Condensed bicyclic heterocyclic compounds or heteroarylamide compounds

Abstract

Novel compounds (e.g., formula K), pharmaceutical compositions, and methods of use for treating various diseases or disorders, such as cancer, are provided herein. TIFF2026522322000251.tif41149

Description

Detailed description of the invention

[0001]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 521,419 filed on 16 June 2023 and U.S. Provisional Patent Application No. 63 / 546,990 filed on 2 November 2023, the contents of which are incorporated herein by reference in their entirety.

[0002]

[0002] In various embodiments, the disclosure generally relates to novel compounds, compositions containing the same, methods for preparing the same, and methods for using the same, for example, to inhibit Polθ enzyme activity and / or to treat or prevent diseases or disorders described herein.

[0003] [background]

[0003] DNA polymerase theta (Polθ) is encoded by the POLQ gene and mediates one of the three major double-strand break (DSB) repair pathways: theta-intermediated end joining (TMEJ). DNA repair-deficient cancers often become dependent on backup DNA repair pathways. When non-homologous end joining (NHEJ) and / or homologous recombination (HR) do not function properly in cancer cells, Polθ is usually overexpressed, activating TMEJ and providing a backup pathway for DSB repair that allows cancer cells to survive (see, for example, Barszczewska-Pietraszek, G. et al., Int.J.Mol.Sci. 24:319 (2023)). TMEJ pathway activation is also observed in cells with NHEJ ability.

[0004]

[0004] Polθ is a promising target for anticancer drug development, particularly in cancers with DNA repair deficiencies. Polθ knockout in non-cancerous cells showed minimal efficacy. However, Polθ overexpression has been identified in various human cancers, such as breast cancer, lung cancer, and ovarian cancer. Polθ overexpression has also been reported to be associated with poor clinical outcomes in breast or liver cancer patients with HR deficiency. Inhibiting Polθ has been shown to kill cancer cells both in vitro and in vivo. Furthermore, inhibiting Polθ has been shown to activate the cGAS-STING pathway and can be used in combination with immune checkpoint inhibitors to treat BRCA-deficient cancers. See, for example, Patterson-Fortin, J. et al., Nature Communications 14:1390 (2023). In addition, inhibiting Polθ can enhance the effects of poly(ADP-ribose) polymerase (PARP) inhibitors and overcome PARP inhibitor resistance.

[0005] [Brief summary]

[0005] In various embodiments, this disclosure is partly based on the discovery of certain novel bicyclic heterocyclic or heteroarylamide compounds that may be Polθ inhibitors and can be used to inhibit Polθ enzyme activity in cells (e.g., cancer cells) and / or to treat or prevent Polθ-related diseases or disorders, such as cancer.

[0006]

[0006] In some embodiments, the present disclosure provides compounds of formula A or pharmaceutically acceptable salts thereof: [ka] (In the formulas, variable symbols are defined herein). In some embodiments, the compound of formula A may be characterized by having a structure consisting of a subformula selected from formulas I, I-1, I-1a, I-1b, I-1c, I-1d, I-1e, I-1f, I-1g, II, II-1, III, III-1, A1, A2, A3, A1a, A1b, A1c, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6 as defined herein.

[0007]

[0007] In some embodiments, the present disclosure provides compounds of formula K or pharmaceutically acceptable salts thereof: [ka] (wherein the formulas, variable symbols are defined herein.) In some embodiments, the compound of formula K may be characterized by having a structure consisting of a subformula selected from formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, K-1b-4, K-3a, K-3b, K-5a, or K-5b as defined herein.

[0008]

[0008] In some embodiments, the disclosure also provides compounds selected from Table 1 of this specification or pharmaceutically acceptable salts thereof. In some embodiments, the disclosure also provides compounds selected from Examples 1 to 145 of this specification or pharmaceutically acceptable salts thereof.

[0009]

[0009] Some embodiments of the present disclosure involve one or more compounds of the present disclosure (e.g., formula A (e.g., formula I, I-1, I-1a, I-1b, I-1c, I-1d, I-1e, I-1f, I-1g, II, II-1, III, III-1, A1, A2, A3, A1a, A1b, A1c, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6)), formula K (e.g. For example, the scope of this specification includes pharmaceutical compositions comprising a compound of formula K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, K-1b-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1 to 145, any of the compounds listed in Table 1 of this specification, or pharmaceutically acceptable salts thereof, and optionally pharmaceutically acceptable excipients. The pharmaceutical compositions described herein may be formulated for different routes of administration, for example, for oral administration or parenteral injection.

[0010]

[0010] Certain embodiments of the present disclosure relate to methods for treating diseases or disorders associated with Polθ as described herein, such as cancer. In some embodiments, the method relates to a therapeutically effective amount of the compounds of the present disclosure as described herein (e.g., formula A (e.g., formulas I, I-1, I-1a, I-1b, I-1c, I-1d, I-1e, I-1f, I-1g, II, II-1, III, III-1, A1, A2, A3, A1a, A1b, A1c, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6), formula K The procedure includes the step of administering a compound of formula K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, K-1b-4, K-3a, K-3b, K-5a, or K-5b, any of Examples 1 to 145, any of the compounds listed in Table 1 of this specification, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition to a subject requiring it.

[0011]

[0011] Certain embodiments of this disclosure relate to methods for treating cancer. In some embodiments, the cancer is homologous recombination (HR) deficiency cancer. In some embodiments, the cancer is characterized by reduced or absent BRCA gene expression, absence of the BRCA gene, and / or reduced function of the BRCA protein. In some embodiments, the cancer is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy. In some embodiments, the method involves a therapeutically effective amount of a compound of the Disclosure (e.g., formula A (e.g., formulas I, I-1, I-1a, I-1b, I-1c, I-1d, I-1e, I-1f, I-1g, II, II-1, III, III-1, A1, A2, A3, A1a, A1b, A1c, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6), formula K (e.g., formula K-1, The procedure includes administering a compound of K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, K-1b-4, K-3a, K-3b, K-5a, or K-5b) to a subject requiring it, any of Examples 1 to 145, any of the compounds listed in Table 1 herein, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as specified herein.

[0012]

[0012] The administration in the methods herein is not limited to any particular route of administration. For example, in some embodiments, administration may be oral, nasal, transdermal, transpulmonary, inhaled, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, transrectal, intrapleural, intrathecal, or parenteral. In some embodiments, administration is oral. In some embodiments, administration is parenteral injection, for example, intravenous injection.

[0013]

[0013] The compounds of the present disclosure may be used as a monotherapy or in combination therapy. In some embodiments according to the methods described herein, one or more compounds of the present disclosure may be administered as the sole active ingredient. In some embodiments, the methods herein further comprise administering to the subject an additional therapeutic agent, such as an additional anti-cancer agent described herein, such as a PARP inhibitor, a signal transduction inhibitor, a chemotherapeutic agent, and / or an immune checkpoint inhibitor.

[0014]

[0014] It should be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and do not limit the invention herein.

[0015] [Detailed Description]

[0015] In various embodiments, novel compounds, pharmaceutical compositions, methods of preparation, and methods of use are provided herein. The compounds of the present disclosure are generally Polθ inhibitors, which are also useful for treating various diseases or disorders, such as those described herein, such as cancer.

[0016] Compound Formula A

[0016] In some embodiments, the present disclosure provides a compound of formula A or a pharmaceutically acceptable salt thereof:

Chem.

[0017]

[0017] In some embodiments, the compounds of formula A (including any of the applicable subforms described herein) may contain one or more chiral centers and / or axial chiralities, and therefore may exist in various stereoisomer forms, for example, as enantiomers and / or diastereomers. In some embodiments, the compounds of formula A may exist, where applicable, in the form of individual enantiomers and / or diastereomers, or in the form of stereoisomer mixtures including racemic mixtures and mixtures containing many of one or more stereoisomers. In some embodiments, where applicable, the compounds of formula A (including any of the applicable subforms described herein) may exist as individual enantiomers that are substantially free of other enantiomers, for example, with an enantiomer excess of more than 60% ("ee"), preferably more than 80%ee, more than 90%ee, more than 95%ee, more than 98%ee, or more than 99%ee. In some embodiments, where applicable, the compound of formula A (including any of the applicable subformulas described herein) may also exist as a mixture of stereoisomers in any proportion, for example, a racemic mixture.

[0018]

[0018] In some embodiments, the compound of formula A (including any of the applicable subformulas described herein) may exist as an isotopically labeled compound, in particular as a deuterated analog in which one or more of the hydrogen atoms of the compound of formula A are substituted with deuterium atoms in amounts exceeding their natural abundance, for example, as a CD3 analog if the compound has a CH3 group. While we do not wish to be constrained by theory, in certain circumstances, substitution with deuterium may result in a deuterated analog with a superior pharmacokinetic profile. Deuterated analogs may generally be prepared by using commercially available deuterating reagents.

[0019]

[0019] It should be apparent to those skilled in the art that in certain cases the compound of formula A may exist as a mixture of tautomers. This disclosure is not limited to any particular tautomer; rather, this disclosure encompasses all such tautomers, whether expressly illustrated or referred to.

[0020]

[0020] In formula A (including any applicable subformula), Z, J 1 , J 2 , and J 3 A five-membered ring containing is a heteroaryl ring having 1 to 3 ring heteroatoms, for example, 2. Typically, Z in a five-membered ring is N. In some embodiments, Z is N, and the five-membered ring has one additional ring heteroatom, for example, an additional ring oxygen, sulfur, or nitrogen. In some embodiments, J 1 CR 10A (For example, CH). In some embodiments, Z is N and J 1 CR 10A (For example, CH). In some preferred embodiments, the five-membered ring is a thiazole ring, Z is N, and J 1 is S, J 2 and J 3 is C. In some embodiments, the five-membered ring may be an oxazole, imidazole, or pyrazole ring. For example, in some embodiments, Z is N and J 1 CR 10A (For example, CH) and J 2 C is J 3 is N. In some embodiments, Z is N and J 1 CR 10A (For example, CH) and J 3 C is J 2 It is N. Typically, J 1 CR 10A In this embodiment, R 10A is a methyl atom which may be substituted with hydrogen, a halogen, or deuterium or F, preferably R 10A is hydrogen. In some embodiments, Z is CR 10AIt may be R 10A This is defined herein.

[0021]

[0021] In formula A (including any applicable subformula), ring B is typically an optionally substituted phenyl ring or an optionally substituted five- or six-membered heteroaryl ring having one to three ring heteroatoms, each independently being N, S, or O. For example, ring B may be a benzene ring, a pyridine ring, a pyridone ring (e.g., pyridine-2-one), a pyrazine ring, a pyridazine ring, or a pyrimidine ring, each of which may be substituted. For clarity, as used herein, pyridone is considered a six-membered heteroaryl ring. When substituted, the phenyl or five- or six-membered heteroaryl ring is preferably independently deuterium, halogen, OH, NH2, SF5, CN, or -Y 1 -Y 2 Y may be substituted with one or more substituents (for example, 1 to 3 substituents), 1 is non-existent, O, S, NH, NY 3 , C(O), SO2, C(O)NH, C(O)NY 3 , P(O)Y 3 , SO2NH, or SO2NY 3 Y 2 and Y 3 Each of these may be substituted independently of each other. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6It is heteroalkyl, an optionally substituted 3- to 10-membered carbocyclic or heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5- or 6-membered heteroaryl. Preferably, in the definition of the variable symbol or substituent in the present specification or in the combination of substituents and / or variable symbols in the present specification, the carbon atom of the carbon-carbon double bond of the alkenyl group or the carbon-carbon triple bond of the alkynyl group is not directly bonded to an oxygen or nitrogen atom. For the sake of clarity, unless otherwise specified or contrary to the context, when used in the present specification, a divalent structure in the present specification, such as -Y 1 - may be bonded in either direction to the rest of the molecule. For example, -Y 1 - is C(O)NY 3 When defined as, -Y 1 -Y 2 The portion of is -C(O)N(Y 3 )-Y 2 Or -N(Y 3 )C(O)-Y 2 May be. Other similar expressions should be understood in the same way.

[0022]

[0022] In some preferred embodiments, the optionally substituted C 2 alkyl, C 3 alkenyl, C 1~6 alkynyl, C 2~6 heteroalkyl, a 3- to 10-membered carbocyclic or heterocyclic ring, phenyl, or a 5- or 6-membered heteroaryl referred to in the definitions of Y 2~6 and Y 1~6 in the present specification may each independently be unsubstituted, deuterium, halogen, OH, NH2, SF5, CN, or -Y 1A -Y 2A Substituted with one or more (e.g., 1 to 3) substituents independently selected from, and Y 1A Is absent, O, S, NH, NY 3A , C(O), SO2, C(O)NH, C(O)NY 3A , P(O)Y 3A , SO2NH, or SO2NY3A Y 2A and Y 3A Each of them exists independently of (i) deuterium, halogen, OH, and C. 1~4 C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. 1~6 Alkyl, (ii) Deuterium, halogen, OH, C respectively, independently 1~4 C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. 2~6 (iii) each independently of deuterium, halogen, OH, and C 1~4 C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. 2~6 Alkynyl, (iv) each independently of deuterium, halogen, OH, and C 1~4 C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. 1~6 Heteroalkyl, (v) independently, deuterium, halogen, oxo, OH, CN, C 1~4 Alkyl, C 1~4 alkoxy, or a 3- to 6-membered ring, which may be substituted with one or more (e.g., 1 to 3) substituents, a 3- to 8-membered carbocyclic or heterocyclic; or (vi) each independently, deuterium, OH, CN, C 1~4 Alkyl, C 1~4 The C is an alkoxy or a 3- to 6-membered ring (preferably a carbocyclic or heterocyclic ring), which may be substituted with one or more substituents (e.g., 1 to 3) or a phenyl or 5- or 6-membered heteroaryl; each of the 3- to 6-membered rings referred to in (i) to (vi) may be independently selected from a 3- to 6-membered carbocyclic or heterocyclic ring, phenyl, or a 5- or 6-membered heteroaryl, as referred to in (i) to (vi). 1~4 Alkyl, C 1~4 Each of the alkoxy or 3- to 6-membered rings may independently be unsubstituted or substituted with deuterium, halogen (e.g., F), CN, OH, oxo (where applicable), deuterium, or F.1~4 C may be substituted with alkyl (e.g., methyl), deuterium, or F. 1~4 It is substituted with one or more substituents (e.g., 1 to 3) independently selected from heteroalkyl (e.g., methoxy) or 3- to 4-membered carboncyclic or heterocyclic rings (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) which may be substituted with deuterium, F, OH, and / or methyl.

