Biaryl derivatives and related uses

Abstract

This disclosure relates to compounds of formula (I), and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods of preparation thereof. The compounds disclosed herein can be used to regulate DNA polymerase Q activity and can be used to treat conditions involving DNA polymerase Q activity, such as cancer.

Description

[0001] Related applications

[0002] This application claims priority and benefit to U.S. Provisional Application No. 63 / 457,293, filed April 5, 2023, and U.S. Provisional Application No. 63 / 539,045, filed September 18, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0003] This disclosure relates to small molecule antagonists of DNA polymerase Θ, which are designed for the treatment of cancer.

[0004] Proper repair of DNA double-strand breaks (DSBs) is crucial for maintaining genome integrity. Inaccurate DSB repair can lead to mutations in critical coding or regulatory regions, and the accumulation of unrepaired DNA damage introduces mitotic stress, which can result in genomic alterations or cell death. In normal cells, DSBs are primarily repaired through two key mechanisms. DNA abnormalities occurring during DNA replication (S phase) are typically repaired via homologous recombination (HR), which uses the replicating “sister chromatids” as templates for error-free repair. In contrast, when no DNA template is available for templated repair, non-homologous end-joining (NHEJ) is the primary repair process for DSBs. A third DSB repair pathway, known as alternative end-joining (Alt-EJ), microhomologous end-joining (MMEJ), or Θ-mediated end-joining (TMEJ), is performed by polymerase-Θ (POLΘ). Compared to NHEJ and HR, TMEJ is considered to play a limited role in healthy cells under normal conditions.

[0005] Some tumors carry inactivating mutations in homologous repair genes, most commonly resulting in the loss of function of BRCA1 or BRCA2. Therefore, these tumors are inherently sensitive to DNA damaging agents and inhibitors of specific DNA repair proteins. Consequently, DNA cross-linking agents (such as platinum-based chemotherapy) are more effective in BRCA-mutant tumors than in tumors with intact BRCA function. Similarly, small molecule inhibitors of PARP1 / 2 are effective in BRCA1 / 2-deficient tumors that rely on PARP enzymes to repair single-strand DNA breaks and prevent their conversion into toxic DSBs, which suppress the repair capacity of HR-deficient cells.

[0006] An alternative approach to therapeutically targeting HR-deficient tumors is through the inhibition of alternative repair pathways, such as POLΘ-mediated TMEJ. Consistent with its role as a backup DNA repair enzyme, ablation of the POLΘ locus is well-tolerated in mouse models, evoking only a mild phenotype characterized by micronuclei in reticulocytes and increased cellular (rather than organismal) sensitivity to DNA cross-linking agents. In contrast, POLΘ DNA repair activity has been shown to be crucial for cell survival in the event of NHEJ or HR inactivation, suggesting that POLΘ is a potential target for cancer therapy in specific mutant contexts.

[0007] The unique POLΘ in the human genome contains both an N-terminal SF2 DNA helicase domain and a C-terminal DNA polymerase domain. In the context of chromosomal DSB, these domains work synergistically to repair DSB containing long 3'-single-stranded DNA overhangs. Specifically, the helicase domain is thought to strip the RPA protein complex from the overhang and facilitate annealing to the opposing DNA end via DNA microhomological regions. The annealed DNA then acts as a primer for the POLΘ polymerase domain, which causes the annealed DNA to extend to fill vacancies in the single-stranded DNA. Given the crucial role of POLΘ catalytic activity in DNA repair processes in HR-deficient tumors, POLΘ represents an attractive target for developing chemical inhibitors to utilize this newly discovered function-dependent mechanism.

[0008] This disclosure stems from the need to provide compounds with improved therapeutic potential for regulating DNA polymerase Θ activity. Specifically, compounds with improved physicochemical, pharmacological, and / or pharmaceutical properties. Summary of the Invention

[0009] In some respects, this disclosure provides a compound of formula (I):

[0010]

[0011] Or its pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, or tautomers, wherein:

[0012] X 1 For CH, S, or N;

[0013] X 2 For N, S, or O;

[0014] X 3 It can be C or N;

[0015] R 1 and R 2 Together with the atoms it is attached to, it forms C6-C. 10aryl or 5 to 10-membered heteroaryl, wherein the C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. a replace;

[0016] Each R a Independently oxo, halogenated, cyano, -OH, -NH2, -C(O)N(R) b (R) c ), -N(R b )C(O)(R c C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C4-C 10 Cycloalkenyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic alkyl, or 4- to 10-membered heterocyclic alkenyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C4-C 10 Cycloalkenyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic alkyl or 4- to 10-membered heterocyclic alkenyl, optionally separated by one or more R a1 replace;

[0017] Each R b and R c Independently H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 alkyl, or C4-C5 alkyl is a cycloalkyl group. 10 The cycloalkyl or 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more -OH or C1-C6 haloalkyl groups; or

[0018] R b and R c Together with the atoms to which they are attached, they form 3 to 10-membered heterocyclic alkyl groups, wherein the 3 to 10-membered heterocyclic alkyl groups are optionally substituted by one or more -OH, -O (C1-C6 haloalkyl), -O (C1-C6 alkyl), -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl or -N (C1-C6 alkyl)2;

[0019] Each R a1 Independently oxo, halogenated, cyano, -OH, -O (C3-C) 10Cycloalkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -C(O)OH, -C(O)O (C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -O- (C3-C 10 cycloalkyl), C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the 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 groups are optionally surrounded by one or more R groups. a2 replace;

[0020] Each R a2 It can be independently oxo, halogenated, cyano, -OH, or -NH2;

[0021] R 3 For C6-C 10 aryl or 6- to 10-membered heteroaryl, wherein the C6-C 10 aryl or 6- to 10-membered heteroaryl groups are substituted with one or more R groups. 3a replace;

[0022] Each R 3a Independently, it is halogenated, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, -O (C6-C 10 Aryl), C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, -O (C6-C 10 Aryl), C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. 3a1 Replace; and

[0023] Each R 3a1 Independently oxo, halogenated, cyano, -NH2, -NH-C(O)O(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl, wherein the C1-C6 alkyl is optionally separated by one or more C3-C10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O (C1-C6 haloalkyl), C3-C 10 cycloalkyl, C6-C 10 Aryl or 5 to 10 heteroaryl substituents;

[0024] Where R 3a Halogenated and R 1 and R 2 When R forms a 6-membered heteroaryl group with the atoms it is attached to, then a It's not -CF3.

[0025] In some embodiments, X 1 It is CH or N; and R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted pyridine.

[0026] In some embodiments, X 2 It is N or O; and R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted pyridine.

[0027] In some embodiments, when R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then X 1 Not S.

[0028] In some embodiments, when R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then X 2 Not S.

[0029] In some embodiments, when R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then no

[0030] In some embodiments, when R a for When, then R 3 no

[0031] In some embodiments, when R a for When, then R 3 no

[0032] In some embodiments, when R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted pyrazines, and R a For one or more R a1 When the phenyl group is substituted, then R a1 It is not -Cl, -F, -CN, -O(CH3), -O(CF3), -O(CHF2), -CH3 or cyclopropyl.

[0033] In some embodiments, when R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted pyrazines, and R a For one or more R a1 When pyridine is substituted, then R a1 It is not -Cl, -CN, -CF3, -O(CH3), -O(CHF2), cyclopropyl, -C(CH3)2(CN) or -C(CH3)2(OH).

[0034] In some embodiments, when R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a When pyrazine is substituted, then R a no

[0035] In some embodiments, the compound of formula (I) is not 5'-methoxy-2',6-dimethyl-N-(6-(tetrahydrofuran-3-yl)thiazo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide.

[0036] In some aspects, this disclosure provides a compound that can be obtained by or through methods for preparing compounds as described herein (e.g., methods comprising one or more steps described in schemes 1-11).

[0037] In some aspects, this disclosure provides a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0038] In some respects, this disclosure provides intermediates as described herein, which are suitable for use in methods of preparing compounds as described herein (e.g., the intermediates are selected from those described in Examples 1-451).

[0039] In some aspects, this disclosure provides a method for regulating DNA polymerase Θ activity (e.g., in vitro or in vivo), the method comprising contacting cells with an effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0040] In some aspects, this disclosure provides a method for treating or preventing a disease or condition disclosed herein in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[0041] In some aspects, this disclosure provides a method for treating a subject with a disease or condition disclosed herein, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[0042] In some aspects, this disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt thereof for regulating DNA polymerase Θ activity (e.g., in vitro or in vivo).

[0043] In some respects, this disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt thereof for the treatment or prevention of the diseases or conditions disclosed herein.

[0044] In some respects, this disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt thereof for treating the diseases or conditions disclosed herein.

[0045] In some respects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof for the preparation of medicaments for regulating DNA polymerase Θ activity (e.g., in vitro or in vivo).

[0046] In some respects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof for the preparation of medicaments for the treatment or prevention of the diseases or conditions disclosed herein.

[0047] In some aspects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating the diseases or conditions disclosed herein. In some aspects, regulation is inhibition.

[0048] In some aspects, this disclosure provides a method for preparing the compounds of this disclosure.

[0049] In some aspects, this disclosure provides a method for preparing a compound, the method comprising one or more steps described herein.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In this specification, the singular form includes the plural unless the context clearly requires otherwise. Although methods and materials similar to or equivalent to those described and used herein may be used to practice or test this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference. References cited herein are not considered prior art to the claimed invention. In case of conflict, this specification, including the definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be restrictive. In case of conflict between the chemical structures and names of compounds disclosed herein, the chemical structures shall prevail.

[0051] Other features and advantages of this disclosure will become apparent from the following detailed description and claims. Detailed Implementation

[0052] This disclosure relates to biaryl derivatives, their prodrugs, and pharmaceutically acceptable salts that can modulate DNA polymerase Θ activity and are therefore used in methods of treating humans or animals. This disclosure also relates to methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and their use in treating conditions involving DNA polymerase Θ, such as cancer.

[0053] definition

[0054] Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below.

[0055] It is not intended to be limited by this description; rather, it should be understood that while various options for the variables are described herein, this disclosure is intended to cover operable embodiments having combinations of options. This disclosure can be interpreted as excluding embodiments that are inoperable due to certain combinations of options. For example, while variable X is described herein... 1 X 2 X 3 R 1 R 2 R a R b R c R a1 R a2 R 3 R 3a and R3a1 Various options, but this disclosure can be interpreted as excluding those determined by variable X. 1 X 2 X 3 R 1 R 2 R a R b R c R a1 R a2 R 3 R 3a and R 3a1 Certain combinations result in the structure of inoperable compounds.

[0056] As used herein, “alkyl,” “C1, C2, C3, C4, C5, or C6 alkyl,” or “C1-C6 alkyl” is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl includes C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl groups include portions having one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, or n-hexyl. In some embodiments, straight-chain or branched alkyl groups have six or fewer carbon atoms (e.g., C1-C6 for straight-chain and C3-C6 for branched-chain), and in another embodiment, straight-chain or branched alkyl groups have four or fewer carbon atoms.

[0057] As used herein, the term "optionally substituted alkyl" means an unsubstituted alkyl or an alkyl having a specified substituent on one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkylamino carbonyl, dialkylamino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonic acid, hypophosphonic acid, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate ester, alkyl thionyl, sulfonic acid, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moieties.

[0058] As used herein, the term "alkenyl" includes an unsaturated aliphatic group with a similar length and possible substitutions to the alkyl groups described above, but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In some embodiments, straight-chain or branched alkenyl groups have six or fewer carbon atoms in their backbone (e.g., C2-C6 for straight chains and C3-C6 for branched chains). 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.

[0059] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkylamino carbonyl, dialkylamino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonic acid, hypophosphonic acid, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amidin, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate ester, alkyl thionyl, sulfonic acid, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclic, alkylaryl, or aromatic or heteroaromatic moieties.

[0060] As used herein, the term "alkynyl" includes an unsaturated aliphatic group with a similar length and possible substitutions to the alkyl groups described above but containing at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, penynyl, hexynyl, hepynyl, octyynyl, nonynyl, decanynyl) and branched alkynyl groups. In some embodiments, the straight-chain or branched alkynyl group has six or fewer carbon atoms in its main chain (e.g., C2-C6 for straight chains and C3-C6 for branched chains). 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 alkenyl linker" or "C2-C6 alkenyl linker" is intended to include C2, C3, C4, C5, or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, the C2-C6 imeneyl linker is intended to include C2, C3, C4, C5 and C6 imeneyl linkers.

[0061] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkylamino carbonyl, dialkylamino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonic acid, hypophosphonic acid, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate ester, alkyl thionyl, sulfonic acid, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moieties.

[0062] Other optionally substituted portions (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups) include both unsubstituted portions and portions having one or more of the specified substituents. For example, substituted heterocycloalkyl groups include heterocycloalkyl groups 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.

[0063] As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system of saturated or partially unsaturated hydrocarbons having 3 to 30 carbon atoms (e.g., C3-C4). 12 C3-C 10 (Or C3-C8). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl, and adamantyl. In the case of polycyclic cycloalkyl groups, only one ring in the cycloalkyl group needs to be non-aromatic.

[0064] As used herein, the term "heterocyclic alkyl" refers to a saturated or partially unsaturated 3-8 member monocyclic, 7-12 member bicyclic (fused, bridging, or spirocyclic), or 11-14 member tricyclic (fused, bridging, or spirocyclic) system having one or more heteroatoms (such as O, N, S, P, or Se), for example, one or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, unless otherwise specified. Examples of heterocyclic alkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolyl, dioxyl, tetrahydrofuranyl, isoindolyl, indololinyl, imidazoalkyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, ethylene oxide, aziridine, thienyl, thienyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiaranyl, 1,4-diazatyl, 1,4-oxazo, 2-oxa-5-azabicyclo[2]. 2.1] Heptyl, 2,5-diazabicyclo[2.2.1] Heptyl, 2-oxa-6-azaspiro[3.3] Heptyl, 2,6-diazaspiro[3.3] Heptyl, 1,4-dioxa-8-azaspiro[4.5] Decyl, 1,4-dioxaspiro[4.5] Decyl, 1-oxaspiro[4.5] Decyl, 1-azaspiro[4.5] Decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5'-furan] 3,4-b]pyridyl]-yl, 3'H-spiro[cyclohexane-1,1'-furan[3,4-c]pyridyl]-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hex-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]pyridinindyl, 5,6,7 ,8-Tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-aza[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxazaspiro[3.4]octyl, 2-oxazaspiro[3.4]oct-6-yl, 5,6-dihydro-4H-cyclopenten[b]thiophene, etc. In the case of polycyclic heterocyclic alkyl groups, only one of the rings in the heterocyclic alkyl group needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0065] It should be understood that when a variable has two connectors attached to the remainder of the compound's formula, these two connectors may be located at the same or different atoms of the variable. For example, when a variable (e.g., variable X) is a cycloalkyl or heterocycloalkyl group and has two connectors attached to the remainder of the compound's formula, these two connectors may be located at the same or different atoms of the cycloalkyl or heterocycloalkyl group.

[0066] As used herein, the term "aryl" includes aromatic groups, including "conjugated" or polycyclic systems having one or more aromatic rings, and which do not contain any heteroatoms in the ring structure. The term aryl includes both monovalent and divalent substances. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, etc.

[0067] As used herein, the term "heteroaryl" is intended to include stable 5-, 6-, or 7-membered monocyclic aromatic heterocycles or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocycles consisting of a carbon atom and one or more heteroatoms, for example, one or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example, one, two, three, four, five, or six heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)). p (where p = 1 or 2). It should be noted that the total number of S and O atoms in an aromatic heterocycle is no greater than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetraazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. Heteroaryl groups can also be fused or bridged with non-aromatic alicyclic rings or heterocycles to form polycyclic systems (e.g., 4,5,6,7-tetrahydrobenzo[c]isooxazolyl).

[0068] In addition, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl, such as tricyclic, bicyclic aryl and heteroaryl, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazolium, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthidine, indole, benzofuran, purine, benzofuran, denitrified heteropurine, and indene.

[0069] When the ring is represented by a circle and all ring members are carbon atoms (e.g., When the ring is represented by a circle and contains at least one ring member as a heteroatom (e.g., ...), the ring is an aryl ring. When the ring is a heteroaryl ring, it is a polycyclic aryl or heteroaryl ring. Polycyclic or heteroaryl rings can be represented by two or more circles (e.g., ).

[0070] Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings may be substituted at one or more ring positions (e.g., cyclic carbon or heteroatom, such as N) with such substituents as described above, said substituents being, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic ester, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, amino Carbonyl, alkylthiocarbonyl, phosphate ester, phosphonic acid group, hypophosphonic acid group, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amidinyl, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate ester, alkylthionyl, sulfonic acid group, aminosulfonyl, sulfonamide group, nitro, trifluoromethyl, cyano, azide, heterocyclic group, alkylaryl, or aromatic or heteroaromatic moieties. Aryl and heteroaryl groups can also be fused or bridged with non-aromatic alicyclic rings or heterocycles to form polycyclic systems (e.g., tetrahydronaphthalene, methylenedioxyphenyl, such as benzo[d][1,3]dioxazol-5-yl).

[0071] As used herein, the term "about" refers to a stated quantity, value, or duration ±10% or less. In some embodiments, "about" refers to a stated quantity, value, or duration ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5%. In other embodiments, "about" refers to a stated quantity, value, or duration ±10%, ±8%, ±6%, ±5%, ±4%, or ±2%. In other embodiments, "about" refers to a stated quantity, value, or duration ±5%. In some embodiments, "about" refers to a listed quantity, value, or duration ±2% or ±1%. For example, in some embodiments, when the term "about" is used when describing a temperature or temperature range, these terms refer to a stated temperature or temperature range ±5°C, ±2°C, or ±1°C. In other embodiments, the term "about" refers to a stated temperature or temperature range ±2°C.

[0072] As used herein, the term "substituted" means that any one or more hydrogen atoms on a specified atom are selectively substituted from an indicator group, provided that the substitution does not exceed the normal valence of the specified atom and produces a stable compound. When the substituent is an oxo or ketone (i.e., =O), then two hydrogen atoms on the atom are substituted. Ketone substituents are not present on the aromatic moiety. As used herein, a cyclic double bond 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 that the compound is robust enough to be isolated from the reaction mixture to a useful degree of purity and formulated into an effective therapeutic agent.

[0073] When the bond on a substituent shows a cross bond with two atoms in the linking ring, then such a substituent can bond with any atom in the ring. When a substituent is listed but not specified through which atom it bonds to the rest of the compound in the given formula, such a substituent can bond with any atom in the formula. Combinations of substituents and / or variables are permitted, provided that such combinations produce a stable compound.

[0074] When any variable (e.g., R) appears more than once in any component or formula of a compound, its definition for each occurrence is independent of its definition for each subsequent occurrence. Thus, for example, if a group is shown to be substituted by 0-2 R moieties, then the group may optionally be substituted by at most two R moieties, and R is independently selected from the definition of R each time it appears. Similarly, combinations of substituents and / or variables are permitted, provided that such combinations produce stable compounds.

[0075] As used herein, the term "hydroxyl" or "hydroxyl" includes those having -OH or -O. - . group.

[0076] As used herein, the term “halogenated” or “halogen” refers to fluorine, chlorine, bromine, and iodine.

[0077] The terms “halogenated alkyl” or “halogenated alkoxy” refer to alkyl or alkoxy groups that are substituted with one or more halogen atoms.

[0078] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkylamino carbonyl, dialkylamino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonic acid, hypophosphonic acid, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate ester, alkyl thionyl, sulfonic acid, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moieties.

[0079] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups can be substituted with the following groups: alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkylamino carbonyl, dialkylamino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonic acid, hypophosphonic acid, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate, alkyl thionyl, sulfonic acid, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0080] As used herein, the expressions “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”, “selected from A, B and C”, etc., are used interchangeably and all refer to the group consisting of A, B and / or C, that is, one or more A, one or more B, one or more C or any combination thereof, unless otherwise stated.

[0081] It should be understood that this disclosure provides methods for synthesizing compounds having any of the formulas described herein. This disclosure also provides detailed methods for synthesizing the various disclosed compounds according to the following schemes and the schemes shown in the examples.

[0082] It should be understood that throughout the description, when a composition is described as having, including, or comprising a specific component, it is assumed that the composition is also substantially composed of or consisting of the stated component. Similarly, when a method or process is described as having, including, or comprising specific process steps, the process is also substantially composed of or consisting of the stated processing steps. Furthermore, it should be understood that the order of steps for performing certain actions is irrelevant as long as the invention remains operable. Moreover, two or more steps or actions may be performed simultaneously.

[0083] It should be understood that the synthetic 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 typically provides the desired final compound at or near the end of the process, but in some cases it may be desirable to further convert the compound into its pharmaceutically acceptable salt.

[0084] It should be understood that the compounds disclosed herein can be prepared in various ways using commercially available starting materials, compounds known in the literature or derived from readily prepared intermediates, and by employing standard synthetic methods and procedures known to those skilled in the art or obvious to those proficient in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules, as well as for functional group conversion and manipulation, are available from relevant scientific literature or from standard textbooks in the field. Although not limited to any one or more sources, references are made to classic texts incorporated into this article, such as Smith, MB, March, J., *March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure*, 5th ed., John Willie & Sons, New York, 2001; Greene, TW, Wuts, PGM, *Protective Groups in Organic Synthesis*, 3rd ed., John Willie & 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*. The books *Synthesis*, John Willie & Sons (1994), and *Encyclopedia of Reagents for Organic Synthesis*, edited by L. Paquette, John Willie & Sons (1995), are known and widely accepted reference textbooks on organic synthesis in the art.

[0085] Those skilled in the art will notice that the order of certain steps, such as the introduction and removal of protecting groups, can be altered during the reaction sequence and synthetic scheme described herein. Those skilled in the art will recognize that certain groups may require protection from the effects of reaction conditions by using protecting groups. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups and how to introduce and remove them can be found in Greene, TW, Wuts, PGM, *Protecting Groups in Organic Synthesis*, 3rd Edition, John Wiley & Sons: New York, 1999.

[0086] It should be understood that, unless otherwise stated, any description of a treatment or prevention method includes the use of compounds to provide such treatment or prevention as described herein. It should be further understood that, unless otherwise stated, any description of a treatment or prevention method includes the use of compounds to prepare a medicament for the treatment or prevention of such conditions. Treatment or prevention includes treatment or prevention in humans or non-human animals, including rodents and other disease models.

[0087] It should be understood that, unless otherwise stated, any description of a treatment method includes the use of compounds to provide such treatment as described herein. It should be further understood that, unless otherwise stated, any description of a treatment method includes the use of compounds to prepare a drug for treating such conditions. Treatment includes treatment of humans or non-human animals, including rodents and other disease models.

[0088] As used herein, the term "subject" includes humans and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. A mammal can be, for example, a human or a suitable non-human mammal such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject can also be a bird or poultry. In some embodiments, the subject is a human.

[0089] As used herein, the term "subject in need" means a subject who has a disease or has an increased risk of developing said disease. A subject in need may be a subject who has been previously diagnosed or identified as having a disease or condition disclosed herein. A subject in need may also be a subject who has a disease or condition disclosed herein. Alternatively, a subject in need may be a subject who has an increased risk of developing such a disease or condition relative to the general population (i.e., a subject who is more susceptible to developing such a condition relative to the general population). A subject in need may have a treatment-resistant or drug-resistant disease or condition disclosed herein (i.e., a disease or condition disclosed herein that is unresponsive to treatment or has not yet responded to treatment). A subject may be drug-resistant at the start of treatment or may become drug-resistant during treatment. In some embodiments, a subject in need has received all known effective therapies for the disease or condition disclosed herein but treatment has failed. In some embodiments, a subject in need has received at least one prior therapy.

[0090] As used herein, the term "treating" or "treatment" describes the management and care of a patient in order to combat a disease, symptom, or condition, and includes the administration of compounds of this disclosure or their pharmaceutically acceptable salts, polymorphs, or solvates to alleviate or eliminate symptoms or complications of the disease, symptom, or condition. The term "treatment" may also include treatment in in vitro cell or animal models. It should be understood that references to "treating" or "treatment" include the relief of identified symptoms of a condition. Therefore, “treating” or “treatment” of a state, condition or symptom includes: (1) preventing or delaying the onset of clinical symptoms of a state, condition or symptom that develops in a person who may have or is susceptible to the state, condition or symptom but has not yet experienced or shown clinical or subclinical symptoms of the state, condition or symptom; (2) suppressing the state, condition or symptom, i.e., preventing, reducing or delaying the development of the disease or its recurrence (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms; or (3) alleviating or slowing the disease, i.e. causing the disappearance of at least one of the state, condition or symptom or its clinical or subclinical symptoms.

[0091] It should be understood that the compounds disclosed herein, or their pharmaceutically acceptable salts, polymorphs, or solvates, may or may not be used for the prevention of related diseases, symptoms, or conditions, or for the identification of suitable candidates for such purposes.

[0092] As used herein, the terms “preventing” or “protecting against” describe reducing or eliminating the onset of symptoms or complications of such diseases, conditions, or ailments.

[0093] It should be understood that those skilled in the art may refer to general reference texts to describe in detail the known or equivalent techniques discussed herein. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Willie & Sons (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd ed.), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Willie & Sons, New York; Enna et al., Current Protocols in Pharmacology, John Willie & Sons, New York; and Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th ed. (1990). Of course, these texts may also be referenced when making or using aspects of this disclosure.

[0094] It should be understood that this disclosure also provides pharmaceutical compositions comprising any of the compounds described herein and at least one pharmaceutically acceptable excipient or carrier.

[0095] As used herein, the term "pharmaceutical composition" is a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. Unit dosage form is any of a variety of forms, including, for example, capsules, IV bags, tablets, single pumps or vials on an aerosol inhaler. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salts, hydrates, solvates or isomers) in a unit dose of the composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will understand that it is sometimes necessary to routinely change the dosage according to the patient's age and condition. The dosage will also depend on the route of administration. A variety of routes are considered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, oral, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal application of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalers. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants.

[0096] As used herein, the term “pharmaceutically acceptable” means those compounds, anionic, cationic, materials, compositions, carriers, and / or dosage forms that are suitable for use in human and animal tissues to the extent of correct medical judgment without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0097] As used herein, the term "pharmaceuticalally acceptable excipient" means an excipient that can be used to prepare a pharmaceutical composition which is generally safe and non-toxic and is biologically or otherwise desirable and includes excipients acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "pharmaceuticalally acceptable excipient" includes one or more such excipients.

[0098] It should be understood that the pharmaceutical compositions of this disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous application may include the following components: sterile diluents, such as water for injection, physiological saline, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetate, citrate, or phosphate; and agents for adjusting tension, such as sodium chloride or dextran. pH may be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral formulations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0099] It should be understood that the compounds or pharmaceutical compositions disclosed herein can be administered to subjects using many well-known methods currently used for chemotherapy. For example, the compounds disclosed herein can be injected into the bloodstream or body cavity, taken orally, or applied through the skin as a patch. The selected dose should be sufficient to constitute an effective treatment, but not high enough to cause unacceptable side effects. Preferably, the patient's disease status (e.g., the disease or condition disclosed herein) and health status should be closely monitored during treatment and for a reasonable period after treatment.

[0100] As used herein, the term "therapeutic effective amount" refers to the amount of a drug agent used to treat, improve, and / or prevent an identified disease or symptom, or to exhibit a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, body type, and health status; the nature and severity of the symptom; and the chosen treatment or combination of treatments. The therapeutic effective amount for a given situation can be determined through routine laboratory testing within the skill and judgment of a clinician.

[0101] It should be understood that for any compound, the therapeutically effective amount can initially be estimated, for example, in cell culture assays of tumor cells, or in animal models (typically rats, mice, rabbits, dogs, or pigs). Animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine the dosage and route of administration that are useful for human use. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell cultures or laboratory animals, such as ED. 50 (The effective dose in 50% of the population) and LD 50 (The dose that would be lethal to 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, and it can be expressed as the ratio LD50. 50 / ED50 Pharmaceutical compositions exhibiting a high therapeutic index are preferred. Dosage can vary within this range, depending on the dosage form used, patient sensitivity, and route of administration.

[0102] Adjust the dosage and administration to provide an adequate level of active agent or maintain the desired effect. Factors that may be considered include the severity of the disease state, the subject's general health condition, the subject's age, weight and sex, diet, administration time and frequency, drug combination, sensitivity to response, and tolerance / response to the therapy. Long-acting drug compositions may be administered every 3 to 4 days, weekly, or every two weeks, depending on the half-life and clearance of the specific formulation.

[0103] Pharmaceutical compositions containing the active compounds of this disclosure can be prepared in commonly known ways, such as by conventional mixing, dissolving, granulation, pelleting, grinding, emulsification, encapsulation, embedding, or lyophilization processes. The pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, said carriers containing excipients and / or adjuvants that facilitate the processing of the active compounds into pharmaceutically usable formulations. Of course, suitable formulations depend on the chosen route of administration.

[0104] Suitable pharmaceutical compositions for injectable applications include sterile aqueous solutions (in the water-soluble case) or dispersions, as well as sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, Cremophor EL... TM (BASF, Parsippany, NJ) or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to facilitate injection. It must be stable under preparation and storage conditions and must be protected against contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), cyclodextrins, and suitable mixtures thereof. For example, by using a coating such as lecithin, the desired particle size can be maintained in the dispersed state, and appropriate flowability can be maintained by using surfactants. Microbial action can be prevented by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include isotonic agents, such as sugars, polyols such as mannitol and sorbitol, and sodium chloride in the composition. Extended absorption of injectable compositions can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin, in the composition.

