of 3-methoxy-5-vinylpyrazine-2-amine (2.58 g, 17.1 mmol) in THF (40 mL) and water (10 mL), 4-methylmorpholine 4-oxide hydrate (2.31 g, 17.1 mmol) and osmium tetroxide (434 mg, 1.71 mmol) were added, and the mixture was stirred at 25°C for 2 hours. Then, sodium metaperiodate (14.6 g, 68.3 mmol) was added, and the mixture was stirred at 25°C for a further 2 hours. The mixture was diluted with water (100 mL), extracted with SiO2 (3 × 100 mL), and the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 5-amino-6-methoxypyrazine-2-carbaldehyde (2.45 g, 94%) as a brown solid. LCMS: m / z = 154 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 9.63 (s, 1H), 8.16 (s, 1H), 7.58 (s, 2H), 3.96 (s, 3H).

[0712] Step 3: To a solution of 5-amino-6-methoxypyrazine-2-carbaldehyde (2.05 g, 13.4 mmol) in DCM (40 mL) under N2 at -78°C, DAST (8.63 g, 53.5 mmol) was added, and the mixture was stirred at -78°C for 3 hours. The mixture was diluted with saturated NaHCO3 aqueous solution (80 mL), extracted with DCM (3 × 80 mL), and the combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / Depositphotos = 2 / 1, volume / volume) and preparative TLC (petroleum ether / Depositphotos = 1 / 1, volume / volume) to obtain 5-(difluoromethyl)-3-methoxypyrazine-2-amine (370 mg, 16%) as a yellow solid. LCMS: m / z = 176 [M + H]. 1 H NMR (400MHz, DMSO-d6) δ 7.73 (t, J = 1.8 Hz, 1H), 6.92~6.62 (m, 3H), 3.91 (s, 3H).

[0713] Step 4: A mixture of 5-(difluoromethyl)-3-methoxypyrazine-2-amine (430 mg, 2.46 mmol), 48% HBr in water (2 mL), and AcOH (6 mL) was stirred at 5°C for 0.5 hours. Sodium nitrite (508.1 mg, 7.37 mmol) was added, and the mixture was stirred for a further 2 hours at 5°C. The mixture was diluted with saturated aqueous NaHCO3 (40 mL), extracted with ethyl acetate (2 × 40 mL), and the combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 15 / 1, volume / volume) to obtain 2-bromo-5-(difluoromethyl)-3-methoxypyrazine (174 mg, 30%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ 8.34 (d, J = 1.6 Hz, 1H), 7.25~6.83 (m, 1H), 4.02 (s, 3H).

[0714] Step 5: To a solution of 2-bromo-5-(difluoromethyl)-3-methoxypyrazine (100 mg, 0.418 mmol) in MeOH (5 mL), Pd(OAc)2 (9.39 mg, 0.042 mmol), 1,1'-ferrocenediylbis(diphenylphosphine) (23.2 mg, 0.042 mmol), and Et3N (127 mg, 1.26 mmol) were added. The mixture was heated at 85°C for 16 hours under a CO atmosphere (2 MPa). The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / siRNA = 3 / 1, volume / volume) to obtain methyl 5-(difluoromethyl)-3-methoxypyrazine-2-carboxylate (68 mg, 75%) as a white solid. LCMS: m / z = 219 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.58 (s, 1H), 7.26~6.93 (m, 1H), 4.01 (s, 3H), 3.91 (s, 3H).

[0715] Step 6: LiOH (9.88 mg, 0.413 mmol) was added to a solution of methyl 5-(difluoromethyl)-3-methoxypyrazine-2-carboxylate (30.0 mg, 0.138 mmol) in a mixture of THF (0.5 mL) and water (0.5 mL). The mixture was stirred at 25°C for 2 hours, then concentrated under reduced pressure to obtain 5-(difluoromethyl)-3-methoxypyrazine-2-carboxylic acid (30 mg, Li salt) as a gray solid. 1 H NMR (400MHz, DMSO-d6) δ 8.16 (s, 1H), 7.08~6.76 (m, 1H), 3.85 (s, 3H).

[0716] Intermediate 51: 5-(difluoromethyl)-6-methoxypyrazine-2-carboxylic acid Step 1: To a solution of 5-bromo-3-methoxypyrazine-2-amine (200 mg, 0.980 mmol) in MeOH (10 mL), Et3N (198 mg, 1.96 mmol) and Pd(dppf)Cl2 (35.9 mg, 0.049 mmol) were added. The mixture was heated at 80°C for 16 hours under a CO atmosphere (1 atm). The mixture was diluted with water (30 mL), extracted with  (2 × 30 mL), and the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (5% MeOH in DCM) to obtain methyl 5-amino-6-methoxypyrazine-2-carboxylate (65 mg, 36%) as a yellow solid. LCMS: m / z = 184[M+H] + . 1 H NMR (400MHz, Chloroform-d) δ 8.36 (s, 1H), 4.09 (s, 3H), 3.92 (s, 3H).

[0717] Step 2: To a solution of methyl 5-amino-6-methoxypyrazine-2-carboxylate (520 mg, 2.84 mmol) in AcOH (7 mL) at 5°C, 48% HBr in water (3 mL) and sodium nitrite (588 mg, 8.52 mmol) were added. The mixture was stirred at 5°C for 2 hours. The mixture was diluted with water (50 mL), extracted with RINKAN (2 × 50 mL), and the combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 10% RINKAN in petroleum ether) to obtain methyl 5-bromo-6-methoxypyrazine-2-carboxylate (300 mg, 43%) as a yellow solid. LCMS: m / z = 247 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.59 (s, 1H), 4.03 (s, 3H), 3.91 (s, 3H). Steps 3-6, Intermediate 50: The reaction for 5-(difluoromethyl)-3-methoxypyrazine-2-carboxylic acid was completed as described in steps 1-3 and 6 to obtain 5-(difluoromethyl)-6-methoxypyrazine-2-carboxylic acid. LCMS: m / z = 203 [MH] - .