[0023]

[0023] In some preferred embodiments, Y 2 and Y 3 C, which may be substituted, is mentioned in the definition. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Heteroalkyls, 3- to 10-membered carbocyclic or heterocyclic rings, phenyls, or 5- or 6-membered heteroaryls are independently substituted with deuterium, halogens, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or F. 1~4 Heteroalkyl, or C which may be substituted with oxo, deuterium, halogen, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 It may be substituted with one or more substituents (e.g., 1 to 3) independently selected from 3 to 6-membered rings (e.g., 3 to 6-membered carbocyclic or heterocyclic rings, phenyl, or 5-membered or 6-membered heteroaryl rings) that may be substituted with heteroalkyl groups.

[0024]

[0024] In some preferred embodiments, Y 2 , Y 3 , Y 2A , or Y 3A C mentioned in the definition 1~6 Each heteroalkyl group appears independently of C 1~6 Alkoxy, NH(C 1~6 Alkyl), N(C 1~4 Alkyl)(C1~4 Alkyl), -(C 1~5 Alkylene)-O-(C 1~5 Alkyl), -(C 1~5 Alkylene)-NH(C) 1~5 Alkyl), -(C 1~4 Alkylene)-N(C) 1~4 Alkyl)(C 1~4 Alkyl), -(C 1~5 Alkilen)-S-(C 1~5 Alkyl), -(C 1~5 Alkylene)-SO2-(C 1~5 Alkyl), SO2(C 1~6 Alkyl), P(O)(C 1~4 Alkyl)(C 1~4 Alkyl), SO2NH(C 1~6 Alkyl), SO2N(C 1~4 Alkyl)(C 1~4 Alkyl), -(C 1~5 Alkylene)-SO2NH-(C 1~5 Alkyl), or -(C 1~4 Alkylene)-SO2N(C) 1~4 Alkyl)(C 1~4 It is an alkyl group, and except for any optional substituents, the total number of carbon atoms does not exceed 6. 1~4 Alkyl)(C 1~4 Regarding "alkyl"), there are two C 1~4 The alkyl groups may be the same or different, for example, both N(CH3)2 and N(CH3)(C2H5) may be N(C) as specified herein. 1~4 Alkyl)(C 1~4 It should be noted that this falls within the definition of alkyl. Unless otherwise specified or contrary to the context, other similar expressions in this specification for variable groups that include two or more groups of the same type (e.g., two alkyl groups) and have the same range of carbon atoms should be understood similarly, i.e., the two or more groups may be independently selected and may be the same or different.

[0025]

[0025] In some preferred embodiments, Y 2 , Y 3 , Y2A , or Y 3A C mentioned in the definition 1~4 Each heteroalkyl group appears independently of C 1~4 Alkoxy, NH(C 1~4 Alkyl), N(C 1~3 Alkyl)(C 1~3 Alkyl), -(C 1~3 Alkylene)-O-(C 1~3 Alkyl), -(C 1~3 Alkylene)-NH(C) 1~3 Alkyl), -(C 1~2 Alkylene)-N(C) 1~2 Alkyl)(C 1~2 Alkyl), -(C 1~3 Alkilen)-S-(C 1~3 Alkyl), -(C 1~3 Alkylene)-SO2-(C 1~3 Alkyl), SO2(C 1~4 Alkyl), P(O)(C 1~3 Alkyl)(C 1~3 Alkyl), SO2NH(C 1~4 Alkyl), SO2N(C 1~3 Alkyl)(C 1~3 Alkyl), -(C 1~3 Alkylene)-SO2NH-(C 1~3 Alkyl), or -(C 1~2 Alkylene)-SO2N(C) 1~2 Alkyl)(C 1~2 It is an alkyl group, except that the total number of carbon atoms does not exceed 4, excluding any optional substituents.

[0026]

[0026] In some preferred embodiments, the compound of formula A (including any applicable subformula) may be characterized by having the structure of formula I: [ka] (In the formula: J 4 CR 11 or N; J 5 CR 12 or N; J6 CR 13A or N, J 7 CR 14 or N; or J 6 is NR 13B And J 7 is C(O); However, J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , and J 7 A bicyclic ring containing is a heteroaryl ring having 1 to 4 ring heteroatoms in addition to the ring nitrogen atom shown in formula I; R 11 , R 12 , R 13A , and R 14 These are, independently, hydrogen, deuterium, halogen, OH, NH2, SF5, CN, or -Y 1 -Y 2 Y 1 is non-existent, O, S, NH, NY 3 , C(O), SO2, C(O)NH, C(O)NY 3 , P(O)Y 3 , SO2NH, or SO2NY 3 Y 2 and Y 3 Each of these can be independently substituted C 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6 The heteroalkyl group is a heteroalkyl group, an optionally substituted 3- to 10-membered carbocyclic or heterocyclic ring, an optionally substituted phenyl group, or an optionally substituted 5- or 6-membered heteroaryl group; R 13B C is hydrogen, which may be substituted. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6A heteroalkyl group, an optionally substituted 3- to 10-membered carbocyclic or heterocyclic ring, an optionally substituted phenyl group, or an optionally substituted 5- or 6-membered heteroaryl group. J 1 , J 2 , J 3 , ring A, R 1 , m, and R 2 (as defined herein).

[0027]

[0027] To clarify, J 6 -J 7 In the condition that the bicyclic ring is aromatic when C=N is substituted, J 6 NR 13B And J 7 A bicyclic ring where is C(O) can be considered a heteroaryl ring. For example, a C(O)-NR ring 13B part (i.e., J 6 -J 7 If ) is replaced by C=N, the resulting ring is aromatic. [ka] Because it has the structure, [ka] The bicyclic ring is considered a heteroaryl ring in this specification.

[0028]

[0028] In some preferred embodiments, J in formula I 1 is S, J 2 and J 3 is C, and the compound may have the structure shown in formula I-1: [ka] (In the formula, variable symbols are defined herein.) J 6 NR 13B And J 7 If C(O), then J 6 and J 7The bond between them may be a single bond. 6 CR 13A or N, J 7 CR 14 or N, J 6 and J 7 The bond between them is a double bond.

[0029]

[0029] In some embodiments, in formula I or I-1, J 4 It is N.

[0030]

[0030] In some embodiments, in formula I or I-1, J 5 It is N.

[0031]

[0031] In some embodiments, in formula I or I-1, J 7 It is N.

[0032]

[0032] In some embodiments, in formula I or I-1, J 4 is N and J 5 CR 12 And J 7 CR 14 That is the case.

[0033]

[0033] In some embodiments, in formula I or I-1, J 5 is N and J 4 CR 11 And J 7 CR 14 That is the case.

[0034]

[0034] In some embodiments, in formula I or I-1, J 7 is N and J 4 CR 11 And J 5 CR 12 That is the case.

[0035]

[0035] In some embodiments, in formula I or I-1, J 4 and J 7 Both are N, and J 5 CR12 That is the case.

[0036]

[0036] In some embodiments, in formula I or I-1, J 4 and J 5 Both are N, and J 7 CR 14 That is the case.

[0037]

[0037] In some embodiments, in formula I or I-1, J 4 CR 11 And J 5 and J 7 Both are N.

[0038]

[0038] Typically, J 4 CR 11 In this embodiment, R 11 is hydrogen. In some embodiments, R 11 This refers to deuterium, halogen, OH, NH2, SF5, CN, or -Y as defined herein. 1 -Y 2 It may also be R 11 This includes halogens, such as F or Cl, CN, and possibly substituted C. 1~6 Alkyl or optionally substituted C 1~6 It may be heteroalkyl. In some embodiments, R 11 C may be substituted with halogen, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 Heteroalkyl (for example, C 1~4 Alkyl(alkoxy) may also be used.

[0039]

[0039] Typically, J 5 CR 12 In this embodiment, R 12 is hydrogen. In some embodiments, R 12 This refers to deuterium, halogen, OH, NH2, SF5, CN, or -Y as defined herein. 1 -Y 2It may also be R 12 This includes halogens, such as F or Cl, CN, and possibly substituted C. 1~6 Alkyl or optionally substituted C 1~6 It may be heteroalkyl. In some embodiments, R 12 C may be substituted with halogen, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 Heteroalkyl (for example, C 1~4 Alkyl(alkoxy) may also be used.

[0040]

[0040] Typically, J 7 CR 14 In this embodiment, R 14 is hydrogen. In some embodiments, R 14 This refers to deuterium, halogen, OH, NH2, SF5, CN, or -Y as defined herein. 1 -Y 2 It may also be R 14 This includes halogens, such as F or Cl, CN, and possibly substituted C. 1~6 Alkyl or optionally substituted C 1~6 It may be heteroalkyl. In some embodiments, R 14 C may be substituted with halogen, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 Heteroalkyl (for example, C 1~4 Alkyl(alkoxy) may also be used.

[0041]

[0041] Typically, in formula I or I-1, J 6 CR 13A And R 13A These terms are defined herein. For example, in some embodiments, a compound of formula I or I-1 may be characterized by having the structure of formula I-1a: [ka] (In the formula, R 13A , ring A, R 1 , m, and R 2 (as defined herein).

[0042]

[0042] In some embodiments, the compound of formula I or I-1 may be characterized by having the structure of formula I-1b: [ka] (In the formula, R 13A , ring A, R 1 , m, and R 2 (as defined herein).

[0043]

[0043] In some embodiments, the compound of formula I or I-1 may be characterized by having the structure of formula I-1c: [ka] (In the formula, R 13A , ring A, R 1 , m, and R 2 (as defined herein).

[0044]

[0044] In some embodiments, the compound of formula I or I-1 may be characterized by having the structure of formula I-1d: [ka] (In the formula, R 13A , ring A, R 1 , m, and R 2 (as defined herein).

[0045]

[0045] In some embodiments, the compound of formula I or I-1 may be characterized by having the structure of formula I-1e: [ka] (In the formula, R 13A , ring A, R1 , m, and R 2 (as defined herein).

[0046]

[0046] In some embodiments, the compound of formula I or I-1 may be characterized by having the structure of formula I-1f: [ka] (In the formula, R 13A , ring A, R 1 , m, and R 2 (as defined herein).

[0047]

[0047] In some embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A It is hydrogen.

[0048]

[0048] In some embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A This is a halogen, such as F, Cl, or Br.

[0049]

[0049] In some embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A is CN.

[0050]

[0050] In some embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A -Y as defined herein 1 -Y 2 For example, in some embodiments, R13A ha-Y 1 -Y 2 Y 1 It does not exist, in other words, R 13A Y as defined herein 2 In some embodiments, R 13A is Y 2 Y 2 C may be substituted. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, or possibly substituted C 2~6 It is an alkynyl. In some embodiments, R 13A is Y 2 Y 2 C may be substituted. 1~6 It is heteroalkyl.

[0051]

[0051] In some embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A ha-Y 1 -Y 2 Y 1 is O, NH, or NY 3 Y 2 and Y 3 This is defined herein.

[0052]

[0052] In some preferred embodiments, R 13A is Y 2 Y 2is a substituted 3- to 10-membered carbocyclic or heterocyclic ring. Preferred 3- to 10-membered carbocyclic or heterocyclic rings are not particularly limited and include those described herein, and may be monocyclic or have condensed, spiro, or cross-linked bicyclic structures. In some embodiments, the 3- to 10-membered carbocyclic ring may have two rings, one of which is phenyl and the other is condensed to a phenyl ring. In some embodiments, the 3- to 10-membered heterocyclic ring may have 1 to 4 ring heteroatoms, each independently being N, O, or S, the S atoms may be oxidized, for example, existing as S=O, SO2, etc. In some embodiments, the 3- to 10-membered heterocyclic ring may have two rings, one of which is phenyl or a 5- or 6-membered heteroaryl and the other is condensed to a phenyl ring or heteroaryl ring.

[0053]

[0053] In some embodiments, Y 2 is C 3~7 It may be a cycloalkyl group, which may be substituted with one or more substituents as specified herein, such as halogens (e.g., F), OH, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 It may be substituted with one or more substituents independently selected from heteroalkyl groups. In some embodiments, Y 2 is non-substituted C 3~6 It may be a cycloalkyl, for example, cyclopropyl.

[0054]

[0054] In some embodiments, Y 2 C may be a 4-10 membered heterocyclic ring having 1-3 ring heteroatoms, each independently being N, O, or S, for example, a 4-8 membered heterocyclic ring (e.g., tetrahydropyran, piperidine, etc.), the S atom may be oxidized (e.g., as SO2), and these heterocyclic rings may be substituted with one or more substituents as specified herein, for example, halogens (e.g., F), OH, deuterium, or F. 1~4C may be substituted with alkyl, deuterium, or fluorine. 1~4 It may be substituted with one or more substituents independently selected from heteroalkyl groups. In some embodiments, Y 2 This may be tetrahydropyran or piperidine, which may be substituted with deuterium or F. 1~4 It may be substituted with alkyl.

[0055]

[0055] In some preferred embodiments, R 13A is Y 2 Y 2 R is a phenyl which may be substituted. In some preferred embodiments, 13A is Y 2 Y 2 R is a substituted or possibly substituted five-membered heteroaryl having 1 to 4 ring heteroatoms, each independently being N, O, or S, for example, a substituted or possibly substituted pyrazolyl. In some preferred embodiments, R 13A is Y 2 Y 2 This is a substituted or otherwise substituted six-membered heteroaryl having one or two ring nitrogens, for example, a substituted or otherwise substituted pyridyl, pyrimidinyl, pyridadinyl, or pyrazinyl.