[0105] Sterile injectable solutions can be prepared by incorporating the active compound in the desired amount with one or a combination of the ingredients listed above into a suitable solvent, followed by filtration sterilization if necessary. Typically, dispersions are prepared by incorporating the active compound into a sterile medium containing a basic dispersion medium and other desired ingredients from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, the preparation method involves vacuum drying and freeze-drying of a powder containing the active ingredient plus any other desired ingredients from its previous sterile filtered solution.

[0106] Oral compositions typically include an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be incorporated with excipients and used in tablet, lozenge, capsule, or sachet form. Oral compositions may also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and gargled, then spat out or swallowed. Pharmaceutically compatible binders and / or adjuvants may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, primordial gelatin, or corn starch; lubricants, such as magnesium stearate or strobilurin; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.

[0107] For administration by inhalation, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser or sprayer containing a suitable propellant (e.g., a gas such as carbon dioxide).

[0108] Systemic application can also be performed via mucosal or transdermal routes. For mucosal or transdermal application, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are generally known in the art and include, for example, mucosal agents, detergents, bile salts, and fusidic acid derivatives. Mucosal application can be achieved by using nasal sprays, powders, or suppositories. For transdermal application, the active compound is formulated as an ointment, cream, gel, or lotion as commonly known in the art.

[0109] 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 microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be readily apparent to those skilled in the art. The materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes containing monoclonal antibodies against viral antigens that target infected cells) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0110] Particularly advantageous is the formulation of oral or parenteral compositions in unit dosage form for ease of administration and dosage uniformity. As used herein, unit dosage form refers to a physically discrete unit suitable as a unit dose for a subject to be treated; each unit contains a predetermined amount of active compound calculated to bind with the desired drug carrier to produce the desired therapeutic effect. The specifications of the unit dosage form of this disclosure are determined by and directly dependent on the unique properties of the active compound and the specific therapeutic effect to be achieved.

[0111] In therapeutic applications, the dosage of the pharmaceutical composition used according to this disclosure varies depending on the pharmaceutical agent, the age, weight, and clinical condition of the receiving patient, the experience and judgment of the clinician or practitioner administering the therapy, and other factors influencing the selected dosage. Generally, the dosage should be sufficient to alleviate, and preferably eliminate, the symptoms of the disease or condition disclosed herein, and even more preferably to achieve complete resolution of the disease or condition. The dosage can range from about 0.01 mg / kg per day to about 5000 mg / kg per day. An effective amount of the pharmaceutical agent is an effective amount that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. Improvement in survival and growth indicates resolution. As used herein, the term "dose-effective manner" refers to the amount of active compound that produces the desired biological effect in a subject or cell.

[0112] It should be understood that pharmaceutical compositions may be included in containers, packages or dispensers together with instructions for use.

[0113] It should be understood that all these forms are also considered within the scope of the claimed disclosure for compounds of this disclosure that are capable of further forming salts.

[0114] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the compounds disclosed herein, wherein the parent compound is modified by preparing its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral organic acid salts containing basic residues such as amines, and base organic salts containing acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, non-toxic salts derived from inorganic and organic acids selected from: 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetate, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, glycolamide arsenoic acid, hexylresorcinol acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, and hydroiodine. Acids, including hydroxymaleic acid, hydroxynaphthyl carboxylic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid; and common amino acids such as glycine, alanine, phenylalanine, and arginine.

[0115] In some embodiments, pharmaceutically acceptable salts are sodium, potassium, calcium, magnesium, diethylamine, choline, meglumine, benzathine penicillin, tromethamine, ammonium, arginine, or lysine.

[0116] Other pharmaceutically acceptable examples of salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, 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]-oct-2-en-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, mucoconic acid, etc. This disclosure also covers salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, alkaline earth ion, or aluminum ion) or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc. In salt form, it should be understood that the ratio of the cation or anion of the compound to the salt can be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0117] It should be understood that all references to pharmaceutically acceptable salts include the same salt in solvent-added forms (solvents) or crystalline forms (polymorphs) as defined herein.

[0118] The compound or a pharmaceutically acceptable salt thereof may be administered orally, nasally, dermally, pulmonaryly, by inhalation, sublingually, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0119] The dosage regimen for a compound is chosen based on a variety of factors, including the patient's type, species, age, weight, sex, and medical condition; the severity of the condition to be treated; the route of administration; the patient's renal or hepatic function; and the specific compound or its salt used. A generally skilled physician or veterinarian can readily determine and prescribe an effective amount of medication required to prevent, counteract, or halt the progression of a condition.

[0120] Techniques for formulating and administering the disclosed compounds are available in Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing, Easton, Pennsylvania (1995). In the examples, the compounds described herein and their pharmaceutically acceptable salts are used in combination with pharmaceutically acceptable carriers or diluents in pharmaceutical formulations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions. The compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dose within the range described herein.

[0121] Unless otherwise stated, all percentages and ratios used herein are by weight. Other features and advantages of this disclosure will be apparent from various examples. The examples provided illustrate different components and methods useful in practicing this disclosure. The examples do not limit the claimed disclosure. Based on this disclosure, those skilled in the art can identify and employ other components and methods that can be used in practicing this disclosure.

[0122] In the synthetic schemes described herein, for simplicity, a particular configuration may be used to plot the compounds. Such a particular configuration should not be construed as limiting this disclosure to one or another isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers; however, it will be understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0123] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document were specifically and individually indicated to be incorporated herein by reference. Reference to publications and patent documents does not imply an admission that any publication or patent document is relevant prior art, nor does it constitute any admission of the content or date of said publication or patent document. The invention has now been described in writing, and those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the foregoing description and the following examples are for illustrative purposes and not for limiting the scope of the following claims.

[0124] As used herein, the phrase “compounds of this disclosure” generally and specifically refers to those compounds disclosed herein.

[0125] The compounds disclosed herein

[0126] In some respects, this disclosure provides a compound of formula (I):

[0127]

[0128] Or its pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, or tautomers, wherein:

[0129] X 1 For CH, S, or N;

[0130] X 2 For N, S, or O;

[0131] X 3 It can be C or N;

[0132] R 1 and R 2 Together with the atoms it is attached to, it forms C6-C. 10 aryl or 5 to 10-membered heteroaryl, wherein the C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. a replace;

[0133] Each R a Independently oxo, halogenated, cyano, -OH, -NH2, -C(O)N(R) b (R) c ), -N(R b )C(O)(R c C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C4-C 10 cycloalkyl, C6-C 10aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic alkyl, or 4- to 10-membered heterocyclic alkenyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C4-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic alkyl or 4- to 10-membered heterocyclic alkenyl, optionally separated by one or more R a1 replace;

[0134] Each R b and R c Independently H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 alkyl, or C4-C5 alkyl is a cycloalkyl group. 10 The cycloalkyl or 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more -OH or C1-C6 haloalkyl groups; or

[0135] R b and R c Together with the atoms to which they are attached, they form 3 to 10-membered heterocyclic alkyl groups, wherein the 3 to 10-membered heterocyclic alkyl groups are optionally substituted by one or more -OH, -O (C1-C6 haloalkyl), -O (C1-C6 alkyl), -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl or -N (C1-C6 alkyl)2;

[0136] Each R a1 Independently oxo, halogenated, cyano, -OH, -O (C3-C) 10 Cycloalkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -C(O)OH, -C(O)O (C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -O- (C3-C 10 cycloalkyl), C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the 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 groups are optionally surrounded by one or more R groups. a2 replace;

[0137] Each R a2It can be independently oxo, halogenated, cyano, -OH, or -NH2;

[0138] R 3 For C6-C 10 aryl or 6- to 10-membered heteroaryl, wherein the C6-C 10 aryl or 6- to 10-membered heteroaryl groups are substituted with one or more R groups. 3a replace;

[0139] Each R 3a Independently, it is halogenated, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, -O (C6-C 10 Aryl), C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, -O (C6-C 10 Aryl), C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. 3a1 Replace; and

[0140] Each R 3a1 Independently oxo, halogenated, cyano, -NH2, -NH-C(O)O(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl, wherein the C1-C6 alkyl is optionally separated by one or more C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O (C1-C6 haloalkyl), C3-C 10 cycloalkyl, C6-C 10 Aryl or 5 to 10 heteroaryl substituents;

[0141] The conditions are:

[0142] (i) When R 3a Halogenated and R 1 and R 2 When R forms a 6-membered heteroaryl group with the atoms it is attached to, then a Not -CF3; or

[0143] (ii)X 1 It is CH or N; and R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms.a Substituted pyridine; or

[0144] (iii)X 2 It is N or O; and R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted pyridine; or

[0145] (iv) When R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then X 1 Not S; or

[0146] (v) When R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then X 2 Not S; or

[0147] (vi) When R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then no or

[0148] (vii) When R a for When, then R 3 no or

[0149] (viii) When R a for When, then R 3 no or

[0150] (ix) When R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted pyrazines, and R a For one or more R a1 When the phenyl group is substituted, then R a1 Not -Cl, -F, -CN, -O(CH3), -O(CF3), -O(CHF2), -CH3, or cyclopropyl; or

[0151] (x) When R 1 and R 2Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted pyrazines, and R a For one or more R a1 When pyridine is substituted, then R a1 Not -Cl, -CN, -CF3, -O(CH3), -O(CHF2), cyclopropyl, -C(CH3)2(CN) or -C(CH3)2(OH); or

[0152] (xi) when R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a When pyrazine is substituted, then R a no or

[0153] (xii) The compound of formula (I) is not 5'-methoxy-2',6-dimethyl-N-(6-(tetrahydrofuran-3-yl)thiazo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide.

[0154] In some respects, this disclosure provides a compound of formula (I):

[0155]

[0156] Or its pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, or tautomers, wherein:

[0157] X 1 For CH, S, or N;

[0158] X 2 For N, S, or O;

[0159] X 3 It can be C or N;

[0160] R 1 and R 2 Together with the atoms it is attached to, it forms C6-C. 10 aryl or 5 to 10-membered heteroaryl, wherein the C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. a replace;

[0161] Each R a Independently oxo, halogenated, cyano, -OH, -NH2, -C(O)N(R) b (R) c ), -N(R b )C(O)(R cC1-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 heterocyclic alkyl, wherein the 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 heterocyclic alkyl, optionally bounded by one or more R a1 replace;

[0162] Each R b and R c Independently H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 alkyl, or C4-C5 alkyl is a cycloalkyl group. 10 The cycloalkyl or 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more -OH or C1-C6 haloalkyl groups; or

[0163] R b and R c Together with the atoms to which they are attached, they form 3 to 10-membered heterocyclic alkyl groups, wherein the 3 to 10-membered heterocyclic alkyl groups are optionally substituted by one or more -OH, -O (C1-C6 haloalkyl), -O (C1-C6 alkyl), -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl or -N (C1-C6 alkyl)2;

[0164] Each R a1 Independently oxo, halogenated, cyano, -OH, -O (C3-C) 10 Cycloalkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -C(O)OH, -C(O)O (C1-C6 alkyl), 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, wherein the 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 groups are optionally surrounded by one or more R groups. a2 replace;

[0165] Each R a2 It can be independently oxo, halogenated, cyano, -OH, or -NH2;

[0166] R 3 For C6-C 10 aryl or 6- to 10-membered heteroaryl, wherein the C6-C 10 aryl or 6- to 10-membered heteroaryl groups are substituted with one or more R groups. 3a replace;

[0167] Each R 3a Independently, it is halogenated, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. 3a1 Replace; and

[0168] Each R 3a1 Independently oxo, halogenated, cyano, -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl, wherein the C1-C6 alkyl is optionally separated by one or more C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O (C1-C6 haloalkyl), C3-C 10 cycloalkyl, C6-C 10 Aryl or 5 to 10 heteroaryl substituents;

[0169] Where R 3a Halogenated and R 1 and R 2 When R forms a 6-membered heteroaryl group with the atoms it is attached to, then a It's not -CF3.

[0170] It should be understood that, for the compounds disclosed herein, variable X 1 X 2 X 3 R 1 R 2 R a R b R c R a1 R a2 R 3 R 3a and R3a1 Each can be selected from the group described in this article as applicable, and this article refers to variable X. 1 X 2 X 3 R 1 R 2 R a R b R c R a1 R a2 R 3 R 3a and R 3a1 Any of the groups mentioned in the text, where applicable, can be used in conjunction with the variable X in this paper. 1 X 2 X 3 R 1 R 2 R a R b R c R a1 R a2 R 3 R 3a and R 3a1 The remainder of any combination of one or more of the aforementioned groups.

[0171] In some embodiments, X 1 It can be CH or S.

[0172] In some embodiments, X 1 It can be S or N.

[0173] In some embodiments, X 1 It can be CH or N.

[0174] In some embodiments, X 1 For CH. In some embodiments, X 1 S. In some embodiments, X 1 Let N be the number of elements in the array.

[0175] In some embodiments, X 2 It can be N or S.

[0176] In some embodiments, X 2 It can be N or O.

[0177] In some embodiments, X 2 It can be O or S.

[0178] In some embodiments, X 2 For N. In some embodiments, X 2 S. In some embodiments, X 2 It is O.

[0179] In some embodiments, X 3 For C. In some embodiments, X 3 Let N be the number of elements in the array.

[0180] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form C6 aryl or 6-membered heteroaryl groups.

[0181] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a C6 aryl or a 6-membered heteroaryl group, wherein the aryl or heteroaryl group is optionally bonded by one or more R groups. a replace.

[0182] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a C6 aryl or a 6-membered heteroaryl group, wherein the aryl or heteroaryl group is bonded by one or more R groups. a replace.

[0183] In some embodiments, R 1 and R 2 Together with the atoms it is attached to, it forms C6-C. 10 Aryl.

[0184] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Replacement C6-C 10 Aryl.

[0185] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Replacement C6-C 10 Aryl.

[0186] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a C6 aryl group.

[0187] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted C6 aryl group.

[0188] In some embodiments, R 1 and R 2Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted C6 aryl group.

[0189] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form 5 to 10 heteroaryl groups.

[0190] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Replaced 5 to 10 heteroaryl groups.

[0191] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Replaced 5 to 10 heteroaryl groups.

[0192] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a 5-membered heteroaryl group.

[0193] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted 5-membered heteroaryl group.

[0194] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted 5-membered heteroaryl group.

[0195] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a 6-membered heteroaryl group.

[0196] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted 6-membered heteroaryl group.

[0197] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted 6-membered heteroaryl group.

[0198] In some embodiments, R 1 and R 2Together with the atoms to which they are attached, they form pyrazinyl, pyridinyl, or diazoleyl groups.

[0199] In some embodiments, R 1 and R 2 Together with the atoms to which they are attached, they form a pyrazinyl, pyridinyl, or diazoleyl group, wherein the pyrazinyl, pyridinyl, or diazoleyl group is optionally surrounded by one or more R groups. a replace.

[0200] In some embodiments, R 1 and R 2 Together with the atoms to which they are attached, they form a pyrazinyl, pyridinyl, or diazoleyl group, wherein the pyrazinyl, pyridinyl, or diazoleyl group is affected by one or more R groups. a replace.

[0201] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a pyrazin group.

[0202] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted pyrazinyl group.

[0203] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted pyrazinyl group.

[0204] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a pyridyl group.

[0205] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted pyridinyl group.

[0206] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted pyridinyl group.

[0207] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached, it forms a diazole group.

[0208] In some embodiments, R 1 and R 2Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted diazole group.

[0209] In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted diazole group.

[0210] In some embodiments, each R a Independently oxidized, halogenated, -C(O)N(R) b (R) c ), -N(R b )C(O)(R c C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C4-C 10 Cycloalkenyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic alkyl or 3- to 10-membered heterocyclic alkenyl.

[0211] In some embodiments, each R a Independently oxidized, halogenated, -C(O)N(R) b (R) c ), -N(R b )C(O)(R c C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C4-C 10 Cycloalkenyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic alkyl, or 3- to 10-membered heterocyclic alkenyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C4-C 10 Cycloalkenyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic alkyl or 3- to 10-membered heterocyclic alkenyl, optionally with one or more R a1 replace.

[0212] In some embodiments, each R a Independently oxidized, halogenated, -C(O)N(R) b (R) c ), -N(R b )C(O)(R c C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclic alkyl.

[0213] In some embodiments, each R a Independently oxidized, halogenated, -C(O)N(R) b (R) c ), -N(R b )C(O)(R c C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic alkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic alkyl, optionally bounded by one or more R a1 replace.

[0214] In some embodiments, each R a Independently oxidized, halogenated, -C(O)N(R) b (R) c ), -N(R b )C(O)(R c C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic alkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic alkyl group with one or more R a1 replace.

[0215] In some embodiments, each R a It is an independent oxygenator.

[0216] In some embodiments, each R a It is an independent halogen.

[0217] In some embodiments, each R a Independently, it is F, Cl, Br, or I. In some embodiments, each R a Independently, it is F, Cl, or Br. In some embodiments, each R a It can be F or Cl independently.

[0218] In some embodiments, each R a Independently for F. In some embodiments, each R a Independently for Cl. In some embodiments, each R aIndependently for Br. In some embodiments, each R a Independently I.

[0219] In some embodiments, each R a It is a cyano group on its own.

[0220] In some embodiments, each R a It is independently -OH.

[0221] In some embodiments, each R a Independently -NH2.

[0222] In some embodiments, each R a Independently -C(O)N(R) b (R) c ).

[0223] In some embodiments, each R a Independently for -N(R) b )C(O)(R c ).

[0224] In some embodiments, each R a It is independently a C1-C6 alkyl group.

[0225] In some embodiments, each R a Independently for optional use by one or more R a1 Substituted C1-C6 alkyl groups.

[0226] In some embodiments, each R a Independently for one or more R a1 Substituted C1-C6 alkyl groups.

[0227] In some embodiments, each R a Independently methyl. In some embodiments, each R a Independently ethyl. In some embodiments, each R a Independently propyl. In some embodiments, each R a Independently butyl. In some embodiments, each R a Independently pentyl. In some embodiments, each R a Independently based on itself. In some embodiments, each R a Independently isopropyl. In some embodiments, each R a Independently isobutyl. In some embodiments, each R a Independently isopentyl. In some embodiments, each R a Independently heterobase. In some embodiments, each R aIndependently sec-butyl. In some embodiments, each R a Independently sec-pentyl. In some embodiments, each R a Independently for Zhongjiji. In some embodiments, each R a It is independently tert-butyl.

[0228] In some embodiments, each R a Independently C2-C6 alkenyl (e.g., vinyl, propenyl, butenyl).

[0229] In some embodiments, each R a Independently for optional use by one or more R a1 Substituted C2-C6 alkenyl groups (e.g., vinyl, propenyl, butenyl).

[0230] In some embodiments, each R a Independently for one or more R a1 Substituted C2-C6 alkenyl groups (e.g., vinyl, propenyl, butenyl).

[0231] In some embodiments, each R a Independently C2-C6 ynyl group (e.g., ethynyl, propynyl, butynyl).

[0232] In some embodiments, each R a Independently for optional use by one or more R a1 Substituted C2-C6 alkynyl groups (e.g., ethynyl, propynyl, butynyl).

[0233] In some embodiments, each R a Independently for one or more R a1 Substituted C2-C6 alkynyl groups (e.g., ethynyl, propynyl, butynyl).

[0234] In some embodiments, each R a It is independently a C1-C6 haloalkyl group.

[0235] In some embodiments, each R a Independently for optional use by one or more R a1 Substituted C1-C6 haloalkyl groups.

[0236] In some embodiments, each R a Independently for one or more R a1 Substituted C1-C6 haloalkyl groups.

[0237] In some embodiments, each R a Independently, it is a halomethyl group. In some embodiments, each R aIndependently, it is a haloethyl. In some embodiments, each R a Independently, it is halopropyl. In some embodiments, each R a Independently halogenated butyl. In some embodiments, each R a Independently, it is halopentyl. In some embodiments, each R a It is independently a halogenated hexyl group.

[0238] In some embodiments, each R a Independently for C3-C 10 Cycloalkyl.

[0239] In some embodiments, each R a Independently for optional use by one or more R a1 Replacement C3-C 10 Cycloalkyl.

[0240] In some embodiments, each R a Independently for one or more R a1 Replacement C3-C 10 Cycloalkyl.

[0241] In some embodiments, each R a It is independently a C3-C7 cycloalkyl group.

[0242] In some embodiments, each R a Independently for optional use by one or more R a1 Substituted C3-C7 cycloalkyl groups.

[0243] In some embodiments, each R a Independently for one or more R a1 Substituted C3-C7 cycloalkyl groups.

[0244] In some embodiments, each R a Independently for C4-C 10 Cycloalkenyl.

[0245] In some embodiments, each R a Independently for optional use by one or more R a1 Replacement C4-C 10 Cycloalkenyl.

[0246] In some embodiments, each R a Independently for one or more R a1 Replacement C4-C 10 Cycloalkenyl.

[0247] In some embodiments, each R a Independently for C6-C 10 Aryl.

[0248] In some embodiments, each R a Independently for optional use by one or more R a1 Replacement C6-C 10 Aryl.

[0249] In some embodiments, each R a Independently for one or more R a1 Replacement C6-C 10 Aryl.

[0250] In some embodiments, each R a It is independently C6 aryl.

[0251] In some embodiments, each R a Independently for optional use by one or more R a1 Substituted C6 aryl group.

[0252] In some embodiments, each R a Independently for one or more R a1 Substituted C6 aryl group.

[0253] In some embodiments, each R a It is independently a 5 to 10-membered heteroaryl group.

[0254] In some embodiments, each R a Independently for optional use by one or more R a1 Replaced 5 to 10 heteroaryl groups.

[0255] In some embodiments, each R a Independently for one or more R a1 Replaced 5 to 10 heteroaryl groups.

[0256] In some embodiments, each R a It is independently a 5- or 6-membered heteroaryl group.

[0257] In some embodiments, each R a Independently for optional use by one or more R a1 Replacement of 5- or 6-membered heteroaryl groups.

[0258] In some embodiments, each R a Independently for one or more R a1 Replacement of 5- or 6-membered heteroaryl groups.

[0259] In some embodiments, each R a Independently, it is a 3- to 10-membered heterocyclic alkyl group.

[0260] In some embodiments, each Ra Independently for optional use by one or more R a1 Substituted 3 to 10-membered heterocyclic alkyl groups.

[0261] In some embodiments, each R a Independently for one or more R a1 Substituted 3 to 10-membered heterocyclic alkyl groups.

[0262] In some embodiments, each R a Independently, it is a 4- to 10-membered heterocyclic alkenyl group.

[0263] In some embodiments, each R a Independently for optional use by one or more R a1 Substituted 4- to 10-membered heterocyclic alkenyl groups.

[0264] In some embodiments, each R a Independently for one or more R a1 Substituted 4- to 10-membered heterocyclic alkenyl groups.

[0265] In some embodiments, each R a Independently for C3-C 10 Cycloalkyl or 3 to 10-membered heterocyclic alkyl.

[0266] In some embodiments, each R a Independently for C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl groups optionally surrounded by one or more R a1 replace.

[0267] In some embodiments, each R a Independently for C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C3-C 10 Cycloalkyl or 3 to 10-membered heterocyclic alkyl groups are formed by one or more R groups. a1 replace.

[0268] In some embodiments, each R a Independently:

[0269] -Cl, -Br, -CH3, -CF3

[0270]

[0271]

[0272]

[0273] In some embodiments, each R a Independently:

[0274] Oxygenated, -Cl, -Br, -CH3, -CF3,

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281] In some embodiments, each R b and R c Independently H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3 to 10-membered heterocyclic alkyl.

[0282] In some embodiments, each R b and R c Independently H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 alkyl, or C4-C5 alkyl is a cycloalkyl group. 10 The cycloalkyl or 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more -OH or C1-C6 haloalkyl groups.

[0283] In some embodiments, each R b and R c Independently H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 alkyl, or C4-C5 alkyl is a cycloalkyl group. 10 The cycloalkyl or 3- to 10-membered heterocycloalkyl group is substituted with one or more -OH or C1-C6 haloalkyl groups.

[0284] In some embodiments, each R b and R c H stands for H independently.

[0285] In some embodiments, each R b and R c It is independently a C1-C6 alkyl group.

[0286] In some embodiments, each Rb and R c Independently, it is a C1-C6 alkyl group optionally substituted with -OH or a C1-C6 haloalkyl group.

[0287] In some embodiments, each R b and R c Independently, it is a C1-C6 alkyl group substituted with -OH or a C1-C6 haloalkyl group.

[0288] In some embodiments, each R b and R c Independently methyl. In some embodiments, each R b and R c Independently ethyl. In some embodiments, each R b and R c Independently propyl. In some embodiments, each R b and R c Independently butyl. In some embodiments, each R b and R c Independently pentyl. In some embodiments, each R b and R c Independently based on itself. In some embodiments, each R b and R c Independently isopropyl. In some embodiments, each R b and R c Independently isobutyl. In some embodiments, each R b and R c Independently isopentyl. In some embodiments, each R b and R c Independently heterobase. In some embodiments, each R b and R c Independently sec-butyl. In some embodiments, each R b and R c Independently sec-pentyl. In some embodiments, each R b and R c Independently for Zhongjiji. In some embodiments, each R b and R c It is independently tert-butyl.

[0289] In some embodiments, each R b and R c Independently for C3-C 10 Cycloalkyl.

[0290] In some embodiments, each R b and R cIndependently, it is a C3-C alkyl group optionally substituted with -OH or C1-C6 haloalkyl groups. 10 Cycloalkyl.

[0291] In some embodiments, each R b and R c Independently, it is a C3-C alkyl group substituted with -OH or C1-C6 haloalkyl groups. 10 Cycloalkyl.

[0292] In some embodiments, each R b and R c Independently, it is a 3- to 10-membered heterocyclic alkyl group.

[0293] In some embodiments, each R b and R c Independently, it is a 3- to 10-membered heterocyclic alkyl group optionally substituted with -OH or C1-C6 haloalkyl groups.

[0294] In some embodiments, each R b and R c Independently, it is a 3- to 10-membered heterocyclic alkyl group substituted with -OH or C1-C6 haloalkyl groups.

[0295] In some embodiments, R b and R c Together with the atoms they are attached to, they form 3 to 10-membered heterocyclic alkyl groups.

[0296] In some embodiments, R b and R c Together with the atoms to which they are attached, they form 3 to 10-membered heterocyclic alkyl groups that are optionally substituted with one or more -OH, -O (C1-C6 haloalkyl), C1-C6 alkyl or -N (C1-C6 alkyl)2.

[0297] In some embodiments, R b and R c Together with the atoms they are attached to, they form 3 to 10-membered heterocyclic alkyl groups that are substituted with one or more -OH, -O (C1-C6 haloalkyl), C1-C6 alkyl or -N (C1-C6 alkyl)2.

[0298] In some embodiments, each R b and R c Independently, H, methyl, ethyl, cyclobutyl, cyclopropyl,

[0299] In some embodiments, R b and R c Together with the atoms to which it is attached, it forms a heterocyclic alkyl group selected from the following:

[0300]

[0301] In some embodiments, R b H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3 to 10-membered heterocyclic alkyl.

[0302] In some embodiments, R b H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 alkyl, or C4-C5 alkyl is a cycloalkyl group. 10 The cycloalkyl or 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more -OH or C1-C6 haloalkyl groups.

[0303] In some embodiments, R b H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3 to 10-membered heterocyclic alkyl groups, wherein C1-C6 alkyl, C3-C6 alkyl, or C4-C6 alkyl 10 The cycloalkyl or 3- to 10-membered heterocycloalkyl group is substituted with one or more -OH or C1-C6 haloalkyl groups.

[0304] In some embodiments, R b For H.

[0305] In some embodiments, R b It is a C1-C6 alkyl group.

[0306] In some embodiments, R b C1-C6 alkyl groups optionally substituted with -OH or C1-C6 haloalkyl groups.

[0307] In some embodiments, R b It is a C1-C6 alkyl group substituted with -OH or C1-C6 haloalkyl group.

[0308] In some embodiments, R b methyl. In some embodiments, R b It is ethyl. In some embodiments, R b It is propyl. In some embodiments, R b It is butyl. In some embodiments, R b It is pentyl. In some embodiments, R b For its own basis. In some embodiments, R b It is isopropyl. In some embodiments, R... b It is isobutyl. In some embodiments, R... b It is isopentyl. In some embodiments, R b It is a heterogroup. In some embodiments, R b It is sec-butyl. In some embodiments, Rb It is sec-pentyl. In some embodiments, R b For Zhongjiji. In some embodiments, R b It is tert-butyl.

[0309] In some embodiments, R b For C3-C 10 Cycloalkyl.

[0310] In some embodiments, R b C3-C alkyl group optionally substituted with -OH or C1-C6 haloalkyl group 10 Cycloalkyl.

[0311] In some embodiments, R b C3-C substituted with -OH or C1-C6 haloalkyl groups 10 Cycloalkyl.

[0312] In some embodiments, R b It is a 3- to 10-membered heterocyclic alkyl group.

[0313] In some embodiments, R b It is a 3- to 10-membered heterocyclic alkyl group optionally substituted with -OH or C1-C6 haloalkyl groups.

[0314] In some embodiments, R b It is a 3- to 10-membered heterocyclic alkyl group substituted with -OH or C1-C6 haloalkyl groups.