[0718] Intermediate 52: 6-(difluoromethyl)-3-methoxypyrazine-2-carboxylic acid Step 1: To a solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (5 g, 0.02 mol) in concentrated H2SO4 (30 mL) at 0°C, sodium nitrite (3 g, 0.04 mol) was added, and the mixture was stirred at 0°C for 30 minutes. The mixture was poured into MeOH (270 mL) and heated under reflux for 5 hours. The solvent was removed under reduced pressure, the residue was diluted with water (100 mL), and extracted with ethyl phosphate (100 mL x 2). The combined organic layers were washed with saturated aqueous NaHCO3 (50 mL) and water (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl phosphate = 5 / 1, volume / volume) to obtain methyl 6-bromo-3-methoxypyrazine-2-carboxylate (1.6 g, 32%) as a grayish-white solid. LCMS: m / z = 247[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 8.38 (s, 1H), 4.06 (s, 3H), 3.98 (s, 3H).

[0719] Steps 2-5 were completed starting from methyl 6-bromo-3-methoxypyrazine-2-carboxylate, as described in steps 1-3 and 6 for intermediate 50: 5-(difluoromethyl)-3-methoxypyrazine-2-carboxylic acid, to obtain 6-(difluoromethyl)-3-methoxypyrazine-2-carboxylic acid. LCMS: m / z = 205 [M + H] + ; 1 H NMR (400MHz, DMSO-d6) δ 8.31 (s, 1H), 6.96 (t, J=54.6Hz, 1H), 3.90 (s, 3H).

[0720] (Table Y): The following intermediates were prepared using a procedure similar to that described for intermediate 52 following steps 2-5. TIFF2026515712000258.tif92160

[0721] Intermediate 55: 6-(difluoromethyl)-5-methoxypyrazine-2-carboxylic acid Step 1: To a solution of methyl 5-chloro-6-methylpyrazine-2-carboxylate (500 mg, 2.68 mmol) in MeOH (5 mL) at 0°C, NaOMe (30 wt%, 1.21 g, 6.70 mmol) was added dropwise over 5 minutes. The mixture was stirred at 25°C for 0.5 hours. The reaction product was quenched with AcOH (2 mL), the mixture was diluted with water (10 mL), and extracted with Depositphotos (6 × 15 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl 5-methoxy-6-methylpyrazine-2-carboxylate (450 mg, 82%) as a grayish-white solid. LCMS: m / z = 183 [M + H] + , 1 H NMR (400MHz, DMSO-d6) δ 8.67 (s, 1H), 4.00 (s, 3H), 3.86 (s, 3H), 2.44 (s, 3H).

[0722] Step 2: To a solution of methyl 5-methoxy-6-methylpyrazine-2-carboxylate (350 mg, 1.92 mmol) in 1,4-dioxane (7 mL), selenium oxide (426 mg, 3.84 mmol) was added, and the mixture was heated at 130°C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 6-formyl-5-methoxypyrazine-2-carboxylate (350 mg, 93%) as a brown solid. LCMS: m / z = 197 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 10.1 (s, 1H), 9.07 (s, 1H), 4.11 (s, 3H), 3.92 (s, 3H).

[0723] Steps 3 and 4 were completed as described in steps 5 and 6 of intermediate 51: 5-(difluoromethyl)-6-methoxypyrazine-2-carboxylic acid, starting from methyl 6-formyl-5-methoxypyrazine-2-carboxylate, to obtain 6-(difluoromethyl)-5-methoxypyrazine-2-carboxylic acid. LCMS: m / z = 203 [MH] - . 1H NMR (400MHz, DMSO-d6) δ 8.80 (s, 1H), 7.04 (t, J=53.4Hz, 1H), 4.00 (s, 3H).

[0724] Intermediate 56: 6-(difluoromethyl)-3-methylpyrazine-2-carboxylic acid Step 1: To a solution of methyl 3-amino-6-chloropyrazine-2-carboxylate (2.00 g, 10.7 mmol) in acetic acid (15 mL) at 0°C, 48% HBr / water (10 mL) was added dropwise, and the mixture was stirred for 30 minutes. Then, a solution of sodium nitrite (2.21 g, 32.0 mmol) in water (5 mL) was added dropwise, and the mixture was stirred at 0°C for 30 minutes. The reaction product was quenched with saturated sodium bisulfite aqueous solution (10 mL), and the mixture was extracted with RINKAN (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / alkyl = 100 / 1, volume / volume) to obtain methyl 3-bromo-6-chloropyrazine-2-carboxylate (1.05 g, 39%) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ 8.87 (s, 1H), 3.95 (s, 3H).

[0725] Step 2: To a solution of methyl 3-bromo-6-chloropyrazine-2-carboxylate (950 mg, 3.78 mmol) in DME (8 mL), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivolinan (1.90 g, 50% by weight in THF, 7.56 mmol), K2CO3 (1.04 g, 7.56 mmol), and Pd(dppf)Cl2.DCM (309 mg, 0.378 mmol) were added. The mixture was heated in a sealed tube at 80°C for 16 hours. The mixture was quenched with water (50 mL), extracted with ₹ (3 × 20 mL), the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / alkyl = 50 / 1, volume / volume) to obtain methyl 6-chloro-3-methylpyrazine-2-carboxylate (250 mg, 36%) as a grayish-white solid. LCMS: m / z = 187 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.89 (s, 1H), 3.91 (s, 3H), 2.72 (s, 3H).

[0726] Steps 3-6 were completed starting from methyl 6-chloro-3-methylpyrazine-2-carboxylate, as described in steps 1-3 and 6 for intermediate 50: 5-(difluoromethyl)-3-methoxypyrazine-2-carboxylic acid, to obtain 6-(difluoromethyl)-3-methylpyrazine-2-carboxylic acid. LCMS: m / z = 189 [M + H] + .

[0727] Intermediate 57: 5-(difluoromethyl)-4-methylpyrimidine-2-carboxylic acid Step 1: Intermediate 50: As described in Step 1 of 5-(difluoromethyl)-3-methoxypyrazine-2-carboxylic acid, the process was completed from 5-bromo-2-chloro-4-methylpyrimidine to obtain 2-chloro-4-methyl-5-vinylpyrimidine (690 mg, 47%) as a white solid. LCMS: m / z = 155 [M + H] + . 1H NMR(400MHz,DMSO-d6)δ 8.81~8.79(m,1H),6.90~6.81(m,1H),5.96(dd,J=17.6,0.8Hz,1H),5.56(dd,J=11.2,0.8Hz,1H),2.51(s,3H),

[0728] Step 2: As described in Step 2 of intermediate 50: 5-(difluoromethyl)-3-methoxypyrazine-2-carboxylic acid, the procedure was completed from 2-chloro-4-methyl-5-vinylpyrimidine to obtain 2-chloro-4-methylpyrimidine-5-carbaldehyde (176 mg, 25%) as a grayish-white solid. 1 H NMR (400MHz, DMSO-d6) δ 10.2 (s, 1H), 9.06 (s, 1H), 3.31 (s, 3H).