[0056]

[0056] In some embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A This includes hydrogen, halogens (e.g., Cl, Br, etc.), CN, and possibly substituted C. 1~4 Alkyl, possibly substituted C 2~4 Alkenyl, C may be substituted 2~4 Alkynyl, C may be substituted. 1~4 Heteroalkyl, SF5, optionally substituted C 3~7It may be a cycloalkyl or a substituted or substituted 4-10 membered heterocyclic ring having 1-3 ring heteroatoms, each independently being N, O, or S. In some preferred embodiments, if substituted, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Heteroalkyl, C 3~7 Cycloalkyl or 4-10 membered heterocyclic rings include deuterium, halogens (e.g., F), OH, SF5, CN, oxo, CONR 30 R 31 , N(R 30 )C(O)R 31 SO2NR 30 R 31 , N(R 30 )SO2R 31 , SR 31 , OR 31 SO2R 31 , C which may be substituted with deuterium or F 1~4 It is substituted with one or more substituents (e.g., 1 to 3) independently selected from alkyl, or 3- to 4-membered carbon-cyclic or heterocyclic rings (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) which may be substituted with deuterium, F, OH, and / or methyl, and R 30 and R 31 Each of these may be independently substituted with hydrogen, deuterium, or F. 1~4 It is a 3- to 6-membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) which may be substituted with alkyl, or deuterium, F, OH, and / or methyl; or, where applicable, R 30 and R 31 It is bonded together with an intervening atom or multiple intervening atoms to form a substituted 4- to 8-membered heterocyclic ring (for example, one that may be substituted with deuterium, F, OH, and / or methyl). For example, in some embodiments, R 13A C may be substituted with hydrogen, halogen (e.g., Cl or Br), CN, deuterium, or F. 1~4C may be substituted with alkyl (e.g., CF2H or CF3), cyclopropyl, deuterium, or F. 1~4 The C11 may be an alkoxy (e.g., OCF2H or OCF3), or a 4-10 membered heterocyclic ring having 1-3 ring heteroatoms, each independently being N, O, or S, which may each independently be substituted with deuterium, halogen, OH, deuterium, or F. 1~4 C may be substituted with alkyl (e.g., CF2H or CF3), or with deuterium or F. 1~4 It may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy (e.g., OCF2H or OCF3). In some embodiments, R 13A C may be a 4-10 membered heterocycloalkyl ring having 1-3 ring heteroatoms, each independently being N, O, or S, for example, a monocyclic 4-8 membered heterocycloalkyl ring, for example, a tetrahydropyran or piperidinyl ring, and each of these heterocycloalkyls may be independently substituted with deuterium, halogen, OH, deuterium, or F. 1~4 Alkyl (e.g., CF2H or CF3), and C which may be substituted with deuterium or F. 1~4 It may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy (e.g., OCF2H or OCF3).

[0057]

[0057] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A is a phenyl that may be substituted. In some embodiments, the phenyl is unsubstituted or independently of deuterium, halogen (e.g., F, Cl, Br, etc.), CN, OH, NH2, SF5, G 1 , or -X 1 -X 2 -G 1 It is substituted with one or more substituents (for example, 1 to 3), X 1is non-existent, C 1~4 Alkylene, or C 1~4 It is a heteroalkylene, X 2 These are O, S, NH, NG 1 , C(O), SO2, C(O)NH, C(O)NG 1 SO2NH, or SO2NG 1 And, G 1 C may be substituted independently for each instance. 1~4 Alkyl, possibly substituted C 2~4 Alkenyl, C may be substituted 2~4 Alkynyl, C may be substituted. 1~4 Heteroalkyl, possibly substituted C 3~6 A cycloalkyl, a substituted or possibly substituted 4- to 7-membered heterocyclic ring having one or two ring heteroatoms, each independently being N, O, or S, or a substituted or possibly substituted 5- or 6-membered heteroaryl having one to three ring heteroatoms, each independently being N, O, or S. Preferably, if substituted, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Heteroalkyl, C 3~6 Cycloalkyls, 4- to 7-membered heterocyclic rings, or 5- or 6-membered heteroaryls may be substituted with deuterium, halogens (e.g., F), OH, CN, oxo, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or F. 1~4 The phenyl ring is substituted with one or more substituents (e.g., 1 to 3) independently selected from alkoxyls or 3-4 membered carbocyclic or heterocyclic rings (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) which may be substituted with deuterium, F, OH, and / or methyl. In some embodiments, phenyl is unsubstituted or independently substituted with deuterium, halogens (e.g., F, Cl, Br, etc.), CN, OH, NH2, SF5, G 1 , or -X 1 -X 2 -G1 It is substituted with one or more substituents (for example, 1 to 3), and X 1 X is nonexistent, CH2, or CH2CH2, 2 and G 1 These terms are defined herein. In some embodiments, phenyl is either unsubstituted or independently of deuterium, halogen (e.g., F, Cl, Br, etc.), CN, OH, NH2, SF5, SCF3, G 1 NHG 1 , NG 1 G 1 OG 1 , or SO2G 1 It is substituted with one or more substituents (for example, 1 to 3), G 1 This is defined herein.

[0058]

[0058] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A This is a substituted five- or six-membered heteroaryl, such as pyrazolyl, pyridinyl, pyrimidinyl, pyridadinyl, or pyrazinyl. In some embodiments, the five- or six-membered heteroaryl is unsubstituted or each independently contains deuterium, a halogen (e.g., F, Cl, Br, etc.), CN, OH, NH2, SF5, G 1 , or -X 1 -X 2 -G 1 It is substituted with one or more substituents (for example, 1 to 3), X 1 is non-existent, C 1~4 Alkylene, or C 1~4 It is a heteroalkylene, X 2 These are O, S, NH, NG 1 , C(O), SO2, C(O)NH, C(O)NG 1 SO2NH, or SO2NG 1 And, G1 C may be substituted independently for each instance. 1~4 Alkyl, possibly substituted C 2~4 Alkenyl, C may be substituted 2~4 Alkynyl, C may be substituted. 1~4 Heteroalkyl, possibly substituted C 3~6 A cycloalkyl, a substituted or possibly substituted 4- to 7-membered heterocyclic ring having one or two ring heteroatoms, each independently being N, O, or S, or a substituted or possibly substituted 5- or 6-membered heteroaryl having one to three ring heteroatoms, each independently being N, O, or S. Preferably, if substituted, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Heteroalkyl, C 3~6 Cycloalkyls, 4- to 7-membered heterocyclic rings, or 5- or 6-membered heteroaryls may be substituted with deuterium, halogens (e.g., F), OH, CN, oxo, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or F. 1~4 The rings are substituted with one or more substituents (e.g., 1 to 3) independently selected from alkoxyls or 3-4 membered carbocyclic or heterocyclic rings (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) which may be substituted with deuterium, F, OH, and / or methyl. In some embodiments, the 5-membered or 6-membered heteroaryl rings are unsubstituted or independently substituted with deuterium, halogens (e.g., F, Cl, Br, etc.), CN, OH, NH2, SF5, G 1 , or -X 1 -X 2 -G 1 It is substituted with one or more substituents (for example, 1 to 3), and X 1 X is nonexistent, CH2, or CH2CH2, 2 and G 1These terms are defined herein. In some embodiments, the 5-membered or 6-membered heteroaryl is either unsubstituted or independently composed of deuterium, halogen (e.g., F, Cl, Br, etc.), CN, OH, NH2, SF5, SCF3, G 1 NHG 1 , NG 1 G 1 OG 1 , or SO2G 1 It is substituted with one or more substituents (for example, 1 to 3), G 1 This is defined herein.

[0059]

[0059] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A is a phenyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridadinyl, or pyrazinyl, which may be substituted. In some embodiments, phenyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridadinyl, or pyrazinyl is unsubstituted or each independently contains deuterium, halogen (e.g., F, Cl, Br, etc.), CN, OH, NH2, SF5, SCF3, G 2 NHG 2 , NG 2 G 2 OG 2 , or SO2G 2 It is substituted with one or more substituents (for example, 1 to 3), G 2 C may be substituted independently for each instance. 1~4 Alkyl, possibly substituted C 3~6 A cycloalkyl or a substituted 4- to 7-membered heterocyclic ring having one or two ring heteroatoms, each independently being N, O, or S. Preferably, if substituted, C 1~4 Alkyl, C 3~6The cycloalkyl or 4- to 7-membered heterocyclic ring may be substituted with deuterium, halogen (e.g., F), OH, CN, oxo, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or F. 1~4 It is substituted with one or more substituents (e.g., 1 to 3) independently selected from alkoxyl or 3- to 4-membered carboncyclic or heterocyclic rings (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) which may be substituted with deuterium, F, OH, and / or methyl.

[0060]

[0060] In some further specific embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A The following can be selected [ka] (In the formula, n is an integer between 0 and 3. G 3 Each element present independently contains deuterium, halogens (e.g., F or Cl), CN, and C. 1~4 Alkyl, O-(C 1~4 Alkyl), SO2-(C 1~4 Alkyl), OH, NH2, NH(C 1~4 Alkyl), N(C 1~4 Alkyl)(C 1~4 Alkyl), 3-4 membered carbon-cyclic or heterocyclic ring, O-(3-4 membered carbon-cyclic or heterocyclic ring), (C 1~4 Alkylene)-(3-4 membered carbocyclic or heterocyclic ring), or O-(C 1~4 It is an alkylene (3-4 membered carbon ring or heterocyclic ring), As mentioned above, C 1~4 Each alkyl group may be independently substituted with 1 to 7 deuterium atoms or fluorine atoms, C 1~4The alkylene or the 3-4 membered carbocyclic or heterocyclic ring may be substituted with one or more substituents (e.g., 1-3) that are independently deuterium, F, OH, or methyl. In some embodiments, the 3-4 membered carbocyclic or heterocyclic ring is cyclopropyl or cyclobutyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, G 3 One example is C which may be substituted with 1 to 7 deuterium atoms or F atoms. 1~4 C may be alkyl or substituted with 1 to 7 deuterium atoms or fluorine atoms. 1~4 Alkoxy, for example, OCH3, OCF2H, OCF3, CF3, CH3, CF2H, or CH2CF3, G 3 Other examples, if any, are defined above. For example, in some embodiments, when n is 2, the remaining G 3 The example may be a halogen.

[0061]

[0061] In some further specific embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A These are deuterium, halogens (e.g., F or Cl), CN, and C 1~4 Alkyl, O-(C 1~4 Alkyl), SO2-(C 1~4 Alkyl), OH, NH2, NH(C 1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 A pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl) substituted with one or two substituents independently selected from alkyl, and the aforementioned C 1~4 Each alkyl group may be independently substituted with 1 to 7 deuterium atoms or fluorine atoms. Preferably, the pyridinyl group is substituted with one substituent selected from OCH3, OCF2H, OCF3, CF3, CH3, CF2H, or CH2CF3, and may be substituted with further substituents selected from fluorine or chlorine atoms.

[0062]

[0062] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A is a 2-pyridinyl molecule substituted with one substituent selected from OCH3, OCF2H, OCF3, SO2CH3, NH2, CN, Cl, isopropyl, CF3, CH3, CF2H, or CH2CF3, and may be substituted with a further substituent selected from F or Cl, for example, selected from the following: [ka]

[0063]

[0063] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] That is the case.

[0064]

[0064] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A is a 3-pyridinyl molecule substituted with one substituent selected from OCH3, OCF2H, OCF3, SO2CH3, NH2, CN, Cl, isopropyl, CF3, CH3, CF2H, or CH2CF3, and may be substituted with a further substituent selected from F or Cl, for example, selected from the following: [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A teeth [ka] That is the case.

[0065]

[0065] In some preferred embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A 4-pyridinyl is substituted with one substituent selected from OCH3, OCF2H, OCF3, SO2CH3, NH2, CN, Cl, isopropyl, CF3, CH3, CF2H, or CH2CF3, and may be substituted with a further substituent selected from F or Cl, for example, R 13A teeth [ka] That is the case.

[0066]

[0066] In some further specific embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A These are phenyl, pyrimidinyl, pyridazinyl, or pyrazinyl, which are deuterium, halogen (e.g., F or Cl), CN, C 1~4 Alkyl, O-(C 1~4 Alkyl), SO2-(C 1~4 Alkyl), OH, NH2, NH(C 1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 Substituted with one or two substituents independently selected from alkyl, as described above. 1~4 Each alkyl group may be independently substituted with 1 to 7 deuterium atoms or fluorine atoms. In some further specific embodiments according to formula I or I-1 (e.g., formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A It is pyrimidinyl, which is composed of deuterium, halogen (e.g., F or Cl), CN, C 1~4 Alkyl, O-(C 1~4 Alkyl), SO2-(C 1~4 Alkyl), OH, NH2, NH(C1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 Substituted with one or two substituents independently selected from alkyl, as described above. 1~4 Each alkyl group may be independently substituted with 1 to 7 deuterium atoms or fluorine atoms. In some further specific embodiments according to formula I or I-1 (e.g., formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A It is pyridazinyl, which is composed of deuterium, halogen (e.g., F or Cl), CN, C 1~4 Alkyl, O-(C 1~4 Alkyl), SO2-(C 1~4 Alkyl), OH, NH2, NH(C 1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 Substituted with one or two substituents independently selected from alkyl, as described above. 1~4 Each alkyl group may be independently substituted with 1 to 7 deuterium atoms or fluorine atoms. In some further specific embodiments according to formula I or I-1 (e.g., formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A It is pyrazinyl, which is composed of deuterium, halogen (e.g., F or Cl), CN, C 1~4 Alkyl, O-(C 1~4 Alkyl), SO2-(C 1~4 Alkyl), OH, NH2, NH(C 1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 Substituted with one or two substituents independently selected from alkyl, as described above. 1~4 Each alkyl group may be independently substituted with 1 to 7 deuterium atoms or F atoms. In some preferred embodiments, R 13A The following can be selected. [ka] In some preferred embodiments, R 13A teeth [ka] In some preferred embodiments, R 13A teeth [ka] In some preferred embodiments, R 13A teeth [ka] In some preferred embodiments, R 13A teeth [ka] In some preferred embodiments, R 13A teeth [ka] That is the case.

[0067]

[0067] In some further specific embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A These are, independently, deuterium, halogens (e.g., F, Cl, Br, etc.), and C. 1~4 Alkyl, 3-4 membered carbon ring or heterocyclic ring, or (C 1~4 A pyrazolyl that is alkylene)-(3-4 membered carbon ring or heterocyclic ring), which may be substituted with one or more substituents (e.g., 1-3 substituents), C 1~4 Alkyl, C 1~4 The alkylene, or the 3-4 membered carbocyclic or heterocyclic ring, may be substituted with one or more substituents (e.g., 1-3) that are independently deuterium, F, OH, or methyl. In some preferred embodiments, R 13A The following can be selected. [ka]

[0068]

[0068] In some further specific embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A These are 5-7 membered heterocyclic rings, such as tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl, and each of these independently contains deuterium, halogen (e.g., F, Cl, Br, etc.), oxo, and C. 1~4 Alkyl, 3-4 membered carbon ring or heterocyclic ring, or (C 1~4 It may be substituted with one or more substituents (e.g., 1 to 3) that are alkylene-(3-4 membered carboncyclic or heterocyclic rings), C 1~4 Alkyl, C 1~4 The alkylene, or the 3-4 membered carbocyclic or heterocyclic ring, may be substituted with one or more substituents (e.g., 1-3) that are independently deuterium, F, OH, or methyl. In some preferred embodiments, R 13A The following can be selected. [ka]

[0069]

[0069] In some embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A LR is defined herein in relation to formula K or a subformula thereof. K This may also apply. In some embodiments according to formula I or I-1 (for example, formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), J 6 CR 13A And R 13A It may also be any of the groups of the compounds shown in Table 1 or Examples 1 to 145 in this specification.

[0070]

[0070] In some embodiments, in formula I or I-1, J 6 is NR 13B And J 7 is C(O).