[0315] In some embodiments, R b H, methyl, ethyl, cyclobutyl, cyclopropyl,

[0316] In some embodiments, R c H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3 to 10-membered heterocyclic alkyl.

[0317] In some embodiments, R c H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 alkyl, or C4-C5 alkyl is a cycloalkyl group. 10 The cycloalkyl or 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more -OH or C1-C6 haloalkyl groups.

[0318] In some embodiments, R c H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 alkyl, or C4-C5 alkyl is a cycloalkyl group. 10The cycloalkyl or 3- to 10-membered heterocycloalkyl group is substituted with one or more -OH or C1-C6 haloalkyl groups.

[0319] In some embodiments, R c For H.

[0320] In some embodiments, R c It is a C1-C6 alkyl group.

[0321] In some embodiments, R c C1-C6 alkyl groups optionally substituted with -OH or C1-C6 haloalkyl groups.

[0322] In some embodiments, R c It is a C1-C6 alkyl group substituted with -OH or C1-C6 haloalkyl group.

[0323] In some embodiments, R c methyl. In some embodiments, R c It is ethyl. In some embodiments, R c It is propyl. In some embodiments, R c It is butyl. In some embodiments, R c It is pentyl. In some embodiments, R c For its own basis. In some embodiments, R c It is isopropyl. In some embodiments, R... c It is isobutyl. In some embodiments, R... c It is isopentyl. In some embodiments, R c It is a heterogroup. In some embodiments, R c It is sec-butyl. In some embodiments, R c It is sec-pentyl. In some embodiments, R c For Zhongjiji. In some embodiments, R c It is tert-butyl.

[0324] In some embodiments, R c For C3-C 10 Cycloalkyl.

[0325] In some embodiments, R c C3-C alkyl group optionally substituted with -OH or C1-C6 haloalkyl group 10 Cycloalkyl.

[0326] In some embodiments, R c C3-C substituted with -OH or C1-C6 haloalkyl groups 10 Cycloalkyl.

[0327] In some embodiments, R c It is a 3- to 10-membered heterocyclic alkyl group.

[0328] In some embodiments, R c It is a 3- to 10-membered heterocyclic alkyl group optionally substituted with -OH or C1-C6 haloalkyl groups.

[0329] In some embodiments, R c It is a 3- to 10-membered heterocyclic alkyl group substituted with -OH or C1-C6 haloalkyl groups.

[0330] In some embodiments, R c H, methyl, ethyl, cyclobutyl, cyclopropyl,

[0331]

[0332] In some embodiments, each R a1 It is an independent oxygenator.

[0333] In some embodiments, each R a1 It is an independent halogen.

[0334] In some embodiments, each R a1 Independently, it is F, Cl, Br, or I. In some embodiments, each R a1 Independently, it is F, Cl, or Br. In some embodiments, each R a1 It can be F or Cl independently.

[0335] In some embodiments, each R a1 Independently for F. In some embodiments, each R a1 Independently for Cl. In some embodiments, each R a1 Independently for Br. In some embodiments, each R a1 Independently I.

[0336] In some embodiments, each R a1 It is a cyano group on its own.

[0337] In some embodiments, each R a1 It is independently -OH.

[0338] In some embodiments, each R a1 Independently for -O(C3-C) 10 cycloalkyl).

[0339] In some embodiments, each R a1 Independently for -O(C3-C) 10 cycloalkyl), wherein the C3-C 10 cycloalkyl groups are optionally surrounded by one or more R a2 replace.

[0340] In some embodiments, each R a1 Independently for -O(C3-C) 10 cycloalkyl), wherein the C3-C 10 cycloalkyl groups are formed by one or more R groups a2 replace.

[0341] In some embodiments, each R a1 Independently -NH2.

[0342] In some embodiments, each R a1 Independently -NH (C1-C6 alkyl).

[0343] In some embodiments, each R a1 Independently -NH (C1-C6 alkyl), wherein the C1-C6 alkyl group is optionally surrounded by one or more R a2 replace.

[0344] In some embodiments, each R a1 Independently -NH (C1-C6 alkyl), wherein the C1-C6 alkyl group is affected by one or more R groups. a2 replace.

[0345] In some embodiments, each R a1 Independently -N(C1-C6 alkyl)2.

[0346] In some embodiments, each R a1 Independently -N(C1-C6 alkyl)2, wherein the C1-C6 alkyl group is optionally surrounded by one or more R a2 replace.

[0347] In some embodiments, each R a1 Independently -N(C1-C6 alkyl)2, wherein the C1-C6 alkyl group is affected by one or more R a2 replace.

[0348] In some embodiments, each R a1 It is independently -C(O)OH.

[0349] In some embodiments, each R a1 Independently -C(O)O (C1-C6 alkyl).

[0350] In some embodiments, each R a1 Independently -C(O)O (C1-C6 alkyl), wherein the C1-C6 alkyl group is optionally separated by one or more R a2 replace.

[0351] In some embodiments, each R a1 Independently -C(O)O (C1-C6 alkyl), wherein the C1-C6 alkyl group is affected by one or more R a2 replace.

[0352] In some embodiments, each R a1 It is independently a C1-C6 alkyl group.

[0353] In some embodiments, each R a1 Independently for optional use by one or more R a2 Substituted C1-C6 alkyl groups.

[0354] In some embodiments, each R a1 Independently for one or more R a2 Substituted C1-C6 alkyl groups.

[0355] In some embodiments, each R a1 Independently methyl. In some embodiments, each R a1 Independently ethyl. In some embodiments, each R a1 Independently propyl. In some embodiments, each R a1 Independently butyl. In some embodiments, each R a1 Independently pentyl. In some embodiments, each R a1 Independently based on itself. In some embodiments, each R a1 Independently isopropyl. In some embodiments, each R a1 Independently isobutyl. In some embodiments, each R a1 Independently isopentyl. In some embodiments, each R a1 Independently heterobase. In some embodiments, each R a1 Independently sec-butyl. In some embodiments, each R a1 Independently for R a1 It is sec-pentyl. In some embodiments, each R a1 Independently for Zhongjiji. In some embodiments, each R a1 It is independently tert-butyl.

[0356] In some embodiments, each R a1 It is independently a C2-C6 alkenyl group.

[0357] In some embodiments, each R a1 Independently for optional use by one or more R a2 Substituted C2-C6 alkenyl groups.

[0358] In some embodiments, each R a1Independently for one or more R a2 Substituted C2-C6 alkenyl groups.

[0359] In some embodiments, each R a1 It is independently a C2-C6 ynyl group.

[0360] In some embodiments, each R a1 Independently for optional use by one or more R a2 Substituted C2-C6 ynyl group.

[0361] In some embodiments, each R a1 Independently for one or more R a2 Substituted C2-C6 ynyl group.

[0362] In some embodiments, each R a1 It is independently a C1-C6 haloalkyl group.

[0363] In some embodiments, each R a1 Independently for optional use by one or more R a2 Substituted C1-C6 haloalkyl groups.

[0364] In some embodiments, each R a1 Independently for one or more R a2 Substituted C1-C6 haloalkyl groups.

[0365] In some embodiments, each R a1 Independently, it is a halomethyl group. In some embodiments, each R a1 Independently, it is a haloethyl. In some embodiments, each R a1 Independently, it is halopropyl. In some embodiments, each R a1 Independently halogenated butyl. In some embodiments, each R a1 Independently, it is halopentyl. In some embodiments, each R a1 It is independently a halogenated hexyl group.

[0366] In some embodiments, each R a1 It is independently a C1-C6 alkoxy group.

[0367] In some embodiments, each R a1 Independently for optional use by one or more R a2 Substituted C1-C6 alkoxy groups.

[0368] In some embodiments, each R a1 Independently for one or more R a2 Substituted C1-C6 alkoxy groups.

[0369] In some embodiments, each R a1 It is independently a C1-C6 haloalkoxy group.

[0370] In some embodiments, each R a1 Independently for optional use by one or more R a2 Substituted C1-C6 haloalkoxy groups.

[0371] In some embodiments, each R a1 Independently for one or more R a2 Substituted C1-C6 haloalkoxy groups.

[0372] In some embodiments, each R a1 Independently -O-(C3-C 10 cycloalkyl).

[0373] In some embodiments, each R a1 Independently for optional use by one or more R a2 Replacement -O-(C3-C) 10 cycloalkyl).

[0374] In some embodiments, each R a1 Independently for one or more R a2 Replacement -O-(C3-C) 10 cycloalkyl).

[0375] In some embodiments, each R a1 Independently for C3-C 10 Cycloalkyl.

[0376] In some embodiments, each R a1 Independently for optional use by one or more R a2 Replacement C3-C 10 Cycloalkyl.

[0377] In some embodiments, each R a1 Independently for one or more R a2 Replacement C3-C 10 Cycloalkyl.

[0378] In some embodiments, each R a1 It is independently a C3-C7 cycloalkyl group.

[0379] In some embodiments, each R a1 Independently for optional use by one or more R a2 Substituted C3-C7 cycloalkyl groups.

[0380] In some embodiments, each R a1 Independently for one or more Ra2 Substituted C3-C7 cycloalkyl groups.

[0381] In some embodiments, each R a1 Independently, it is a 3- to 10-membered heterocyclic alkyl group.

[0382] In some embodiments, each R a1 Independently for optional use by one or more R a2 Substituted 3 to 10-membered heterocyclic alkyl groups.

[0383] In some embodiments, each R a1 Independently for one or more R a2 Substituted 3 to 10-membered heterocyclic alkyl groups.

[0384] In some embodiments, each R a1 It is independently a 3- to 7-membered heterocyclic alkyl group.

[0385] In some embodiments, each R a1 Independently for optional use by one or more R a2 Substituted 3- to 7-membered heterocyclic alkyl groups.

[0386] In some embodiments, each R a1 Independently for one or more R a2 Substituted 3- to 7-membered heterocyclic alkyl groups.

[0387] In some embodiments, each R a1 Independently for C6-C 10 Aryl.

[0388] In some embodiments, each R a1 Independently for optional use by one or more R a2 Replacement C6-C 10 Aryl.

[0389] In some embodiments, each R a1 Independently for one or more R a2 Replacement C6-C 10 Aryl.

[0390] In some embodiments, each R a1 It is independently C6 aryl.

[0391] In some embodiments, each R a1 Independently for optional use by one or more R a2 Substituted C6 aryl group.

[0392] In some embodiments, each R a1 Independently for one or more R a2 Substituted C6 aryl group.

[0393] In some embodiments, each R a1 It is independently a 5 to 10-membered heteroaryl group.

[0394] In some embodiments, each R a1 Independently for optional use by one or more R a2 Replaced 5 to 10 heteroaryl groups.

[0395] In some embodiments, each R a1 Independently for one or more R a2 Replaced 5 to 10 heteroaryl groups.

[0396] In some embodiments, each R a1 It is independently a 5- or 6-membered heteroaryl group.

[0397] In some embodiments, each R a1 Independently for optional use by one or more R a2 Replacement of 5- or 6-membered heteroaryl groups.

[0398] In some embodiments, each R a1 Independently for one or more R a2 Replacement of 5- or 6-membered heteroaryl groups.

[0399] In some embodiments, each R a1 Independently, it can be oxo, -OH, -CH2OH, -CHF2, -CF3, -F, -Cl, -CN, -OCH3, -OCHF2, -OCF3, -NHCH3, -N(CH3)2, -CH3, -CH2CF3, -CH2CN,

[0400] In some embodiments, each R a2 It can be either a cyano group or -OH.

[0401] In some embodiments, each R a2 It is an independent oxygenator.

[0402] In some embodiments, each R a2 It is an independent halogen.

[0403] In some embodiments, each R a2 Independently, it is F, Cl, Br, or I. In some embodiments, each R a2 Independently, it is F, Cl, or Br. In some embodiments, each R a2 It can be F or Cl independently.

[0404] In some embodiments, each R a2Independently for F. In some embodiments, each R a2 Independently for Cl. In some embodiments, each R a2 Independently for Br. In some embodiments, each R a2 Independently I.

[0405] In some embodiments, each R a2 It is a cyano group on its own.

[0406] In some embodiments, each R a2 It is independently -OH.

[0407] In some embodiments, each R a2 Independently -NH2.

[0408] In some embodiments, R 3 For C6-C 10 Aryl.

[0409] In some embodiments, R 3 To be optionally used by one or more R 3a Replacement C6-C 10 Aryl.

[0410] In some embodiments, R 3 For one or more R 3a Replacement C6-C 10 Aryl.

[0411] In some embodiments, R 3 It is a C6 aryl group.

[0412] In some embodiments, R 3 To be optionally used by one or more R 3a Substituted C6 aryl group.

[0413] In some embodiments, R 3 For one or more R 3a Substituted C6 aryl group.

[0414] In some embodiments, R 3 It consists of 6 to 10 heteroaryl groups.

[0415] In some embodiments, R 3 To be optionally used by one or more R 3a Replaced 6 to 10 heteroaryl groups.

[0416] In some embodiments, R 3 For one or more R 3a Replaced 6 to 10 heteroaryl groups.

[0417] In some embodiments, R3 It is a 6-membered heteroaryl group.

[0418] In some embodiments, R 3 To be optionally used by one or more R 3a Substituted 6-membered heteroaryl group.

[0419] In some embodiments, R 3 For one or more R 3a Substituted 6-membered heteroaryl group.

[0420] In some embodiments, R 3 for:

[0421]

[0422]

[0423]

[0424]

[0425] In some embodiments, each R 3a It is an independent halogen.

[0426] In some embodiments, each R 3a Independently cyano, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 10-membered heterocyclic alkyl, C6-C 10 Aryl or 5 to 10 heteroaryl compounds.

[0427] In some embodiments, each R 3a Independently cyano, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. 3a1 replace.

[0428] In some embodiments, each R 3a Independently cyano, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl groups are substituted with one or more R groups. 3a1 replace.

[0429] In some embodiments, each R 3a Independently, it is F, Cl, Br, or I. In some embodiments, each R 3a Independently, it is F, Cl, or Br. In some embodiments, each R 3a It can be F or Cl independently.

[0430] In some embodiments, each R 3a Independently for F. In some embodiments, each R 3a Independently for Cl. In some embodiments, each R 3a Independently for Br. In some embodiments, each R 3a Independently I.

[0431] In some embodiments, each R 3a It is a cyano group on its own.

[0432] In some embodiments, each R 3a It is independently -OH.

[0433] In some embodiments, each R 3a Independently -NH2.

[0434] In some embodiments, each R 3a It is independently a C1-C6 alkyl group.

[0435] In some embodiments, each R 3a Independently for optional use by one or more R 3a1 Substituted C1-C6 alkyl groups.

[0436] In some embodiments, each R 3a Independently for one or more R 3a1 Substituted C1-C6 alkyl groups.

[0437] In some embodiments, each R 3a Independently methyl. In some embodiments, each R 3a Independently ethyl. In some embodiments, each R 3a Independently propyl. In some embodiments, each R 3a Independently butyl. In some embodiments, each R 3a Independently pentyl. In some embodiments, each R 3a Independently based on itself. In some embodiments, each R 3a Independently isopropyl. In some embodiments, each R 3a Independently isobutyl. In some embodiments, each R 3aIndependently isopentyl. In some embodiments, each R 3a Independently heterobase. In some embodiments, each R 3a Independently sec-butyl. In some embodiments, each R 3a Independently sec-pentyl. In some embodiments, each R 3a Independently for Zhongjiji. In some embodiments, each R 3a It is independently tert-butyl.

[0438] In some embodiments, each R 3a It is independently a C2-C6 alkenyl group.

[0439] In some embodiments, each R 3a Independently for optional use by one or more R 3a1 Substituted C2-C6 alkenyl groups.

[0440] In some embodiments, each R 3a It is independently a C2-C6 ynyl group.

[0441] In some embodiments, each R 3a Independently for optional use by one or more R 3a1 Substituted C2-C6 ynyl group.

[0442] In some embodiments, each R 3a It is independently a C1-C6 haloalkyl group.

[0443] In some embodiments, each R 3a Independently for optional use by one or more R 3a1 Substituted C1-C6 haloalkyl groups.

[0444] In some embodiments, each R 3a Independently for one or more R 3a1 Substituted C1-C6 haloalkyl groups.

[0445] In some embodiments, each R 3a Independently, it is a halomethyl group. In some embodiments, each R 3a Independently, it is a haloethyl. In some embodiments, each R 3a Independently, it is halopropyl. In some embodiments, each R 3a Independently halogenated butyl. In some embodiments, each R 3a Independently, it is halopentyl. In some embodiments, each R 3a It is independently a halogenated hexyl group.

[0446] In some embodiments, each R 3a Independently for C3-C10 Cycloalkyl.

[0447] In some embodiments, each R 3a Independently for optional use by one or more R 3a1 Replacement C3-C 10 Cycloalkyl.

[0448] In some embodiments, each R 3a Independently for one or more R 3a1 Replacement C3-C 10 Cycloalkyl.

[0449] In some embodiments, each R 3a It is independently a C3-C7 cycloalkyl group.

[0450] In some embodiments, each R 3a Independently for optional use by one or more R 3a1 Substituted C3-C7 cycloalkyl groups.

[0451] In some embodiments, each R 3a Independently for one or more R 3a1 Substituted C3-C7 cycloalkyl groups.

[0452] In some embodiments, each R 3a Independently, it is a 3- to 10-membered heterocyclic alkyl group.

[0453] In some embodiments, each R 3a Independently for optional use by one or more R 3a1 Substituted 3 to 10-membered heterocyclic alkyl groups.

[0454] In some embodiments, each R 3a Independently for one or more R 3a1 Substituted 3 to 10-membered heterocyclic alkyl groups.

[0455] In some embodiments, each R 3a It is independently a 3- to 7-membered heterocyclic alkyl group.

[0456] In some embodiments, each R 3a Independently for optional use by one or more R 3a1 Substituted 3- to 7-membered heterocyclic alkyl groups.

[0457] In some embodiments, each R 3a Independently for one or more R 3a1 Substituted 3- to 7-membered heterocyclic alkyl groups.

[0458] In some embodiments, each R 3a Independently for -O(C6-C)10 Aryl).

[0459] In some embodiments, each R 3a Independently for optional use by one or more R 3a1 Substituted -O(C6-C) 10 Aryl).

[0460] In some embodiments, each R 3a Independently for one or more R 3a1 Substituted -O(C6-C) 10 Aryl).

[0461] In some embodiments, each R 3a Independently for C6-C 10 Aryl.

[0462] In some embodiments, each R 3a Independently for optional use by one or more R 3a1 Replacement C6-C 10 Aryl.

[0463] In some embodiments, each R 3a Independently for one or more R 3a1 Replacement C6-C 10 Aryl.

[0464] In some embodiments, each R 3a It is independently C6 aryl.

[0465] In some embodiments, each R 3a Independently for optional use by one or more R 3a1 Substituted C6 aryl group.

[0466] In some embodiments, each R 3a Independently for one or more R 3a1 Substituted C6 aryl group.

[0467] In some embodiments, each R 3a It is independently a 5 to 10-membered heteroaryl group.

[0468] In some embodiments, each R 3a Independently for optional use by one or more R 3a1 Replaced 5 to 10 heteroaryl groups.

[0469] In some embodiments, each R 3a Independently for one or more R 3a1 Replaced 5 to 10 heteroaryl groups.

[0470] In some embodiments, each R3a It is independently a 5- or 6-membered heteroaryl group.

[0471] In some embodiments, each R 3a Independently for optional use by one or more R 3a1 Replacement of 5- or 6-membered heteroaryl groups.

[0472] In some embodiments, each R 3a Independently for one or more R 3a1 Replacement of 5- or 6-membered heteroaryl groups.

[0473] In some embodiments, each R 3a Independently -Br, -CH3, -CF3, -CN,

[0474]

[0475]

[0476] In some embodiments, each R 3a1 Independently oxo, halogenated, cyano, -NH2, -NH-C(O)O(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl, wherein the C1-C6 alkyl is optionally separated by one or more C3-C 10 Cycloalkyl, C1-C6 alkoxy, -O (C1-C6 haloalkyl), C3-C 10 Cycloalkyl or 5 to 10 heteroaryl substitutions.

[0477] In some embodiments, each R 3a1 Independently oxo, halogenated, cyano, -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl, wherein the C1-C6 alkyl is optionally separated by one or more C3-C 10 Cycloalkyl, C1-C6 alkoxy, -O (C1-C6 haloalkyl), C3-C 10 Cycloalkyl or 5 to 10 heteroaryl substitutions.

[0478] In some embodiments, each R 3a1 Independently oxo, halogenated, cyano, -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl, wherein the C1-C6 alkyl group is separated by one or more C3-C... 10 Cycloalkyl, C1-C6 alkoxy, -O (C1-C6 haloalkyl), C3-C 10 Cycloalkyl or 5 to 10 heteroaryl substitutions.

[0479] In some embodiments, each R 3a1 It is an independent oxygenator.

[0480] In some embodiments, each R 3a1 It is an independent halogen.

[0481] In some embodiments, each R 3a1 Independently, it is F, Cl, Br, or I. In some embodiments, each R 3a1 Independently, it is F, Cl, or Br. In some embodiments, each R 3a1 It can be F or Cl independently.

[0482] In some embodiments, each R 3a1 Independently for F. In some embodiments, each R 3a1 Independently for Cl. In some embodiments, each R 3a1 Independently for Br. In some embodiments, each R 3a1 Independently I.

[0483] In some embodiments, each R 3a1 It is a cyano group on its own.

[0484] In some embodiments, each R 3a1 Independently -NH2.

[0485] In some embodiments, each R 3a1 Independently -NH-C(O)O (C1-C6 alkyl).

[0486] In some embodiments, each R 3a1 Independently -C(O)(C1-C6 alkyl).

[0487] In some embodiments, each R 3a1 Independently -C(O)(O-(C1-C6 alkyl)).

[0488] In some embodiments, each R 3a1 It is independently -C(O)NH2.

[0489] In some embodiments, each R 3a1 It is independently a C1-C6 alkyl group.

[0490] In some embodiments, each R 3a1 Independently, optionally by one or more C3-C 10 Cycloalkyl-substituted C1-C6 alkyl groups.

[0491] In some embodiments, each R 3a1Independently for one or more C3-C 10 Cycloalkyl-substituted C1-C6 alkyl groups.

[0492] In some embodiments, each R 3a1 Independently methyl. In some embodiments, each R 3a1 Independently ethyl. In some embodiments, each R 3a1 Independently propyl. In some embodiments, each R 3a1 Independently butyl. In some embodiments, each R 3a1 Independently pentyl. In some embodiments, each R 3a1 Independently based on itself. In some embodiments, each R 3a1 Independently isopropyl. In some embodiments, each R 3a1 Independently isobutyl. In some embodiments, each R 3a1 Independently isopentyl. In some embodiments, each R 3a1 Independently heterobase. In some embodiments, each R 3a1 Independently sec-butyl. In some embodiments, each R 3a1 Independently sec-pentyl. In some embodiments, each R 3a1 Independently for Zhongjiji. In some embodiments, each R 3a1 It is independently tert-butyl.

[0493] In some embodiments, each R 3a1 It is independently a C2-C6 alkenyl group.

[0494] In some embodiments, each R 3a1 It is independently a C2-C6 ynyl group.

[0495] In some embodiments, each R 3a1 It is independently a C1-C6 haloalkyl group.

[0496] In some embodiments, each R 3a1 Independently, it is a halomethyl group. In some embodiments, each R 3a1 Independently, it is a haloethyl. In some embodiments, each R 3a1 Independently, it is halopropyl. In some embodiments, each R 3a1 Independently halogenated butyl. In some embodiments, each R 3a1 Independently, it is halopentyl. In some embodiments, each R 3a1 It is independently a halogenated hexyl group.

[0497] In some embodiments, each R 3a1 It is independently a C1-C6 alkoxy group.

[0498] In some embodiments, each R 3a1 Independently -O (C1-C6 haloalkyl).

[0499] In some embodiments, each R 3a1 Independently for C3-C 10 Cycloalkyl.

[0500] In some embodiments, each R 3a1 Independently for C6-C 10 Aryl.

[0501] In some embodiments, each R 3a1 It is independently a 5 to 10-membered heteroaryl group.

[0502] In some embodiments, each R 3a1 Independently, it can be oxo, -Cl, -CH3, -OCH3, -CF2H, -NH2, -NHC(O)OC(CH3)3, -OCHF2, -C(O)OC(CH3)3, -C(O)CH3, -C(O)NH2,

[0503] In some embodiments, when R 3a Halogenated and R 1 and R 2 When R forms a 6-membered heteroaryl group with the atoms it is attached to, then a It's not -CF3.

[0504] In some embodiments, when R 3a Halogenated and R 1 and R 2 When R forms a 6-membered heteroaryl group with the atoms it is attached to, then a Halogenated, cyano, -OH, -NH2, -C(O)N(R) b (R) c C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclic alkyl.

[0505] In some embodiments, X 1 It is CH or N; and R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted pyridine.

[0506] In some embodiments, X 2 It is N or O; and R 1 and R2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted pyridine.

[0507] In some embodiments, when R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then X 1 Not S.

[0508] In some embodiments, when R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then X 2 Not S.

[0509] In some embodiments, when R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then no

[0510] In some embodiments, when R a for When, then R 3 no

[0511] In some embodiments, when R a for When, then R 3 no

[0512] In some embodiments, when R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted pyrazines, and R a For one or more R a1 When the phenyl group is substituted, then R a1 It is not -Cl, -F, -CN, -O(CH3), -O(CF3), -O(CHF2), -CH3 or cyclopropyl.

[0513] In some embodiments, when R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted pyrazines, and R a For one or more R a1When pyridine is substituted, then R a1 It is not -Cl, -CN, -CF3, -O(CH3), -O(CHF2), cyclopropyl, -C(CH3)2(CN) or -C(CH3)2(OH).

[0514] In some embodiments, when R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a When pyrazine is substituted, then R a no

[0515] In some embodiments, the compound of formula (I) is not 5'-methoxy-2',6-dimethyl-N-(6-(tetrahydrofuran-3-yl)thiazo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide.

[0516] In some embodiments, the compound has formula (I), wherein:

[0517] X 1 For CH or N;

[0518] X 2 For N, S, or O;

[0519] X 3 It can be C or N;

[0520] R 1 and R 2 Together with the atoms it is attached to, it forms C6-C. 10 aryl or 5 to 10-membered heteroaryl, wherein the C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. a replace;

[0521] Each R a Independently oxo, halogenated, cyano, -OH, -NH2, -C(O)N(R) b (R) c 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 heterocyclic alkyl, wherein the 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 heterocyclic alkyl, optionally bounded by one or more R a1 replace;

[0522] R b and R c Together with the atoms they are attached to, they form 3- to 10-membered heterocyclic alkyl groups;

[0523] Each R a1 Independently oxo, halogenated, cyano, -OH, -O (C3-C) 10 Cycloalkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, 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, wherein the 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 groups are optionally surrounded by one or more R groups. a2 replace;

[0524] Each R a2 It can be independently oxo, halogenated, cyano, -OH, or -NH2;

[0525] R 3 For C6-C 10 aryl or 6- to 10-membered heteroaryl, wherein the C6-C 10 aryl or 6- to 10-membered heteroaryl groups are substituted with one or more R groups. 3a replace;

[0526] Each R 3a Independently, it is halogenated, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. 3a1 Replace; and

[0527] Each R 3a1 Independently oxo, halogenated, cyano, -C(O)(C1-C6 alkyl), -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl, wherein the C1-C6 alkyl is optionally separated by one or more C3-C...10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O (C1-C6 haloalkyl), C3-C 10 cycloalkyl, C6-C 10 Aryl or 5 to 10 heteroaryl substituents;

[0528] Where R 3a Halogenated and R 1 and R 2 When R forms a 6-membered heteroaryl group with the atoms it is attached to, then a It's not -CF3.

[0529] In some embodiments, the compound has formula (I), wherein:

[0530] Each R a Independently oxidized, halogenated, -C(O)N(R) b (R) c ), -N(R b )C(O)(R c C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic alkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic alkyl, optionally bounded by one or more R a1 replace;

[0531] Each R a1 Independently oxo, halogenated, cyano, -OH, -O (C3-C) 10 Cycloalkyl), -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -C(O)O (C1-C6 alkyl), C1-C6 alkyl, 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, wherein the C1-C6 alkyl, 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 groups are optionally surrounded by one or more R groups. a2 replace;

[0532] Each R a2 It can be either a cyano group or -OH.

[0533] Each R 3a Independently cyano, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. 3a1 Replace; and

[0534] Each R 3a1 Independently oxo, halogenated, cyano, -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl, wherein the C1-C6 alkyl is optionally separated by one or more C3-C 10 Cycloalkyl, C1-C6 alkoxy, -O (C1-C6 haloalkyl), C3-C 10 Cycloalkyl or 5 to 10 heteroaryl substitutions.

[0535] In some embodiments, the compound has the formula (IA), (IB), or (IC):

[0536]

[0537] Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof.

[0538] In some embodiments, the compound has the formula (ID), (IE), (IF), (IG), (IH), (II), (IJ), (IK), or (IL):

[0539]

[0540] Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof.

[0541] In some embodiments of the compound of formula (IF), X 1 Not S.

[0542] In some embodiments, the compound has the formula (I-F'):

[0543]

[0544] Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof.

[0545] In some embodiments, the compound has the formula (IM), (IN), (IO), (IP), (IQ), (IR), (IS), (IT), (IU), or (IV):

[0546]

[0547] Or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or mixture thereof.