[0729] Step 3: As described in Step 3 of Intermediate 50: 5-(difluoromethyl)-3-methoxypyrazine-2-carboxylic acid, the process was completed from 2-chloro-4-methylpyrimidine-5-carbaldehyde to obtain 2-chloro-5-(difluoromethyl)-4-methylpyrimidine (160 mg, 82%) as a brown oily substance. 1 H NMR (400MHz, DMSO-d6) δ 8.85 (s, 1H), 7.46~7.16 (m, 1H), 2.59 (s, 3H).

[0730] Step 4: To a solution of 2-chloro-5-(difluoromethyl)-4-methylpyrimidine (100 mg, 0.560 mmol) in MeOH (8 mL), Et3N (68.0 mg, 0.672 mmol) and Pd(dppf)Cl2 (20.5 mg, 0.028 mmol) were added. The mixture was heated at 80°C for 16 hours under a CO atmosphere (2 MPa). The mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (petroleum ether / siRNA = 2 / 1, volume / volume) to obtain methyl 5-(difluoromethyl)-4-methylpyrimidine-2-carboxylate (78 mg, 69%) as a yellow oily substance. LCMS: m / z = 203 [M + H] + ; 1H NMR (400MHz, DMSO-d6) δ 9.04 (d, J = 1.6 Hz, 1H), 7.52~7.22 (m, 1H), 3.92 (s, 3H), 2.65 (s, 3H).

[0731] Step 5: Intermediate 50: As described in Step 6 for 5-(difluoromethyl)-3-methoxypyrazine-2-carboxylic acid, the process was completed from methyl 5-(difluoromethyl)-4-methylpyrimidine-2-carboxylic acid to obtain 5-(difluoromethyl)-4-methylpyrimidine-2-carboxylic acid (37 mg, Li salt) as a brown solid. LCMS: m / z = 189 [M + H] + .

[0732] Intermediate 58: 5-(difluoromethyl)-3-methylpyrazine-2-carboxylic acid The synthesis of 5-(difluoromethyl)-3-methylpyrazine-2-carboxylic acid was completed as described in steps 1-3 and 6 of intermediate 50: 5-(difluoromethyl)-3-methoxypyrazine-2-carboxylic acid, starting from methyl 5-chloro-3-methylpyrazine-2-carboxylic acid (synthesized according to International Publication No. 2014 / 138484). LCMS: m / z = 189 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.62 (s, 1H), 7.04 (t, J = 54.2Hz, 1H), 2.59 (s, 3H).

[0733] Intermediate 59: 3-(difluoromethyl)-6-methylpyrazine-2-carboxylic acid Step 1: To a solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (500 mg, 2.15 mmol) in DME (5 mL), K2CO3 (596 mg, 4.31 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivolinan (50% by weight in THF, 1.62 g, 6.46 mmol), and Pd(dppf)Cl2 (158 mg, 0.215 mmol) were added, and the mixture was heated in a sealed tube under N2 at 80°C for 16 hours. The mixture was diluted with water (40 mL), extracted with siRNA (2 × 40 mL), and the combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient: 0 to 20% siRNA in petroleum ether) to obtain methyl 3-amino-6-methylpyrazine-2-carboxylate (230 mg, 64%) as a yellow solid. LCMS: m / z = 168.20 [M + H] + ; 1 ¹H NMR (400 MHz, chloroform-d) δ 8.11 (s, 1H), 3.98 (s, 3H), 2.48 (s, 3H).

[0734] Step 2: To a solution of methyl 3-amino-6-methylpyrazine-2-carboxylate (100 mg, 0.598 mmol) in AcOH (3 mL) at 5°C, 48% HBr (0.5 mL) and potassium nitrite (153 mg, 1.79 mmol) were added, and the mixture was stirred at 5°C for 1 hour. The mixture was diluted with saturated aqueous NaHCO3 (10 mL), extracted with ethyl phosphate (2 × 20 mL), and the combined organic layers were washed with saturated NaHCO3 solution (20 mL) and brine (10 mL). The mixture was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (50% ethyl phosphate in petroleum ether) to obtain methyl 3-bromo-6-methylpyrazine-2-carboxylate (30 mg, 22%) as a colorless oil. LCMS: m / z = 231.10 [M + H] + ; 1 ¹H NMR (400 MHz, chloroform-d) δ 8.34 (s, 1H), 4.02 (s, 3H), 2.59 (s, 3H).

[0735] Steps 3-6 were completed starting from methyl 3-bromo-6-methylpyrazine-2-carboxylate, as described in steps 1-3 and 6 for intermediate 50: 5-(difluoromethyl)-3-methoxypyrazine-2-carboxylic acid, to obtain 3-(difluoromethyl)-6-methylpyrazine-2-carboxylic acid. LCMS: m / z = 187 [MH] - . 1 H NMR (400MHz, DMSO-d6) δ 8.46 (s, 1H), 7.50 (t, J=54.8Hz, 1H), 2.51 (s, 3H).

[0736] Intermediate 60: 3-(difluoromethyl)-6-methoxypyrazine-2-carboxylic acid Step 1: To a solution of methyl 6-chloro-3-methylpyrazine-2-carboxylate (1.75 g, 9.38 mmol) in MeOH (40 mL), NaOMe (10.1 g, 30 wt% 56.3 mmol) was added, and the mixture was heated at 70°C for 2 hours. The mixture was allowed to cool to room temperature, diluted with DCM (60 mL), washed with water (60 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl 6-methoxy-3-methylpyrazine-2-carboxylate (1.24 g, 72%) as a yellow solid. LCMS: m / z = 183 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.41 (s, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 2.60 (s, 3H).