[0071]

[0071] For example, in some embodiments, the compound of formula I or I-1 may be characterized by having the structure of formula I-1g. [ka] (In the formula, variable symbols are defined herein.)

[0072]

[0072] In some embodiments, in formula I or I-1, J 6 is NR 13B And R 13B C may be substituted. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6 A heteroalkyl group, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl group, or an optionally substituted 5- or 6-membered heteroaryl group, preferably, if substituted, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Heteroalkyls, 3- to 10-membered carbocyclic or heterocyclic rings, phenyls, or 5- or 6-membered heteroaryls are each independently deuterium, halogen, OH, NH2, SF5, CN, or -Y 1 -Y 2 It is substituted with one or more substituents (e.g., 1 to 3), Y 1 is non-existent, O, S, NH, NY 3 , C(O), SO2, C(O)NH, C(O)NY 3 , P(O)Y 3 , SO2NH, or SO2NY 3 Y 2and Y 3 Each of these may be substituted independently of each other. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6 The components are heteroalkyl groups, optionally substituted 3- to 10-membered carbocyclic or heterocyclic rings, optionally substituted phenyl groups, or optionally substituted 5- or 6-membered heteroaryl groups.

[0073]

[0073] In some embodiments, the compound of formula I may also have a bicyclic heteroaryl in which one of the fused rings is a pyrazole or imidazole ring. For example, in some embodiments, J in formula I 1 CH may also be J 2 and J 3 One of them is C, and J 2 and J 3 The other side is N.

[0074]

[0074] In some embodiments of formula A (including any applicable subformula), ring B may also be a substituted 5- to 7-membered carbocyclic or heterocyclic ring. For example, in some embodiments, ring B is a 5- to 7-membered carbocyclic ring, such as a cyclohexylene ring. [ka] This may be the case, and the 5- to 7-membered carbon-cyclic ring may be substituted.

[0075]

[0075] For example, in some embodiments, the compound of formula A has the structure according to formula II: [ka] (In the formula: n1 is 0, 1, 2, 3, or 4. R B1 Each element may be independently substituted with deuterium, halogen, OH, CN, NH2, or C. 1~6Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6 A heteroalkyl group, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl group, or an optionally substituted 5- or 6-membered heteroaryl group, preferably, if substituted, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Heteroalkyls, 3- to 10-membered carbocyclic or heterocyclic rings, phenyls, or 5- or 6-membered heteroaryls are each independently deuterium, halogen, OH, NH2, SF5, CN, or -Y 1 -Y 2 It is substituted with one or more substituents (e.g., 1 to 3), Y 1 is non-existent, O, S, NH, NY 3 , C(O), SO2, C(O)NH, C(O)NY 3 , P(O)Y 3 , SO2NH, or SO2NY 3 Y 2 and Y 3 Each of these may be substituted independently of each other. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6 The heteroalkyl group is a heteroalkyl group, an optionally substituted 3- to 10-membered carbocyclic or heterocyclic ring, an optionally substituted phenyl group, or an optionally substituted 5- or 6-membered heteroaryl group; Other variable symbols are defined herein.

[0076]

[0076] In some embodiments, n1 in formula II is 0.

[0077]

[0077] In some embodiments, n1 in formula II is 1, and the compound has the structure according to formula II-1: [ka] (wherein the formula, variable symbols are defined herein). In some embodiments, R B1 R is a phenyl or a 5-membered or 6-membered heteroaryl which may be substituted. In some embodiments, R B1 This is a substituted phenyl, for example, phenyl or 4-chlorophenyl. If substituted, the phenyl or 5-membered or 6-membered heteroaryl ring is preferably independently deuterium, halogen, OH, NH2, SF5, CN, or Y 1 -Y 2 Y may be substituted with one or more substituents (for example, 1 to 3 substituents), 1 is non-existent, O, S, NH, NY 3 , C(O), SO2, C(O)NH, C(O)NY 3 , P(O)Y 3 , SO2NH, or SO2NY 3 Y 2 and Y 3 Each of these may be substituted independently of each other. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6 The components are heteroalkyl groups, optionally substituted 3- to 10-membered carbocyclic or heterocyclic rings, optionally substituted phenyl groups, or optionally substituted 5- or 6-membered heteroaryl groups.

[0078]

[0078] In some embodiments, ring B is a 5- to 7-membered heterocyclic ring having one or two ring heteroatoms, for example [ka] This may also be the case, and this 5- to 7-membered complex ring may be substituted.

[0079]

[0079] For example, in some embodiments, the compound of formula A has the structure according to formula III: [ka] (In the formula: n2 is 0, 1, 2, 3, or 4. R C1 Each element may be independently substituted with deuterium, halogen, OH, CN, NH2, or C. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6 A heteroalkyl group, an optionally substituted 3-10 membered carbocyclic or heterocyclic ring, an optionally substituted phenyl group, or an optionally substituted 5- or 6-membered heteroaryl group, preferably, if substituted, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Heteroalkyls, 3- to 10-membered carbocyclic or heterocyclic rings, phenyls, or 5- or 6-membered heteroaryls are each independently deuterium, halogen, OH, NH2, SF5, CN, or -Y 1 -Y 2 It is substituted with one or more substituents (e.g., 1 to 3), Y 1 is non-existent, O, S, NH, NY 3 , C(O), SO2, C(O)NH, C(O)NY 3 , P(O)Y 3 , SO2NH, or SO2NY 3 Y 2 and Y 3 Each of these may be substituted independently of each other. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6 The heteroalkyl group is a heteroalkyl group, an optionally substituted 3- to 10-membered carbocyclic or heterocyclic ring, an optionally substituted phenyl group, or an optionally substituted 5- or 6-membered heteroaryl group; Other variable symbols are defined herein.

[0080]

[0080] In some embodiments according to formula III, n2 is 0.

[0081]

[0081] In some embodiments of formula III, the compound has the structure of formula III-1: [ka] (In the formula, R C2 C may be substituted. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6 (A heteroalkyl group, an optionally substituted 3- to 10-membered carbocyclic or heterocyclic ring, an optionally substituted phenyl group, or an optionally substituted 5- or 6-membered heteroaryl group, other variable symbols as defined herein). In some embodiments, R C2 This is a substituted phenyl or a 5-membered or 6-membered heteroaryl ring. If substituted, the phenyl or 5-membered or 6-membered heteroaryl ring is preferably independently deuterium, halogen, OH, NH2, SF5, CN, or -Y 1 -Y 2 Y may be substituted with one or more substituents (for example, 1 to 3 substituents), 1 is non-existent, O, S, NH, NY 3 , C(O), SO2, C(O)NH, C(O)NY 3 , P(O)Y 3 , SO2NH, or SO2NY 3 Y 2 and Y 3 These can be substituted independently of each other. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6The components are heteroalkyl groups, optionally substituted 3- to 10-membered carbocyclic or heterocyclic rings, optionally substituted phenyl groups, or optionally substituted 5- or 6-membered heteroaryl groups.

[0082]

[0082] In formula A (for example, formulas I, II, or III, or any of the subformulas), ring A is typically a phenyl ring, or a 5 or 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O, and S, such as a pyridine ring. In some embodiments, ring A in formula A may also be a fused bicyclic heteroaryl having 1 to 4 ring heteroatoms independently selected from N, O, and S.

[0083]

[0083] In some embodiments, ring A in formula A (for example, formula I, II, or III, or any of the subformulas) is a phenyl, pyridinyl, pyrimidinyl, or imidazo[1,2-a]pyridinyl ring.

[0084]

[0084] In some preferred embodiments, ring A in formula A (for example, formula I, II, or III, or any of the subformulas) is a phenyl ring.

[0085]

[0085] In some preferred embodiments, ring A in formula A (for example, formula I, II, or III, or any of the subformulas) is a pyridinyl ring.

[0086]

[0086] For example, in some embodiments, the compound of formula A may have the structure according to formula A1: [ka] (In the formula, variable symbols are defined herein.)

[0087]

[0087] In some embodiments, the compound of formula A may have the structure of formula A2: [ka] (In the formula, variable symbols are defined herein.)

[0088]

[0088] In some embodiments, the compound of formula A may have the structure of formula A3: [ka] (In the formula, variable symbols are defined herein.)

[0089]

[0089] In some embodiments, any of the formulas A1, A2, or A3, or subformulas described herein [ka] Some of these have the same definitions as described herein with respect to Formula I (e.g., I-1, I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), Formula II (e.g., II-1), or Formula III (e.g., III-1).

[0090]

[0090] In some embodiments, the subscript "m" in formula A (e.g., any of the applicable subformulas) is either 0 or 1, and is typically 1. Typically, when m is 1, R 2 R 1 It exists in the meta position relative to this.

[0091]

[0091] For example, in some embodiments, the compound of formula A1 may have the structure of formula A1a: [ka] (In the formula, variable symbols are defined herein.)

[0092]

[0092] In some embodiments, the compound of formula A2 may have the structure of formula A2a: [ka] (In the formula, variable symbols are defined herein.)

[0093]

[0093] Typically, in embodiments using formula A (e.g., any of the applicable subformulas), R 2 Each element independently contains deuterium, halogen, CN, OH, and (C 1~4 Alkylene)-CN, G A , or X a -X b -G A And, X a Each existence is independent of non-existence, C 1~4 Alkylene, or C 1~4 It is a heteroalkylene; X b Each existence is independent of non-existence, O, NH, N(G) B ), C(O), C(O)O, C(O)NH, C(O)N(G B ), NHC(O), N(G B )C(O), SO2, SO2NH, or SO2N(G B ) and; G A Each existence is independent: (i) Deuterium, halogen, OH, C 1~4 C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. 1~6 alkyl; (ii) Deuterium, halogen, C 1~4 Alkyl, C 1~4 C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. 1~6 Heteroalkyl; (iii) Each independently: deuterium, halogen, oxo, OH, CN, C 1~4 Alkyl, C 1~4 An alkoxy, or a 3- to 6-membered ring, which may be substituted with one or more (e.g., 1 to 3) substituents, a 3- to 7-membered carbocyclic or heterocyclic ring; or (iv) Deuterium, halogen, OH, CN, C 1~4 Alkyl, C1~4 Five-membered or six-membered heteroaryls that may be substituted with one or more substituents (e.g., one to three) that are alkoxy or 3- to 6-membered rings (preferably carbocyclic or heterocyclic rings). And, C in each of (i) to (iv) 1~4 Alkyl or C 1~4 Alkoxy compounds are each independently composed of deuterium, halogen, OH, and C. 1~4 It may be independently substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3-4 membered carbon-cyclic or heterocyclic rings. Each of the 3-6 membered rings in (i) to (iv) may be independently substituted with oxo, deuterium, halogen, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 It may be independently substituted with one or more (e.g., 1 to 3) substituents that are alkoxy; G B C may be independently substituted with deuterium, halogen, OH, deuterium, or F in each instance. 1~4 C may be substituted with alkoxy, oxo, deuterium, halogen, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 A 3-6 membered ring (preferably a carbocyclic or heterocyclic ring) which may be substituted with an alkoxy, and which may be substituted with one or more substituents (e.g., 1-3) C 1~6 It is alkyl, or Where applicable, G A and G B These atoms are bonded together to form a 4- to 7-membered heterocyclic ring, and each of these 4- to 7-membered heterocyclic rings may be independently substituted with a halogen, oxo, OH, or F. 1~4 C may be substituted with alkyl or fluorine. 1~4 It may be substituted with one or more (e.g., 1 to 3) substituents that are alkoxy.

[0094]

[0094] In some preferred embodiments, in formula A (for example, any of the applicable subformulas), R 2 One example is C which may be substituted with deuterium, F, and / or OH. 1~4 Alkyl, for example, methyl, difluoromethyl, or hydroxymethyl, and if present, any of the remaining R 2 Examples of are also defined herein, and preferably C may be substituted with halogen, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 Selected from alkoxy.

[0095]

[0095] In some embodiments, in formula A (for example, any of the applicable subformulas), R 2 An example is a 5-membered or 6-membered heteroaryl, which independently consists of a halogen, OH, CN, and C. 1~4 Alkyl, C 1~4 It may be substituted with 1 to 3 substituents that are alkoxy or 3 to 5 membered carboncyclic or heterocyclic rings, C 1~4 Alkyl or C 1~4 Each alkoxy is independently composed of deuterium, halogen (e.g., F), OH, and C. 1~4 It may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 5-membered carbon-cyclic or heterocyclic rings, each of which, if present, may be independently substituted with deuterium, F, OH, and / or methyl, and if present, any of the remaining R 2 Examples of are also defined herein, and preferably C may be substituted with halogen, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 Selected from alkoxy.

[0096]

[0096] In some embodiments, in formula A (for example, any of the applicable subformulas), R 2 One example is -(C 1~4Alkylene)-C(O)NHG A ,-(C 1~4 Alkylene)-C(O)N(G) A )(G B ), or -(C 1~4 It is alkylene)-CN and G A and G B G is defined herein. In some embodiments, G A and G B Each of these C atoms may be independently substituted with deuterium, F, and / or OH. 1~4 It is alkyl, and if present, any remaining R 2 Examples of are also defined herein, and preferably C may be substituted with halogen, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 Selected from alkoxys. For example, in some embodiments, m is 1 and R 2 This can be either CH2C(O)NHCH3 or CH2C(O)N(CH3)2.