[0548] In some embodiments of the compound of formula (IT), X 1 Not S.

[0549] In some embodiments, the compound has the formula (I-T').

[0550]

[0551] Or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or mixture thereof.

[0552] In some embodiments, the compound has the formula (IW):

[0553]

[0554] Or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or mixture thereof.

[0555] In some embodiments, the compound is a compound described in Table 1 or a prodrug or a pharmaceutically acceptable salt thereof.

[0556] In some embodiments, the compound is a compound described in Table 1 or a pharmaceutically acceptable salt thereof.

[0557] In some embodiments, the compound is a prodrug of the compound described in Table 1 or a pharmaceutically acceptable salt thereof.

[0558] In some embodiments, the compound is one of the compounds described in Table 1.

[0559] In some embodiments, the compound is a compound described in Table 2 or a prodrug or a pharmaceutically acceptable salt thereof.

[0560] In some embodiments, the compound is a compound described in Table 2 or a pharmaceutically acceptable salt thereof.

[0561] In some embodiments, the compound is a prodrug of the compound described in Table 2 or a pharmaceutically acceptable salt thereof.

[0562] In some embodiments, the compound is one of the compounds described in Table 2.

[0563] In some embodiments, the compound is a compound described in Table 3 or a prodrug or a pharmaceutically acceptable salt thereof.

[0564] In some embodiments, the compound is a compound described in Table 3 or a pharmaceutically acceptable salt thereof.

[0565] In some embodiments, the compound is a prodrug of the compound described in Table 3 or a pharmaceutically acceptable salt thereof.

[0566] In some embodiments, the compound is one of the compounds described in Table 3.

[0567] In some embodiments, the compound is a compound described in Table 4 or a prodrug or a pharmaceutically acceptable salt thereof.

[0568] In some embodiments, the compound is a compound described in Table 4 or a pharmaceutically acceptable salt thereof.

[0569] In some embodiments, the compound is a prodrug of the compound described in Table 4 or a pharmaceutically acceptable salt thereof.

[0570] In some embodiments, the compound is one of the compounds described in Table 4.

[0571] The compounds in Table 1-4 are each assigned a compound number, and some alternative compound numbers are indicated in parentheses. For compounds with two compound numbers, the two compound numbers can be used interchangeably to refer to the same compound.

[0572] Table 1

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601] Table 2

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610] Table 3

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623] Table 4

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds described in Table 1.

[0653] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds described in Table 2.

[0654] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds described in Table 3.

[0655] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds described in Table 4.

[0656] In some embodiments, the compound is a compound described in Tables 1-3 or a prodrug or a pharmaceutically acceptable salt thereof.

[0657] In some embodiments, the compound is a compound described in Tables 1-3 or a pharmaceutically acceptable salt thereof.

[0658] In some embodiments, the compound is a prodrug of a compound described in Tables 1-3 or a pharmaceutically acceptable salt thereof.

[0659] In some embodiments, the compound is one of the compounds described in Tables 1-3.

[0660] In some embodiments, the compound is a compound described in Tables 1-4 or a prodrug or a pharmaceutically acceptable salt thereof.

[0661] In some embodiments, the compound is a compound described in Tables 1-4 or a pharmaceutically acceptable salt thereof.

[0662] In some embodiments, the compound is a prodrug of the compound described in Tables 1-4 or a pharmaceutically acceptable salt thereof.

[0663] In some embodiments, the compound is one of the compounds described in Tables 1-4.

[0664] In some embodiments, the compound is not compound number 61 (i.e., N-(6-(4-chlorophenyl)thiazo[4,5-b]pyrazin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide).

[0665] In some embodiments, the compound is not compound number 75 (i.e., N-(6-(4-chlorophenyl)thiazo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)-6-methylnicotinamide).

[0666] In some embodiments, the compound is not compound number 118 (i.e., N-(5-(4-chlorophenyl)thiazo[5,4-b]pyridin-2-yl)-4-(2-methoxyphenyl)-6-methylnicotinamide).

[0667] In some embodiments, the compounds are selected from compounds 1-60, 62-74, 76-117, and 119-358.

[0668] In some aspects, this disclosure provides a compound that is an isotopic derivative (e.g., an isotopically labeled compound) of any of the compounds of the formula disclosed herein.

[0669] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof.

[0670] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 1 or a pharmaceutically acceptable salt thereof.

[0671] In some embodiments, the compound is an isotopic derivative of any of the prodrugs of the compounds described in Table 1 or a pharmaceutically acceptable salt thereof.

[0672] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 1.

[0673] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 2, or a prodrug or a pharmaceutically acceptable salt thereof.

[0674] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 2 or a pharmaceutically acceptable salt thereof.

[0675] In some embodiments, the compound is an isotopic derivative of any of the prodrugs of the compounds described in Table 2 or a pharmaceutically acceptable salt thereof.

[0676] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 2.

[0677] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 3, or a prodrug or a pharmaceutically acceptable salt thereof.

[0678] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 3 or a pharmaceutically acceptable salt thereof.

[0679] In some embodiments, the compound is an isotopic derivative of any of the prodrugs of the compounds described in Table 3 or a pharmaceutically acceptable salt thereof.

[0680] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 3.

[0681] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 4, or a prodrug or a pharmaceutically acceptable salt thereof.

[0682] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 4 or a pharmaceutically acceptable salt thereof.

[0683] In some embodiments, the compound is an isotopic derivative of any of the prodrugs of the compounds described in Table 4 or a pharmaceutically acceptable salt thereof.

[0684] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 4.

[0685] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Tables 1-3, or a prodrug or pharmaceutically acceptable salt thereof.

[0686] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Tables 1-3 or a pharmaceutically acceptable salt thereof.

[0687] In some embodiments, the compound is an isotopic derivative of any of the prodrugs of the compounds described in Tables 1-3 or a pharmaceutically acceptable salt thereof.

[0688] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Tables 1-3.

[0689] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Tables 1-4, or a prodrug or pharmaceutically acceptable salt thereof.

[0690] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Tables 1-4 or a pharmaceutically acceptable salt thereof.

[0691] In some embodiments, the compound is an isotopic derivative of any of the prodrugs of the compounds described in Tables 1-4 or a pharmaceutically acceptable salt thereof.

[0692] In some embodiments, the compound is an isotopic derivative of any of the compounds described in Tables 1-4.

[0693] In some embodiments, the compound is selected from compounds No. 1, 10, 24, 25, 59, 207, 211, 212, 224, 235, 238, 239 and 244, or their prodrugs or pharmaceutically acceptable salts.

[0694] In some embodiments, the compound is selected from compounds 1, 10, 24, 25, 59, 207, 211, 212, 224, 235, 238, 239 and 244 or pharmaceutically acceptable salts thereof.

[0695] In some embodiments, the compound is selected from compounds No. 1, 10, 24, 25, 59, 207, 211, 212, 224, 235, 238, 239 and 244.

[0696] In some embodiments, the compound is selected from compounds No. 3, 12, 280, 282, 288, 308, 359, 360, 361B, 368, 377, 386, 391, 394, 403, 427, 432, 447, 451A, 454, 462, 464, 467, 486, 489, 498, 502, 504, 506, 514, 518, 520, 521 and 522, or their prodrugs or pharmaceutically acceptable salts.

[0697] In some embodiments, the compound is selected from compounds 3, 12, 280, 282, 288, 308, 359, 360, 361B, 368, 377, 386, 391, 394, 403, 427, 432, 447, 451A, 454, 462, 464, 467, 486, 489, 498, 502, 504, 506, 514, 518, 520, 521 and 522 or pharmaceutically acceptable salts thereof.

[0698] In some embodiments, the compound is selected from compounds No. 3, 12, 280, 282, 288, 308, 359, 360, 361B, 368, 377, 386, 391, 394, 403, 427, 432, 447, 451A, 454, 462, 464, 467, 486, 489, 498, 502, 504, 506, 514, 518, 520, 521 and 522.

[0699] In some embodiments, the compound is selected from compounds No. 1, 10, 24, 25, 59, 207, 211, 212, 224, 235, 238, 239, 244, 3, 12, 280, 282, 288, 308, 359, 360, 361B, 368, 377, 386, 391, 394, 403, 427, 432, 447, 451A, 454, 462, 464, 467, 486, 489, 498, 502, 504, 506, 514, 518, 520, 521 and 522, or their prodrugs or pharmaceutically acceptable salts.

[0700] In some embodiments, the compound is selected from compounds 1, 10, 24, 25, 59, 207, 211, 212, 224, 235, 238, 239, 244, 3, 12, 280, 282, 288, 308, 359, 360, 361B, 368, 377, 386, 391, 394, 403, 427, 432, 447, 451A, 454, 462, 464, 467, 486, 489, 498, 502, 504, 506, 514, 518, 520, 521, and 522, or pharmaceutically acceptable salts thereof.

[0701] In some embodiments, the compound is selected from compounds No. 1, 10, 24, 25, 59, 207, 211, 212, 224, 235, 238, 239, 244, 3, 12, 280, 282, 288, 308, 359, 360, 361B, 368, 377, 386, 391, 394, 403, 427, 432, 447, 451A, 454, 462, 464, 467, 486, 489, 498, 502, 504, 506, 514, 518, 520, 521, and 522.

[0702] In some embodiments, the compound is a compound that can be obtained by the methods described herein; optionally, the methods comprise one or more steps described in schemes 1-11.

[0703] It should be understood that isotope derivatives can be prepared using any of the various techniques recognized in the art. For example, isotope derivatives can generally be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents by performing the procedures disclosed in the schemes and / or examples described herein.

[0704] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[0705] In some embodiments, the isotope derivative is a deuterium-labeled compound of any of the compounds of the formulas disclosed herein.

[0706] As used herein, the term "isotope derivative" refers to a derivative of a compound in which one or more atomic isotopes are enriched or labeled. For example, an isotope derivative of a compound of formula (I) is isotopically enriched relative to one or more isotopes, or labeled with said one or more isotopes, compared to a corresponding compound of formula (I). In some embodiments, the isotope derivative is isotopically enriched relative to a compound selected from... 2 H, 13 C 14 C 15 N、 18 O、 29 Si、 31 P and 34 One or more atoms of S are enriched or labeled with said one or more atoms. In some embodiments, the isotope derivative is a deuterium-labeled compound (i.e., enriched relative to one or more of its atoms). 2 H). In some embodiments, the compound is 18 F-labeled compounds. In some embodiments, the compound is 123 I-labeled compounds, 124 I-labeled compounds, 125 I-labeled compounds, 129 I-labeled compounds, 131 I-labeled compounds, 135 I-labeled compounds or any combination thereof. In some embodiments, the compound is 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compounds or any combination thereof.

[0707] It should be understood that 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and / or 36 S-labeled compounds can be prepared using any of the various techniques recognized in this art. For example, deuterium-labeled compounds can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, by using... 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S,34 S, 35 S and / or 36 The preparation is carried out by replacing the non-isotope labeled reagent with an S-labeled reagent.

[0708] Containing the above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and 36 One or more of the S atoms in the compounds of the present invention, or their pharmaceutically acceptable salts or solvates, are within the scope of the present invention. Further, 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 S) substitution can provide certain therapeutic advantages, which stem from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements.

[0709] For the avoidance of doubt, it should be understood that in this specification, if a group is defined as “described herein”, then the group encompasses the earliest and broadest definition as well as each and all specific definitions of that group.

[0710] The various functional groups and substituents of compounds of formula (I) are typically chosen such that the molecular weight of the compound does not exceed 1000 Daltons. More typically, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700 or less than 650 Daltons. More conveniently, the molecular weight is less than 600 and, for example, 550 Daltons or less.

[0711] Suitable pharmaceutically acceptable salts of the compounds disclosed herein are, for example, acid addition salts of the compounds of this disclosure that are sufficiently basic, such as acid addition salts formed with, for example, inorganic or organic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citrate methanesulfonate, or maleic acid). Additionally, suitable pharmaceutically acceptable salts of the compounds of this disclosure that are sufficiently acidic are alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts of organic bases that provide pharmaceutically acceptable cations, such as salts formed with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris(2-hydroxyethyl)amine.

[0712] It will be understood that any compound of any formula disclosed herein and any pharmaceutically acceptable salt thereof comprises stereoisomers of said compound, mixtures of stereoisomers, and polymorphs of all isomeric forms.

[0713] It will be understood that while the compounds disclosed herein may be presented in a particular configuration, such particular configuration should not be construed as limiting this disclosure to one or another isomer, tautomer, regio isomer, or stereoisomer, nor preclude mixtures of isomers, tautomers, regio isomers, or stereoisomers. In some embodiments, compounds presented herein in a particular configuration are intended to cover and refer to each of the available isomers, tautomers, regio isomers, and stereoisomers of the compound or any mixture thereof; and presentation is further intended to refer to a specific configuration of the compound.

[0714] It will be understood that while the compounds disclosed herein may be presented without specifying a configuration (e.g., without specifying a stereochemistry), such presentation is intended to cover all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, compounds presented herein without specifying a configuration are intended to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound or any mixture thereof.

[0715] As used herein, the term "isomer" refers to compounds with the same molecular formula but different atomic bonding sequences or different spatial arrangements. Isomers with different atomic spatial arrangements are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomers with opposite chirality is called a "racemic mixture."

[0716] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0717] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds having more than one chiral center may exist as individual diastereomers or as mixtures of diastereomers (referred to as "diastereomer mixtures"). In the presence of one chiral center, the stereoisomer can be characterized by the absolute configuration (R or S) of said chiral center. Absolute configuration refers to the spatial arrangement of the substituents connected to the chiral center. The substituents considered for connection to the chiral center were ordered according to the following sequence rule: Cahn, 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, Journal of the Chemical Society (J. Chem. Soc.), 1951 (London), 612; Cahn et al., Experientia, 1956, 12, 81; Cahn, J. Chem. Educ., 1964, 41, 116).

[0718] As used herein, the term "geometric isomer" refers to a diastereomer that exists due to hindered rotation around a double bond or cycloalkyl linking group (e.g., 1,3-cyclobutyl). These configurations are distinguished by the prefixes cis and trans or Z and E, which, according to the Cahn-Ingold-Prelog rule, indicate that the group is located on the same or opposite side of the double bond in the molecule.

[0719] It should be understood that the compounds of this disclosure may be described as different chiral isomers or geometric isomers. It should also be understood that when a compound has chiral or geometric isomers, all isomers are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any isomer. It should be understood that not all isomers may have the same level of activity.

[0720] It should be understood that the structures and other compounds discussed in this disclosure include all their atropicisomers. It should also be understood that not all atropicisomers possess the same level of activity.

[0721] As used herein, the term "transisomer" refers to a class of stereoisomers in which the atoms of two isomers are arranged differently in space. Transisomers exist due to rotational restriction caused by the impaired rotation of the large group around the central bond. Such transisomers are usually present as mixtures; however, due to recent advances in chromatographic techniques, mixtures of two transisomers can now be separated under selected conditions.

[0722] As used herein, the term "tautomer" is one of two or more structural isomers existing in equilibrium and readily transforming from one isomer to another. This transformation results in the transfer of hydrogen atoms accompanied by the conversion of adjacent conjoined double bonds. Tautomers exist in solution as a mixture of tautomer groups. In solutions where tautomerization is possible, tautomers will reach chemical equilibrium. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that interconvert through tautomerization is called tautomerism. Among the various possible types of tautomerism, two tautomers are typically observed. In keto-enol tautomerism, simultaneous transfer of electrons and hydrogen atoms occurs. Cyclic-chain tautomerism arises from the reaction of an aldehyde group (-CHO) in a sugar molecule with one of a hydroxyl group (-OH) in the same molecule, resulting in a cyclic (ring-like) form, as exhibited by glucose.

[0723] It should be understood that the compounds of this disclosure can be described as different tautomers. It should also be understood that when a compound has tautomer forms, all tautomer forms are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any tautomer form. It will be understood that some tautomers may have higher activity levels than others.

[0724] Compounds with the same molecular formula but different atomic bonding properties or sequences, or different spatial arrangements of atoms, are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetry center and described by the R- and S-ordering rules of Cahn and Prelog, or by rotating the molecule in a plane of polarized light and designating it as dextrorotatory or levorotatory (i.e., (+) or (--)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0725] The compounds disclosed herein may have one or more asymmetric centers; therefore, such compounds may be produced as individual (R) or (S) stereoisomers or mixtures thereof. Unless otherwise stated, the description or naming of particular compounds in the specification and claims is intended to include individual enantiomers and mixtures thereof, racemic or other forms. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of *Advanced Organic Chemistry*, 4th edition, J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by decomposition of racemic forms. Some compounds of this disclosure may have geometric isomer centers (E and Z isomers). It should be understood that this disclosure covers all optical, diastereomers and geometric isomers with polymerase Θ inhibitory activity, as well as mixtures thereof.

[0726] This disclosure also covers compounds of this disclosure that contain one or more isotope substitutions as defined herein.

[0727] It should be understood that, where applicable, compounds having any formula described herein include the compound itself as well as its salts and solvates. For example, salts can be formed between an anion on a substituted compound disclosed herein and a positively charged group (e.g., an amino group). Suitable anions include chlorides, bromides, iodides, sulfates, hydrogen sulfates, aminosulfonates, nitrates, phosphates, citrates, methanesulfonates, trifluoroacetates, glutamates, glucurons, glutarates, malates, maleates, succinates, fumarates, tartrates, toluenesulfonates, salicylates, lactates, naphthalenesulfonates, and acetates (e.g., trifluoroacetates).

[0728] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation on the substituted compounds disclosed herein and a negatively charged group (e.g., a carboxylate). Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine ions. The substituted compounds disclosed herein also include salts containing a tetravalent nitrogen atom.

[0729] It should be understood that the compounds disclosed herein, such as salts of the compounds, may exist in hydrated or unhydrated (anhydrous) forms, or as solvates containing other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0730] As used herein, the term "solvent" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in a crystalline solid state, thereby forming a solvate. If the solvent is water, the formed solvate is a hydrate, and if the solvent is an alcohol, the formed solvate is an alcohol. A hydrate is formed by combining one or more water molecules with a molecule of a substance in which water retains its molecular state as H₂O.

[0731] As used herein, the term "analogue" refers to a compound that is structurally similar to another compound but differs slightly in composition (e.g., an atom is substituted by an atom of a different element, or a specific functional group is present, or a functional group is substituted by another functional group). Thus, an analogue is a compound that is functionally similar or equivalent to a reference compound but not structurally similar or equivalent in origin.

[0732] As used herein, the term “derivative” refers to a compound having a common core structure and being substituted by various groups as described herein.

[0733] As used herein, the term "bioisostere" refers to a compound resulting from the exchange of one atom or group of atoms with another substantially similar atom or group of atoms. The aim of bioisostere substitution is to produce new compounds with biological properties similar to those of the parent compound. Bioisostere substitution can be based on physicochemical or topological principles. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazolium, sulfonates, and phosphonates. See, for example, Patani and LaVoie, *Chem. Rev.*, 96, 3147-3176, 1996.

[0734] It should also be understood that certain compounds of any of the formulas disclosed herein may exist in both solvated and non-solvated forms (e.g., hydrated forms). Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that this disclosure covers all such solvated forms having polymerase Θ inhibitory activity.

[0735] It should also be understood that certain compounds of any of the formulas disclosed herein may exhibit polymorphism, and this disclosure covers all such forms or mixtures thereof having polymerase Θ inhibitory activity. It is well known that crystalline materials can be analyzed 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, solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0736] Compounds of any formula disclosed herein may exist in a variety of different tautomer forms, and references to compounds of formula (I) include all such forms. For the avoidance of ambiguity, if a compound may exist in one of several tautomer forms and only one tautomer form is specifically described or shown, formula (I) still covers all other forms. Examples of tautomer forms include ketone forms, enol forms, and enol salt forms, such as in, for example, the following tautomer pairs: ketone / enol (as shown below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / acid-nitro.

[0737]

[0738] Compounds of any of the formulas containing amine functional groups disclosed herein can also form N-oxides. References to compounds of formula (I) containing amine functional groups herein also include N-oxides. In the case of compounds containing several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms in nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, *Advanced Organic Chemistry*, Jerry March, 4th ed., Wiley Interscience, p. More specifically, N-oxides can be prepared using the LWDeady procedure (*Synthetic Communications*, 1977, 7, 509-514), in which the amine compound is reacted, for example, with m-chloroperoxybenzoic acid (mCPBA) in an inert solvent (e.g., dichloromethane).

[0739] Compounds of any of the formulas disclosed herein can be administered as prodrugs, which are broken down in the human or animal body to release the disclosed compounds. Prodrugs can be used to modify the physical properties and / or pharmacokinetic properties of the disclosed compounds. Prodrugs can be formed when the disclosed compounds contain suitable groups or substituents to which a characteristic modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any of the formulas disclosed herein.

[0740] Therefore, this disclosure includes compounds of any of the formulas disclosed herein as defined above, when they are available through organic synthesis and in humans or animals through the cleavage of their prodrugs. Thus, this disclosure includes compounds of any of the formulas disclosed herein produced by organic synthesis, as well as such compounds produced in humans or animals through the metabolism of precursor compounds; that is, compounds of any of the formulas disclosed herein can be synthetically produced or metabolically produced compounds.

[0741] The appropriate pharmaceutically acceptable prodrug of any of the formulas disclosed herein is a prodrug that is suitable for administration to humans or animals without undesirable pharmacological activity and without excessive toxicity, based on reasonable medical judgment. Various forms of prodrugs have been described in documents such as: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985); c) Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5, “Design and Application of Prodrugs”, by H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Review of Advanced Drug Delivery. e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, Pro-Drugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14; and h) E. Roche (ed.), Bioreversible Carriers in Drug Design, Pergamon Press, 1987.

[0742] Suitable pharmaceutically acceptable prodrugs of compounds having any of the hydroxyl groups disclosed herein are, for example, esters or ethers that are cleavable in vivo. Suitable pharmaceutically acceptable ester-forming groups for the hydroxyl groups include inorganic esters, such as phosphate esters (including cyclic aminophosphate esters). Other suitable pharmaceutically acceptable ester-forming groups for the hydroxyl groups include: C1-C... 10 Alkyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups; C1-C 10 Alkoxycarbonyl groups, such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2-carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Examples of cyclic substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinemethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxyl group include α-acyloxyalkyl groups, such as acetoxymethyl and neopentyloxymethyl.

[0743] Suitable pharmaceutically acceptable prodrugs of any of the compounds having a carboxyl group disclosed herein are, for example, amides that are cleavable in vivo, such as amides formed with: amines, such as ammonia; C 1-4 Alkylamines, such as methylamine; (C1-C4 alkyl)2amines, such as dimethylamine; N-ethyl-N-methylamine or diethylamine; C1-C4 alkoxy-C2-C4 alkylamines, such as 2-methoxyethylamine; phenyl-C1-C4 alkylamines, such as benzylamine; and amino acids, such as glycine or its esters.

[0744] Suitable pharmaceutically acceptable prodrugs of compounds having any of the amino groups disclosed herein are, for example, their in vivo cleavable amide derivatives. Suitable pharmaceutically acceptable amides derived from amino groups include, for example, those using C1-C... 10 Alkyl groups, such as acetyl, benzoyl, phenylacetyl, and amides formed by substituted benzoyl and phenylacetyl groups. Examples of cyclic substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinemethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl.

[0745] The in vivo effects of compounds of any of the formulas disclosed herein may be exerted in part by one or more metabolites formed in the human or animal body following administration of a compound of any of the formulas disclosed herein. As stated above, the in vivo effects of compounds of any of the formulas disclosed herein may also be exerted by the metabolism of a prodrug.

[0746] Appropriately, this disclosure excludes any individual compound that does not have the biological activity defined herein.

[0747] Synthesis method

[0748] In some aspects, this disclosure provides a method for preparing the compounds of this disclosure.

[0749] In some aspects, this disclosure provides a method for processing a compound, the method comprising one or more steps as described herein.

[0750] In some aspects, this disclosure provides a compound that can be obtained by, or by, the methods described herein for preparing compounds as described, or directly by the methods described herein.

[0751] In some respects, this disclosure provides intermediates as described herein, which are suitable for use in methods of preparing compounds as described herein.

[0752] The compounds disclosed herein can be prepared by any suitable technique known in the art. Specific processes for preparing these compounds are further described in the appended examples.

[0753] In the description of the synthetic methods described herein and any reference synthetic methods for preparing starting materials, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and operating procedure, can be selected by those skilled in the art.

[0754] Those skilled in the art of organic synthesis should understand that the functionality present in each part of a molecule must be compatible with the reagents and reaction conditions used.

[0755] It will be understood that during the synthesis of the compounds of this disclosure in the process defined herein, or during the synthesis of certain starting materials, it may be necessary to protect certain substituents to prevent them from undergoing undesirable reactions. Skilled chemists will understand when such protection is needed and how such protecting groups can be placed in place and subsequently removed. For examples of protecting groups, see one of the many general textbooks on the subject, such as Theodora Green's *Protecting Groups in Organic Synthesis* (published by John Willie & Sons). Protecting groups can be removed as needed by any convenient method described in the literature or known to skilled chemists for removing the protecting groups in question, chosen to achieve removal with minimal interference to groups elsewhere in the molecule. Thus, for example, if the reactants include groups such as amino, carboxyl, or hydroxyl groups, it may be desirable to protect said groups in some of the reactions mentioned herein.

[0756] For example, suitable protecting groups for amino or alkylamino groups are: acyl groups, such as alkanoyl groups, like acetyl groups; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl groups; arylmethoxycarbonyl groups, such as benzyloxycarbonyl groups; or aromatic acyl groups, such as benzoyl groups. The deprotection conditions for these protecting groups must vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl, alkoxycarbonyl, or aromatic acyl groups can be removed, for example, by hydrolysis with 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, for example, by treatment with a suitable acid (such as hydrochloric acid, sulfuric acid, or phosphoric acid or trifluoroacetic acid), and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed, for example, by hydrogenation over a catalyst such as palladium / carbon or by treatment with a Lewis acid such as tri(trifluoroacetate)borane. Suitable alternative protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with alkylamines (e.g., dimethylaminopropylamine) or with hydrazine.

[0757] Suitable protecting groups for hydroxyl groups are, for example, acyl groups, such as alkanoyl groups, like acetyl groups; aromatic acyl groups, such as benzoyl groups; or arylmethyl groups, such as benzyl groups. The deprotection conditions for these protecting groups will necessarily vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl or aromatic acyl groups can be removed, for example, by hydrolysis with a suitable base (such as an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, or ammonia). Alternatively, arylmethyl groups such as benzyl groups can be removed, for example, by hydrogenation over a catalyst such as palladium / carbon.

[0758] Suitable protecting groups for the carboxyl group are, for example, esterification groups, such as methyl or ethyl, which can be removed, for example, by alkaline hydrolysis with a base such as sodium hydroxide; or, for example, tert-butyl, which can be removed, for example, by treatment with an acid (such as an organic acid such as trifluoroacetic acid); or, for example, benzyl, which can be removed, for example, by hydrogenation on a catalyst such as palladium / carbon.

[0759] Once a compound of formula (I) has been synthesized by any of the processes defined herein, the processes defined herein may further include the following additional steps: (i) removal of any existing protecting groups; (ii) conversion of a compound of formula (I) into another compound of formula (I); (iii) formation of its pharmaceutically acceptable salt, hydrate or solvate; and / or (iv) formation of its prodrug.

[0760] The resulting compound (I) can be separated and purified using techniques well known in the art.

[0761] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the corresponding reaction conditions. Examples of suitable solvents include, but are not limited to: 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, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE), or dioxane; ethyl... Glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diethylene glycol dimethyl ether); ketones, such as acetone, methyl isobutyl ketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidone (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 the solvents or mixtures with water.

[0762] Depending on the reaction steps and the conditions used, the reaction temperature is appropriately between approximately -100°C and 300°C.

[0763] Reaction times typically range from fractions of a minute to several days, depending on the reactivity of the corresponding compound and the relevant reaction conditions. Suitable reaction times can be readily determined using methods known in the art, such as reaction monitoring. Based on the reaction temperatures given above, suitable reaction times are generally between 10 minutes and 48 hours.

[0764] Furthermore, other compounds disclosed herein can be readily prepared using the procedures described herein in conjunction with common techniques in the art. Those skilled in the art will readily understand that known variations of the conditions and processes in the following preparation procedures can be used to prepare these compounds.

[0765] As will be understood by those skilled in the art of organic synthesis, the compounds of this disclosure can be readily obtained by a variety of synthetic routes, some of which are illustrated in the appended examples. Those skilled in the art will readily recognize which types of reagents and reaction conditions to use, and how to apply and adjust these reagents and reaction conditions in any particular case, when necessary or useful, to obtain the compounds of this disclosure. Furthermore, some of the compounds of this disclosure can be readily synthesized by reacting other compounds of this disclosure under suitable conditions, for example by converting a particular functional group present in the compounds of this disclosure or a suitable precursor molecule thereof into another functional group via standard synthetic methods (such as reduction, oxidation, addition, or substitution reactions); these methods are well known to those skilled in the art. Similarly, those skilled in the art will apply synthetic protecting (or protective) groups when necessary or useful; suitable protecting groups and methods for their introduction and removal are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in PGM Wuts, TW Greene, “Greene's Protective Groups in Organic Synthesis”, 4th edition (2006) (John Willie & Sons).

[0766] The general route for preparing the compounds of this application is described in Schemes 1-11 herein.