[0737] Step 2: To a solution of methyl 6-methoxy-3-methylpyrazine-2-carboxylate (1.2 g, 6.6 mmol) in CCl4 (20 mL), NBS (5.9 g, 33 mmol) and AIBN (0.11 g, 0.66 mmol) were added, and the mixture was heated overnight at 80°C. The mixture was diluted with saturated sodium thiosulfate aqueous solution (50 mL) and water (50 mL), extracted with DCM (100 mL), washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / Depositphotos = 35 / 1, volume / volume) to obtain methyl 3-(dibromomethyl)-6-methoxypyrazine-2-carboxylate (1.8 g, 80%) as a grayish-white solid. LCMS: m / z = 339 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.67 (s, 1H), 7.69 (s, 1H), 3.98 (s, 3H), 3.94 (s, 3H).

[0738] Step 3: To a solution of methyl 3-(dibromomethyl)-6-methoxypyrazine-2-carboxylate (400 mg, 1.18 mmol) in EtOH (12 mL) and water (1.2 mL), silver nitrate (600 mg, 3.53 mmol) was added, and the mixture was heated overnight at 50°C. The mixture was diluted with water (50 mL), extracted with DCM (50 mL), the organic phase was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / Â=2 / 1, volume / volume) to obtain methyl 3-formyl-6-methoxypyrazine-2-carboxylate (65 mg, 28%) as a grayish-white solid. LCMS: m / z=197[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 10.1 (s, 1H), 8.64 (s, 1H), 4.03 (s, 3H), 3.93 (s, 3H).

[0739] Steps 4 and 5 were completed as described in steps 5 and 6 for intermediate 51: 5-(difluoromethyl)-6-methoxypyrazine-2-carboxylic acid to obtain 3-(difluoromethyl)-6-methoxypyrazine-2-carboxylic acid. LCMS: m / z = 205 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.18 (s, 1H), 7.39 (t, J = 54.8Hz, 1H), 3.92 (s, 3H).

[0740] Intermediate 61: 5-(difluoromethyl)-3,6-dimethylpyrazine-2-carboxylic acid Step 1: To a solution of 3-chloro-2,5-dimethylpyrazine (7.00 g, 49.1 mmol) in MeOH (30 mL), Pd(dppf)Cl2 (1.80 g, 2.45 mmol) and KOAc (9.64 g, 98.2 mmol) were added, and the mixture was heated at 95°C for 16 hours under a CO atmosphere (3 MPa). The mixture was diluted with water (200 mL), extracted with DCM (3 × 150 mL), and the combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / alkyl = 20 / 1, volume / volume) to obtain methyl 3,6-dimethylpyrazine-2-carboxylate (6.75 g, 83%) as a grayish-white solid. LCMS: m / z = 167[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.61 (s, 1H), 3.89 (s, 3H), 2.64 (s, 3H), 2.50 (s, 3H).

[0741] Step 2: To a solution of methyl 3,6-dimethylpyrazine-2-carboxylate (3.00 g, 18.1 mmol) in DCM (20 mL), 3-chlorobenzoperoxoic acid (85 wt%, 7.33 g, 36.1 mmol) was added, and the mixture was heated at 50°C for 16 hours. The mixture was diluted with water (20 mL), extracted with DCM (3 × 10 mL), and the combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 3-(methoxycarbonyl)-2,5-dimethylpyrazine 1-oxide (7.2 g, 40% purity, 88%), which was used directly in the next step without further purification. LCMS: m / z = 183 [M + H] + .

[0742] Step 3: To a solution of 3-(methoxycarbonyl)-2,5-dimethylpyrazine 1-oxide (400 mg, 40% purity, 0.878 mmol) in CCl4 (6 mL), POCl3 (1.21 g, 7.90 mmol) was added, and the mixture was heated at 90°C for 16 hours. The mixture was concentrated under reduced pressure, the residue was diluted with water (20 mL), and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / siRNA = 5 / 1, volume / volume) to obtain methyl 5-chloro-3,6-dimethylpyrazine-2-carboxylate (114 mg, 64%) as a grayish-white solid. LCMS: m / z = 201 [M + H] + ; 1 H NMR (400MHz, DMSO-d6) δ 3.89 (s, 3H), 2.65 (s, 3H), 2.58 (s, 3H).

[0743] Steps 4-7 were completed as described in steps 1-3 and 6 for intermediate 50: 5-(difluoromethyl)-3-methoxypyrazine-2-carboxylic acid to obtain 5-(difluoromethyl)-3,6-dimethylpyrazine-2-carboxylic acid. LCMS: m / z = 203 [M + H] + .

[0744] Intermediate 62: 6-Chloro-5-methoxy-3-methylpyrazine-2-carboxylic acid Step 1: Under a nitrogen atmosphere, 500 mg, 2.68 mmol of methyl 6-chloro-3-methylpyrazine-2-carboxylate was added dropwise to a solution of methyl 6-chloro-3-methylpyrazine-2-carboxylate in 5 mL of dry DCM at 0°C. Urea peroxide (504 mg, 5.36 mmol), followed by anhydrous trifluoroacetic acid (1.01 g, 4.82 mmol). The mixture was stirred at 0°C for 1 hour, then at 25°C for a further 2 hours. The mixture was diluted with water (40 mL), adjusted to pH 7-8 with saturated aqueous NaHCO3 solution, and extracted with DCM (3 × 40 mL). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / alkyl = 10 / 1, volume / volume) to obtain 5-chloro-3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (476 mg, 87%) as a grayish-white solid. LCMS: m / z = 203 [M + H] + . 1 ¹H NMR (400 MHz, chloroform-d): δ 8.30 (s, 1H), 4.02 (s, 3H), 2.64 (s, 3H).

[0745] Step 2: To a solution of 5-chloro-3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (300 mg, 1.48 mmol) in toluene (5 mL) at 0°C, POCl3 (568 mg, 3.70 mmol) was added dropwise, followed by the addition of DMF (21.6 mg, 0.296 mmol). The mixture was stirred at 25°C for 1 hour, then heated at 85°C for 20 hours. The mixture was concentrated under reduced pressure, and the residue was diluted with saturated NaHCO3 aqueous solution (30 mL) and extracted with  (2 × 30 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether /  = 5 / 1, volume / volume) to obtain methyl 5,6-dichloro-3-methylpyrazine-2-carboxylate (200 mg, 61%) as a grayish-white solid. LCMS: m / z = 221[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 4.00 (s, 3H), 2.83 (s, 3H).