[0097]

[0097] In formula A (for example, any of the applicable subformulas), R 1 R is typically a substituted or possibly substituted phenyl or a substituted 5-10 member heteroaryl. For example, in some embodiments, 1 R is a phenyl which may be substituted. In some embodiments, R 1 R is a pyridinyl which may be substituted. In some embodiments, R 1is pyrimidinyl, benzopyrazolyl, benzimidazolyl, imidazolyl, pyridazinyl, imidazo[1,2-a]pyrimidinyl, oxazolo[4,5-b]pyridinyl, oxazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridinyl, benzo[d]thiazole, indazolyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-b]pyridazinyl, or tetrazolo[1,5-a]pyridinyl, which may be substituted. When substituted, phenyl which may be substituted or 5- to 10-membered heteroaryl which may be substituted, for example, phenyl which may be substituted or pyridinyl is preferably deuterium, halogen, CN, OH, NH2, COOH, CONH2, (C 1~4 alkylene)-CN, G C , or X c -X d -G C and is substituted with one or more (for example, 1 to 3) substituents independently selected from; X c is, independently for each occurrence, absent, C 1~4 alkylene, or C 1~4 heteroalkylene; X d is, independently for each occurrence, absent, O, NH, N(G D ), C(O), C(O)O, C(O)NH, C(O)N(G D ), NHC(O), N(G D )C(O), P(O)(G D ), SO2, SO2NH, or SO2N(G D ); G C is, independently for each occurrence: (i) independently deuterium, halogen, OH, C 1~4 alkoxy, or C 1~6 alkyl which may be substituted with one or more (for example, 1 to 3) substituents and is a 3- to 6-membered ring; (ii) independently deuterium, halogen, C 1~4 alkyl, C 1~4C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. 1~6 Heteroalkyl; (iii) Each independently: deuterium, halogen, oxo, OH, CN, C 1~4 Alkyl, C 1~4 An alkoxy, or a 3- to 6-membered ring, which may be substituted with one or more (e.g., 1 to 3) substituents, a 3- to 7-membered carbocyclic or heterocyclic ring; or (iv) Deuterium, halogen, OH, CN, C 1~4 Alkyl, C 1~4 Five-membered or six-membered heteroaryls that may be substituted with one or more substituents (e.g., one to three) that are alkoxy or 3- to 6-membered rings (preferably carbocyclic or heterocyclic rings). And, C in each of (i) to (iv) 1~4 Alkyl or C 1~4 Alkoxy compounds are each independently composed of deuterium, halogen, OH, and C. 1~4 It may be independently substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3-4 membered carbon-cyclic or heterocyclic rings. Each of the 3-6 membered rings in (i) to (iv) may be substituted with oxo, deuterium, halogen, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 They may also be independently substituted with alkoxy compounds; G D C may be independently substituted with deuterium, halogen, OH, deuterium, or F in each instance. 1~4 C may be substituted with alkoxy, oxo, deuterium, halogen, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 A 3- to 6-membered ring which may be substituted with an alkoxy, and which may be substituted with one or more substituents (e.g., 1 to 3) C 1~6 It is alkyl, or Where applicable, G C and G D These two atoms are bonded together with the heteroatom to form a 4- to 7-membered heterocyclic ring, and each of these 4- to 7-membered heterocyclic rings may be independently substituted with a halogen, oxo, OH, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 The alkoxy may be substituted with one or more substituents (e.g., 1 to 3). In some embodiments, the one or more substituents relating to the substituted phenyl or substituted 5- to 10-membered heteroaryl may be deuterium, halogen, CN, OH, NH2, COOH, CONH2, (C 1~4 Alkylene)-CN, G C , or X c -X d -G C Each is independently selected from X c X does not exist, d and G C The terms are defined herein. In some embodiments, one or more substituents relating to an optionally substituted phenyl or optionally substituted 5- to 10-membered heteroaryl are optionally substituted with halogens, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkyl, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkoxy, deuterium, F, CN, methyl, and / or OH. 3~6 Cycloalkyl, NH2, NH(C 1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 Each is independently selected from alkyl. In some embodiments, one or more substituents relating to an optionally substituted phenyl or optionally substituted 5- to 10-membered heteroaryl are optionally substituted with halogen, deuterium, F, and / or OH. 1~4 C may be substituted with alkyl, deuterium, or F. 1~4 C may be substituted with alkoxy, deuterium, F, CN, methyl, and / or OH.3~4 Cycloalkyl, NH2, NH(C 1~3 Alkyl), or N(C 1~3 Alkyl)(C 1~3 Each substituent is independently selected from alkyl. In some further specific embodiments, one or more substituents relating to a substituted or substituted phenyl or substituted or 5-10 membered heteroaryl are independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, -NH2, hydroxymethyl, and 1-hydroxyethyl, preferably the substituent is independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, and cyclopropyl.

[0098]

[0098] In some embodiments, in formula A (for example, any of the applicable subformulas), R 1 R may be a phenyl or pyridinyl compound substituted with a single substituent. In such embodiments, the single substituent is preferably located in the ortho position relative to ring A. For example, in some embodiments, R 1 teeth, [ka] It may be R 1b C may be substituted with a halogen, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkyl, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkoxy, deuterium, F, CN, methyl, and / or OH. 3~6 Cycloalkyl, NH2, NH(C 1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 It may also be alkyl.

[0099]

[0099] In some embodiments, in formula A (for example, any of the applicable subformulas), R 1It may be phenyl or pyridinyl substituted with two substituents. Typically, the two substituents are para to each other, and one of the substituents is ortho to ring A.

[0100]

[0100] For example, in some embodiments, the compound of formula A may have a structure according to formula A1b:

Chemical formula

[0101]

[0101] In some embodiments, the compound of formula A may have a structure according to formula A1c:

Chemical formula

[0102]

[0102] In some embodiments, the compound of formula A may have the structure of formula A2b: [ka] (In the formula, R 1a and R 1b Each of these C atoms may be independently substituted with a halogen, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkyl, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkoxy, deuterium, F, CN, methyl, and / or OH. 3~6 Cycloalkyl, NH2, NH(C 1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 (Alkyl) and other variable symbols are defined herein.

[0103]

[0103] In some embodiments, the compound of formula A may have the structure of formula A2c: [ka] (In the formula, R 1a and R 1b Each of these C atoms may be independently substituted with a halogen, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkyl, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkoxy, deuterium, F, CN, methyl, and / or OH. 3~6 Cycloalkyl, NH2, NH(C 1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 (Alkyl) and other variable symbols are defined herein.

[0104]

[0104] In some embodiments, in formulas A1a, A1b, A1c, A2a, A2b, or A2c [ka] Some of the terms have the definitions described herein with respect to formula I (e.g., I-1, I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f), formula II (e.g., II-1), or formula III (e.g., III-1), preferably any of the definitions described herein with respect to formula I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f.

[0105]

[0105] For illustrative purposes, in some embodiments, the formula A2b [ka] Some of these may have any of the definitions described herein with respect to formulas I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f, in which case the compound of formula A2b may have a structure according to any of the following formulas: A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6: [ka] (In the formula, R 1a , R 1b , R 2 , and R 13A (as defined herein).

[0106]

[0106] In some preferred embodiments, in formulas A1b, A1c, A2b, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, A2b-6, or A2c, R 1a and R 1b is independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, -NH2, hydroxymethyl, and 1-hydroxyethyl, and more preferably R 1a and R 1bThe compounds are independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, and cyclopropyl.

[0107]

[0107] In some preferred embodiments, in formulas A1b, A1c, A2b, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, A2b-6, or A2c, R 1b C may be substituted with 1 to 3 deuterium atoms or F atoms. 1~2 It is an alkoxy, preferably R 1b These are methoxy, ethoxy, or difluoromethoxy.

[0108]

[0108] In some preferred embodiments, in formulas A1b, A1c, A2b, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, A2b-6, or A2c, R 1a C may be substituted with a halogen, 1 to 3 deuterium atoms, or F. 1~3 It is alkyl or cyclopropyl, preferably R 1a These are methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, or cyclopropyl.

[0109]

[0109] In some preferred embodiments, in formulas A1b, A1c, A2b, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, A2b-6, or A2c, R 1b C may be substituted with 1 to 3 deuterium atoms or F atoms. 1~2 It is an alkoxy, preferably R 1b is methoxy, ethoxy, or difluoromethoxy; R 1a C may be substituted with a halogen, 1 to 3 deuterium atoms, or F. 1~3 It is alkyl or cyclopropyl, preferably R 1a These are methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, or cyclopropyl.

[0110] formula K

[0110] In some embodiments, the present disclosure provides compounds of formula K or pharmaceutically acceptable salts thereof: [ka] (In the formula: Ring A is either a phenyl ring or a 5-10 membered heteroaryl ring having 1-4 ring heteroatoms independently selected from N, O, and S; R 1 is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 3-10 membered carbocyclic, or optionally substituted 5-10 membered heterocyclic or heteroaryl, preferably R 1 It is located in the ortho position relative to the amide group (-C(O)-NH-) shown in formula K; The subscript m is an integer between 0 and 4, as far as the valence allows; R 2 Each of these is independently present in the following order: deuterium, halogen, OH, NH2, CN, SF5, COOH, CONH2, SO2NH2, R 20 , OR 20 , SR 20 , N(R 20 )(R 21 ), SO2R 20 , S(=O)(=NR 21 )R 20 SO2N(R 20 )(R 21 ), N(R 21 )SO2R 20 COR 20 COOR 20 ,OC(O)R 20 CON(R 20 )(R 21 ), or N(R 21 )COR 20 And R 20 C may be substituted independently for each instance. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6A heteroalkyl or possibly substituted 3- to 10-membered ring structure; R 21 Each element independently contains hydrogen, and may be substituted with C. 1~6 Alkyl, possibly substituted C 3~6 Alkenyl, C may be substituted 3~6 Alkynyl, C may be substituted. 1~6 It is a heteroalkyl or possibly substituted 3- to 10-membered ring structure; or, where applicable, R 20 and R 21 It is bonded together with one or more interfacing atoms (e.g., nitrogen atoms) to form a substituted 4- to 8-membered heterocyclic ring; or R 2 Two of these molecules are joined together to form a 4- to 7-membered ring, which may be substituted; R J C may be hydrogen, halogen, or substituted C 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6 It is a heteroalkyl or possibly substituted 3- to 10-membered ring structure; L is C 1~4 Alkilen, C 2~4 Alkenylene, C 2~4 Alkynylene, or C 1~4 These are heteroalkylenes, each of which may be substituted with deuterium and / or F. R K C may be hydrogen, deuterium, or substituted C 1~6 Alkyl, possibly substituted C 1~6 (It is a heteroalkyl or possibly substituted 3- to 10-membered ring structure.)

[0111]

[0111] In some embodiments, the compounds of formula K (including any of the applicable subformulas described herein) may contain one or more chiral centers and / or axial chirality, and therefore may exist as various stereoisomers, e.g., enantiomers and / or diastereomers. In some embodiments, the compounds of formula K may, where applicable, exist as individual enantiomers and / or diastereomers, or as a mixture of stereoisomers including racemic mixtures and mixtures containing many of one or more stereoisomers. In some embodiments, where applicable, the compounds of formula K (including any of the applicable subformulas described herein) may exist as individual enantiomers that are substantially free of other enantiomers, e.g., with an enantiomer excess of more than 60% ("ee"), preferably more than 80% ee, more than 90% ee, more than 95% ee, more than 98% ee, or more than 99% ee. In some embodiments, where applicable, the compound of formula K (including any of the applicable subformulas described herein) may exist as a mixture of stereoisomers in any proportion, for example, a racemic mixture.

[0112]

[0112] In some embodiments, the compound of formula K (including any of the applicable subformulas described herein) may exist as an isotopically labeled compound, in particular as a deuterated analog, in which one or more hydrogen atoms of the compound of formula K are substituted with deuterium atoms in an abundance exceeding its natural abundance, for example, a CD3 analog if the compound has a CH3 group. While we do not wish to be bound by theory, in certain circumstances, substitution with deuterium may yield a deuterated analog with a superior pharmacokinetic profile. Deuterated analogs can generally be prepared using commercially available deuterating reagents.

[0113]

[0113] It should be apparent to those skilled in the art that in certain cases the compound of formula K may exist as a mixture of tautomers. This disclosure is not limited to any particular tautomer; rather, this disclosure encompasses all such tautomers, whether explicitly illustrated or referred to.

[0114]

[0114] In some preferred embodiments, L in formula K is C 2~4 It is an alkynylene, which may be substituted with deuterium and / or F. For example, in some preferred embodiments, the compound of formula K may be characterized by having the structure according to formula K-1. [ka]

[0115]

[0115] In some embodiments, L may also be substituted with deuterium and / or F. 3~4 Alkynylene, for example [ka] It may also be the case that, typically in such embodiments, the CH2 terminus is R K It is connected to this.

[0116]

[0116] In some embodiments, L in formula K is C 1~4 It is an alkylene, which may be substituted with deuterium and / or F. 1~4 Alkylene may be linear or branched. For example, in some embodiments, L is linear C 1~4 Alkylenes, such as CH2CH2, CH2CH2CH2, or CH2CH2CH2CH2, may also be used.

[0117]

[0117] In some embodiments, L in formula K is C 2~4 It is an alkenylene, which may be substituted with deuterium and / or F. For example, in some embodiments, L is a C2 alkenylene, for example, [ka] That's fine.

[0118]

[0118] In some embodiments, L in formula K is C 1~4 It is a heteroalkylene, which may be substituted with deuterium and / or F. For example, in some embodiments, L is [ka] It may also be the case that the oxygen atom is R K It may be bound to the thiazolopyrazine ring, or it may be bound to the thiazolopyrazine ring.

[0119]

[0119] In some preferred embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K C may be substituted. 3~8 It may also be a cycloalkyl group. Typically, C 3~8 Cycloalkyls are monocyclic rings. However, in some embodiments, C 3~8 Cycloalkyls may also have bicyclic ring structures, such as condensed, cross-linked, or spiro-dicyclic ring structures. If substituted, C 3~8 Cycloalkyls are preferably deuterium, halogen, OH, CN, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 It is substituted with one or more substituents (e.g., one, two, or three) independently selected from heteroalkyl or 3- to 10-membered rings, and each C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 The heteroalkyl or 3-10 membered ring may be substituted with deuterium, halogen, CN, OH, oxo, deuterium and / or F. 1~4 C may be substituted with alkyl, deuterium, and / or F. 1~4The heteroalkyl group may be independently substituted with one or more substituents independently selected from a 3- to 6-membered ring (e.g., a carbocyclic, heterocyclic, heteroaryl, or phenyl ring), each of which may be substituted with deuterium, halogen, CN, OH, oxo, deuterium, and / or F. 1~4 C which may be substituted with alkyl and deuterium and / or F 1~4 The heteroalkyl group may be independently substituted with one or more substituents independently selected from the heteroalkyl group.

[0120]

[0120] In some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K This may be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which may be substituted with deuterium, F, OH, CN, or F. 1~4 C may be substituted with alkyl or fluorine. 1~4 C may be substituted with heteroalkyl, deuterium, halogen, CN, OH, oxo, or F. 1~4 C which may be substituted with alkyl and F 1~4 The ring may be substituted with one or more substituents independently selected from the heteroalkyl ring, or it may be substituted with one or more substituents independently selected from the 3-6 membered ring, for example, 1-5 or 1-3 substituents.

[0121]

[0121] For example, in some further specific embodiments, R in formula K (e.g., any of the subformulas described herein, where applicable) K teeth: [ka] It may be selected from the following.

[0122]

[0122] For example, in some preferred embodiments, the compound of formula K-1 may have the structure according to formula K-1a: [ka] (In the formulas, variable symbols are defined herein and are preferred.)