[0767] Although the invention has been described with reference to the specific examples set forth above, many alternatives, modifications, and variations will be apparent to those skilled in the art. In some cases, the order of steps in performing the reaction scheme can be altered to promote the reaction or avoid unwanted reaction products. Starting materials and intermediates are commercially available, prepared by known procedures, or otherwise described.

[0768] Several methods for preparing the compounds of the present invention are described in the following schemes and examples. Unless otherwise stated, all variables are as previously defined.

[0769] Option 1

[0770]

[0771] In Scheme 1, boronic ester or boric acid 2 is suzuki-coupling with halopyridine 1 to give ester 3. The ester can be hydrolyzed under alkaline conditions (e.g., by using NaOH) to give carboxylic acid 4.

[0772] Option 2

[0773]

[0774] In scheme 2, carboxylic acid 4 can be prepared in two steps via Suzuki coupling with borate 5 and aryl halide 6. Ester 7 can be hydrolyzed under alkaline conditions (e.g., by using NaOH) to form carboxylic acid 4.

[0775] Option 3

[0776]

[0777] In scheme 3, S with amine 8 and halopyridine 1 N Ar yields ester 9. Alkaline hydrolysis (e.g., by using NaOH) yields carboxylic acid 10.

[0778] Option 4

[0779]

[0780] In Scheme 4, amide 13 can be prepared in one step by amide coupling of carboxylic acid 11 and amine 12 using a coupling agent (e.g., by using HATU or other common amide coupling agents) and a base (e.g., DIPEA).

[0781] Option 5

[0782]

[0783] In scheme 5, amine 15 can be formed by Suzuki coupling with aryl halide 14 and boronic ester or boric acid, followed by a deprotection step (e.g., by removing the Boc group using an acid). Amide coupling with carboxylic acid 16 (e.g., by using HATU or other common amide coupling agents) yields halopyridine 17, which can be functionalized by the Suzuki reaction to give amide 18. Alternatively, the amine can be formed by S... N Ar is added to 17 to get 19.

[0784] Option 6

[0785]

[0786] In Scheme 6, amine 20 can be prepared by Ullman coupling of aryl halide 14 and amine, followed by a deprotection step to obtain amine 21 (e.g., by removing the Boc group using an acid). Amine 21 can be converted to amide 22 by amide coupling with carboxylic acid 11 (e.g., by using HATU or other common amide coupling agents).

[0787] Option 7

[0788]

[0789] In scheme 7, aryl halide 25 can be formed by adding amine 24 to α-haloketone 23. Amination yields primary amine 26, which is then coupled with an amide of carboxylic acid 11 (e.g., by using EDCI or other common coupling agents) to yield amide 27.

[0790] Option 8

[0791]

[0792] In Scheme 8, the amide coupling between acid 11 and diamine 28 yields amide 29. The condensation reaction between amine 29 and an α-haloketone yields carboxylic acid 30, which can undergo amide coupling with an amine to yield amide 31. Alternatively, amine 29 can be condensed with an α-haloketone 32 to yield amide 27.

[0793] Option 9

[0794]

[0795] In scheme 9, amide 33 can be formed by amide coupling between carboxylic acid 11 and amine 32. The amide 34 is then obtained by the Suzuki reaction with aryl halide 33. Alternatively, amide 34 is obtained by Stillecoupling with a tin reagent and aryl bromide 33. Aryl bromide 33 can be converted to arylamine 35 by Buchwald or Ullmann coupling. In another method, aryl halide 33 can be converted to borate 36, followed by Suzuki coupling with an aryl halide to obtain amide 34.

[0796] Option 10

[0797]

[0798] In scheme 10, aryl bromide 33 can be obtained through S N Ar is converted into arylamine 35.

[0799] Option 11

[0800]

[0801] In scheme 11, aryl halide 33 can be converted into amide 36 via a three-step process, the three steps being carbonylation, hydrolysis under basic conditions, and amide coupling. Alternatively, aryl bromide 33 can be converted into amide 37 via palladium-catalyzed cross-coupling of a primary amide.

[0802] Bioassay

[0803] Once compounds designed, selected, and / or optimized using the methods described above are generated, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds possess biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether these molecules possess predicted activity, binding activity, and / or binding specificity.

[0804] Furthermore, high-throughput screening can be used to accelerate analyses using such assays. Therefore, the activity of the molecules described herein can be rapidly screened using techniques known in the art. General methods for performing high-throughput screening are described, for example, in the following literature: Devlin (1998), "High Throughput Screening," Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can be performed using one or more different assay techniques, including, but not limited to, those described below.

[0805] Various in vitro or in vivo bioassays may be suitable for detecting the effects of the compounds disclosed herein. These in vitro or in vivo bioassays may include, but are not limited to, enzyme activity assays, electrophoretic mobility variation assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0806] In some embodiments, bioassays are described in the examples herein.

[0807] In some embodiments, the bioassay is an ATPase assay.

[0808] In some embodiments, the ATPase assay of the compounds of this disclosure is combined with biotinylated Avi-POLΘ[2-894], 50 nucleotide polythymidine repeat single-stranded DNA, and ATP in a buffer. In some embodiments, the mixture is incubated and ADP-Glo ​​reagent is added, followed by a subsequent incubation. In some embodiments, a kinase detection reagent may be added, followed by a third incubation.

[0809] In some embodiments, activity is measured by luminescence signals (e.g., using an EnVision multi-mode reader).

[0810] Pharmaceutical Composition

[0811] In some aspects, this disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, this disclosure provides a pharmaceutical composition comprising at least one compound of each formula described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, this disclosure provides a pharmaceutical composition comprising compounds described in Tables 1-4. In some embodiments, this disclosure provides a pharmaceutical composition comprising at least one compound selected from Tables 1-4. In some aspects, this disclosure provides a pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0812] As used herein, the term "composition" is intended to cover products containing specified amounts of specified ingredients, and any products directly or indirectly produced by combinations of specified amounts of specified ingredients.

[0813] The compounds disclosed herein can be formulated into forms for oral administration, such as tablets, capsules (each of which includes a sustained-release or delayed-release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds disclosed herein can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those skilled in the art of pharmacy.

[0814] The formulations disclosed herein may be in the form of an aqueous solution comprising an aqueous mediator. The aqueous mediator component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of: solubilizers, chelating agents, preservatives, tensile agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0815] Any suitable solubilizer may be used. Examples of solubilizers include cyclodextrins, such as those selected from the group consisting of: hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonium)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfonyl ether, branched-chain-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, random methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin and mixtures thereof.

[0816] 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 salt, disodium edetate, trisodium edetate, and tetrasodium edetate and mixtures thereof.

[0817] Any suitable preservative can be used. Examples of preservatives include those selected from the group consisting of: quaternary ammonium salts, such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzyl chloride, hexadecylpyridine chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, polyurethane biguanide, and butylparaben and sorbic acid and mixtures thereof.

[0818] Aqueous mediators may also include tensioning agents to adjust tension (osmotic pressure). Tensileing agents may be selected from the group consisting of: ethylene glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextran, glycerin, mannitol, potassium chloride and sodium chloride, and mixtures thereof.

[0819] Aqueous mediators may also contain viscosity agents / suspending agents. Suitable viscosity agents / suspending agents include those selected from the group consisting of: cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropyl methylcellulose, and crosslinked acrylic polymers (carbomers), such as polymers of acrylic acid crosslinked with polyolefin ethers or divinyl glycol (carbomers such as carbomer 934, carbomer 934P, carbomer 971, carbomer 974, and carbomer 974P) and mixtures thereof.

[0820] To adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, specifically 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 a pH adjuster. The pH adjuster is typically a mineral acid or a metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to a target acceptable pH range. Therefore, it may not be necessary to use both an acid and a base, depending on the formulation; adding either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0821] Aqueous mediators may also contain buffers to stabilize pH. When used, buffers are selected from the group consisting of: phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts, including disodium tetraborate), citrate buffers (such as citric acid or its salts, including sodium citrate), and ε-aminocaproic acid and mixtures thereof.

[0822] The formulation may further include a wetting agent. Suitable types of wetting agents include those selected from the group consisting of: polyoxypropylene-polyoxyethylene block copolymers (poloxamer), polyethoxylated ethers of castor oil, polyoxyethylene-modified sorbitan esters (polysorbate), polymers of oxyethylene-modified octylphenol (Tyloxapol), polyethylene glycol 40 stearate, ethylene glycol esters of fatty acids, glyceryl esters of fatty acids, sucrose fatty acid esters, and polyoxyethylene fatty acid esters and mixtures thereof.

[0823] Oral compositions typically include an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be incorporated with excipients and used in tablet, lozenge, or capsule form. Oral compositions may also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and gargled, then spat out or swallowed. Pharmaceutically compatible binders and / or adjuvants may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, primordial gluten, or corn starch; lubricants, such as magnesium stearate or strobilurin; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.

[0824] According to another aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0825] The compositions disclosed herein may be in the form suitable for oral use (e.g., as tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), in the form suitable for topical use (e.g., as creams, ointments, gels or aqueous or oily solutions or suspensions), in the form suitable for inhalation (e.g., as finely divided powders or liquid aerosols), in the form suitable for inhalation (e.g., as finely divided powders), or in the form suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0826] The compositions disclosed herein can be obtained using conventional procedures employing conventional pharmaceutical excipients well known in the art. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0827] An effective amount of the compound disclosed herein for treatment is sufficient to treat or prevent the polymerase Θ-related symptoms mentioned herein, slow their progression, and / or alleviate symptoms associated with the symptoms.

[0828] An effective amount of the compound disclosed herein for treatment is sufficient to treat the polymerase Θ-related symptoms mentioned herein, slow its progression, and / or alleviate symptoms associated with the symptoms.

[0829] According to well-known medical principles, the dosage of a compound of formula (I) used for therapeutic or preventative purposes will vary naturally depending on the nature and severity of the symptoms, the age and sex of the animal or patient, and the route of administration.

[0830] How to use

[0831] In some aspects, this disclosure provides a method for regulating DNA polymerase Θ activity, the method comprising contacting cells with a compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0832] In some aspects, this disclosure provides a method for regulating DNA polymerase Θ activity (e.g., in vitro or in vivo), the method comprising contacting cells with an effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0833] In some aspects, this disclosure provides a method for regulating DNA polymerase Θ activity (e.g., in vitro or in vivo), the method comprising contacting cells with a compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0834] In some aspects, this disclosure provides a method for regulating DNA polymerase Θ activity (e.g., in vitro or in vivo), the method comprising contacting cells with an effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0835] In some aspects, this disclosure provides a method for regulating DNA polymerase Θ activity (e.g., in vitro or in vivo), the method comprising contacting cells with a compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0836] In some aspects, this disclosure provides a method for treating or preventing a disease or condition in a subject in need, the method comprising administering to the subject a compound of the disclosure or a pharmaceutically acceptable salt thereof.

[0837] In some aspects, this disclosure provides a method for treating or preventing a disease or condition disclosed herein in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0838] In some aspects, this disclosure provides a method for treating a subject with a disease or condition disclosed herein, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[0839] In some aspects, this disclosure provides a method for treating or preventing a disease or condition disclosed herein in a subject of need, the method comprising administering to the subject a compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0840] In some aspects, this disclosure provides a method for treating a subject with a disease or condition disclosed herein, the method comprising administering to the subject a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[0841] In some aspects, this 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 present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure. In some embodiments, the cancer is a HR-deficient cancer.

[0842] In some aspects, this disclosure provides a method for treating and / or preventing cancer in a patient, wherein the cancer is characterized by reduced or absent BRCA gene expression, absence of the BRCA gene, or reduced function of the BRCA protein, the method comprising administering to a subject a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

[0843] In some embodiments, the disease or condition is related to the activity of DNA polymerase Θ involved. In some embodiments, the disease or condition is a disease or condition involving DNA polymerase Θ activity.

[0844] In some embodiments, the disease or condition is related to the activity of DNA polymerase Θ involved. In some embodiments, the disease or condition is a disease or condition involving DNA polymerase Θ activity.

[0845] In some embodiments, the disease or condition is cancer.

[0846] In some aspects, this disclosure provides a method for treating or preventing cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[0847] In some aspects, this disclosure provides a method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[0848] In some aspects, this disclosure provides a method for treating or preventing cancer in a subject of need, the method comprising administering to the subject a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[0849] In some aspects, this disclosure provides a method of treating cancer in a subject in need, the method comprising administering to the subject a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[0850] In some aspects, this disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for regulating DNA polymerase Θ activity.

[0851] In some aspects, this disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt thereof for regulating DNA polymerase Θ activity (e.g., in vitro or in vivo).

[0852] In some aspects, this disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt thereof for regulating DNA polymerase Θ activity (e.g., in vitro or in vivo).

[0853] In some aspects, this disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for inhibiting DNA repair by DNA polymerase Θ in cells. In some embodiments, the cells are HR-deficient cells.

[0854] In some aspects, this disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating and / or preventing a disease in a patient, wherein the disease is characterized by overexpression of DNA polymerase Θ.

[0855] In some aspects, this disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating and / or preventing cancer in patients, wherein said cancer is characterized by reduced or absent BRCA gene expression, absence of the BRCA gene, or reduced function of the BRCA protein.

[0856] In some embodiments, BRCA is BRCA1. In some embodiments, BRCA is BRCA2.

[0857] In some aspects, this disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of HR-deficient cancer in patients.

[0858] In some aspects, this disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the treatment or prevention of a disease or condition.

[0859] In some respects, this disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt thereof for the treatment or prevention of the diseases or conditions disclosed herein.

[0860] In some respects, this disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt thereof for treating the diseases or conditions disclosed herein.

[0861] In some respects, this disclosure provides a compound of the disclosure or a pharmaceutically acceptable salt thereof for the treatment or prevention of cancer in a subject in need.

[0862] In some aspects, this disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating cancer in a subject of need. In some aspects, this disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for the preparation of a medicament for regulating DNA polymerase Θ activity.

[0863] In some respects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof for the preparation of medicaments for regulating DNA polymerase Θ activity (e.g., in vitro or in vivo).

[0864] In some respects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof for the preparation of medicaments for the treatment or prevention of the diseases or conditions disclosed herein.

[0865] In some respects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof for the preparation of medicaments for the treatment of the diseases or conditions disclosed herein.

[0866] In some respects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of cancer in a subject of need.

[0867] In some respects, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof for the preparation of medicaments for the treatment of cancer in subjects of need.

[0868] This disclosure provides compounds that can be used as regulators of DNA polymerase Θ activity.

[0869] In some embodiments, the compounds disclosed herein are antagonists of the DNA polymerase Θ receptor.

[0870] In some embodiments, regulation of the DNA polymerase Θ receptor is the activation of the DNA polymerase Θ receptor.

[0871] In some embodiments, regulation is inhibition.

[0872] The effectiveness of the compounds disclosed herein can be determined according to standard practices as described in the art, through industry-accepted assays / disease models, and can be found in current common sense.

[0873] This disclosure also provides a method for treating a disease or condition 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 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0874] In some embodiments, cancers include lymphoma, soft tissue tumor, rhabdoid tumor, multiple myeloma, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, prostate cancer, breast cancer, ovarian cancer, uterine cancer, lung cancer, fibroblastic cancer, central nervous system cancer, urinary tract cancer, upper respiratory and digestive tract cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer (data from large-scale exit screening of cancer cell lines indicate that some cell lines from the above cancers rely on polymerase Θ for proliferation, see https: / / depmap.org / portal / ).

[0875] In some embodiments, HR-deficient cancer is breast cancer. Breast cancer includes, but is 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 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 teratoma, dysgerminoma, endothelial sinus tumor, granulosa-theca cell tumor, Sertoli-stromal cell tumor, and primary peritoneal cancer. In some cases, ovarian cancer originates from cells of the fallopian tubes.

[0876] In some embodiments, the cancer is selected from ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, or uterine cancer.

[0877] In some embodiments, the cancer is resistant to treatment with at least one PARP inhibitor.

[0878] In some embodiments, the compounds disclosed herein are administered after treatment with at least one PARP inhibitor.

[0879] In some embodiments, the cancer is resistant to treatment with a PARP inhibitor.

[0880] In some embodiments, the subject had previously received treatment with a PARP inhibitor, and the cancer was recurrent or refractory.

[0881] In some embodiments, the PARP inhibitor is a selective PARP inhibitor.

[0882] In some embodiments, the PARP inhibitor is a non-selective PARP inhibitor.

[0883] In some embodiments, the PARP inhibitor is olaparib.

[0884] In some embodiments, cancer is defective in the DNA damage repair process.

[0885] In some embodiments, cancer is sensitive to POLΘ inhibition.

[0886] In some embodiments, cancer has evidence of elevated POLΘ activity.

[0887] In some embodiments, cancer has elevated POLΘ mRNA or protein expression.

[0888] In some embodiments, cancer has elevated POLΘ mRNA expression.

[0889] In some embodiments, cancer has elevated POLΘ protein expression.

[0890] In some embodiments, cancer is classified according to genotype.

[0891] In some embodiments, genotype has a regulatory function.

[0892] In some embodiments, the regulatory function is an inactivating mutation, deletion, or other genomic alteration.

[0893] In some embodiments, genotype is the loss of mRNA or protein expression.

[0894] In some embodiments, cancer has a regulatory function of at least one gene.

[0895] In some embodiments, the gene is selected from ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.

[0896] In some embodiments, the cancer is homologous recombination defective (HRD) cancer.

[0897] In some embodiments, cancer is classified as HRD cancer because the tumor is unable to accurately repair double-strand breaks in DNA through homologous recombination.

[0898] In some embodiments, the mutation occurs in the gene that causes HRD when lost.

[0899] In some embodiments, the homologous recombination (HR) or non-homologous DNA end-joining (NHEJ) repair pathways in cancer are impaired.

[0900] In some embodiments, cancers with impaired HR depend on PolΘ activity.

[0901] In some embodiments, cancers with impaired NHEJ depend on PolΘ activity.

[0902] In some embodiments, cancer is a tumor. In some embodiments, cancer is a solid tumor.

[0903] Application route

[0904] The disclosed compounds or pharmaceutically acceptable salts thereof can be administered alone as a monotherapy or in combination with one or more other substances and / or therapeutic agents. Such combination therapy can be achieved by administering the individual components of the treatment simultaneously, sequentially, or separately.

[0905] For example, the therapeutic effect can be enhanced by administering an adjuvant (i.e., the adjuvant itself may have only a minimal therapeutic benefit, but when combined with another therapeutic agent, it enhances the overall therapeutic benefit to the individual). Alternatively, by way of example only, the benefit experienced by an individual can be increased by administering a compound of formula (I) together with another therapeutic agent (which also includes a treatment regimen) that has the same therapeutic benefit.

[0906] When the compounds of this disclosure are used 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 can be administered via different routes due to their different physical and chemical properties. For example, the compounds of this disclosure can be administered orally to produce and maintain their good blood levels, while another therapeutic agent can be administered intravenously. Initial administration can be performed according to established protocols known in the art, and then, based on the observed effects, a skilled clinician can modify the dosage, administration mode, and timing.

[0907] The specific choice of other therapeutic agents will depend on the attending physician's diagnosis and their judgment of the individual's condition and appropriate treatment plan. According to this aspect of the disclosure, a combination is provided for treating diseases involving DNA polymerase Θ activity, the combination comprising a compound of the present disclosure as defined above or a pharmaceutically acceptable salt thereof and another suitable agent.

[0908] According to another aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a suitable pharmaceutically acceptable diluent or carrier.

[0909] In addition to their uses in therapeutic medicine, compounds of formula (I) and their pharmaceutically acceptable salts can also be used as pharmacological tools in the development and standardization of in vitro and in vivo testing systems to evaluate the effects of regulators of DNA polymerase Θ activity in laboratory animals such as dogs, rabbits, monkeys, miniature pigs, rats and mice as part of research into new therapeutic agents.

[0910] Any alternative embodiments of the macromolecules described herein in any of the above-described pharmaceutical compositions, processes, methods, uses, pharmaceuticals, and preparation characteristics of this disclosure are also applicable.

[0911] The compounds disclosed herein or pharmaceutical compositions comprising these compounds may be administered to a subject via any convenient route of administration, whether systemically / peripherally or locally (i.e., at the desired site of action).

[0912] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; percutaneous (including, for example, by patches, plasters, etc.); mucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal sprays or powders); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, such as by using aerosols, such as through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by a pessary); parenteral, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; and by implantation of a depot or reservoir, for example, subcutaneously or intramuscularly.

[0913] Exemplary embodiments

[0914] Exemplary Example No. 1. A compound of formula (I):

[0915]

[0916] Or its pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, or tautomers, wherein:

[0917] X 1 For CH, S, or N;

[0918] X 2 For N, S, or O;

[0919] X 3 It can be C or N;

[0920] R 1 and R 2 Together with the atoms it is attached to, it forms C6-C. 10 aryl or 5 to 10-membered heteroaryl, wherein the C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. a replace;

[0921] Each R a Independently oxo, halogenated, cyano, -OH, -NH2, -C(O)N(R) b (R) c ), -N(R b )C(O)(R c C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C4-C 10 Cycloalkenyl, C6-C 10aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic alkyl, or 4- to 10-membered heterocyclic alkenyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C4-C 10 Cycloalkenyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic alkyl or 4- to 10-membered heterocyclic alkenyl, optionally separated by one or more R a1 replace;

[0922] Each R b and R c Independently H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 alkyl, or C4-C5 alkyl is a cycloalkyl group. 10 The cycloalkyl or 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more -OH or C1-C6 haloalkyl groups; or

[0923] R b and R c Together with the atoms to which they are attached, they form 3 to 10-membered heterocyclic alkyl groups, wherein the 3 to 10-membered heterocyclic alkyl groups are optionally substituted by one or more -OH, -O (C1-C6 haloalkyl), -O (C1-C6 alkyl), -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl or -N (C1-C6 alkyl)2;

[0924] Each R a1 Independently oxo, halogenated, cyano, -OH, -O (C3-C) 10 Cycloalkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -C(O)OH, -C(O)O (C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -O- (C3-C 10 cycloalkyl), C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the 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 groups are optionally surrounded by one or more R groups. a2 replace;

[0925] Each R a2It can be independently oxo, halogenated, cyano, -OH, or -NH2;

[0926] R 3 For C6-C 10 aryl or 6- to 10-membered heteroaryl, wherein the C6-C 10 aryl or 6- to 10-membered heteroaryl groups are substituted with one or more R groups. 3a replace;

[0927] Each R 3a Independently, it is halogenated, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, -O (C6-C 10 Aryl), C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, -O (C6-C 10 Aryl), C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. 3a1 Replace; and

[0928] Each R 3a1 Independently oxo, halogenated, cyano, -NH2, -NH-C(O)O(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl, wherein the C1-C6 alkyl is optionally separated by one or more C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O (C1-C6 haloalkyl), C3-C 10 cycloalkyl, C6-C 10 Aryl or 5 to 10 heteroaryl substituents;

[0929] Where R 3a Halogenated and R 1 and R 2 When R forms a 6-membered heteroaryl group with the atoms it is attached to, then a It's not -CF3.

[0930] Exemplary Example No. 2. A compound of formula (I):

[0931]

[0932] Or its pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, or tautomers, wherein:

[0933] X 1 For CH, S, or N;

[0934] X 2 For N, S, or O;

[0935] X 3 It can be C or N;

[0936] R 1 and R 2 Together with the atoms it is attached to, it forms C6-C. 10 aryl or 5 to 10-membered heteroaryl, wherein the C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. a replace;

[0937] Each R a Independently oxo, halogenated, cyano, -OH, -NH2, -C(O)N(R) b (R) c ), -N(R b )C(O)(R c 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 heterocyclic alkyl, wherein the 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 heterocyclic alkyl, optionally bounded by one or more R a1 replace;

[0938] Each R b and R c Independently H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 alkyl, or C4-C5 alkyl is a cycloalkyl group. 10 The cycloalkyl or 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more -OH or C1-C6 haloalkyl groups; or

[0939] R b and R cTogether with the atoms to which they are attached, they form 3 to 10-membered heterocyclic alkyl groups, wherein the 3 to 10-membered heterocyclic alkyl groups are optionally substituted by one or more -OH, -O (C1-C6 haloalkyl), -O (C1-C6 alkyl), -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl or -N (C1-C6 alkyl)2;

[0940] Each R a1 Independently oxo, halogenated, cyano, -OH, -O (C3-C) 10 Cycloalkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -C(O)OH, -C(O)O (C1-C6 alkyl), 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, wherein the 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 groups are optionally surrounded by one or more R groups. a2 replace;

[0941] Each R a2 It can be independently oxo, halogenated, cyano, -OH, or -NH2;

[0942] R 3 For C6-C 10 aryl or 6- to 10-membered heteroaryl, wherein the C6-C 10 aryl or 6- to 10-membered heteroaryl groups are substituted with one or more R groups. 3a replace;

[0943] Each R 3a Independently, it is halogenated, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. 3a1 Replace; and

[0944] Each R 3a1Independently oxo, halogenated, cyano, -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl, wherein the C1-C6 alkyl is optionally separated by one or more C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O (C1-C6 haloalkyl), C3-C 10 cycloalkyl, C6-C 10 Aryl or 5 to 10 heteroaryl substituents;

[0945] Where R 3a Halogenated and R 1 and R 2 When R forms a 6-membered heteroaryl group with the atoms it is attached to, then a It's not -CF3.

[0946] Exemplary Example No. 3. The compound according to Exemplary Example 1 or Exemplary Example 2, wherein:

[0947] (ii)X 1 It is CH or N; and R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted pyridine; or

[0948] (iii)X 2 It is N or O; and R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted pyridine; or

[0949] (iv) When R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then X 1 Not S; or

[0950] (v) When R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then X 2 Not S; or

[0951] (vi) When R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then no or

[0952] (vii) When R a for When, then R 3 no or

[0953] (viii) When R a for When, then R 3 no or

[0954] (ix) When R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted pyrazines, and R a For one or more R a1 When the phenyl group is substituted, then R a1 Not -Cl, -F, -CN, -O(CH3), -O(CF3), -O(CHF2), -CH3, or cyclopropyl; or

[0955] (x) When R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted pyrazines, and R a For one or more R a1 When pyridine is substituted, then R a1 Not -Cl, -CN, -CF3, -O(CH3), -O(CHF2), cyclopropyl, -C(CH3)2(CN) or -C(CH3)2(OH); or

[0956] (xi) when R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a When pyrazine is substituted, then R a no or

[0957] (xii) The compound of formula (I) is not 5'-methoxy-2',6-dimethyl-N-(6-(tetrahydrofuran-3-yl)thiazo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide.

[0958] Exemplary Example No. 4. The compound according to any one of the foregoing exemplary embodiments, wherein X 1 It can be CH or N.

[0959] Exemplary Example No. 5. The compound according to any one of the foregoing exemplary embodiments, wherein:

[0960] Each R a Independently oxidized, halogenated, -C(O)N(R) b (R) c ), -N(R b )C(O)(R c C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic alkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic alkyl, optionally bounded by one or more R a1 replace;

[0961] Each R a1 Independently oxo, halogenated, cyano, -OH, -O (C3-C) 10 Cycloalkyl), -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -C(O)O (C1-C6 alkyl), C1-C6 alkyl, 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, wherein the C1-C6 alkyl, 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 groups are optionally surrounded by one or more R groups. a2 replace;

[0962] Each R a2 It can be either a cyano group or -OH.

[0963] Each R 3a Independently cyano, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. 3a1 Replace; and

[0964] Each R 3a1Independently oxo, halogenated, cyano, -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl, wherein the C1-C6 alkyl is optionally separated by one or more C3-C 10 Cycloalkyl, C1-C6 alkoxy, -O (C1-C6 haloalkyl), C3-C 10 Cycloalkyl or 5 to 10 heteroaryl substitutions.

[0965] Exemplary Example No. 6. The compound according to any one of the foregoing exemplary embodiments, wherein R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted C6 aryl or 6-membered heteroaryl.

[0966] Exemplary Example No. 7. The compound according to any one of the foregoing exemplary embodiments, wherein R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted 5-membered heteroaryl group.

[0967] Exemplary Example No. 8. The compound according to any one of the foregoing exemplary embodiments, wherein R 1 and R 2 Together with the atoms to which they are attached, they form a pyrazinyl, pyridinyl, or diazoleyl group, wherein the pyrazinyl, pyridinyl, or diazoleyl group is optionally surrounded by one or more R groups. a replace.

[0968] Exemplary Example No. 9. The compound according to any one of the foregoing exemplary embodiments, wherein each R a Independently: oxo, -Cl, -Br, -CH3, -CF3,

[0969]

[0970]

[0971]

[0972]

[0973]

[0974] Exemplary Example No. 10. The compound according to any one of the foregoing exemplary embodiments, wherein each R... b and R cIndependently, H, methyl, ethyl, cyclobutyl, cyclopropyl,

[0975]

[0976] Exemplary Example No. 11. The compound according to any one of the foregoing exemplary embodiments, wherein R b and R c Together with the atoms to which it is attached, it forms a heterocyclic alkyl group selected from the following:

[0977]

[0978] Exemplary Example No. 12. The compound according to any one of the foregoing exemplary embodiments, wherein R 3 for:

[0979]

[0980]

[0981]

[0982]

[0983] Exemplary Example No. 13. The compound according to any one of the foregoing exemplary embodiments, wherein each R... a1 Independently, it can be oxo, -OH, -CH2OH, -CHF2, -CF3, -F, -Cl, -CN, -OCH3, -OCHF2, -OCF3, -NHCH3, -N(CH3)2, -CH3, -CH2CF3, -CH2CN,

[0984] Exemplary Example No. 14. The compound according to any one of the foregoing exemplary embodiments, wherein each R... 3a Independently -Br, -CH3, -CF3, -CN,

[0985]

[0986] Exemplary Example No. 15. The compound according to any one of the foregoing exemplary embodiments, wherein each R... 3a1 Independently oxo, -Cl, -CH3, -OCH3, -CF2H, -NH2, -NHC(O)OC(CH3)3, -OCHF2, -C(O)OC(CH3)3, -C(O)CH3, -C(O)NH2, -CN,

[0987] Exemplary Example No. 16. The compound according to any one of the foregoing exemplary embodiments, wherein each R... a2 It is a cyano group on its own.