[0746] Step 3: Under a nitrogen atmosphere, a solution of methyl 5,6-dichloro-3-methylpyrazine-2-carboxylate (170 mg, 0.769 mmol) in MeOH (8 mL) at 0°C was mixed with K2CO3 (128 mg, 0.923 mmol) in fractional amounts, and the mixture was stirred at 0°C for 0.5 hours. The mixture was diluted with water (20 mL), extracted with siRNA (2 × 20 mL), and the combined organic layers were washed with water (20 mL) and brine (20 mL). The mixture was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl 6-chloro-5-methoxy-3-methylpyrazine-2-carboxylate (140 mg, 84%) as a grayish-white solid. LCMS: m / z = 217 [M + H] + ; 1 ¹H NMR (400 MHz, chloroform-d) δ 4.10 (s, 3H), 3.96 (s, 3H), 2.78 (s, 3H).

[0747] Step 4: To a solution of methyl 6-chloro-5-methoxy-3-methylpyrazine-2-carboxylate (30 mg, 0.14 mmol) in THF (2 mL), a solution of NaOH (17 mg, 0.42 mmol) in water (2 mL) was added. The mixture was stirred at 25°C for 3 hours, then concentrated under reduced pressure to obtain 6-chloro-5-methoxy-3-methylpyrazine-2-carboxylic acid (30 mg, sodium salt) as a grayish-white solid. LCMS: m / z = 201 [MH] - . 1 H NMR (400MHz, DMSO-d6) δ 3.93 (s, 3H), 2.48 (s, 3H).

[0748] Intermediate 63: 5-Chloro-6-methoxy-3-methylpyrazine-2-carboxylic acid Step 1: Sodium methanolate (4.05 g, 22.5 mmol) was added to a solution of methyl 6-chloro-3-methylpyrazine-2-carboxylate (700 mg, 3.75 mmol) in MeOH (20 mL), and the mixture was heated at 70°C for 3 hours. After cooling to room temperature, the mixture was diluted with water (15 mL), extracted with DCM (3 × 15 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain methyl 6-methoxy-3-methylpyrazine-2-carboxylate (461 mg, 64%) as a pale pink solid. LCMS: m / z = 183 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.42 (s, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 2.60 (s, 3H).

[0749] Steps 2-4 were completed as described in steps 1, 2, and 4 of intermediate 62:6-chloro-5-methoxy-3-methylpyrazine-2-carboxylic acid, respectively, to obtain 5-chloro-6-methoxy-3-methylpyrazine-2-carboxylic acid. LCMS: m / z = 203 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 3.89 (s, 3H), 2.35 (s, 3H).

[0750] Intermediate 64: 5-Chloro-3,6-dimethylpyrazine-2-carboxylic acid Step 1: To a solution of methyl 6-chloro-3-methylpyrazine-2-carboxylate (500 mg, 2.68 mmol) in DME (10 mL), K2CO3 (370 mg, 2.68 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivolinan (1.35 g, 10.7 mmol), and Pd(dppf)Cl2 (196 mg, 0.268 mmol) were added. The mixture was heated in a sealed tube under N2 at 80°C for 16 hours. The mixture was diluted with water (20 mL), extracted with DCM (3 × 30 mL), and the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / alkyl group = 5 / 1 to 3 / 1, volume / volume) to obtain methyl 3,6-dimethylpyrazine-2-carboxylate (380 mg, 86%) as a white solid. LCMS: m / z = 167 [M + H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 8.49 (s, 1H), 4.00 (s, 3H), 2.79 (s, 3H), 2.61 (s, 3H).

[0751] Steps 2-4 were completed as described in steps 1, 2, and 4 of intermediate 62:6-chloro-5-methoxy-3-methylpyrazine-2-carboxylic acid, respectively, to obtain 5-chloro-3,6-dimethylpyrazine-2-carboxylic acid. LCMS: m / z = 187 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 2.45(s,3H),2.42(s,3H).

[0752] Intermediate 65: 3-chloro-5-(difluoromethyl)-4,6-dimethylpicolinic acid Step 1: To a solution of 3-amino-5-bromopicolinic acid (10.0 g, 46.1 mmol) and methyl iodide (13.1 g, 92.2 mmol) in DMF (100 mL), K2CO3 (12.7 g, 92.2 mmol) was added, and the mixture was stirred under N2 at 25°C for 16 hours. The mixture was diluted with water (500 mL), extracted with siRNA (5 × 300 mL), and the combined organic layers were washed with brine (5 × 200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl 3-amino-5-bromopicolinic acid (10.2 g, 96%) as a yellow solid. LCMS: m / z = 231 [M + H] + ; 1 H NMR (400MHz, DMSO-d6) δ 7.88 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 6.84 (s, 2H), 3.80 (s, 3H).

[0753] Step 2: To a solution of methyl 3-amino-5-bromopicolinate (10.2 g, 44.1 mmol), potassium trifluoro(vinyl)borate (11.8 g, 88.3 mmol), and K2CO3 (18.3 g, 3 equivalents, 132 mmol) in toluene / EtOH (1 / 2, 120 mL), Pd(PPh3)4 (5.10 g, 4.41 mmol) was added, and the mixture was heated at 130 °C for 0.5 hours under microwave irradiation. The mixture was diluted with water (500 mL), extracted with DCM (10 × 200 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / acetate = 10 / 1 to 3 / 1, volume / volume) to obtain methyl 3-amino-5-vinylpicolinate (4.00 g, 56%) as a yellow solid. LCMS: m / z = 179 [M + H] + . 1H NMR(400MHz,DMSO-d6)δ 7.99(d,J=1.8Hz,1H),7.23(d,J=1.8Hz,1H),6.75~6.63(m,3H),5.95(d,J=17.6Hz,1H),5.47(d,J=11.0Hz,1H),3.80(s,3H).

[0754] Step 3: To a solution of methyl 3-amino-5-vinylpicolinate (3.80 g, 21.3 mmol) and di-tert-butyl dicarbonate (18.6 g, 85.3 mmol) in DCM (40 mL), DMAP (261 mg, 2.13 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (100 mL), extracted with DCM (5 × 80 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / Depositphotos = 10 / 1 to 3 / 1, volume / volume) to obtain methyl 3-(bis(tert-butoxycarbonyl)amino)-5-vinylpicolinate (5.79 g, 72%) as a grayish-white solid. LCMS: m / z = 379 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.71(d,J=1.8Hz,1H),8.08(d,J=1.8Hz,1H),6.85(dd,J=17.6,11.0Hz,1H) ,6.20(d,J=17.6Hz,1H),5.58(d,J=11.0Hz,1H),3.82(s,3H),1.33(s,18H).