[0123]

[0123] In some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K The 4-8 member heterocycline may be substituted or otherwise substituted. Typically, the 4-8 member heterocycline has 1-3 ring heteroatoms, each independently being O, S, or N, and the sulfur atom may be oxidized if present. The 4-8 member heterocycline is typically a monocyclic ring. In some embodiments, the 4-8 member heterocycline may also be a condensed, cross-linked, or spirodicyclic ring structure. If substituted, the 4-8 member heterocycline is preferably deuterium, halogen, OH, oxo, CN, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 It is substituted with one or more substituents (e.g., one, two, or three) independently selected from heteroalkyl or 3- to 10-membered rings, and each C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 The heteroalkyl or 3-10 membered ring may be substituted with deuterium, halogen, CN, OH, oxo, deuterium and / or F. 1~4 C may be substituted with alkyl, deuterium, and / or F. 1~4 The heteroalkyl group may be independently substituted with one or more substituents independently selected from a 3- to 6-membered ring (e.g., a carbocyclic, heterocyclic, heteroaryl, or phenyl ring), each of which may be substituted with deuterium, halogen, CN, OH, oxo, deuterium, and / or F. 1~4 C which may be substituted with alkyl and deuterium and / or F 1~4 The heteroalkyl group may be independently substituted with one or more substituents independently selected from the heteroalkyl group.

[0124]

[0124] In some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K Each is a 4-6 membered heterocycline having one or two ring heteroatoms, each independently being O, S, or N, wherein the sulfur atom, if present, may be oxidized, and the 4-6 membered heterocycline may be substituted with deuterium, F, oxo, OH, CN, deuterium and / or F. 1~4 C may be substituted with alkyl, deuterium and / or F. 1~4 Heteroalkyl, 3-6 membered ring, (C 1~4 Alkylene)-(3-6 member ring), or (C 1~4 It may be substituted with one or more substituents (e.g., 1 to 3) independently selected from heteroalkylenes (3-6 membered rings), C 1~4 Alkylene or C 1~4 The heteroalkylene may be substituted with deuterium and / or fluorine, and each of the 3- to 6-membered rings may be substituted with deuterium, halogen, CN, OH, oxo, or fluorine. 1~4 C which may be substituted with alkyl and F 1~4 It may be substituted with one or more substituents independently selected from the heteroalkyl group.

[0125]

[0125] For example, in some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K C may be a monocyclic 4-6 membered heterocycline having one ring heteroatom, the ring heteroatom being O, and the 4-6 membered heterocycline may be unsubstituted or each independently substituted with deuterium, F, OH, deuterium and / or F. 1~4 C may be substituted with alkyl, deuterium, and / or F. 1~4 It is a heteroalkyl group, substituted with 1 to 3 substituents.

[0126]

[0126] For example, in some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable)K teeth: [ka] It may be selected from the following.

[0127]

[0127] In some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K These may be substituted five-membered or six-membered heteroaryls. Typically, a five-membered heteroaryl has 1 to 3 ring heteroatoms, each independently being O, S, or N; a six-membered heteroaryl has 1 or 2 ring nitrogen atoms. When substituted, the five-membered or six-membered heteroaryl is preferably deuterium, halogen, OH, CN, or C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 It is substituted with one or more substituents (e.g., one, two, or three) independently selected from heteroalkyl or 3- to 10-membered rings, and each C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 The heteroalkyl or 3-10 membered ring may be substituted with deuterium, halogen, CN, OH, oxo, deuterium and / or F. 1~4 C may be substituted with alkyl, deuterium, and / or F. 1~4 The heteroalkyl group may be independently substituted with one or more substituents independently selected from a 3- to 6-membered ring (e.g., a carbocyclic, heterocyclic, heteroaryl, or phenyl ring), each of which may be substituted with deuterium, halogen, CN, OH, oxo, deuterium, and / or F. 1~4 C which may be substituted with alkyl and deuterium and / or F 1~4 The heteroalkyl group may be independently substituted with one or more substituents independently selected from the heteroalkyl group.

[0128]

[0128] In some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K This may be a five-membered heteroaryl having 1 to 4 ring heteroatoms, each independently being O, S, or N, and the five-membered heteroaryl may be substituted with F, Cl, OH, CN, deuterium and / or F. 1~4 C may be substituted with alkyl, deuterium and / or F. 1~4 Heteroalkyl, 3-6 membered ring, (C 1~4 Alkylene)-(3-6 member ring), or (C 1~4 It may be substituted with 1 to 3 substituents independently selected from heteroalkylene (3-6 membered rings), C 1~4 Alkylene or C 1~4 The heteroalkylene may be substituted with deuterium and / or fluorine, and each of the 3- to 6-membered rings may be substituted with deuterium, halogen, CN, OH, oxo, or fluorine. 1~4 C which may be substituted with alkyl and F 1~4 The rings may be substituted with one or more substituents independently selected from the heteroalkyl groups. Each 3-6 membered ring may, independently, be a 3-6 membered carbocyclic, a 4-6 membered heterocyclic, a 5- or 6-membered heteroaryl, or a phenyl ring.

[0129]

[0129] In some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K This may be a five-membered heteroaryl selected from pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and the five-membered heteroaryl may be substituted with F, Cl, OH, CN, deuterium and / or F, to the extent that the valence allows. 1~4 C may be substituted with alkyl, deuterium and / or F. 1~4 Heteroalkyl, 3-6 membered ring, (C 1~2 Alkylene)-(3-6 member ring), or (C 1~2 It may be substituted with 1 to 3 substituents independently selected from heteroalkylene (3-6 membered rings), C 1~2Alkylene or C 1~2 The heteroalkylene may be substituted with deuterium and / or fluorine, and preferably, each of the 3-6 membered rings may be substituted with (a) methyl and / or fluorine. 3~6 Cycloalkyl; or (b) A 4-6 membered heterocycline independently selected from one or two ring heteroatoms independently selected from O, S, and N, wherein the sulfur atom may be oxidized if present, and the 4-6 membered heterocycline may be substituted with deuterium, F, OH, oxo, CN, or F. 1~4 C may be substituted with alkyl or fluorine. 1~4 It may be substituted with 1 to 3 substituents independently selected from the heteroalkyl group.

[0130]

[0130] In some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K teeth, [ka] It is fine (In the formula: q is 0, 1, 2, or 3; G 10 Each of these is independently of the others, and may be substituted with F, Cl, CN, deuterium and / or F. 1~4 C may be substituted with alkyl, deuterium and / or F. 1~4 Heteroalkyl, 3-6 membered ring, (C 1~2 Alkylene)-(3-6 member ring), or (C 1~2 It is a heteroalkylene (3-6 membered ring), and C 1~2 Alkylene or C 1~2 The heteroalkylene may be substituted with deuterium and / or fluorine, and preferably, each of the 3-6 membered rings may be substituted with (a) methyl and / or fluorine. 3~6Cycloalkyl; or (b) A 4-6 membered heterocycline independently selected from one or two ring heteroatoms independently selected from O, S, and N, wherein the sulfur atom may be oxidized if present, and the 4-6 membered heterocycline may be substituted with deuterium, F, OH, oxo, CN, or F. 1~4 C may be substituted with alkyl or fluorine. 1~4 (May be substituted with 1 to 3 substituents independently selected from the heteroalkyl group.)

[0131]

[0131] For example, in some embodiments, the compound of formula K-1 may have the structure according to formula K-1b: [ka] (In the formulas, variable symbols are defined herein and are preferred.)

[0132]

[0132] In some embodiments, the compound of formula K-1 may have the structure of formula K-1c: [ka] (In the formulas, variable symbols are defined herein and are preferred.)

[0133]

[0133] In formula K-1b or K-1c or a similar structure or substructure as described herein, G 10 It should be understood that, if present, the group may be bonded to any of the available positions on the pyrazole ring, including the ring nitrogen atom.

[0134]

[0134] In some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K teeth: [ka] It may be selected from (In the formula: G10A Each C may be independently substituted with deuterium and / or F. 1~4 Alkyl, 3-6 membered ring, or (C 1~2 It is an alkylene (3-6 member ring), C 1~2 Alkylene or C 1~2 The heteroalkylene may be substituted with deuterium and / or fluorine, and preferably, each of the 3-6 membered rings may be substituted with (a) methyl and / or fluorine. 3~6 Cycloalkyl; or (b) A 4-6 membered heterocycline independently selected from one or two ring heteroatoms independently selected from O, S, and N, wherein the sulfur atom may be oxidized if present, and the 4-6 membered heterocycline may be substituted with deuterium, F, OH, oxo, CN, or F. 1~4 C may be substituted with alkyl or fluorine. 1~4 It may also be substituted with 1 to 3 substituents independently selected from the heteroalkyl group; G 10B Each instance independently contains F, Cl, CN, or G 10A (That is.)

[0135]

[0135] For example, in some embodiments, the compound of formula K-1 may have a structure according to formula K-1b-1, K-1b-2, K-1b-3, or K-1b-4: [ka] (In the formulas, variable symbols are defined herein and are preferred.)

[0136]

[0136] In some embodiments, G 10A Each C may be independently substituted with deuterium and / or F. 1~4 Alkyl (e.g., methyl), cyclopropyl, cyclobutyl, (C 1~2 Alkylene)-(cyclopropyl), or (C 1~2 It is alkylene)-(cyclobutyl). For example, in some embodiments, in formula K-1b-2 or K-1b-4, G 10AC may be substituted with deuterium and / or F. 1~4 Alkyl, for example, methyl.

[0137]

[0137] In some embodiments, G 10B Each C may be independently substituted with F, Cl, deuterium and / or F. 1~4 Alkyl (e.g., methyl), cyclopropyl, cyclobutyl, (C 1~2 Alkylene)-(cyclopropyl), or (C 1~2 It is alkylene)-(cyclobutyl). For example, in some embodiments, in formula K-1b-3 or K-1b-4, G 10B C may be substituted with deuterium and / or F. 1~4 Alkyl, for example, methyl.

[0138]

[0138] In some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K teeth: [ka] It may be selected from the following.

[0139]

[0139] In some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K This may be a six-membered heteroaryl having one or two ring nitrogen atoms, such as pyridyl, pyrimidyl, etc., and the six-membered heteroaryl may be substituted with F, Cl, OH, CN, deuterium and / or F. 1~4 C may be substituted with alkyl, deuterium and / or F. 1~4 Heteroalkyl, 3-6 membered ring, (C 1~4 Alkylene)-(3-6 member ring), or (C 1~4 It may be substituted with 1 to 3 substituents independently selected from heteroalkylene (3-6 membered rings), C 1~4 Alkylene or C 1~4The heteroalkylene may be substituted with deuterium and / or fluorine, and each of the 3- to 6-membered rings may be substituted with deuterium, halogen, CN, OH, oxo, or fluorine. 1~4 C which may be substituted with alkyl and F 1~4 It may be substituted with one or more substituents independently selected from the heteroalkyl group.

[0140]

[0140] In some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K It may also be hydrogen.

[0141]

[0141] In some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K Also, C may be substituted. 1~6 It may also be alkyl. If substituted, C 1~6 The alkyl group is preferably deuterium, halogen, OH, CN, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 The C11 may be substituted with one or more substituents (e.g., one, two, or three) independently selected from heteroalkyl or 3- to 10-membered rings, each C11 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 The heteroalkyl or 3-10 membered ring may be substituted with deuterium, halogen, CN, OH, oxo, deuterium and / or F. 1~4 C may be substituted with alkyl, deuterium, and / or F. 1~4 The heteroalkyl group may be independently substituted with one or more substituents independently selected from a 3- to 6-membered ring (e.g., a carbocyclic, heterocyclic, heteroaryl, or phenyl ring), each of which may be substituted with deuterium, halogen, CN, OH, oxo, deuterium, and / or F. 1~4 C which may be substituted with alkyl and deuterium and / or F 1~4The heteroalkyl group may be independently substituted with one or more substituents independently selected from the heteroalkyl group.

[0142]

[0142] In some embodiments, R in formula K (for example, any of the subformulas described herein, where applicable) K C may also be substituted with deuterium and / or F. 1~4 It may be an alkyl group. For example, in some embodiments, the LR in formula K (e.g., any of the subformulas described herein, where applicable) K teeth, [ka] That's fine.

[0143]

[0143] Typically, R in formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4) J It is hydrogen.

[0144]

[0144] For example, in some embodiments, the compound of formula K may be characterized by having the structure according to formula K-2: [ka] (In the formulas, variable symbols are defined herein and are preferred.)

[0145]

[0145] In some embodiments, ring A in formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4) may be a phenyl ring. In some embodiments, ring A in formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4) may be a five-membered or six-membered heteroaryl ring having one to three ring heteroatoms independently selected from N, O, and S. In some embodiments, ring A may be a pyridinyl, pyrimidinyl, or imidazo[1,2-a]pyridinyl ring.

[0146]

[0146] In some preferred embodiments, ring A in formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4) is a phenyl ring or a pyridyl ring. For example, in some embodiments, in formula K [ka] Part of it is: [ka] Selected from.

[0147]

[0147] In some embodiments, the compound of formula K may be characterized by having the structure of formula K-3: [ka] (In the formulas, variable symbols are defined herein and are preferred.)

[0148]

[0148] In some embodiments, the compound of formula K may be characterized by having the structure of formula K-5: [ka] (In the formulas, variable symbols are defined herein and are preferred.)

[0149]

[0149] In equation K, the integer m is typically 1 or 2. When m is 1, R 2 Typically, R 1 It exists in the meta position relative to it. For example, in some embodiments, in formula K [ka] Some of them [ka] That is the case.

[0150]

[0150] In some embodiments, m may also be 0.

[0151]

[0151] In some embodiments, the compound of formula K may be characterized by having the structure of formula K-4: [ka] (In the formulas, variable symbols are defined herein and are preferred.)

[0152]

[0152] In some embodiments, the compound of formula K may be characterized by having the structure of formula K-6: [ka] (In the formulas, variable symbols are defined herein and are preferred.)