[0988] Exemplary Example No. 17. A compound according to any one of the foregoing exemplary embodiments, wherein the compound has the formula (IA), (IB), or (IC):

[0989]

[0990] Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof.

[0991] Exemplary Example No. 18. A compound according to any one of Exemplary Examples 1 to 6, wherein the compound has the formula (ID), (IE), (IF), (IG), (IH), (II), (IJ), (IK), or (IL):

[0992]

[0993]

[0994] Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof.

[0995] Exemplary Example No. 19. A compound according to any one of Exemplary Examples 1 to 6, wherein the compound has the formula (I-F'):

[0996]

[0997] Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof.

[0998] Exemplary Example No. 20. A compound according to any one of Exemplary Examples 1 to 6, wherein the compound has the formula (IM), (IN), (IO), (IP), (IQ), (IR), (IS), (IT), (IU), or (IV):

[0999]

[1000]

[1001] Or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or mixture thereof.

[1002] Exemplary Example No. 21. A compound according to any one of Exemplary Examples 1 to 6, wherein the compound has the formula (I-T'):

[1003]

[1004] Or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or mixture thereof.

[1005] Exemplary Example No. 22. A compound according to any one of Exemplary Examples 1 to 6, wherein the compound has the formula (IW):

[1006]

[1007] Or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or mixture thereof.

[1008] Exemplary Example No. 23. A compound according to any of the foregoing exemplary embodiments, wherein the compound is selected from the compounds described in Tables 1-4 or pharmaceutically acceptable salts thereof.

[1009] Exemplary Example No. 24. A compound according to any one of the foregoing exemplary embodiments, wherein the compound is selected from No. 1, 10, 24, 25, 59, 207, 211, 212, 224, 235, 238, 239, 244, 3, 12, 280, 282, 288, 308, 359, 360, and 361B. Compounds No. 368, 377, 386, 391, 394, 403, 427, 432, 447, 451A, 454, 462, 464, 467, 486, 489, 498, 502, 504, 506, 514, 518, 520, 521 and 522, or pharmaceutically acceptable salts thereof.

[1010] Exemplary Example No. 25. A compound that can be obtained by the methods described herein or by the methods described herein; optionally, the methods comprise one or more steps described in embodiments 1-11.

[1011] Exemplary Example No. 26. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing exemplary embodiments and a pharmaceutically acceptable diluent or carrier.

[1012] Exemplary Example No. 27. The pharmaceutical composition according to Exemplary Example 26, wherein the compound is selected from the compounds described in Tables 1-4.

[1013] Exemplary Example No. 28. A method for regulating the activity of DNA polymerase Θ, the method comprising contacting a cell with a compound according to any one of Exemplary Examples 1 to 25 or a pharmaceutical composition according to Exemplary Example 26 or Exemplary Example 27.

[1014] Exemplary Example No. 29. A method for treating or preventing a disease or condition in a subject in need, the method comprising administering to the subject a compound according to any one of Exemplary Examples 1 to 25 or a pharmaceutical composition according to Exemplary Example 26 or Exemplary Example 27.

[1015] Exemplary Example No. 30. The compound according to any one of Exemplary Examples 1 to 25 or the pharmaceutical composition according to Exemplary Example 26 or Exemplary Example 27, which is used to regulate DNA polymerase Θ activity.

[1016] Exemplary Example No. 31. A compound according to any one of Exemplary Examples 1 to 25 or a pharmaceutical composition according to Exemplary Example 26 or Exemplary Example 27, for treating or preventing a disease or condition.

[1017] Exemplary Example No. 32. Use of the compound according to any one of Exemplary Examples 1 to 25 for the preparation of a medicament for regulating the activity of DNA polymerase Θ.

[1018] Exemplary Example No. 33. Use of the compound according to any one of Exemplary Examples 1 to 25, for the preparation of a medicament for treating or preventing a disease or ailment.

[1019] Exemplary Example No. 34. A method, compound, pharmaceutical composition, or use according to any one of Exemplary Examples 28 to 33, wherein the disease or symptom is related to the activity of the DNA polymerase Θ involved.

[1020] Exemplary Example No. 35. A method, compound, pharmaceutical composition, or use according to any one of Exemplary Examples 28 to 34, wherein the disease or condition is cancer.

[1021] Example

[1022] For illustrative purposes, the neutral compound of formula (I) was synthesized and tested in the examples. It should be understood that the neutral compound of formula (I) can be converted into the corresponding pharmaceutically acceptable salt of the compound using conventional techniques in the art (e.g., by saponifying the ester to a carboxylate, or by hydrolyzing the amide to form the corresponding carboxylic acid, and then converting the carboxylic acid to a carboxylate).

[1023] abbreviation:

[1024] ACN or MeCN acetonitrile

[1025] AcOH (acetic acid)

[1026] BFMO N1,N2-bis(furan-2-ylmethyl)oxalamide

[1027] Boc tert-butoxycarbonyl

[1028] (Boc)2O ditert-butyl dicarbonate

[1029] DBA Tris(Dibenzylacetone)

[1030] DAST diethylaminosulfonium trifluoride

[1031] DCE 1,2-Dichloroethane

[1032] DCM dichloromethane

[1033] DIC N,N'-Diisopropylcarbodiimide

[1034] DIPEA or DIEA (diisopropylethylamine)

[1035] DMA N,N-dimethylacetamide

[1036] DMAP 4-Dimethylaminopyridine

[1037] DME dimethoxyethane

[1038] DMF (dimethylformamide)

[1039] DMSO (dimethyl sulfoxide)

[1040] dppf 1,1'-bis(diphenylphosphine)ferrocene

[1041] dtpby 1,1'-bis(di-tert-butylphosphine)ferrocene

[1042] (dtpby)NiBr2 [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine]nickel(II) dichloride

[1043] EDCI-HCl N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride

[1044] ESI Electrospray Ionization

[1045] EtOAc (ethyl acetate)

[1046] EtOH (ethanol)

[1047] FA Formic acid

[1048] g gram

[1049] h hours

[1050] HATU (Azabenzotriazole Tetramethylurea Hexafluorophosphate)

[1051] HCl hydrochloric acid

[1052] HOBt 1-hydroxybenzotriazole hydrate

[1053] HPLC (High Performance Liquid Chromatography)

[1054] Hz Hertz

[1055] [Ir(dtbbpy)(PPy)2][PF6] [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1, [N1']bis[2-(2-pyridyl-N)phenyl-C]iridium(III)hexafluorophosphate

[1056] K2CO3 (potassium carbonate)

[1057] KI potassium iodide

[1058] KOAc potassium acetate

[1059] L rise

[1060] LDA lithium isopropylamide

[1061] LCMS (Liquid Chromatography-Mass Spectrometry)

[1062] LiOH (Lithium hydroxide)

[1063] M Moore

[1064] m-CPBA (m-chloroperoxybenzoic acid)

[1065] Mn(dpm)3 tris(2,2,6,6-tetramethyl-3,5-heptadecyl)manganese(III)

[1066] m / z mass-to-charge ratio

[1067] MeOH (methanol)

[1068] mg

[1069] MHz

[1070] min minutes

[1071] mL

[1072] mmol millimole

[1073] MPa

[1074] MsCl methanesulfonyl chloride

[1075] MTBE (methyl tert-butyl ether)

[1076] NaBH4 sodium borohydride

[1077] NH4Cl ammonium chloride

[1078] NaHMDS Sodium Bis(trimethylsilyl)amino

[1079] Sodium ethanol (NaOEt)

[1080] NaOH (sodium hydroxide)

[1081] Na2SO4 Sodium sulfate

[1082] NCS N-chlorosuccinimide

[1083] NIS N-iodosuccinimide

[1084] nm nanometer

[1085] NMI 1-Methylimidazolium

[1086] NMP 1-Methyl-2-pyrrolidone

[1087] NMR (Nuclear Magnetic Resonance)

[1088] PCy3 Tricyclohexylphosphine

[1089] Pd-PEPPSI TM iPent [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II) dichloride

[1090] Pet ether petroleum ether

[1091] Pin2B2 bis(pinacol)diboron

[1092] PPh3 triphenylphosphine

[1093] (PPh3)4 Tetra(triphenylphosphine)

[1094] Prep preparation

[1095] PyBop Benzotriazole-1-yloxytripyrrolidinephosphide hexafluorophosphate

[1096] PtO2 (platinum oxide)

[1097] RT room temperature

[1098] SFC Supercritical Fluid Chromatography

[1099] SOCl2 thionyl chloride

[1100] t-BuOK potassium tert-butoxide

[1101] T3P propanephosphonic anhydride

[1102] TBAF Tetrabutylammonium Fluoride

[1103] TBAI Tetrabutylammonium Iodide

[1104] TBSC1 tert-butyldimethylchlorosilane

[1105] TCFH N′-Tetramethylformamidin hexafluorophosphate

[1106] TEA Triethylamine

[1107] Tf2O trifluoromethanesulfonic anhydride

[1108] TFA (trifluoroacetic acid)

[1109] THF Tetrahydrofuran

[1110] TLC (Thin Layer Chromatography)

[1111] TMSCHN2 Trimethylsilyldiazomethane

[1112] TMSCl Trimethylchlorosilane

[1113] wt weight

[1114] Xantphos (9,9-dimethyl-9H-oxanthracene-4,5-diyl)bis(diphenylphosphine)

[1115] X-phos 2-Dicyclohexylphosphine-2′,4′,6′-Triisopropylbiphenyl

[1116] 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, preparative C18, 250 × 21.2 mm. Solvent / gradient: 5-80% acetonitrile / water, containing 0.1% HCOOH. Flow rate: 20 mL / min.

[1117] Synthesis of intermediates

[1118] Intermediate 1: 4-(2-methoxyphenyl)-6-methylnicotinic acid

[1119]

[1120] 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 warmed 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 (6.6–12.5% ​​petroleum ether / EtOAc) to yield methyl 4-chloro-6-methylnicotinic acid (10.4 g, 85%) as a colorless oil. LCMS (ESI, m / z): 186 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),7.57(s,1H),3.87(s,3H),2.52(s,3H).

[1121] Step 2: Add (2-methoxyphenyl)boric acid (5.73 g, 37.7 mmol), Pd(PPh3)4 (2.18 g, 1.88 mmol), and Cs2CO3 (36.9 g, 113 mmol) to a solution of 4-chloro-6-methylnicotinic acid methyl ester (7.00 g, 37.7 mmol) in dried 1,4-dioxane (80 mL), and heat the mixture overnight at 85 °C. Dilute the mixture with water (100 mL), extract with EtOAc (3 × 300 mL), and wash the combined organic layers with water (100 mL) and brine (100 mL), dry to Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (6.6-25% petroleum ether / EtOAc) to yield 4-(2-methoxyphenyl)-6-methylnicotinic acid methyl ester (8.0 g, 82%) as a yellow oil. LCMS(ESI,m / z):258[M+H] + , 1 HNMR (400MHz, DMSO-d6) δ8.73(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).

[1122] Step 3: NaOH (3.73 g, 93.0 mmol) was added to a solution of methyl 4-(2-methoxyphenyl)-6-methylnicotinic acid (8.0 g, 31.0 mmol) in water (40 mL) and MeOH (40 mL), and the mixture was heated at 50 °C for 2 hours. The mixture was adjusted to pH 5 with 1 M HCl aqueous solution, extracted with a 10:1 mixture of DCM / MeOH (30 mL × 10), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to yield 4-(2-methoxyphenyl)-6-methylnicotinic acid (5.5 g, 73%) as a white solid. LCMS (ESI, m / z): 244 [M+H] + , 1 HNMR (400MHz, DMSO-d6) δ8.75(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).

[1123] Intermediate 2: 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid

[1124]

[1125] 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 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 under reflux overnight. The mixture was diluted with water (200 mL), extracted with EtOAc (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 / EtOAc = 5 / 1, v / v) to yield methyl 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinate (5.0 g, 63%) as a yellow solid. LCMS(ESI,m / z):283[M+H] + .

[1126] Step 2: To a solution of methyl 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid (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 EtOAc (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 / EtOAc = 1 / 1, v / v) to yield 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid (3.9 g, 83%) as a grayish-white solid. LCMS (ESI, m / z): 269 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.82(s,1H),7.88(dd,J=8.6,2.2Hz,1H),7.71(d,J=2.2Hz,1H),7.28–7.20(m,2H),3.75(s,3H),2.54(s,3H).

[1127] Table AI: The following intermediates are prepared using a procedure similar to that described for intermediate 2:

[1128]

[1129] Intermediate 3: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[1130]

[1131] Step 1: Pd(dtbpf)Cl2 (2.1 g, 3.2 mmol) and K2CO3 (13.3 g, 96.3 mmol) were added to a solution of methyl 4-chloro-6-methylnicotinate (6.00 g, 32.1 mmol) and (2-chloro-5-methoxypyridin-4-yl)boronic acid (15.0 g, 80.2 mmol) in 1,4-dioxane (140 mL) and water (14 mL), and the mixture was heated at 80 °C for 2 hours. The mixture was diluted with water (200 mL), extracted with EtOAc (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 (EtOAc / petroleum ether = 1 / 1) to yield methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (7.3 g, 31%) as a yellow solid. LCMS (ESI, m / z): 293 [M+H] + , 1 ¹H NMR (400MHz, 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).

[1132] Step 2: NaOH (6.00 g, 150 mmol) was added to a solution of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (14.6 g, 50.0 mmol) in MeOH (140 mL) and water (140 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 5–6 with 2 M HCl and concentrated under reduced pressure. The residue was purified on a silica gel column (DCM / MeOH = 10 / 1, v / v) to yield 14.5 g of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid as a yellow solid. LCMS (ESI, m / z): 279 [M+H] + , 1 HNMR (400MHz, DMSO-d6) δ8.75(s,1H),8.09(s,1H),7.16(s,1H),6.95(s,1H),3.74(s,3H),2.45(s,3H).

[1133] Table AJ: The following intermediates are prepared using a procedure similar to that described for intermediate 3.

[1134]

[1135] Intermediate 4: 4-(6-methoxyimidazo[1,5-a]pyridin-7-yl)-6-methylnicotinic acid

[1136]

[1137] Step 1: At 25°C, KOAc (2.6 g, 26 mmol) and Pd(dppf)Cl2 (1.4 g, 1.9 mmol) were added in a single step to a solution of methyl 4-bromo-6-methylpyridine-3-carboxylate (2.0 g, 8.7 mmol) and B2Pin2 (2.7 g, 10 mmol) in 1,4-dioxane (30 mL). N2 was introduced into the reaction mixture three times at 25°C. The resulting mixture was heated to 80°C and stirred at 90°C for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (1 / 1), to give methyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)nicotinic acid (1.5 g, 62% yield) as a pale yellow solid. LCMS(ESI):[M+H] + =278.

[1138] Step 2: At 25°C, methyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)nicotinic acid (610 mg, 2.2 mmol), Pd(dppf)Cl2 (359 mg, 0.4 mmol), 7-bromo-6-methoxyimidazo[1,5-a]pyridine (500 mg, 2.2 mmol), Cs2CO3 (2.2 g, 6.6 mmol), 1,4-dioxane (10 mL), and H2O (1 mL) were added to a 30 mL sealed tube. N2 was introduced into the reaction mixture three times at 25°C. The resulting mixture was heated at 90°C and stirred at 90°C for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C, diluted with water (10 mL), and extracted with EtOAc (3 × 20 mL). 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 reversed-phase rapid chromatography (0-100% ACN / water, containing 0.1% FA modifier) ​​to give methyl 4-{6-methoxyimidazo[1,5-a]pyridin-7-yl}-6-methylpyridin-3-carboxylate (330 mg, 50% yield) as a pale yellow solid. LCMS (ESI): [M+H] + =298.

[1139] Step 3: Add methyl 4-{6-methoxyimidazo[1,5-a]pyridin-7-yl}-6-methylpyridin-3-carboxylic acid (300 mg, 1.0 mmol), NaOH (121 mg, 3.0 mmol), MeOH (3 mL), and water (1 mL) to an 8 mL vial at 25 °C. Stir the reaction mixture overnight at 25 °C. Concentrate the resulting mixture under reduced pressure. Purify the residue by reversed-phase rapid chromatography (0-100% ACN / water, containing 0.1% FA modifier) ​​to give 4-{6-methoxyimidazo[1,5-a]pyridin-7-yl}-6-methylpyridin-3-carboxylic acid (290 mg, 89% yield) as a pale yellow solid. LCMS (ESI): [M+H] + =284.

[1140] Table AK: The following intermediates are prepared using a procedure similar to that described for intermediate 4.

[1141]

[1142] Intermediate 60: 4-(6-(difluoromethyl)-3-methoxypyridazine-4-yl)-6-methylnicotinic acid

[1143]

[1144] Step 1: Under a nitrogen atmosphere and at 25°C, bis(pinacol)diborane (22 g, 87 mmol), Pd(dppf)Cl2-CH2Cl2 (3.5 g, 4.3 mmol), and potassium acetate (13 g, 8.2 mL, 0.13 mol) were added in a single step to a stirred solution of methyl 4-bromo-6-methylnicotinate (10 g, 43 mmol) in 1,4-dioxane (300 mL). The reaction mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with petroleum ether:EtOAc (1:1) to give (5-(methoxycarbonyl)-2-methylpyridin-4-yl)boronic acid (15 g) as a brown oil, which was used as the crude product in the next step.

[1145] Step 2: Under a nitrogen atmosphere and at 25°C, Pd(dppf)Cl2-CH2Cl2 (2 g, 3 mmol) and potassium carbonate (10 g, 0.08 mol) were added in portions to a stirred solution of (5-(methoxycarbonyl)-2-methylpyridin-4-yl)boronic acid (10 g, 0.05 mol) and 6-chloro-4-iodo-3-methoxypyridazine (7 g, 0.03 mol) in 1,4-dioxane (250 mL) and H2O (25 mL). The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with petroleum ether:EtOAc (1:1) to give methyl 4-(6-chloro-3-methoxypyridazine-4-yl)-6-methylnicotinate (4.7 g, 60% yield) as a yellow solid.

[1146] Step 3: Under a nitrogen atmosphere, potassium carbonate (9.2 g, 3.9 mL, 66 mmol) and Pd(dppf)Cl2-CH2Cl2 (1.8 g, 2.2 mmol) were added in portions to a stirred solution of methyl 4-(6-chloro-3-methoxypyridazin-4-yl)-6-methylnicotinate (6.5 g, 22 mmol) and pinacol vinylborate (6.8 g, 7.5 mL, 44 mmol) in 1,4-dioxane (200 mL) and H2O (20 mL) at 25 °C. The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The mixture was cooled to 25 °C and concentrated under reduced pressure. The mixture was extracted with EtOAc (3 × 50 mL), and the combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with petroleum ether:EtOAc (1:1) to give methyl 4-(3-methoxy-6-vinylpyridazine-4-yl)-6-methylnicotinate (4 g, 60% yield) as a white solid.

[1147] Step 4: Under a nitrogen atmosphere and at 25°C, potassium osmium tetroxide (VI) dihydrate (0.5 g, 1 mmol) and sodium metaiodate (10 g, 3 mL, 0.06 mol) were added in portions to a stirred solution of 4-(3-methoxy-6-vinylpyridinium-4-yl)-6-methylnicotinate (4 g, 0.01 mol) and N-methylmorpholine N-oxide (2 g, 0.01 mol) in DMA (80 mL). The resulting mixture was stirred at 25°C under a nitrogen atmosphere for 2 days. The mixture was extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with brine (5 × 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with petroleum ether:EtOAc (1:1) to give methyl 4-(6-formyl-3-methoxypyridazine-4-yl)-6-methylnicotinate (2 g, 50% yield) as a white solid.

[1148] Step 5: A solution of methyl 4-(6-formyl-3-methoxypyridazine-4-yl)-6-methylnicotinate (580 mg, 2.02 mmol) in DCM (20 mL) was stirred at -78 °C for 20 min under a nitrogen atmosphere. DAST (1.46 g, 1.18 mL, 9.09 mmol) was added dropwise to the mixture over 10 min at -78 °C. The resulting mixture was stirred at -78 °C to -25 °C for 16 h. The reaction was quenched at 0 °C with an aqueous solution of NaHCO3 (15 mL). The resulting mixture was extracted with DCM (3 × 50 mL), and the combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with petroleum ether:EtOAc (1:1) to give methyl 4-(6-(difluoromethyl)-3-methoxypyridazine-4-yl)-6-methylnicotinate (600 mg, 96% yield) as a white solid.

[1149] Step 6: LiOH (217 mg, 144 μL, 5.17 mmol) was added in portions to a stirred solution of methyl 4-(6-(difluoromethyl)-3-methoxypyridazin-4-yl)-6-methylnicotinic acid (800 mg, 2.59 mmol) in THF (9 mL) and H₂O (3 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The resulting mixture was concentrated under reduced pressure to give 4-(6-(difluoromethyl)-3-methoxypyridazin-4-yl)-6-methylnicotinic acid (600 mg, 79% yield) as a white solid. LCMS (ESI): [M+H] + =296.

[1150] Table AL: The following intermediates are prepared using a procedure similar to that described for intermediate 60.

[1151]

[1152] Intermediate 62: 4-(6-methoxy-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-6-methylnicotinic acid

[1153]

[1154] Step 1: Under a nitrogen atmosphere, 2-chloroacetyl chloride (1.4 g, 12 mmol) was added dropwise to a stirred solution of 2-amino-5-chloro-6-methoxypyridin-3-ol (1.9 g, 11 mmol) and TEA (1.4 g, 1.9 mL, 14 mmol) in THF (30 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 2 hours under a nitrogen atmosphere. The reaction was quenched with water (30 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give 2-chloro-N-(5-chloro-3-hydroxy-6-methoxypyridin-2-yl)acetamide (2.2 g, crude product) as a brown solid. LCMS (ESI, m / z): 251 [M+H] + .

[1155] Step 2: KI (97 mg, 583 μmol) was added to a stirred solution of 2-chloro-N-(5-chloro-3-hydroxy-6-methoxypyridin-2-yl)acetamide (2.1 g, 8.4 mmol) and K₂CO₃ (1.4 g, 10.1 mmol) in DMF (20 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 2 hours. The reaction was quenched with water (30 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give 7-chloro-6-methoxy-2H-pyrido[3,2-b][1,4]oxazine-3(4H)-one (1.4 g, crude product) as a gray solid. LCMS (ESI, m / z): 215 [M+H] + .

[1156] Step 3: LiAlH4 (0.3 g, 7.8 mmol) was added in portions to a stirred solution of 7-chloro-6-methoxy-2H-pyrido[3,2-b][1,4]oxazine-3(4H)-one (1.4 g, 6.5 mmol) in THF (8 mL) at 0 °C for 20 minutes. The reaction mixture was stirred at 60 °C for 3 hours. The resulting mixture was cooled to 25 °C and quenched successively at 0 °C with water (0.3 mL), NaOH (15%, 0.3 mL), and water (0.3 mL). After filtration, the filter cake was washed with EtOAc (3 × 50 mL). The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 7-chloro-6-methoxy-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (1.4 g, crude product), which was a brown oil and could be used directly in the next step without further purification. LCMS(ESI,m / z):201[M+H] + .

[1157] Step 4: K₂CO₃ (2.8 g, 20.2 mmol) was added in a single addition to a solution of 7-chloro-6-methoxy-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (1.4 g, 6.7 mmol) and methyl 4-toluenesulfonate (1.9 g, 10 mmol) in DMF (10 mL) at 25 °C. The reaction mixture was stirred at 60 °C for 2 hours. The resulting mixture was cooled to 25 °C and then quenched with water (100 mL). The mixture was extracted with EtOAc (3 × 50 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 reversed-phase rapid chromatography (55-63% MeCN / water, containing 0.1% formic acid modifier) ​​to give 7-chloro-6-methoxy-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine as a gray solid (770 mg, 53% yield). LCMS (ESI, m / z): 215 [M+H] + .

[1158] Step 5: Tricyclohexylphosphine (131 mg, 466.0 μmol), tetramethylammonium acetate (931 mg, 7.0 mmol), and Pd2(dba)3 (213 mg, 233.0 μmol) were added sequentially to a stirred solution of 7-chloro-6-methoxy-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (500 mg, 2.3 mmol) and bis(pinacol)diboron (887 mg, 3.5 mmol) in 1,4-dioxane (10 mL) at 25 °C. Nitrogen was purged into the reaction mixture three times, and the resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 °C and diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 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 silica gel column chromatography with elution of petroleum ether:EtOAc(5 / 1) to give 6-methoxy-4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (600 mg, 84% yield) as a yellow solid. LCMS (ESI, m / z): 307 [M+H] + .

[1159] Step 6: At 25°C, Pd(dppf)Cl2 CH2Cl2 (160 mg, 196 μmol) and K3PO4 (1.3 g, 5.9 mmol) were added sequentially to a stirred mixture of 6-methoxy-4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxapentoboron-2-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (600 mg, 2.0 mmol) and 4-bromo-6-methylnicotinic acid methyl ester (451 mg, 2.0 mmol) in 1,4-dioxane (20 mL). The reaction mixture was purged with nitrogen three times and stirred at 100°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). 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 silica gel column chromatography with elution of petroleum ether:EtOAc (1 / 1) to give methyl 4-(6-methoxy-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-6-methylnicotinate (500 mg, 56% yield) as a yellow solid. LCMS (ESI, m / z): 330 [M+H] + .

[1160] Step 7: A mixture of methyl 4-(6-methoxy-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-6-methylnicotinic acid (400 mg, 1.2 mmol) and LiOH (86 mg, 3.6 mmol) in MeOH (6 mL) and H₂O (2 mL) was stirred at 25 °C for 2 hours. The resulting mixture was acidified to pH 4 with HCl (1N) and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (10-50% ACN / water, containing 0.1% formic acid modifier) ​​to give 4-(6-methoxy-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-6-methylnicotinic acid (320 mg, 84% yield) as a yellow solid. LCMS(ESI,m / z):316[M+H] + .

[1161] Intermediate 63: 2'-chloro-6-cyclopropyl-5'-methoxy-[4,4'-bipyridine]-3-carboxylic acid

[1162]

[1163] Step 1: 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 in a single addition to a solution of methyl 4,6-dichloronicotinic acid (15 g, 73 mmol) in 1,4-dioxane (120 mL) and water (12 mL) at 25 °C. N2 was introduced into the reaction mixture three times, and the mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The resulting mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of petroleum ether:EtOAc (3 / 1) to give methyl 4-chloro-6-cyclopropylnicotinic acid (5.6 g, 36% yield) as a white oil. LCMS (ESI, m / z): 212 [M+H] + .

[1164] Step 2: A single addition of (2-chloro-6-cyclopropylnicotinic acid methyl ester (5.6 g, 26 mmol), Pd(dppf)Cl2 (1.0 g, 1.3 mmol), and K2CO3 (11 g, 79 mmol) to a solution of 4-chloro-6-cyclopropylnicotinic acid methyl ester (5.6 g, 26 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was made at 25 °C. N2 was introduced into the reaction mixture, and the mixture was stirred at 120 °C for 16 hours under a nitrogen atmosphere. The resulting mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of petroleum ether:EtOAc(2 / 1) to give methyl 2'-chloro-6-cyclopropyl-5'-methoxy-[4,4'-bipyridine]-3-carboxylate (1.6 g, 20% yield) as a white solid. LCMS(ESI,m / z):319[M+H] + .

[1165] Step 3: Lithium hydroxide (360 mg, 15.0 mmol) was added in a single addition to a solution of methyl 2'-chloro-6-cyclopropyl-5'-methoxy-[4,4'-bipyridine]-3-carboxylic acid (1.6 g, 5.0 mmol) in THF (12 mL) and water (4 mL) 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 filter cake was washed with MeOH (3 × 20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (10-50% ACN / water, containing 0.1% formic acid modifier) ​​to give 2'-chloro-6-cyclopropyl-5'-methoxy-[4,4'-bipyridine]-3-carboxylic acid (880 mg, 58% yield) as a white solid. LCMS(ESI,m / z):305[M+H] + .

[1166] Intermediate 64: 4-(6-methoxy-1-methyl-1H-indazol-5-yl)-6-methylnicotinic acid

[1167]

[1168] Step 1: NaH (60% w / w in oil, 708 mg, 17.7 mmol) and MeI (1.9 g, 13 mmol) were added to a solution of 5-bromo-6-methoxy-1H-indazole (2.00 g, 8.85 mmol) in DMF (20 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (50 mL), extracted with EtOAc (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 (petroleum ether / EtOAc = 5 / 1, v / v) to give 5-bromo-6-methoxy-1-methyl-1H-indazole (1.2 g, 57% yield) as a white solid. 1 ¹H NMR (400MHz, chloroform-d) δ 7.89 (s, 1H), 7.83 (s, 1H), 6.74 (s, 1H), 4.03 (s, 3H), 3.98 (s, 3H).