[0755] Step 4: To a solution of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-vinylpicolinate (5.79 g, 15.3 mmol) and methylmorpholine 4-oxide hydrate (2.07 g, 15.3 mmol) in THF / water (4 / 1, 2.5 mL), osmium tetraoxide (389 mg, 1.53 mmol) was added, and the mixture was stirred at 25°C for 2 hours. Sodium periodate (13.1 g, 61.2 mmol) was added, and stirring continued at 25°C for 1 hour. The mixture was diluted with water (10 mL), extracted with DCM (5 × 10 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 50 / 1, volume / volume) to obtain methyl 3-(bis(tert-butoxycarbonyl)amino)-5-formylpicolinate (2.3 g, 40%) as a yellow solid. LCMS: m / z = 381 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.2(s,1H),9.11(d,J=1.8Hz,1H),8.36(d,J=1.8Hz,1H),3.87(s,3H),1.33(s,18H).

[0756] Step 5: To a solution of 3-(bis(tert-butoxycarbonyl)amino)-5-formylpicolinate methyl (2.31 g, 6.07 mmol) in DCM (40 mL) under N2 at -78°C, DAST (3.92 g, 24.3 mmol) was added, and the mixture was stirred at -78°C for 4 hours, then at 25°C for a further 16 hours. The mixture was diluted with saturated NaHCO3 aqueous solution (50 mL) and water (100 mL), extracted with DCM (6 × 50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 3-(bis(tert-butoxycarbonyl)amino)-5-(difluoromethyl)picolinate methyl (2.6 g) as a yellow solid, which was directly incorporated into the next step. 1 H NMR (400MHz, DMSO-d6) δ 8.85 (s, 1H), 8.21 (s, 1H), 7.25 (t, J = 54.8Hz, 1H), 3.86 (s, 3H), 1.33 (s, 18H).

[0757] Step 6: A mixture of 3-(bis(tert-butoxycarbonyl)amino)-5-(difluoromethyl)picolinate (2.6 g) and a 4 M HCl-MeOH solution (30 mL) was stirred at 25°C for 1 hour. The mixture was adjusted to pH 7-8 with saturated NaHCO3 aqueous solution, diluted with water (100 mL), and extracted with DCM (8 × 60 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / alkyl = 10 / 1 to 3 / 1, volume / volume) to obtain 3-amino-5-(difluoromethyl)picolinate (1.00 g, 82% over two steps) as a yellow solid. LCMS: m / z = 203 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.98 (s, 1H), 7.40 (s, 1H), 7.09 (t, J = 55.2Hz, 1H), 6.90 (s, 2H), 3.83 (s, 3H).

[0758] Step 7: To a solution of methyl 3-amino-5-(difluoromethyl)picolinate (700 mg, 3.46 mmol) and N-chlorosuccinimide (462 mg, 3.46 mmol) in DMF (10 mL), acetic acid (208 mg, 3.46 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (20 mL), extracted with ethyl acetate (6 × 25 mL), and the combined organic layers were washed with brine (4 × 20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1 to 15 / 1, volume / volume) and preparative TLC (petroleum ether / ethyl acetate = 3 / 1, volume / volume) to obtain methyl 3-amino-4,6-dichloro-5-(difluoromethyl)picolinate (200 mg, 21%) as a grayish-white solid. LCMS: m / z = 271 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.41 (t, J = 51.8 Hz, 1H), 7.21 (s, 2H), 3.88 (s, 3H).

[0759] Step 8: To a solution of methyl 3-amino-4,6-dichloro-5-(difluoromethyl)picolinate (200 mg, 0.738 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivolinan (278 mg, 2.21 mmol), and K2CO3 (306 mg, 2.21 mmol) in DME (5 mL), Pd(dppf)Cl2 (54.0 mg, 0.074 mmol) was added, and the mixture was heated under N2 at 90°C for 16 hours. The mixture was diluted with water (10 mL), extracted with ethyl acetate (5 × 15 mL), and the combined organic layers were washed with brine (3 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / alkyl = 3 / 1, volume / volume) to obtain methyl 3-amino-5-(difluoromethyl)-4,6-dimethylpicolinate (130 mg, 77%) as a brown solid. LCMS: m / z = 231 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.33 (t, J = 53.0 Hz, 1H), 6.58 (s, 2H), 3.83 (s, 3H), 2.46 (s, 3H), 2.25 (s, 3H).

[0760] Step 9: To a solution of methyl 3-amino-5-(difluoromethyl)-4,6-dimethylpicolinate (50 mg, 0.22 mmol) and copper(II) chloride (35 mg, 0.26 mmol) in MeCN (3 mL) at 0 °C, isoamyl nitrite (51 mg, 0.43 mmol) was added, and the mixture was heated at 60 °C for 16 hours. The mixture was diluted with water (15 mL), extracted with DCM (10 mL x 5), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / Ã=5 / 1, volume / volume) to obtain methyl 3-chloro-5-(difluoromethyl)-4,6-dimethylpicolinate (35 mg, 64%) as a colorless oil. LCMS: m / z = 250 [M + H] + . 1H NMR (400MHz, DMSO-d6) δ 7.43 (t, J = 52.4 Hz, 1H), 3.92 (s, 3H), 2.62 (s, 3H), 2.54 (s, 3H).

[0761] Step 10: LiOH (9.5 mg, 0.40 mmol) was added to a solution of methyl 3-chloro-5-(difluoromethyl)-4,6-dimethylpicolinate (33 mg, 0.13 mmol) in THF (2 mL) and water (1 mL). The mixture was stirred at 25°C for 1.5 hours, then concentrated under reduced pressure to obtain 3-chloro-5-(difluoromethyl)-4,6-dimethylpicolinate (35 mg, Li salt) as a white solid. LCMS: m / z = 236 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.29 (t, J = 53.0 Hz, 1H), 2.49 (s, 3H), 2.42 (s, 3H).