[0153]

[0153] In some embodiments, formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4), R 2 Each element independently contains deuterium, halogen, CN, OH, and (C 1~4 Alkylene)-CN, G A , or X a -X b -G A And, X a Each existence is independent of non-existence, C 1~4 Alkylene, or C 1~4 It is a heteroalkylene; X b Each existence is independent of non-existence, [ka] , O, NH, N(G B ), C(O), C(O)O, C(O)NH, C(O)N(G B ), NHC(O), N(G B )C(O), SO2, S(=O)(=NH), S(=O)(=NG B ), SO2NH, or SO2N(G B ) and; G A Each existence is independent: (i) Deuterium, halogen, OH, C 1~4 Alkoxy, C(O)-NH(C 1~4 Alkyl), C(O)-N(C 1~4 Alkyl)(C 1~4 C may be substituted with one or more substituents (e.g., 1 to 3) that are alkyl or 3- to 6-membered rings. 1~6 alkyl; (ii) Deuterium, halogen, oxo, C 1~4 Alkyl, C 1~4 C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. 1~6 Heteroalkyl; (iii) Each independently: deuterium, halogen, oxo, OH, CN, C 1~4 Alkyl, C 1~4 alkoxy, C(O)NH2, C(O)-NH(C 1~4 Alkyl), C(O)-N(C 1~4 Alkyl)(C 1~4 Alkyl), [ka] The nitrogen-containing ring E is a 3-8 membered carbocyclic or heterocyclic ring, which may be substituted with one or more substituents (e.g., 1-3 substituents), and the nitrogen-containing ring E is a 4-8 membered heterocyclic ring or a 3-6 membered ring; or (iv) Deuterium, halogen, OH, CN, C 1~4 Alkyl, C 1~4 Five-membered or six-membered heteroaryls that may be substituted with one or more substituents (e.g., one to three) that are alkoxy or 3- to 6-membered rings (preferably carbocyclic or heterocyclic rings). And, Each C in (i) to (iv) 1~4 Alkyl or C 1~4 Alkoxy compounds are each independently composed of deuterium, halogen, OH, and C. 1~4 It may be independently substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3-4 membered carbon-cyclic or heterocyclic rings. (i)~(iv) or each of the 3-6 membered rings in ring E may be independently substituted with oxo, deuterium, halogen, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 It may be independently substituted with one or more (e.g., 1 to 3) substituents that are alkoxy; G B C may be independently substituted with deuterium, halogen, OH, deuterium, or F in each instance. 1~4 C may be substituted with alkoxy, oxo, deuterium, halogen, OH, CN, deuterium, or F.1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 A 3- to 6-membered ring which may be substituted with an alkoxy, and which may be substituted with one or more substituents (e.g., 1 to 3) C 1~6 It is alkyl, or Where applicable, G A and G B These atoms are bonded together to form a 4- to 8-membered heterocyclic ring, and each of these heterocyclic rings may be independently substituted with a halogen, oxo, OH, or F. 1~4 C may be substituted with alkyl or fluorine. 1~4 It may be substituted with one or more (e.g., 1 to 3) substituents that are alkoxy.

[0154]

[0154] In some embodiments, formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4), R 2 Each existence is independently G A G A This is defined herein.

[0155]

[0155] In some embodiments, formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4), R 2 Each C may be independently substituted with deuterium, F, and / or OH. 1~4 Alkyl compounds, such as methyl, difluoromethyl, or hydroxymethyl.

[0156]

[0156] In some embodiments, formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4), R 2 Each of these is independently a 5-membered or 6-membered heteroaryl, and these are independently a halogen, OH, CN, and C, respectively. 1~4 Alkyl, C 1~4 It may be substituted with 1 to 3 substituents that are alkoxy or 3 to 5 membered carboncyclic or heterocyclic rings, C 1~4 Alkyl or C 1~4 Each alkoxy is independently composed of deuterium, halogen (e.g., F), OH, and C. 1~4 It may be substituted with one or more substituents (e.g., 1 to 3) which are alkoxy or 3- to 5-membered carbocyclic or heterocyclic rings, each of which, if present, may be independently substituted with deuterium, F, OH, and / or methyl.

[0157]

[0157] In some embodiments, formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4), R 2 Each existence is independently -(C 1~4 Alkylene)-C(O)NHG A ,-(C 1~4 Alkylene)-C(O)N(G) A )(G B ), or -(C 1~4 It is alkylene)-CN and G A and G B The terms are defined herein. For example, in some embodiments, G A and G B Each of these C atoms may be independently substituted with deuterium, F, and / or OH. 1~4 It is alkyl. In some embodiments, G A and GB These atoms bond together with the nitrogen atoms to which they are bonded, forming a 4- to 8-membered heterocyclic ring, which may be substituted as described herein.

[0158]

[0158] R in formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4) 1 R is typically a phenyl or heteroaryl which may be substituted. For example, in some embodiments, 1 These are phenyl, pyridinyl, pyrimidinyl, benzopyrazolyl, benzimidazolyl, imidazolyl, pyridazyl, imidazo[1,2-a]pyrimidinyl, oxazolo[4,5-b]pyrimidinyl, oxazolo[5,4-b]pyrimidinyl, thiazolo[4,5-b]pyrimidinyl, benzo[d]thiazole, indazolyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-b]pyrimidinyl, or tetrazolo[1,5-a]pyrimidinyl, each of which may be substituted.

[0159]

[0159] In some embodiments, formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4), R 1 These are phenyl or pyridinyl, each of which is deuterium, halogen, CN, OH, NH2, COOH, CONH2, (C 1~4 Alkylene)-CN, G C , or X c -X d -G C It may also be substituted with 1 to 3 substituents independently selected from the above. X c Each existence is independent of non-existence, C 1~4 Alkylene, or C 1~4It is a heteroalkylene; X d Each existence is independent of non-existence, O, NH, N(G) D ), C(O), C(O)O, C(O)NH, C(O)N(G D ), NHC(O), N(G D )C(O), P(O)(G D ), SO2, SO2NH, or SO2N(G D ) and; G C Each existence is independent: (i) Deuterium, halogen, OH, C 1~4 C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. 1~6 alkyl; (ii) Deuterium, halogen, C 1~4 Alkyl, C 1~4 C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. 1~6 Heteroalkyl; (iii) Each independently: deuterium, halogen, oxo, OH, CN, C 1~4 Alkyl, C 1~4 An alkoxy, or a 3- to 6-membered ring, which may be substituted with one or more (e.g., 1 to 3) substituents, a 3- to 7-membered carbocyclic or heterocyclic ring; or (iv) Deuterium, halogen, OH, CN, C 1~4 Alkyl, C 1~4 Five-membered or six-membered heteroaryls that may be substituted with one or more substituents (e.g., one to three) that are alkoxy or 3- to 6-membered rings (preferably carbocyclic or heterocyclic rings). And, C in each of (i) to (iv) 1~4 Alkyl or C 1~4 Alkoxy compounds are each independently composed of deuterium, halogen, OH, and C. 1~4 It may be independently substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3-4 membered carbon-cyclic or heterocyclic rings. Each of the 3-6 membered rings in (i) to (iv) may be substituted with oxo, deuterium, halogen, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 They may also be independently substituted with alkoxy compounds; G D C may be independently substituted with deuterium, halogen, OH, deuterium, or F in each instance. 1~4 C may be substituted with alkoxy, oxo, deuterium, halogen, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 A 3- to 6-membered ring which may be substituted with an alkoxy, and which may be substituted with one or more substituents (e.g., 1 to 3) C 1~6 It is alkyl, or Where applicable, G C and G D These two atoms are bonded together with the heteroatom to form a 4- to 7-membered heterocyclic ring, and each of these 4- to 7-membered heterocyclic rings may be independently substituted with a halogen, oxo, OH, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 It may be substituted with one or more (e.g., 1 to 3) substituents that are alkoxy.

[0160]

[0160] In some embodiments, formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4), R 1 C may be phenyl or pyridinyl, and each of these may be substituted with a halogen, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkyl, deuterium, F, CN, and / or OH. 1~6C may be substituted with alkoxy, deuterium, F, CN, methyl, and / or OH. 3~6 Cycloalkyl, NH2, NH(C 1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 It may be substituted with one or more substituents (e.g., 1 to 3) independently selected from alkyl groups.

[0161]

[0161] In some embodiments, formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4), R 1 C may be phenyl or pyridinyl, and each of these may be substituted with a halogen, deuterium, F, and / or OH. 1~4 C may be substituted with alkyl, deuterium, or F. 1~4 C may be substituted with alkoxy, deuterium, F, CN, methyl, and / or OH. 3~4 Cycloalkyl, NH2, NH(C 1~3 Alkyl), or N(C 1~3 Alkyl)(C 1~3 It may be substituted with one or more substituents (e.g., 1 to 3) independently selected from alkyl groups.

[0162]

[0162] In some embodiments, formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4), R 1The substituent may be phenyl or pyridinyl, each of which may be substituted with 1 to 3 substituents independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, -NH2, hydroxymethyl, and 1-hydroxyethyl, preferably the substituents are independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, and cyclopropyl.

[0163]

[0163] In some embodiments, formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, or K-1b-4), R 1 teeth, [ka] Even if that is the case, R 1a and R 1b Each of these may be independently substituted with a halogen, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkyl, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkoxy, deuterium, F, CN, methyl, and / or OH. 3~6 Cycloalkyl, NH2, NH(C 1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 It is alkyl.

[0164]

[0164] For example, in some embodiments, the compound of formula K may be characterized by having a structure according to formula K-3a or K-3b: [ka] (In the formulas, variable symbols are defined herein and are preferred.)

[0165]

[0165] In some embodiments, the compound of formula K may be characterized by having a structure according to formula K-5a or K-5b: [ka] (In the formulas, variable symbols are defined herein and are preferred.)

[0166]

[0166] In some embodiments, in any of the applicable formulas or substructures, for example, in formulas K-3a, K-3b, K-5a, or K-5b, R 1a and R 1b These may be independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, -NH2, hydroxymethyl, and 1-hydroxyethyl.

[0167]

[0167] In some embodiments, in any of the applicable formulas or substructures, for example, in formulas K-3a, K-3b, K-5a, or K-5b, R 1b C may be substituted with 1 to 3 deuterium atoms or F atoms. 1~4 The alkoxy may be, for example, methoxy, ethoxy, or difluoromethoxy.

[0168]

[0168] In some embodiments, in any of the applicable formulas or substructures, for example, in formulas K-3a, K-3b, K-5a, or K-5b, R 1a (i) a halogen (e.g., F or Cl); (ii) C which may be substituted with 1 to 3 deuterium atoms or F atoms. 1~4 Alkyl compounds, such as methyl, trifluoromethyl, difluoromethyl, etc.; or (iii) cyclopropyl or cyclobutyl compounds which may be substituted with methyl and / or F.

[0169]

[0169] Rings A, R in formula K (for example, any of the subformulas described herein where applicable, e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, K-1b-4, K-3a, K-3b, K-5a, or K-5b) 1 , R 2 , and m may also have any of the definitions set forth herein in relation to formula A or its subformula.

[0170]