[1169] Step 2: Add Pin2B2 (1.33 g, 5.25 mmol), Pd(dppf)Cl2 (152.3 mg, 0.21 mmol), and KOAc (617.4 mg, 6.3 mmol) to a solution of 5-bromo-6-methoxy-1-methyl-1H-indazole (500 mg, 2.1 mmol) in 1-,4-dioxane (8 mL), and heat the mixture overnight at 100 °C under N2. Filter the mixture and concentrate the filtrate under reduced pressure to give 6-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)-1H-indazole (600 mg, 99% yield), which was used directly in the next step. LCMS (ESI, m / z): 289 [M+H]+.

[1170] Step 3: Add methyl 4-chloro-6-methylnicotinate (772 mg, 4.17 mmol), Pd(dtbpf)Cl2 (134 mg, 0.208 mmol), and K2CO3 (861 mg, 6.24 mmol) to a solution of 6-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1H-indazole (600 mg, 2.08 mmol) in 1,4-dioxane (8 mL) and water (2 mL), and heat the mixture overnight at 100 °C under N2. Dilute the mixture with water (50 mL), extract with EtOAc (2 × 50 mL), and wash the combined organic layers with brine (50 mL), dry to Na2SO4, filter, and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 1 / 1) to give methyl 4-(6-methoxy-1-methyl-1H-indazol-5-yl)-6-methylnicotinate (450 mg, 69% yield) as a yellow solid. LCMS (ESI, m / z): 312 [M+H] + .

[1171] Step 4: Add NaOH (20 mg, 0.48 mmol) to a solution of methyl 4-(6-methoxy-1-methyl-1H-indazole-5-yl)-6-methylnicotinic acid (50 mg, 0.16 mmol) in MeOH (2 mL) and water (2 mL), and heat the mixture at 50 °C for 3 hours. Adjust the pH of the mixture to 5-6 with 2 M HCl aqueous solution, and collect the resulting precipitate by filtration to give 4-(6-methoxy-1-methyl-1H-indazole-5-yl)-6-methylnicotinic acid (40 mg, 84% yield) as a yellow solid. LCMS (ESI, m / z): 298 [M+H] + .

[1172] Intermediates 65 and 66: 3-bromo-2-methyl-2H-pyrazolo[4,3-c]pyridine (65) and 3-bromo-1-methyl-1H-pyrazolo[4,3-c]pyridine (66).

[1173]

[1174] A solution of 3-bromo-2H-pyrazolo[4,3-c]pyridine (10 g, 50 mmol), K₂CO₃ (10 g, 76 mmol), and methyl 4-methylbenzenesulfonate (9.4 g, 50 mmol) in DMSO (60 mL) was added to a 25 mL three-necked round-bottom flask at 0 °C. The resulting mixture was stirred at 25 °C for 5 hours. The reaction was quenched with water (700 mL) at 0 °C. The resulting mixture was extracted with DCM / MeOH (20 / 1, 3 × 500 mL). The combined organic layers were washed with brine (3 × 500 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (30–45% ACN / water, containing 10 mmol / L NH₄HCO₃ modifier) ​​to give two compounds:

[1175] 3-Bromo-2-methyl-2H-pyrazolo[4,3-c]pyridine (600 mg, 5.6% yield), a white solid, LCMS (ESI, m / z): 212 and 214 [M+H] + .

[1176] 3-Bromo-1-methyl-1H-pyrazolo[4,3-c]pyridine (4.9 g, 46% yield), white solid. LCMS (ESI, m / z): 212 and 214 [M+H] + .

[1177] Intermediate 5: 6-bromothiazo[4,5-b]pyridine-2-amine

[1178]

[1179] Step 1: Ammonium thiocyanate (51 g, 675 mmol) and benzoyl chloride (78 g, 556 mmol) were added to a solution of 3,5-dibromopyridin-2-amine (100 g, 397 mmol) in THF (1 L), and the mixture was heated under reflux for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to produce N-((3,5-dibromopyridin-2-yl)aminomethylthio)benzamide, which was used directly in the next step. LCMS (ESI, m / z): 414, 416 [M+H] +

[1180] Step 2: NaOH (121 g, 3.02 mmol) was added to a solution of N-((3,5-dibromopyridin-2-yl)aminomethylthio)benzamide (165 g, 398 mmol) in MeOH (320 mL) and water (400 mL) at 0 °C, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove MeOH. The residue was poured into water, and the resulting precipitate was collected by filtration and dried to give 1-(3,5-dibromopyridin-2-yl)thiourea (90 g, 73%) as a green solid. 1 H NMR (400MHz, DMSO-d6) δ9.69(s,1H),9.32(s,1H),8.61(s,1H),8.51(s,1H),8.43(s,1H).

[1181] Step 3: 1-(3,5-dibromopyridin-2-yl)thiourea (40 g, 129 mmol) was added to a mixture of NaH (60%, 15.4 g, 386 mmol) and DMF (640 mL) at 0 °C. The mixture was stirred at 0 °C for 15 min, then at room temperature for 15 min, and then heated at 80 °C for 3 h. After cooling to room temperature, the reaction was quenched with ice-cold saturated NH4Cl aqueous solution (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 10 / 1-1 / 1, then DCM / MeOH = 50 / 1-20 / 1) to yield 6-bromothiazo[4,5-b]pyridin-2-amine (16.4 g, 54%) as a light gray solid. LCMS(ESI,m / z):230,232[M+H] + , 1 HNMR (400MHz, DMSO-d6) δ8.31 (d, J = 2.2 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.09 (s, 2H).

[1182] Intermediate 6: 6-(4-chlorophenyl)thiazo[4,5-b]pyridine-2-amine

[1183]

[1184] Step 1: Add (Boc)₂O (19 g, 87 mmol), TEA (13.2 g, 130 mmol), and DMAP (1.1 g, 8.7 mmol) to a solution of 6-bromothiazo[4,5-b]pyridin-2-amine (10 g, 44 mmol) in DMF (2 mL), and stir the mixture at room temperature for 2 hours. Dilute the mixture with water (200 mL), extract with EtOAc (3 × 300 mL), and wash the combined organic layers with water (200 mL) and brine (200 mL), dry to Na₂SO₄, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (petroleum ether / EtOAc = 100 / 0-3 / 1, v / v) to produce tert-butyl (6-bromothiazo[4,5-b]pyridin-2-yl)carbamate (9 g, 65%) as a yellow solid. LCMS(ESI,m / z):330,332[M+H] + , 1 H NMR (400MHz, DMSO-d6) δ12.2 (s, 1H), 8.68 (d, J = 2.2Hz, 1H), 8.56 (d, J = 2.4Hz, 1H), 1.52 (s, 9H).

[1185] Step 2: To a solution of (6-bromothiazo[4,5-b]pyridin-2-yl)carbamate tert-butyl ester (2 g, 6 mmol) in 1,4-dioxane (40 mL) and water (8 mL), add (4-chlorophenyl)boronic acid (2.8 g, 18 mmol), Pd(dppf)Cl2 (440 mg, 0.6 mmol), and Na2CO3 (1.9 g, 18 mmol), and heat the mixture at 100 °C overnight. Dilute the mixture with water (30 mL), extract with EtOAc (50 mL × 3), and wash the combined organic layers with brine, dry over Na2SO4, filter, and concentrate under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: EtOAc = 5 / 1-1 / 1, then DCM, then DCM / MeOH = 100 / 1-20 / 1, v / v) to give 6-(4-chlorophenyl)thiazo[4,5-b]pyridine-2-amine (2.3 g, 72%) as a brown solid. LCMS (ESI, m / z): 262, 264 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.53(d,J=2.4Hz,1H),8.39(d,J=2.2Hz,1H),8.04(s,2H),7.74–7.68(m,2H),7.54–7.50(m,2H).

[1186] Table A: The following intermediates were prepared using a procedure similar to that described for intermediate 6.

[1187]

[1188]

[1189] Intermediate 9: 6-Phenylthiazo[5,4-c]pyridine-2-amine

[1190]

[1191] Step 1: A mixture of (6-chlorothiazo[5,4-c]pyridin-2-yl)carbamate tert-butyl ester (200 mg, 0.7 mmol), phenylboronic acid (102 mg, 0.8 mmol), potassium carbonate (290 mg, 2.1 mmol), and Pd(PPh3)4 (81 mg, 0.1 mmol, 0.1 equivalent) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was stirred at 90 °C for 16 hours under a nitrogen atmosphere. The resulting mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (10-50% ACN / water, containing 0.1% FA modifier) ​​to give (6-phenylthiazo[5,4-c]pyridin-2-yl)carbamate tert-butyl ester (180 mg, 56% yield) as a yellow solid. LCMS (ESI, m / z): [M+H] + =328

[1192] Step 2: Under a nitrogen atmosphere, TFA (0.6 mL) was added dropwise to a stirred solution of (6-phenylthiazo[5,4-c]pyridin-2-yl)carbamate (340 mg, 1.0 mmol) in DCM (6 mL) at 0 °C. The reaction mixture was warmed to 25 °C and stirred at 25 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (0-40% ACN / water, containing 0.1% FA modifier) ​​to give 6-phenylthiazo[5,4-c]pyridin-2-amine (70.1 mg, 30% yield) as a yellow solid. LCMS (ESI, m / z): [M+H] + =228.

[1193] Table B: The following intermediates were prepared using a procedure similar to that described for intermediate 9.

[1194]

[1195] Intermediate 11: 6-bromothiazo[4,5-b]pyrazin-2-amine

[1196]

[1197] Step 1: Add ethyl O-isothiocyanate (104 g, 791 mmol) to a solution of 3,5-dibromopyrazin-2-amine (20 g, 79 mmol) in acetone (280 mL), and heat the mixture at 100 °C for 1 hour in a sealed container. After cooling to room temperature, add MeOH (50 mL), and continue heating at 80 °C for 1 hour in a sealed container. Cool the mixture to 0 °C and stir for 0.5 hours. Collect the resulting precipitate by filtration, wash with 2 / 1H₂O / MeOH = (60 mL), then wash with MeOH (20 mL), and dry under reduced pressure to produce ethyl (6-bromothiazo[4,5-b]pyrazin-2-yl)carbamate (18 g, 75%) as a pale yellow solid. LCMS (ESI, m / z): 303, 305 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ12.7(s,1H),8.71(s,1H),4.33–4.25(m,2H),1.32–1.27(m,3H).

[1198] Step 2: A mixture of (6-bromothiazo[4,5-b]pyrazin-2-yl)carbamate (10 g, 33 mmol) and 2 M NaOH aqueous solution (115 mL) in MeOH (115 mL) was heated under reflux for 5 hours. After cooling to room temperature, the mixture was adjusted to pH 5-6 with 2 M HCl aqueous solution, neutralized with saturated NaHCO3 aqueous solution, and extracted with EtOAc (3 × 200 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was ground with petroleum ether / EtOAc = 10 / 1 (40 mL) to produce 6-bromothiazo[4,5-b]pyrazin-2-amine (6.5 g, 85%) as a yellow solid. LCMS (ESI, m / z): 231, 233 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.61 (s, 2H), 8.36 (s, 1H).

[1199] Intermediate 12: 6-(tetrahydrofuran-3-yl)thiazo[4,5-b]pyrazine-2-amine

[1200]

[1201] Step 1: At 25°C, K₂CO₃ (1.9 g, 14 mmol) and Pd(dppf)Cl₂·DCM (0.4 g, 0.5 mmol) were added to a solution of N-{6-bromo-[1,3]thiazo[4,5-b]pyrazin-2-yl}carbamate (1.4 g, 4.6 mmol) and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxapentylborane (1.0 g, 5.1 mmol) in 1,4-dioxane (50 mL) and H₂O (10 mL). N₂ was added to the reaction mixture three times at 25°C. The reaction mixture was heated to 110°C and stirred at 110°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated under reduced pressure to remove the dioxane. The residue was acidified to pH 4 with 1 M HCl aqueous solution. The mixture was extracted with DCM / MeOH (5 / 1, 3 × 100 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution using DCM / MeOH (30 / 1) to give N-[6-(2,5-dihydrofuran-3-yl)-[1,3]thiazo[4,5-b]pyrazin-2-yl]carbamate (1.2 g, 89% yield) as a brown solid. LCMS (ESI, m / z): [M+H] + =293

[1202] Step 2: In a pressure vessel, Pd / C (10%, 300 mg) was added to a suspension of N-[6-(2,5-dihydrofuran-3-yl)-[1,3]thiazo[4,5-b]pyrazin-2-yl]carbamate (1.0 g, 3.4 mmol) in MeOH (100 mL) and THF (100 mL) at 25 °C. The resulting mixture was heated to 60 °C and stirred at 60 °C for 12 hours under hydrogen (30 psi). The reaction mixture was cooled to 25 °C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution using DCM / MeOH (20 / 1) to give N-[6-(oxacyclopentan-3-yl)-[1,3]thiazo[4,5-b]pyrazin-2-yl]carbamate (700 mg, 70% yield) as a yellow solid. LCMS(ESI,m / z):[M+H] + =295.

[1203] Step 3: Add NaOH (950 mg, 24 mmol) to a suspension of N-[6-(oxacyclopentan-3-yl)-[1,3]thiazo[4,5-b]pyrazin-2-yl]carbamate (700 mg, 2.4 mmol) in MeOH (10 mL) and H₂O (10 mL) at 25 °C. Heat the reaction mixture at 90 °C for 4 hours. Cool the reaction mixture to 25 °C and concentrate under reduced pressure. Acidify the residue to pH 7 with 1 M HCl aqueous solution, and extract the mixture with DCM / MeOH (10 / 1) (3 × 100 mL). Wash the combined organic layers with brine (20 mL) and dry over anhydrous Na₂SO₄. Filter and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography with elution using DCM / MeOH (10 / 1) to give 6-(oxacyclopentan-3-yl)-[1,3]thiazo[4,5-b]pyrazin-2-amine (400 mg, 76% yield) as a yellow solid. LCMS (ESI, m / z): [M+H] + =223.

[1204] Intermediate 13: 6-(4-chlorophenyl)thiazo[4,5-b]pyrazine-2-amine

[1205]

[1206] Step 1: Add (4-chlorophenyl)boronic acid (1.55 g, 9.90 mmol), Na₂CO₃ (1.05 g, 9.90 mmol), and Pd(dppf)Cl₂ (240 mg, 0.33 mmol) to a mixture of (6-bromothiazo[4,5-b]pyrazin-2-yl)carbamate (1 g, 3.3 mmol) in 1,4-dioxane (10 mL) and water (2 mL), and heat the mixture in a sealed tube at 120 °C for 16 hours. After cooling to room temperature, dilute the mixture with water (5 mL), extract with EtOAc (3 × 20 mL), and dry the combined organic phases to Na₂SO₄, filter, and concentrate under reduced pressure. The residue was ground with petroleum ether / EtOAc = 10 / 1 (10 mL) to produce ethyl (6-(4-chlorophenyl)thiazo[4,5-b]pyrazin-2-yl)carbamate (1.9 g, 86%) as a gray solid. LCMS (ESI, m / z): 335 [M+H] + .

[1207] Step 2: A mixture of ethyl (6-(4-chlorophenyl)thiazo[4,5-b]pyrazin-2-yl)carbamate (1.9 g, 5.7 mmol) and 2 M NaOH aqueous solution (18 mL) in MeOH (18 mL) was heated under reflux for 3.5 h. After cooling to room temperature, the mixture was adjusted to pH 5-6 with 2 M HCl aqueous solution, neutralized with saturated NaHCO3 aqueous solution, and extracted with EtOAc (3 × 30 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was ground with 5 / 1 petroleum ether / EtOAc (15 mL) to produce 6-(4-chlorophenyl)thiazo[4,5-b]pyrazin-2-amine (1.2 g, 82%) as a gray solid. LCMS (ESI, m / z): 263 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.92–8.83(m,1H),8.53–8.47(m,2H),8.10–8.04(m,2H),7.56–7.51(m,2H).

[1208] Table C: The following intermediates are prepared using a procedure similar to that described for intermediate 13.

[1209]

[1210] Intermediate 16: 6-(4-chlorophenyl)thiazo[4,5-c]pyridine-2-amine

[1211]

[1212] Step 1: Add (4-chlorophenyl)boronic acid (959 mg, 6.1 mmol), Pd(dppf)Cl2 (445 mg, 0.61 mmol), and Na2CO3 (1.95 g, 18.3 mmol) to a solution of 4,6-dichloropyridin-3-amine (1.0 g, 6.1 mmol) in 1,4-dioxane (10 mL) and water (2 mL), and heat the mixture overnight in a sealed tube at 80 °C. Dilute the mixture with water (30 mL), extract with EtOAc (3 × 20 mL), and wash the combined organic layers with water (30 mL) and brine (30 mL), dry to Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0.6–1% MeOH / DCM) to produce 4-chloro-6-(4-chlorophenyl)pyridin-3-amine (1.36 g, 93%) as a pink solid. LCMS(ESI,m / z):239[M+H] + , 1H NMR (400MHz, DMSO-d6): δ 8.17 (s, 1H), 7.98 (d, J = 8.6 Hz, 2H), 7.88 (s, 1H), 7.44 (d, J = 8.6 Hz, 2H), 5.83 (s, 2H).

[1213] Step 2: Add KSCN (2.7 g, 28 mmol) and concentrated HCl aqueous solution (2 mL) to a solution of 4-chloro-6-(4-chlorophenyl)pyridin-3-amine (1.36 g, 5.68 mmol) in 1,4-dioxane (10 mL), and heat the mixture under reflux for 2 days. Dilute the mixture with water (200 mL), extract with EtOAc (3 × 50 mL), and wash the combined organic layers with water (100 mL) and brine (100 mL), dry to Na₂SO₄, filter, and concentrate under reduced pressure to produce 1.62 g of 6-(4-chlorophenyl)thiazo[4,5-c]pyridin-2-amine as a solid, which can be used without further purification. LCMS (ESI, m / z): 262 [M+H] + , 1 H NMR (400MHz, DMSO-d6): δ 8.62 (s, 1H), 8.38 (s, 1H), 8.07 (d, J = 8.6 Hz, 2H), 7.87 (s, 2H), 7.51 (d, J = 8.6 Hz, 2H).

[1214] Intermediate 67: (1r,4r)-4-(2-aminothiazo[4,5-b]pyrazin-6-yl)cyclohexane-1-nitrile

[1215]

[1216] Step 1: A solution of (6-bromothiazo[4,5-b]pyrazin-2-yl)carbamate (10 g, 33 mmol) in a mixture of MeOH (100 mL) and 2 M NaOH aqueous solution (100 mL) was heated overnight at 80 °C. The MeOH was removed under reduced pressure, and the aqueous residue was adjusted to pH 7 with 6 M HCl aqueous solution. The resulting precipitate was collected by filtration and dried to give 6-bromothiazo[4,5-b]pyrazin-2-amine (6.5 g, 85% yield) as a yellow solid. LCMS (ESI, m / z): 231 and 233 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.59 (s, 2H), 8.37 (s, 1H).

[1217] Step 2: Add (Boc)₂O (12 g, 56 mmol) to a solution of 6-bromothiazo[4,5-b]pyrazin-2-amine (6.5 g, 28 mmol), DMAP (0.69 g, 5.6 mmol), and TEA (8.5 g, 84 mmol) in DMF (18 mL), and stir the mixture overnight at room temperature. Pour the mixture into water (200 mL), extract with EtOAc (80 mL × 3), and wash the combined organic layers with brine (100 mL), dry to Na₂SO₄, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography with DCM / MeOH (1 / 0 to 50 / 1, v / v) to give tert-butyl (6-bromothiazo[4,5-b]pyrazin-2-yl)carbamate (7.7 g, 83% yield) as a yellow solid. LCMS(ESI, m / z): 331 and 333 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.5(s,1H),8.71(s,1H),1.53(s,9H).

[1218] Step 3: Part A: Add 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-onium tetrafluoroborate (597 mg, 1.51 mmol) to a solution of 4-hydroxycyclohexane-1-onitrile (189 mg, 1.51 mmol) in 1,4-dioxane (5 mL), and stir the mixture at room temperature for 10 minutes under a nitrogen atmosphere. Add pyridine (119 mg, 1.51 mmol), and continue stirring at room temperature for another 15 minutes. A white solid precipitates during this period.

[1219] Part B: Under a nitrogen atmosphere, at room temperature, (dtpby)NiBr2 (58.8 mg, 0.121 mmol) and [Ir(dtbbpy)(ppy)2][PF6] (55.2 mg, 0.0604 mmol) were added to a solution of (6-bromothiazo[4,5-b]pyrazin-2-yl)carbamate tert-butyl (200 mg, 0.604 mmol) and quinine ring (118 mg, 1.06 mmol) in DMA (5 mL). Part A was filtered, and the filtrate was injected into part B through a syringe filter. The resulting mixture was irradiated under a 450 nm blue LED module and stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was poured into water (50 mL), extracted with EtOAc (40 mL × 3), 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 with DCM / MeOH (1 / 0 to 80 / 1, v / v) followed by preparative HPLC to give tert-butyl (6-((1s,4s)-4-cyanocyclohexyl)thiazo[4,5-b]pyrazin-2-yl)carbamate (32 mg, 13% yield) as a white solid and tert-butyl (6-((1r,4r)-4-cyanocyclohexyl)thiazo[4,5-b]pyrazin-2-yl)carbamate (40 mg, 17%) as a white solid.

[1220] (6-((1s,4s)-4-cyanocyclohexyl)thiazo[4,5-b]pyrazin-2-yl)tert-butyl carbamate (first elution peak from p-HPLC): LCMS (ESI, m / z): 360 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.2(s,1H),8.46(s,1H),3.27–3.21(m,1H),2.97–2.8 7(m,1H),2.06–1.96(m,2H),1.95–1.88(m,2H),1.87–1.69(m,4H),1.52(s,9H).

[1221] (6-((1r,4r)-4-cyanocyclohexyl)thiazo[4,5-b]pyrazin-2-yl)tert-butyl carbamate (second elution peak from p-HPLC): LCMS (ESI, m / z): 360 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ8.36(s,1H),2.92–2.73(m,2H),2.19–2.08(m,2H),1.95–1.86(m,2H),1.73–1.59(m,4H),1.50(s,9H).

[1222] Step 4: A mixture of (6-((1r,4r)-4-cyanocyclohexyl)thiazo[4,5-b]pyrazin-2-yl)carbamate tert-butyl ester (38 mg, 0.11 mmol) and 4 M HCl in 1,4-dioxane (3 mL) was stirred overnight at room temperature. The mixture was adjusted to pH 8 with saturated NaHCO3 aqueous solution, extracted with DCM (30 mL × 4), and the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (1r,4r)-4-(2-aminothiazo[4,5-b]pyrazin-6-yl)cyclohexane-1-onitrile (20 mg, 74%) as a yellow solid. LCMS (ESI, m / z): 260 [M+H] + .

[1223] Intermediate 68: 6-(4-methoxytetrahydro-2H-pyran-4-yl)thiazo[4,5-b]pyrazin-2-amine

[1224] Step 1: A mixture of (6-bromothiazo[4,5-b]pyrazin-2-yl)carbamate (2 g, 7 mmol), (Boc)₂O (4 g, 5 mL, 0.02 mol), DMAP (0.4 g, 3 mmol), and TEA (2 g, 3 mL, 0.02 mol) in DCM (40 mL) was stirred at 25 °C for 16 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with 0–30% EtOAc / petroleum ether elution to give (6-bromothiazo[4,5-b]pyrazin-2-yl)iminodicarbonate tert-butyl ester (800 mg, 30% yield) as a white solid.

[1225] Step 2: A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxapentoboran-2-yl)-3,6-dihydro-2H-pyran (500 mg, 2.38 mmol), (6-bromothiazo[4,5-b]pyrazin-2-yl)iminodicarbonate tert-butyl ester (800 mg, 1.98 mmol), PdCl2(dppf)-CH2Cl2 adduct (162 mg, 198 μmol), and K2CO3 (823 mg, 5.95 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc / petroleum ether (0-40%) to give (6-(3,6-dihydro-2H-pyran-4-yl)thiazo[4,5-b]pyrazin-2-yl)iminodicarbonate tert-butyl ester (680 mg, 84% yield) as a white solid.

[1226] Step 3: A mixture of (6-(3,6-dihydro-2H-pyran-4-yl)thiazo[4,5-b]pyrazin-2-yl)iminodicarbonate tert-butyl ester (400 mg, 984 μmol), Mn(dpm)3 (59.5 mg, 98.4 μmol), and phenylsilane (320 mg, 366 μL, 2.95 mmol) in isopropanol (9 mL) and DCM (1 mL) was stirred at 25 °C for 18 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography by elution with MeOH and DCM (0-15%) to give (6-(4-hydroxytetrahydro-2H-pyran-4-yl)thiazo[4,5-b]pyrazin-2-yl)iminodicarbonate tert-butyl ester (150 mg, 36% yield) as a yellow solid.

[1227] Step 4: Sodium hydride (61.3 mg, 60% wt, 1.53 mmol) was added to a solution of (6-(4-hydroxytetrahydro-2H-pyran-4-yl)thiazo[4,5-b]pyrazin-2-yl)iminodicarbonate tert-butyl ester (260 mg, 0.613 mmol) in THF (8 mL) at 0 °C. The mixture was stirred at 25 °C for 30 min. MeI (261 mg, 115 μL, 1.84 mmol) was added to a solution of THF (2 mL) at 0 °C, and the mixture was warmed to 25 °C and stirred for 1.5 h. The reaction mixture was quenched with water and extracted with DCM (3 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with EtOAc and petroleum ether (0-50%) to give (6-(4-methoxytetrahydro-2H-pyran-4-yl)thiazo[4,5-b]pyrazin-2-yl)iminodicarbonate tert-butyl ester (160 mg, 60% yield) as a white solid. LCMS (ESI, m / z): 339 [M+H-Boc] + .

[1228] Step 5: A solution of (6-(4-methoxytetrahydro-2H-pyran-4-yl)thiazo[4,5-b]pyrazin-2-yl)iminodicarbonate tert-butyl ester (140 mg, 319 μmol) and TFA (1 g, 1 mL, 0.01 mol) in DCM (2 mL) was stirred at 25 °C for 12 hours. The resulting mixture was concentrated under reduced pressure to give (180 mg, crude product) of (6-(4-methoxytetrahydro-2H-pyran-4-yl)thiazo[4,5-b]pyrazin-2-yl)carbamate as a yellow oil. LCMS (ESI, m / z): 339 [M+H] + .

[1229] Step 6: A mixture of ethyl (6-(4-methoxytetrahydro-2H-pyran-4-yl)thiazo[4,5-b]pyrazin-2-yl)carbamate (110 mg, 325 μmol) and LiOH (77.9 mg, 3.25 mmol) in MeOH (1.5 mL) and H₂O (0.5 mL) was stirred at 80 °C for 5 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (0-100% MeOH / water) to give 6-(4-methoxytetrahydro-2H-pyran-4-yl)thiazo[4,5-b]pyrazin-2-amine (60 mg, 69% yield) as a white solid. LCMS (ESI, m / z): 267 [M+H] + .

[1230] Intermediate 17: 4-Bromo-6-methyl-N-(6-(pyridin-4-yl)thiazo[4,5-b]pyridin-2-yl)nicotinamide

[1231]

[1232] TCFH (780 mg, 2.80 mmol), NMI (600 mg, 7.40 mmol), and 6-(pyridin-4-yl)thiazo[4,5-b]pyridin-2-amine (211 mg, 0.91 mmol) were added to a solution of 4-bromo-6-methylnicotinic acid (400 mg, 1.82 mmol) in NMP (10 mL), and the mixture was stirred overnight at room temperature. The mixture was diluted with water (200 mL), extracted with EtOAc (100 mL × 4), and the combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 50 / 1–20 / 1, v / v) to give 4-bromo-6-methyl-N-(6-(pyridin-4-yl)thiazo[4,5-b]pyridin-2-yl)nicotinamide (100 mg, 25%) as a white solid. LCMS (ESI, m / z): 426, 428 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ13.5(s,1H),9.05(d,J=2.2Hz,1H),8.99(d,J=2.4Hz,1H ),8.74(s,1H),8.71–8.69(m,2H),7.87–7.85(m,2H),7.80(s,1H),2.55(s,3H).

[1233] Table D: The following intermediates are prepared using a procedure similar to that described for intermediate 17.

[1234]

[1235]

[1236] Intermediate 21: 4-chloro-6-methyl-N-(6-(pyridin-4-yl)thiazo[4,5-b]pyridin-2-yl)nicotinamide

[1237]

[1238] A mixture of 4-chloro-6-methylnicotinic acid (30 mg, 0.17 mmol), 6-(pyridin-4-yl)thiazo[4,5-b]pyridin-2-amine (48 mg, 0.21 mmol), TCFH (74 mg, 0.26 mmol), and NMI (57 mg, 0.7 mmol) in DMF (0.5 mL) and ACN (0.5 mmol) was stirred overnight at room temperature. The resulting precipitate was collected by filtration, washed with petroleum ether / EtOAc (50 / 1, 10 mL), ACN (10 mL), and dried under reduced pressure to yield 4-chloro-6-methyl-N-(6-(pyridin-4-yl)thiazo[4,5-b]pyridin-2-yl)nicotinamide (15 mg, 22%) as a brown solid. LCMS (ESI, m / z): 382 [M+H] + , 1 HNMR (400MHz, DMSO-d6) δ13.5(s,1H),9.02(dd,J=22.8,2.4Hz,2H),8.80(s,1H),8.72–8.66(m,2H),7.89–7.80(m,2H),7.65(s,1H),2.57(s,3H).