[0762] Intermediate 66: 3,6-dimethyl-5-(trifluoromethyl)pyrazine-2-carboxylic acid Step 1: To a solution of methyl 3,6-dimethylpyrazine-2-carboxylate (100 mg, 0.602 mmol) in MeCN (3 mL), bis(trifluoroacetoxy)iodopentafluorobenzene (782 mg, 1.50 mmol) and tris(2,2'-bipyridine)ruthenium bis(hexafluorophosphate) (10.3 mg, 0.012 mmol) were added. The mixture was stirred and irradiated under 450 nm blue LED light at 35°C for 12 hours under an N2 atmosphere. The mixture was diluted with water (30 mL), extracted with siRNA (3 × 20 mL), and the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / alkyl = 5 / 1, volume / volume) to obtain methyl 3,6-dimethyl-5-(trifluoromethyl)pyrazine-2-carboxylate (85 mg, 60%) as a grayish-white solid. LCMS: m / z = 235 [M + H] + . 1H NMR (400MHz, DMSO-d6) δ 3.94 (s, 3H), 2.71 (s, 3H), 2.67 (s, 3H).

[0763] Step 2: To a solution of methyl 3,6-dimethyl-5-(trifluoromethyl)pyrazine-2-carboxylate (40 mg, 0.17 mmol) in THF (2 mL), LiOH (8.2 mg, 0.34 mmol), EtOH (1 mL), and water (...

Claims

1. Compounds of the following formula (I): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein the formula, X １ is CH, S, or N, X ２ is N, S, or O, R １ and R ２ together with the atoms to which they are attached form a C ５ -C １０ cycloalkyl or 5- to 10-membered heterocycloalkyl, and the C ５ -C １０ cycloalkyl or 5- to 10-membered heterocycloalkyl may be substituted with one or more R ａ and may be Each R ａ These are independently oxo, halo, cyano, -OR ａ１ , -N(R ａ１ ) ２ , -C(O)R ａ１ , -C(O)N(R ａ１ ) ２ , -C(O)OR ａ１ , -S(O) ２ N(R) ａ１ ) ２ , -S(O) ２ (R ａ１ ), C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ The C is an aryl, a 5-10 member heteroaryl, or a 3-10 member heterocycloalkyl. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocycloalkyl, one or more R ａ１ It may also be replaced with Each R ａ１ These are independently H, oxo, halo, cyano, -OH, and -NH. ２ , -C(O)(C １ -C ６ Alkyl), -C(O)(C ３ -C １０ Cycloalkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６ -C １０ The aryl or 5-10 member heteroaryl is the -C(O)(C ３ -C １０ Cycloalkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６ -C １０ Aryl, or 5- to 10-membered heteroaryl, contains one or more R ａ２ It may also be replaced with Each R ａ２ is independently oxo, halo, cyano, -OH, -NH ２ , -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl), ２ C １ -C ６ alkyl optionally substituted with C １ -C ６ alkyl, C ３ -C １０ cycloalkyl, C １ -C ６ haloalkoxy, C １ -C ６ haloalkyl, C １ -C ６ alkoxy, optionally substituted with oxo, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, R ３ C ６ -C １０ The C is an aryl or a 5-10 member heteroaryl, ６ -C １０ Aryl or 5-10 membered heteroaryls include one or more R ３ａ It has been replaced with, Each R ３ａ These are independently: halo, cyano, -OH, -NH ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C ３ -C １０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６ -C １０ The C is an aryl or a 5- to 10-membered heteroaryl, and １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C ３ -C １０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６ -C １０ Aryl, or 5- to 10-membered heteroaryl, contains one or more R ３ａ１ It may be replaced with, and Each R ３ａ１ These are independently oxo, halo, cyano, -OH, -C(O)(C １ -C ６ Alkyl), -C(O)(O-(C １ -C ６ Alkyl)), C ３ -C １０ C may be substituted with a cycloalkyl group. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, C １ -C ６ Alkoxy, -O(C) １ -C ６ Haloalkyl), C ３ -C １０ Cycloalkyl, C ６ -C １０ It is an aryl or a 5- to 10-membered heteroaryl. The aforementioned compound, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

2. Compounds of the following formula (I): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein the formula, X １ is CH, S, or N, X ２ is N, S, or O, R １ and R ２ Together with the atoms they bond to, C ５ -C １０ Forming a cycloalkyl or 5-10 member heterocycloalkyl, the C ５ -C １０ Cycloalkyl or 5-10 member heterocycloalkyl groups include one or more R ａ It may also be replaced with Each R ａ These are independently oxo, halo, cyano, -OR ａ１ , -N(R ａ１ ) ２ , -C(O)R ａ１ , -C(O)N(R ａ１ ) ２ , -C(O)OR ａ１ , -S(O) ２ N(R) ａ１ ) ２ , -S(O) ２ (R ａ１ ), C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ The C is an aryl, a 5-10 member heteroaryl, or a 3-10 member heterocycloalkyl. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocycloalkyl, one or more R ａ１ It may also be replaced with Each R ａ１ These are independently H, oxo, halo, cyano, -OH, and -NH. ２ , -C(O)(C １ -C ６ Alkyl), C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６ -C １０ The C is an aryl or a 5- to 10-membered heteroaryl, and １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６ -C １０ Aryl, or 5- to 10-membered heteroaryl, contains one or more R ａ２ It may also be replaced with Each R ａ２ These are independently oxo, halo, cyano, -OH, and -NH. ２ , C １ -C ６ C may be substituted with an alkoxy group. １ -C ６ Alkyl, C １ -C ６ A 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl that may be substituted with a haloalkoxy or oxo. R ３ C ６ -C １０ The C is an aryl or a 5-10 member heteroaryl, ６ -C １０ Aryl or 5-10 membered heteroaryls include one or more R ３ａ It has been replaced with, Each R ３ａ These are independently: halo, cyano, -OH, -NH ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C ３ -C １０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６ -C １０ The C is an aryl or a 5- to 10-membered heteroaryl, and １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C ３ -C １０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６ -C １０ Aryl, or 5- to 10-membered heteroaryl, contains one or more R ３ａ１ It may be replaced with, and Each R ３ａ１ These are independently oxo, halo, cyano, -OH, -C(O)(C １ -C ６ Alkyl), -C(O)(O-(C １ -C ６ Alkyl)), C ３ -C １０ C may be substituted with a cycloalkyl group. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, C １ -C ６ Alkoxy, -O(C) １ -C ６ Haloalkyl), C ３ -C １０ Cycloalkyl, C ６ -C １０ It is an aryl or a 5- to 10-membered heteroaryl. The aforementioned compound, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