[1239] Intermediate 22: 4-chloro-6-methyl-N-(6-(pyridin-4-yl)thiazo[4,5-b]pyrazin-2-yl)nicotinamide

[1240]

[1241] A solution of 6-(pyridin-4-yl)-[1,3]thiazo[4,5-b]pyrazin-2-amine (1.0 g, 4.3 mmol) and 4-chloro-6-methylpyridin-3-carboxylic acid (374 mg, 2.2 mmol) was treated with TEA (1.32 g, 13.1 mmol), followed by the addition of HATU (2.0 g, 5.2 mmol) in portions at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min under a nitrogen atmosphere. The resulting mixture was directly purified by preparative HPLC (10-50% ACN / water, containing 0.1% FA modifier) ​​to give 4-chloro-6-methyl-N-[6-(pyridin-4-yl)-[1,3]thiazo[4,5-b]pyrazin-2-yl]pyridin-3-carboxamide (320.1 mg, 36.4% yield) as a pale yellow solid. LCMS(ESI):[M+H]+=383. 1H NMR (300MHz, DMSO-d6) δ13.73(s,1H),9.40(s,1H),8.82(s,1H),8.76–8.75(m,2H),8.18–8.13(m,2H),7.65(s,1H),2.57(s,3H).

[1242] Table E: The following intermediates are prepared using a procedure similar to that described for intermediate 22.

[1243]

[1244] Intermediate 24: N-(6-bromothiazo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)-6-methylnicotinamide

[1245]

[1246] HOBt (1.67 g, 12.3 mmol), EDCI.HCl (2.36 g, 12.3 mmol), and DIPEA (3.19 g, 24.6 mmol) were added to a solution of 4-(2-methoxyphenyl)-6-methylnicotinic acid (2 g, 8.2 mmol) in NMP (20 mL), and the mixture was stirred at room temperature for 1 hour. 6-bromothiazo[4,5-b]pyrazin-2-amine (1.33 g, 5.76 mmol) was added, and the mixture was heated at 50 °C overnight. The mixture was diluted with water (40 mL), extracted with EtOAc (60 mL × 3), and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 90 / 1 to 50 / 1, v / v) to give N-(6-bromothiazo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)-6-methylnicotinamide (1.37 g, 33%) as a yellow solid. LCMS (ESI, m / z): 456, 458 [M+H] + , 1 H NMR (400MHz, DMSO-d6): δ13.4(s,1H),8.76(d,J=14.0Hz,2H),7.41(ddd,J=7.4,4.4,2.6Hz, 2H),7.35(s,1H),7.11(td,J=7.6,1.0Hz,1H),7.00–6.96(m,1H),3.50(s,3H),2.59(s,3H).

[1247] Intermediate 25: N-(6-bromothiazo[4,5-b]pyrazin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide

[1248]

[1249] To a solution of 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid (174 mg, 0.649 mmol) in DMF (7.5 mL), 6-bromothiazo[4,5-b]pyrazin-2-amine (200 mg, 0.865 mmol), EDCI.HCl (214 mg, 1.12 mmol), and DMAP (136 mg, 1.12 mmol) were added, and the mixture was stirred overnight at room temperature. The mixture was diluted with water (75 mL), extracted with EtOAc (50 mL × 6), and the combined organic layers were washed with brine (120 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 30 / 1, v / v) to yield N-(6-bromothiazo[4,5-b]pyrazin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylnicotinamide (203 mg, 65%) as a pale yellow solid. LCMS (ESI, m / z): 481, 483 [M+H] + , 1 H NMR (400MHz, DMSO-d6): δ13.5 (s, 1H), 8.80 (d, J = 12.4Hz, 2H), 7.91 (dt, J = 4. 6, 2.4Hz, 2H), 7.45 (s, 1H), 7.17 (d, J = 9.2Hz, 1H), 3.59 (s, 3H), 2.60 (s, 3H).

[1250] Table F: The following intermediates were prepared using a procedure similar to that described for intermediate 25.

[1251]

[1252] Intermediate 27: N-(6-bromothiazo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)-2-methylpyrimidin-5-carboxamide

[1253]

[1254] Step 1: Pd(dppf)Cl2 (93 mg, 0.1 mmol, 0.1 equivalent) was added in a single step to a stirred mixture of 2-(2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxapentylborane (300 mg, 1.2 mmol, 1.0 equivalent), 4-chloro-2-methylpyrimidin-5-carboxylic acid (219 mg, 1.2 mmol, 1.0 equivalent), and potassium carbonate (535 mg, 3.8 mmol, 3.0 equivalent) in 1,4-dioxane (1 mL) and H2O (0.1 mL). N2 was introduced into the reaction mixture three times at room temperature. The reaction mixture was heated to 110 °C and stirred at 110 °C for 16 hours under a nitrogen atmosphere. The resulting mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN / water (0.1% FA), in a 10% to 50% gradient over 10 minutes; detector, UV 254 nm, to give 4-(2-methoxyphenyl)-2-methylpyrimidine-5-carboxylic acid (160.5 mg, 51.1% yield) as a yellow solid. LCMS (ESI, m / z): [M+H] + =245.0.

[1255] Step 2: At room temperature, add methyl 4-(2-methoxyphenyl)-2-methylpyrimidin-5-carboxylate (160 mg, 0.6 mmol, 1.0 equivalent), 6-bromo-[1,3]thiazo[4,5-b]pyrazin-2-amine (158 mg, 0.6 mmol, 1.0 equivalent), HATU (392 mg, 1.1 mmol, 1.5 equivalent), and DIPEA (267 mg, 2.1 mmol, 3.0 equivalent) to a solution of DMF (2 mL). Purge the reaction mixture three times with N2 at room temperature. Stir the reaction mixture at 25 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was then purified directly by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN / water (0.1% FA), in a 10% to 50% gradient over 10 minutes; detector, UV 254 nm, to give N-(6-bromothiazo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)-2-methylpyrimidine-5-carboxamide (80.0 mg, 26.7% yield) as a yellow solid. LCMS (ESI, m / z): [M+H] + =457.0.

[1256] Table G: Using a procedure similar to that described in step 2 for intermediate 27, prepare the following intermediates with intermediate 36.

[1257]

[1258] Intermediate 29: N-(6-bromothiazo[4,5-b]pyrazin-2-yl)-2'-cyano-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1259]

[1260] Step 1: Pd(PPh3)4 (315 mg, 0.3 mmol) was added to a solution of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (400 mg, 1.4 mmol) and zinc cyanide (481 mg, 4.2 mmol) in DMF (4 mL) at 25 °C. N2 was introduced into the reaction mixture three times at 25 °C, and the mixture was heated to 90 °C and stirred at 90 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was cooled to 25 °C and diluted with EtOAc (50 mL). The mixture was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of petroleum ether / EtOAc (1 / 1) to give methyl 2'-cyano-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (350 mg, 90% yield) as a pale yellow solid. LCMS (ESI): [M+H]+=284.

[1261] Step 2: LiOH·H₂O (52 mg, 1.2 mmol) was added to a solution of methyl 2'-cyano-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (350 mg, 1.2 mmol) in THF (6 mL) and water (2 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The resulting mixture was acidified to pH 7 with 1 M HCl aqueous solution. The resulting mixture was concentrated under reduced pressure. The residue was directly purified by preparative HPLC (3-14% ACN / water, containing 0.1% formic acid modifier) ​​to give 2'-cyano-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (180 mg, 54% yield) as a grayish-white solid. LCMS (ESI): [M+H]+=270.

[1262] Step 3: A solution of 2'-cyano-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (150 mg, 0.6 mmol) and 6-bromo-[1,3]thiazo[4,5-b]pyrazin-2-amine (129 mg, 0.6 mmol) in DMF (3 mL) was treated with HOBt (113 mg, 0.9 mmol) and DIPEA (216 mg, 1.8 mmol) at 25 °C, followed by a single addition of EDCI (160 mg, 0.9 mmol) at 25 °C. N2 was introduced into the reaction mixture three times at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours under a nitrogen atmosphere. The resulting mixture was directly purified by reversed-phase rapid chromatography (0-100% ACN / water, containing 0.1% formic acid modifier) ​​to yield N-{6-bromo-[1,3]thiazo[4,5-b]pyrazin-2-yl}-2'-cyano-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (200 mg, 74% yield) as a pale yellow solid. LCMS (ESI): [M+H]+ = 482,484.

[1263] Intermediate 69: N-(6-bromothiazo[4,5-b]pyrazin-2-yl)-6-methyl-4-(2-methyl-2H-pyrazolo[4,3-c]pyridin-3-yl)nicotinamide

[1264]

[1265] A solution of 6-methyl-4-(2-methyl-2H-pyrazolo[4,3-c]pyridin-3-yl)nicotinic acid (300 mg, 1.1 mmol) in DMF (3 mL) was treated with PyBOP (873 mg, 1.6 mmol) and DIEA (867 mg, 6.7 mmol) for 5 min at 25 °C, followed by a single addition of 6-bromothiazo[4,5-b]pyrazin-2-amine (258 mg, 1.1 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h. The resulting mixture was purified by reversed-phase rapid chromatography (0-100% MeCN / water, containing 10 mmol / L NH4HCO3 modifier) ​​to give N-(6-bromothiazo[4,5-b]pyrazin-2-yl)-6-methyl-4-(2-methyl-2H-pyrazolo[4,3-c]pyridin-3-yl)nicotinamide (300 mg, 56% yield) as a pale yellow solid. LCMS (ESI, m / z): 481 [M+H] + .

[1266] Table AM: The following intermediates are prepared using a procedure similar to that described for intermediate 69.

[1267]

[1268]

[1269] Intermediate 30: N-(5-amino-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1270]

[1271] Under a nitrogen atmosphere, a solution of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (200 mg, 0.7 mmol) and 1,3,4-thiadiazole-2,5-diamine (167 mg, 1.4 mmol) in pyridine (2.5 mL) was treated with HOBt (102 mg, 0.7 mmol) for 2 min at 25 °C, followed by a single addition of EDCI (206 mg, 1.0 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 48 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (0-100% ACN / water, containing 0.1% NH3-H2O) to give N-(5-amino-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (90.0 mg, 33% yield) as a pale yellow solid. LCMS (ESI): [M+H]+ = 377.

[1272] Table H: The following intermediates were prepared using a procedure similar to that described for intermediate 30.

[1273]

[1274] Intermediate 32: 2-{2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-amido}imidazo[2,1-b][1,3,4]thiadiazole-6-carboxylic acid

[1275]

[1276] N-(5-amino-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (2.5 g, 6.6 mmol), DBU (3.0 g, 20 mmol), and 3-bromo-2-oxopropionic acid (3.3 g, 20 mmol) were added to a 250 mL three-necked round-bottom flask at 25 °C. The reaction mixture was heated at 110 °C for 1 hour. The resulting mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by grinding with water (300 mL). After filtration, the filter cake was washed with water (2 × 100 mL). The solid was collected and concentrated under reduced pressure to give 2-{2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-amido}imidazo[2,1-b][1,3,4]thiadiazole-6-carboxylic acid (2.3 g, crude product), a light brown solid. The crude product could be used directly for the next step without further purification. LCMS (ESI, m / z): [M+H] + =445.

[1277] Intermediate 33: 2-(2-aminoimidazo[2,1-b][1,3,4]thiadiazol-6-yl)prop-1-ol

[1278]

[1279] Step 1: Under a nitrogen atmosphere, bromine (6.1 g, 38 mmol) was added dropwise to a stirred solution of ethyl 2-methyl-3-oxobutyrate (5.0 g, 35 mmol) in Et₂O (50 mL) at -78 °C. The resulting mixture was slowly heated to 25 °C and stirred at 25 °C for 12 hours. The mixture was alkalized to pH 8 with a saturated aqueous solution of NaHCO₃. The resulting mixture was extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give ethyl 4-bromo-2-methyl-3-oxobutyrate (6.9 g, crude product), a brown oil. The crude product was used directly for the next step without further purification. GCMS: 222.

[1280] Step 2: Under a nitrogen atmosphere, a mixture of ethyl 4-bromo-2-methyl-3-oxobutyrate (3.0 g, 13 mmol) and 1,3,4-thiadiazole-2,5-diamine (780 mg, 6.7 mmol) in EtOH (50 mL) was stirred at 90 °C for 12 hours. The resulting mixture was slowly cooled to 25 °C and purified by reversed-phase rapid chromatography (5-30% ACN / water, containing 0.1% formic acid modifier) ​​to give ethyl 2-(2-aminoimidazo[2,1-b][1,3,4]thiadiazole-6-yl)propionate (208 mg, 6.1% yield) as a brown oil. LCMS (ESI): [M+H] + =241.1

[1281] Step 3: Under a nitrogen atmosphere, LiAlH4 (31 mg, 0.8 mmol) was added in portions to a stirred solution of ethyl 2-(2-aminoimidazo[2,1-b][1,3,4]thiadiazol-6-yl)propionate (198 mg, 0.8 mmol) in THF (5 mL) at -78 °C. The reaction mixture was slowly heated to 0 °C and quenched at 0 °C by adding Na2SO4·10H2O (2 mL). After filtration, the filter cake was washed with DCM (3 × 10 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (147 mg) was purified by preparative HPLC (2-14% ACN / water, containing 10 mmol / L NH4HCO3 modifier) ​​to give 2-{2-aminoimidazo[2,1-b][1,3,4]thiadiazol-6-yl}prop-1-ol (23.2 mg, 14.1% yield) as a colorless solid. LCMS (ESI): [M+H] + =199.

[1282] Intermediate 34: 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-methylnicotinic acid

[1283]

[1284] Step 1: Under a nitrogen atmosphere, at room temperature, Pd(PPh3)4 (251 mg, 0.2 mmol) and K2CO3 (907 mg, 6.5 mmol) were added in portions to a stirred solution of methyl 4-bromo-6-methylpyridine-3-carboxylate (500 mg, 2.2 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (806 mg, 2.6 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred at 80 °C for 2 hours. The resulting mixture was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). 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 with elution of petroleum ether / EtOAc (2:1) to give 3'-methyl 6'-methyl-3,6-dihydro-2H-[4,4'-bipyridine]-1,3'-dicarboxylic acid 1-tert-butyl ester (700.0 mg, 97% yield) as a white solid. LCMS (ESI, m / z): [M+H] + =333.

[1285] Step 2: Add MeOH (10 mL) to a mixture of 1-tert-butyl 3'-methyl 6'-methyl 6'-methyl-3'-methyl 6'-methyl-3'-methyl-3'-methyl-6 ... + =335.

[1286] Step 3: A solution of LiOH·H₂O (207 mg, 4.9 mmol) in water (2 mL) was added dropwise to a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)piperidin-4-yl]-6-methylpyridine-3-carboxylate (550 mg, 1.64 mmol) in THF (4.5 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure. The crude product was ready for use without further purification. LCMS (ESI, m / z): [M+H] + =321.

[1287] Intermediate 35: 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-cyanonic acid

[1288]

[1289] Step 1: Under a nitrogen atmosphere, DIPEA (2 mL, 12.3 mmol) was added dropwise to a stirred solution of ethyl 4,6-dichloropyridine-3-carboxylate (900 mg, 4.1 mmol) and tert-butyl piperazine-1-carboxylate (800 mg, 4.3 mmol) in ACN (9 mL) at 0 °C. The resulting mixture was heated and stirred at 80 °C for 12 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution using DCM / EtOAc (4 / 1) to give tert-butyl 4-[2-chloro-5-(ethoxycarbonyl)pyridine-4-yl]piperazine-1-carboxylate (1.4 g, 92.5% yield) as a colorless solid. LCMS (ESI, m / z): [M+H] + =370.

[1290] Step 2: Under a nitrogen atmosphere, at room temperature, Zn (55 mg, 0.9 mmol) and Pd(dppf)Cl2 (316 mg, 0.4 mmol) were added in portions to a stirred solution of 4-[2-chloro-5-(ethoxycarbonyl)pyridin-4-yl]piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.3 mmol) and Zn(CN)2 (66 mg, 0.6 mmol) in DMF (3 mL). The resulting mixture was stirred at 100 °C for 12 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The crude product mixture could be used directly for the next step without further purification. LCMS (ESI, m / z): [M+H] + =361.

[1291] Step 3: LiOH·H₂O (16 mg, 0.7 mmol) was added in a single addition to a stirred solution of tert-butyl 4-[2-cyano-5-(ethoxycarbonyl)pyridin-4-yl]piperazine-1-carboxylate (80 mg, 0.2 mmol) in DMF (1.5 mL) and water (0.5 mL). The resulting mixture was heated at 40 °C for 12 hours. The resulting mixture was purified by reversed-phase rapid chromatography (5%–50% ACN / water, containing 0.1% formic acid modifier) ​​to yield 4-[4-(tert-butoxycarbonyl)piperazine-1-yl]-6-cyanopyridin-3-carboxylic acid (35.0 mg, 47.4% yield) as a brown solid. LCMS (ESI, m / z): [M+H] + =333.

[1292] Intermediate 36: Lithium 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methylpyrimidin-5-carboxylate

[1293] Step 1: Under a nitrogen atmosphere, DIPEA (0.3 mL, 1.5 mmol) was added dropwise to a stirred solution of ethyl 4-chloro-2-methylpyrimidin-5-carboxylate (100 mg, 0.5 mmol) and piperazine-1-carboxylate tert-butyl ester (102 mg, 0.5 mmol) in 1 mL of ACN at 0 °C. The resulting mixture was warmed to room temperature and stirred at room temperature for 12 hours. The resulting mixture was concen...

Claims

1. A compound of formula (I): Or its pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, or tautomers, wherein: X 1 For CH, S, or N; X 2 For N, S, or O; X 3 It can be C or N; R 1 and R 2 Together with the atoms it is attached to, it forms C6-C. 10 aryl or 5 to 10-membered heteroaryl, wherein the C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. a replace; Each R a Independently oxo, halogenated, cyano, -OH, -NH2, -C(O)N(R) b (R) c ), -N(R b )C(O)(R c C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C4-C 10 Cycloalkenyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic alkyl, or 4- to 10-membered heterocyclic alkenyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C4-C 10 Cycloalkenyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic alkyl or 4- to 10-membered heterocyclic alkenyl, optionally separated by one or more R a1 replace; Each R b and R c Independently H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 alkyl, or C4-C5 alkyl is a cycloalkyl group. 10 The cycloalkyl or 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more -OH or C1-C6 haloalkyl groups; or R b and R c Together with the atoms to which they are attached, they form 3 to 10-membered heterocyclic alkyl groups, wherein the 3 to 10-membered heterocyclic alkyl groups are optionally substituted by one or more -OH, -O (C1-C6 haloalkyl), -O (C1-C6 alkyl), -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl or -N (C1-C6 alkyl)2; Each R a1 Independently oxo, halogenated, cyano, -OH, -O (C3-C) 10 Cycloalkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -C(O)OH, -C(O)O (C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -O- (C3-C 10 cycloalkyl), C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the 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 groups are optionally surrounded by one or more R groups. a2 replace; Each R a2 It can be independently oxo, halogenated, cyano, -OH, or -NH2; R 3 For C6-C 10 aryl or 6- to 10-membered heteroaryl, wherein the C6-C 10 aryl or 6- to 10-membered heteroaryl groups are substituted with one or more R groups. 3a replace; Each R 3a Independently, it is halogenated, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, -O (C6-C 10 Aryl), C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, -O (C6-C 10 Aryl), C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. 3a1 Replace; and Each R 3a1 Independently oxo, halogenated, cyano, -NH2, -NH-C(O)O(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl, wherein the C1-C6 alkyl is optionally separated by one or more C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O (C1-C6 haloalkyl), C3-C 10 cycloalkyl, C6-C 10 Aryl or 5 to 10 heteroaryl substituents; Where R 3a Halogenated and R 1 and R 2 When R forms a 6-membered heteroaryl group with the atoms it is attached to, then a It's not -CF3.

2. A compound of formula (I): Or its pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, or tautomers, wherein: X 1 For CH, S, or N; X 2 For N, S, or O; X 3 It can be C or N; R 1 and R 2 Together with the atoms it is attached to, it forms C6-C. 10 aryl or 5 to 10-membered heteroaryl, wherein the C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. a replace; Each R a Independently oxo, halogenated, cyano, -OH, -NH2, -C(O)N(R) b (R) c ), -N(R b )C(O)(R c 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 heterocyclic alkyl, wherein the 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 heterocyclic alkyl, optionally bounded by one or more R a1 replace; Each R b and R c Independently H, C1-C6 alkyl, C3-C 10 Cycloalkyl or 3- to 10-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 alkyl, or C4-C5 alkyl is a cycloalkyl group. 10 The cycloalkyl or 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more -OH or C1-C6 haloalkyl groups; or R b and R c Together with the atoms to which they are attached, they form 3 to 10-membered heterocyclic alkyl groups, wherein the 3 to 10-membered heterocyclic alkyl groups are optionally substituted by one or more -OH, -O (C1-C6 haloalkyl), -O (C1-C6 alkyl), -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl or -N (C1-C6 alkyl)2; Each R a1 Independently oxo, halogenated, cyano, -OH, -O (C3-C) 10 Cycloalkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -C(O)OH, -C(O)O (C1-C6 alkyl), 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, wherein the 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 groups are optionally surrounded by one or more R groups. a2 replace; Each R a2 It can be independently oxo, halogenated, cyano, -OH, or -NH2; R 3 For C6-C 10 aryl or 6- to 10-membered heteroaryl, wherein the C6-C 10 aryl or 6- to 10-membered heteroaryl groups are substituted with one or more R groups. 3a replace; Each R 3a Independently, it is halogenated, cyano, -OH, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. 3a1 Replace; and Each R 3a1 Independently oxo, halogenated, cyano, -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl, wherein the C1-C6 alkyl is optionally separated by one or more C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, -O (C1-C6 haloalkyl), C3-C 10 cycloalkyl, C6-C 10 Aryl or 5 to 10 heteroaryl substituents; Where R 3a Halogenated and R 1 and R 2 When R forms a 6-membered heteroaryl group with the atoms it is attached to, then a It's not -CF3.

3. The compound according to claim 1 or claim 2, wherein: (ii)X 1 It is CH or N; and R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted pyridine; or (iii)X 2 It is N or O; and R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted pyridine; or (iv) When R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then X 1 Not S; or (v) When R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then X 2 Not S; or (vi) When R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a When pyridine is substituted, then no or (vii) When R a for When, then R 3 no or (viii) When R a for When, then R 3 no or (ix) When R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted pyrazines, and R a For one or more R a1 When the phenyl group is substituted, then R a1 Not -Cl, -F, -CN, -O(CH3), -O(CF3), -O(CHF2), -CH3, or cyclopropyl; or (x) When R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a Substituted pyrazines, and R a For one or more R a1 When pyridine is substituted, then R a1 Not -Cl, -CN, -CF3, -O(CH3), -O(CHF2), cyclopropyl, -C(CH3)2(CN) or -C(CH3)2(OH); or (xi) when R 1 and R 2 Together with the atoms they are attached to, they form a group consisting of one or more R atoms. a When pyrazine is substituted, then R a no or (xii) The compound of formula (I) is not 5'-methoxy-2',6-dimethyl-N-(6-(tetrahydrofuran-3-yl)thiazo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide.

4. The compound according to any one of the preceding claims, wherein X 1 It can be CH or N.

5. The compound according to any one of the preceding claims, wherein: Each R a Independently oxidized, halogenated, -C(O)N(R) b (R) c ), -N(R b )C(O)(R c C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic alkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclic alkyl, optionally bounded by one or more R a1 replace; Each R a1 Independently oxo, halogenated, cyano, -OH, -O (C3-C) 10 Cycloalkyl), -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -C(O)O (C1-C6 alkyl), C1-C6 alkyl, 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, wherein the C1-C6 alkyl, 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 groups are optionally surrounded by one or more R groups. a2 replace; Each R a2 It can be either a cyano group or -OH. Each R 3a Independently cyano, C1-C6 alkyl, C1-C6 haloalkyl, 3- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl groups are optionally surrounded by one or more R groups. 3a1 Replace; and Each R 3a1 Independently oxo, halogenated, cyano, -C(O)(C1-C6 alkyl), -C(O)NH2, -C(O)(O-(C1-C6 alkyl)), C1-C6 alkyl, wherein the C1-C6 alkyl is optionally separated by one or more C3-C 10 Cycloalkyl, C1-C6 alkoxy, -O (C1-C6 haloalkyl), C3-C 10 Cycloalkyl or 5 to 10 heteroaryl substitutions.

6. The compound according to any one of the preceding claims, wherein R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted C6 aryl or 6-membered heteroaryl.

7. The compound according to any one of the preceding claims, wherein R 1 and R 2 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. a Substituted 5-membered heteroaryl group.

8. The compound according to any one of the preceding claims, wherein R 1 and R 2 Together with the atoms to which they are attached, they form a pyrazinyl, pyridinyl, or diazoleyl group, wherein the pyrazinyl, pyridinyl, or diazoleyl group is optionally surrounded by one or more R groups. a replace.

9. The compound according to any one of the preceding claims, wherein each R a Independently: oxo, -Cl, -Br, -CH3, -CF3, 10. The compound according to any one of the preceding claims, wherein each R b and R c Independently, H, methyl, ethyl, cyclobutyl, cyclopropyl, 11. The compound according to any one of the preceding claims, wherein R b and R c Together with the atoms to which it is attached, it forms a heterocyclic alkyl group selected from the following:

12. The compound according to any one of the preceding claims, wherein R 3 for:

13. The compound according to any one of the preceding claims, wherein each R a1 Independently, it can be oxo, -OH, -CH2OH, -CHF2, -CF3, -F, -Cl, -CN, -OCH3, -OCHF2, -OCF3, -NHCH3, -N(CH3)2, -CH3, -CH2CF3, -CH2CN, 14. The compound according to any one of the preceding claims, wherein each R 3a Independently -Br, -CH3, -CF3, -CN, 15. The compound according to any one of the preceding claims, wherein each R 3a1 Independently oxo, -Cl, -CH3, -OCH3, -CF2H, -NH2, -NHC(O)OC(CH3)3, -OCHF2, -C(O)OC(CH3)3, -C(O)CH3, -C(O)NH2, -CN, 16. The compound according to any one of the preceding claims, wherein each R a2 It is a cyano group on its own.

17. The compound according to any one of the preceding claims, wherein the compound has the formula (IA), (IB), or (IC): Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof.

18. The compound according to any one of claims 1 to 6, wherein the compound has the formula (ID), (IE), (IF), (IG), (IH), (II), (IJ), (IK), or (IL): Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof.

19. The compound according to any one of claims 1 to 6, wherein the compound has the formula (I-F'): Or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof.

20. The compound according to any one of claims 1 to 6, wherein the compound has the formula (IM), (IN), (IO), (IP), (IQ), (IR), (IS), (IT), (IU), or (IV): Or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or mixture thereof.

21. The compound according to any one of claims 1 to 6, wherein the compound has the formula (I-T'): Or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or mixture thereof.

22. The compound according to any one of claims 1 to 6, wherein the compound has the formula (IW): Or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or mixture thereof.

23. The compound according to any one of the preceding claims, wherein the compound is selected from the compounds described in Tables 1-4 or pharmaceutically acceptable salts thereof.

24. The compound according to any one of the preceding claims, wherein the compound is selected from compounds No. 1, 10, 24, 25, 59, 207, 211, 212, 224, 235, 238, 239, 244, 3, 12, 280, 282, 288, 308, 359, 360, 361B, and 368. Compounds No. 377, 386, 391, 394, 403, 427, 432, 447, 451A, 454, 462, 464, 467, 486, 489, 498, 502, 504, 506, 514, 518, 520, 521 and 522, or pharmaceutically acceptable salts thereof.

25. A compound that can be obtained by the methods described herein, or obtained by the methods described herein; Optionally, the method includes one or more steps described in schemes 1-11.

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

27. The pharmaceutical composition according to claim 26, wherein the compound is selected from the compounds described in Tables 1-4.

28. A method for regulating DNA polymerase Θ activity, the method comprising contacting cells with a compound according to any one of claims 1 to 25 or a pharmaceutical composition according to claim 26 or 27.

29. A method for treating or preventing a disease or condition in a subject in need, the method comprising administering to the subject a compound according to any one of claims 1 to 25 or a pharmaceutical composition according to claim 26 or 27.

30. The compound according to any one of claims 1 to 25 or the pharmaceutical composition according to claim 26 or 27, for regulating DNA polymerase Θ activity.

31. The compound according to any one of claims 1 to 25 or the pharmaceutical composition according to claim 26 or 27, for the treatment or prevention of a disease or condition.

32. Use of a compound according to any one of claims 1 to 25, for the preparation of a medicament for regulating DNA polymerase Θ activity.

33. Use of a compound according to any one of claims 1 to 25 for the preparation of a medicament for treating or preventing a disease or ailment.

34. The method, compound, pharmaceutical composition, or use according to any one of claims 28 to 33, wherein the disease or symptom is related to the activity of the DNA polymerase Θ involved.

35. The method, compound, pharmaceutical composition, or use according to any one of claims 28 to 34, wherein the disease or condition is cancer.

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