3. X １ is S or N, X ２ is N or S, R １ and R ２ Together with the atoms they bond to, C ５ -C ６ Forming a cycloalkyl or 5-6 member heterocycloalkyl, the C ５ -C ６ Cycloalkyl or 5-6 member heterocycloalkyl groups include one or more R ａ It may also be replaced with Each R ａ These are independently oxo, -OR ａ１ , -N(R ａ１ ) ２ , -C(O)R ａ１ , -C(O)N(R ａ１ ) ２ , -C(O)OR ａ１ , -S(O) ２ N(R) ａ１ ) ２ , -S(O) ２ (R ａ１ ), C １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ The C is an aryl, a 5-10 member heteroaryl, or a 3-10 member heterocycloalkyl. １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ Aryl, 5-10 membered heteroaryl, or 3-10 membered heterocycloalkyl, one or more R ａ１ It may also be replaced with Each R ａ１ These are independently H, halo, cyano, -C(O)(C １ -C ６ Alkyl), -C(O)(C ３ -C １０ Cycloalkyl), C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C １０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６ -C １０ The aryl or 5-10 membered heteroaryl is the -C(O)(C ３ -C １０ Cycloalkyl), C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C １０ Cycloalkyl, 3-10 member heterocycloalkyl, C ６ -C １０ Aryl, or 5- to 10-membered heteroaryl, contains one or more R ａ２ It may also be replaced with Each R ａ２ These are independently oxo, cyano, -OH, -N(C) １ -C ６ Alkyl) ２ , C １ -C ６ C may be substituted with an alkoxy or -OH group. １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, C １ -C ６ Haloalkoxy, C １ -C ６ Haloalkyl, C １ -C ６ A 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl, which may be substituted with alkoxy or oxo. R ３ is one R ３ａ It is a 5-10 member heteroaryl substituted with, R ３ａ is one or more R ３ａ１ C may be replaced with ６ -C １０ It is aryl, and Each R ３ａ１ These are independently cyano or C １ -C ６ It is an alkoxy. The compound according to claim 1 or claim 2.

4. R １ and R ２ Together with the atoms to which they are bonded, they form a five-membered heterocycloalkyl or C ６ The compound according to claim 1 or claim 2, which forms a cycloalkyl group.

5. Each R ａ They are independent, The compound according to any one of the prior claims.

6. Each R ａ１ These are independently H, -OH, and -CH ３ , The compound according to any one of the prior claims.

7. Each R ａ２ These are independently oxo, -CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ , -Cl, -F, -CN, -CHF ２ , -OCH ３ , -CF ３ , -OCHF ２ -OH, -CH ２ CHF ２ ien-CH ２ CF ３ ien-CH ２ OH, -CH ２ OCH ３ , -OCF ３ , -N(CH ３ ) ２ , -OCH(CH ３ ) ２ , The compound according to any one of the prior claims.

8. R ３ teeth, The compound according to any one of the prior claims.

9. R ３ａ is, -CH ３ cyclopropyl, The compound according to any one of the prior claims.

10. Each R ３ａ１ These are independently oxo, methyl, and -CF ２ H, cyano, -F, -Cl, -OH, -OCF ２ H, or -OCH ３ The compound according to any one of the prior claims.

11. The compound of the following formula (I-A): The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

12. Compounds of the following formulas (I-B), (I-C), (I-D), or (I-E): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is 0 to 6, n is 0 to 8, and p is 0 to 6, according to any one of claims 1 to 4.

13. Compounds of the following formulas (I-F) or (I-Fa): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein p is 0 to 4, the compound according to any one of claims 1 to 4.

14. Compounds of the following formulas: (I-Fb), (I-Fb'), (I-Fc), (I-Fc'), (I-Fd), or (I-Fd'): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein p is 0 to 4 and q is 0 to 4, the compound according to any one of claims 1 to 4.

15. Compounds of the following formulas: (I-G), (I-Ga), or (I-Ga'): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein q is 1 to 4, the compound according to any one of claims 1 to 4.

16. Compounds according to any one of the prior claims, selected from compound numbers 7, 9, 10, 15, 18, 379, 387, 389, 400, 404, 415, 425, 450, 508, 548, 584, 585, 586, 592, 594, 2, 5, 14, 49, 146, 652, 653, 655, 691, 793, 820, 828, 908, 922, 951, 952, 964, 980, 987, 990, 996, 1003, 1005, 1010, 1013, 1014, 1016, 1019, 1023, 1029, 1032, 1039, 1041, and 1046, or pharmaceutically acceptable salts thereof.

17. A compound according to any one of the prior claims, selected from the compounds listed in Table 1, Table 2, or Table 3, or pharmaceutically acceptable salts thereof.

18. Compounds that can be obtained or obtained by the methods described herein, Optionally, the method includes one or more steps described in schemes 1 to 7. The aforementioned compound.

19. A pharmaceutical composition comprising a compound according to any one of the prior claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

20. The pharmaceutical composition according to claim 18, wherein the compound is selected from the compounds listed in Table 1, Table 2, or Table 3.

21. A method for regulating DNA polymerase Θ activity, comprising contacting a cell with a compound described in any one of the prior claims.

22. A method for treating or preventing a disease or disorder in a subject in need, comprising administering to the subject a compound according to any one of claims 1 to 18 or a pharmaceutical composition according to claim 19 or claim 20.

23. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19 or 20, for use in regulating DNA polymerase Θ activity.

24. A compound according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19 or claim 20, for use in the treatment or prevention of a disease or disorder.

25. Use of a compound according to any one of claims 1 to 18 in the manufacture of a pharmaceutical product for regulating DNA polymerase Θ activity.

26. Use of a compound according to any one of claims 1 to 18 in the manufacture of a pharmaceutical product for treating or preventing a disease or disorder.

27. The disease or disorder is related to the DNA polymerase Θ activity involved, according to any one of claims 21 to 26, by the method, compound, pharmaceutical composition, or use.

28. The disease or disorder is cancer, according to any one of claims 21 to 27, a method, compound, pharmaceutical composition, or use.

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