[0170] In some embodiments, the present disclosure provides compounds according to any of the embodiments A1 to A44 listed below: Embodiment A1. Compound of formula A or a pharmaceutically acceptable salt thereof: [ka] (In the formula: J 1 S, O, N, CR 10A or NR 10B and; J 2 is C or N; J 3 is C or N; Z is N or CR 10A And preferably, Z is N; However, Z, J 1 , J 2 , and J 3 A five-membered ring containing is a heteroaryl ring having 1 to 3 ring heteroatoms; Ring A is either a phenyl ring or a 5-10 membered heteroaryl ring having 1-4 ring heteroatoms independently selected from N, O, and S; Ring B is a substituted or alternatively substituted 5- to 7-membered carbocyclic or heterocyclic ring, or a substituted or alternatively substituted phenyl ring, or a substituted or alternatively substituted 5- or 6-membered heteroaryl ring having 1 to 3 ring heteroatoms, each independently being N, S, or O; preferably, ring B is a substituted or alternatively substituted 6-membered heteroaryl ring having 1 or 2 ring nitrogen atoms; R 1 is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 3-10 membered carbocyclic, or optionally substituted 5-10 membered heterocyclic or heteroaryl, preferably R 1 It is located in the ortho position relative to the amide group (-C(O)-NH-) shown in formula A; The subscript m is an integer between 0 and 4, as far as the valence allows; R 2 Each of these is independently present in the following order: deuterium, halogen, OH, NH2, CN, SF5, COOH, CONH2, SO2NH2, R 20 , OR 20 , SR 20 , N(R 20 )(R 21 ), SO2R 20 SO2N(R 20 )(R 21 ), N(R 21 )SO2R 20 COR 20 COOR 20 ,OC(O)R 20 CON(R 20 )(R 21 ), or N(R 21 )COR 20 And R 20 C may be substituted independently for each instance. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6 A heteroalkyl or possibly substituted 3- to 10-membered ring structure; R 21 Each element independently contains hydrogen, and may be substituted with C. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6 It is a heteroalkyl or possibly substituted 3- to 10-membered ring structure; or, where applicable, R 20 and R 21It is bonded together with one or more interfacing atoms (e.g., nitrogen atoms) to form a substituted, possibly substituted, 4- to 8-membered heterocyclic ring; R 10A Each instance may independently contain hydrogen, deuterium, halogen, CN, or C which may be substituted with deuterium or F. 1~3 It is alkyl; R 10B C is either hydrogen or may be substituted with deuterium or F. 1~3 (It is alkyl.) Embodiment A2.J 1 S is J 2 and J 3 C is preferable, Z is N, and J 1 S is J 2 and J 3 A compound of Embodiment A1 or a pharmaceutically acceptable salt thereof, wherein C is C. Embodiment A3. (i) Z is N; (ii) J 1 (iii) Z is N and J 1 However, the compound of Embodiment A1 or a pharmaceutically acceptable salt thereof is CH. Embodiment A4.J 2 C is J 3 A compound of Embodiment A1 or 3, or a pharmaceutically acceptable salt thereof, wherein N is present. Embodiment A5.J 3 C is J 2 A compound of Embodiment A1 or 3, or a pharmaceutically acceptable salt thereof, wherein N is present. Embodiment A6. A compound according to any one of Embodiments A1 to A5 or a pharmaceutically acceptable salt thereof, wherein ring B is a benzene, pyridine, pyridone (e.g., pyridine-2-one), pyrazine, pyridazine, or pyrimidine ring, each of which may be substituted. Embodiment A7. Ring B is a cyclohexene ring, [ka] , or a 5-7 membered heterocyclic ring having one or two ring heteroatoms, for example [ka] The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments A1 to 5, wherein each of these may be substituted. Embodiment A8. A compound according to any one of Embodiments A1 to A5, or a pharmaceutically acceptable salt thereof, characterized by having the structure according to Formula I: [ka] (In the formula: J 4 CR 11 or N; J 5 CR 12 or N; J 6 CR 13A or N, J 7 CR 14 or N; or J 6 is NR 13B and J 7 is C(O); However, J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , and J 7 A bicyclic ring containing the above is a heteroaryl ring having 1 to 4 ring heteroatoms in addition to the ring nitrogen atom shown in formula I; R 11 , R 12 , R 13A , and R 14 These are, independently, hydrogen, deuterium, halogen, OH, NH2, SF5, CN, or -Y 1 -Y 2 Y 1 is non-existent, O, S, NH, NY 3 , C(O), SO2, C(O)NH, C(O)NY 3 , P(O)Y 3 , SO2NH, or SO2NY 3 Y 2 and Y 3Each of these may be substituted independently of each other. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6 The heteroalkyl group is a heteroalkyl group, an optionally substituted 3- to 10-membered carbocyclic or heterocyclic ring, an optionally substituted phenyl group, or an optionally substituted 5- or 6-membered heteroaryl group; R 13B C is hydrogen, which may be substituted. 1~6 Alkyl, possibly substituted C 2~6 Alkenyl, C may be substituted 2~6 Alkynyl, C may be substituted. 1~6 (A heteroalkyl group, a substituted 3- to 10-membered carbocyclic or heterocyclic ring, a substituted phenyl group, or a substituted 5- or 6-membered heteroaryl group). Embodiment A9. The compound described in Embodiment A8 or a pharmaceutically acceptable salt thereof, characterized by having the structure according to formula I-1: [ka] Embodiment A10.J 7 A compound according to Embodiment A8 or 9, or a pharmaceutically acceptable salt thereof, wherein is N. Embodiment A11.J 4 A compound according to Embodiment A8 or 9, or a pharmaceutically acceptable salt thereof, wherein is N. Embodiment A12.J 5 A compound according to Embodiment A8 or 9, or a pharmaceutically acceptable salt thereof, wherein is N. Embodiment A13.(i)J 4 N is J 5 CR 12 And J 7 CR 14 (ii)J 5 N is J 4 CR 11 And J 7 CR 14(iii) J 7 N is J 4 CR 11 And J 5 CR 12 The compound described in Embodiment A8 or 9, or a pharmaceutically acceptable salt thereof. Embodiment A14.(i)J 4 and J 7 Both are N, and J 5 CR 12 (ii) J 4 and J 5 Both are N, and J 7 CR 14 (iii) J 4 CR 11 It is preferably CH and J 5 and J 7 A compound according to Embodiment A8 or 9, or a pharmaceutically acceptable salt thereof, wherein both are N. Embodiment A15. Where applicable, (i) J 5 CR 12 If R 12 (ii) J 4 CR 11 If R 11 H is H; and / or (iii) J 7 CR 14 If R 14 A compound according to any one of embodiments A8 to A14, or a pharmaceutically acceptable salt thereof, wherein is H. Embodiment A16.J 6 CR 13A The compound described in any one of embodiments A8 to A15, or a pharmaceutically acceptable salt thereof. Embodiment A17. A compound according to Embodiment A8 or 9, or a pharmaceutically acceptable salt thereof, characterized by having a structure according to formula I-1a, I-1b, I-1c, I-1d, I-1e, or I-1f. [ka] TIFF2026522322000100.tif92149 Embodiment A18.R 13A However, if present, hydrogen, halogens (e.g., Cl, Br, etc.), CN, and possibly substituted C 1~4 Alkyl, possibly substituted C 2~4 Alkenyl, C may be substituted 2~4 Alkynyl, C may be substituted. 1~4 Heteroalkyl, SF5, optionally substituted C 3~7 A cycloalkyl or a substituted 4-10 membered heterocyclic ring having 1-3 ring heteroatoms, each independently being N, O, or S, preferably, if substituted, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Heteroalkyl, C 3~7 Cycloalkyl or 4-10 membered heterocyclic rings containing deuterium, halogens (e.g., F), OH, SF5, CN, oxo, CONR 30 R 31 , N(R 30 )C(O)R 31 SO2NR 30 R 31 , N(R 30 )SO2R 31 , SR 31 , OR 31 SO2R 31 , C which may be substituted with deuterium or F 1~4 It is substituted with one or more substituents (e.g., 1 to 3) independently selected from alkyl, or 3- to 4-membered carbon-cyclic or heterocyclic rings (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) which may be substituted with deuterium, F, OH, and / or methyl, and R 30 and R 31 Each of these may be independently substituted with hydrogen, deuterium, or F. 1~4It is a 3- to 6-membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) which may be substituted with alkyl, or deuterium, F, OH, and / or methyl; or, where applicable, R 30 and R 31 The intervening atom or multiple intervening atoms bond together to form a substituted 4- to 8-membered heterocyclic ring (for example, substituted with deuterium, F, OH, and / or methyl); For example, R 13A However, C may be substituted with hydrogen, halogen (e.g., Cl or Br), CN, deuterium, or F. 1~4 C may be substituted with alkyl (e.g., CF2H or CF3), cyclopropyl, deuterium, or F. 1~4 Alkoxy (e.g., OCF2H or OCF3), or a 4-10 membered heterocyclic ring having 1-3 ring heteroatoms, each independently of N, O, or S, where each may be independently substituted with deuterium, halogen, OH, deuterium, or F. 1~4 C may be substituted with alkyl (e.g., CF2H or CF3), or with deuterium or F. 1~4 A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments A8 to 17, which may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy (e.g., OCF2H or OCF3). Embodiment A19.R 13A However, if present, it is an optionally substituted phenyl or an optionally substituted 5-membered or 6-membered heteroaryl, preferably, if substituted, the phenyl or 5-membered or 6-membered heteroaryl is independently a deuterium, halogen (e.g., F, Cl, Br, etc.), CN, OH, NH2, SF5, G 1 , or -X 1 -X 2 -G 1 It is substituted with one or more substituents (e.g., 1 to 3), X 1 However, non-existent, C 1~4 Alkylene, or C 1~4It is a heteroalkylene, X 2 However, O, S, NH, NG 1 , C(O), SO2, C(O)NH, C(O)NG 1 SO2NH, or SO2NG 1 And, G 1 However, each instance of C may be substituted independently. 1~4 Alkyl, possibly substituted C 2~4 Alkenyl, C may be substituted 2~4 Alkynyl, C may be substituted. 1~4 Heteroalkyl, possibly substituted C 3~6 A cycloalkyl, a substituted or alternatively substituted 4- to 7-membered heterocyclic ring having one or two ring heteroatoms, each independently being N, O, or S, or a substituted or alternatively substituted 5- or 6-membered heteroaryl, each independently being N, O, or S, Preferably, if substituted, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Heteroalkyl, C 3~6 A cycloalkyl, a 4- to 7-membered heterocyclic ring, or a 5- or 6-membered heteroaryl may be substituted with deuterium, a halogen (e.g., F), OH, CN, oxo, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or F. 1~4 A compound according to any one of Embodiments A8 to 17, or a pharmaceutically acceptable salt thereof, which is substituted with one or more substituents (e.g., 1 to 3) independently selected from alkoxyl, or a 3-4 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) which may be substituted with deuterium, F, OH, and / or methyl. Embodiment A20.R 13AHowever, if present, they may be substituted phenyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridadinyl, or pyrazinyl, and preferably, if substituted, phenyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridadinyl, or pyrazinyl may be independently deuterium, halogen (e.g., F, Cl, Br, etc.), CN, OH, SF5, SCF3, NH2, G 2 NHG 2 , NG 2 G 2 OG 2 , or SO2G 2 It is substituted with one or more substituents (e.g., 1 to 3), G 2 However, each instance of C may be substituted independently. 1~4 Alkyl, possibly substituted C 3~6 A cycloalkyl or a substituted 4-7 membered heterocyclic ring having one or two ring heteroatoms, each independently being N, O, or S, preferably, if substituted, C 1~4 Alkyl, C 3~6 The cycloalkyl or 4- to 7-membered heterocyclic ring may be substituted with deuterium, halogen (e.g., F), OH, CN, oxo, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or F. 1~4 A compound according to any one of Embodiments A8 to 17, or a pharmaceutically acceptable salt thereof, which is substituted with one or more substituents (e.g., 1 to 3) independently selected from alkoxyl, or a 3-4 membered carbocyclic or heterocyclic ring (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.) which may be substituted with deuterium, F, OH, and / or methyl. Embodiment A21.R 13A However, if present, the compound described in any one of Embodiments A8 to A17 or a pharmaceutically acceptable salt thereof, selected from the following: [ka] (In the formula, n is an integer between 0 and 3. G 3 Each element present independently contains deuterium, halogens (e.g., F or Cl), CN, and C. 1~4 Alkyl, O-(C 1~4 Alkyl), SO2-(C 1~4 Alkyl), OH, NH2, NH(C 1~4 Alkyl), N(C 1~4 Alkyl)(C 1~4 Alkyl), 3-4 membered carbon-cyclic or heterocyclic ring, O-(3-4 membered carbon-cyclic or heterocyclic ring), (C 1~4 Alkylene)-(3-4 membered carbocyclic or heterocyclic ring), or O-(C 1~4 It is an alkylene (3-4 membered carbon ring or heterocyclic ring), and as mentioned above, C 1~4 Each alkyl group may be independently substituted with 1 to 7 deuterium atoms or fluorine atoms, C 1~4 The alkylene or the 3-4 membered carbocyclic or heterocyclic ring may be substituted with one or more substituents (e.g., 1-3) that are independently deuterium, F, OH, or methyl, preferably G 3 One example is C which may be substituted with 1 to 7 deuterium atoms or F atoms. 1~4 C may be substituted with alkyl or 1 to 7 deuterium atoms or fluorine atoms. 1~4 It is an alkoxy, for example, OCH3, OCF2H, OCF3, CF3, CH3, CF2H, or CH2CF3. Embodiment A22.R 13A However, if present, deuterium, halogens (e.g., F or Cl), CN, C 1~4 Alkyl, O-(C 1~4 Alkyl), SO2-(C 1~4 Alkyl), OH, NH2, NH(C 1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 A pyridinyl (e.g., 2-pyridinyl or 3-pyridinyl) substituted with one or two substituents independently selected from alkyl, and the aforementioned C 1~4 Each alkyl group may be independently substituted with 1 to 7 deuterium atoms or fluorine atoms, for example, R 13A However, it may also be selected from the following: [ka] Preferably, the pyridinyl is substituted with one substituent selected from OCH3, OCF2H, OCF3, SO2CH3, NH2, CN, Cl, isopropyl, CF3, CH3, CF2H, or CH2CF3, and may be substituted with a further substituent selected from F or Cl, as described in any one of Embodiments A8 to 17 or a pharmaceutically acceptable salt thereof. Embodiment A23.R 13A However, if present, these are phenyl, pyrimidinyl, pyridazinyl, or pyrazinyl, which are deuterium, halogen (e.g., F or Cl), CN, C 1~4 Alkyl, O-(C 1~4 Alkyl), SO2-(C 1~4 Alkyl), OH, NH2, NH(C 1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 Substituted with one or two substituents independently selected from alkyl, as described above. 1~4 Each alkyl group may be independently substituted with 1 to 7 deuterium atoms or fluorine atoms, for example, R 13A However, the compound described in any one of Embodiments A8 to A17 or a pharmaceutically acceptable salt thereof may be selected from the following. [ka] Embodiment A24.R 13A However, if present, they are independently deuterium, halogens (e.g., F, Cl, Br, etc.), and C. 1~4 Alkyl, 3-4 membered carbon ring or heterocyclic ring, or (C 1~4 A pyrazolyl that is alkylene)-(3-4 membered carbon ring or heterocyclic ring), which may be substituted with one or more substituents (e.g., 1-3 substituents), C 1~4 Alkyl, C 1~4 The alkylene, or the 3-4 membered carbocyclic or heterocyclic ring, may be substituted with one or more substituents (e.g., 1-3) that are independently deuterium, F, OH, or methyl. For example, R 13A However, the compound described in any one of Embodiments A8 to A17 or a pharmaceutically acceptable salt thereof may be selected from the following. [ka] Embodiment A25.R 13A However, if present, they are 5-7 membered heterocyclic rings, such as tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl, and these independently contain deuterium, halogens (e.g., F, Cl, Br, etc.), oxo, and C. 1~4 Alkyl, 3-4 membered carbon ring or heterocyclic ring, or (C 1~4 It may be substituted with one or more substituents (e.g., 1 to 3) that are alkylene-(3-4 membered carboncyclic or heterocyclic rings), C 1~4 Alkyl, C 1~4 The alkylene, or the 3-4 membered carbocyclic or heterocyclic ring, may be substituted with one or more substituents (e.g., 1-3) that are independently deuterium, F, OH, or methyl. For example, R 13A However, the compound described in any one of Embodiments A8 to A17 or a pharmaceutically acceptable salt thereof may be selected from the following. [ka] Embodiment A26. A compound according to any one of Embodiments A1 to A25 or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl ring or a 5-membered or 6-membered heteroaryl having 1 to 3 ring heteroatoms independently selected from N, O, and S, such as a pyridine ring. Embodiment A27. A compound according to any one of Embodiments A1 to A25 or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl, pyridinyl, pyrimidinyl, or imidazo[1,2-a]pyridinyl ring, preferably a phenyl or pyridinyl ring. Embodiment A28. A compound according to any one of Embodiments A1 to A25, or a pharmaceutically acceptable salt thereof, characterized by having a structure according to formula A1, A2, or A3. [ka] Embodiment A29.m is 0, 1, or 2, and R 2 However, independently of each presence, deuterium, halogen, CN, OH, (C 1~4 Alkylene)-CN, G A , or X a -X b -G A And, X a However, each existence is independent of non-existence, C 1~4 Alkylene, or C 1~4 It is a heteroalkylene; X b However, each existence is independent of non-existence, O, NH, N(G) B ), C(O), C(O)O, C(O)NH, C(O)N(G B ), NHC(O), N(G B )C(O), SO2, SO2NH, or SO2N(G B ) and; G A However, each entity exists independently: (i) Deuterium, halogen, OH, C 1~4 C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. 1~6 alkyl; (ii) Deuterium, halogen, C 1~4 Alkyl, C 1~4 C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. 1~6 Heteroalkyl; (iii) Each independently: deuterium, halogen, oxo, OH, CN, C 1~4 Alkyl, C 1~4 An alkoxy, or a 3- to 6-membered ring, which may be substituted with one or more (e.g., 1 to 3) substituents, a 3- to 7-membered carbocyclic or heterocyclic ring; or (iv) Deuterium, halogen, OH, CN, C 1~4 Alkyl, C 1~4An alkoxy, or a 5-membered or 6-membered heteroaryl which is a 3- to 6-membered ring (preferably a carbocyclic or heterocyclic ring), may be substituted with one or more substituents (e.g., 1 to 3), C in each of i) to (iv) 1~4 Alkyl or C 1~4 Each alkoxy independently contains deuterium, halogen, OH, and C. 1~4 It may be independently substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3-4 membered carbon-cyclic or heterocyclic rings. Each of the 3-6 membered rings in (i) to (iv) may be independently substituted with oxo, deuterium, halogen, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 It may be independently substituted with one or more (e.g., 1 to 3) substituents that are alkoxy; G B However, each C may be independently substituted with deuterium, halogen, OH, deuterium, or F. 1~4 C may be substituted with alkoxy, oxo, deuterium, halogen, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 A 3- to 6-membered ring which may be substituted with an alkoxy, and which may be substituted with one or more substituents (e.g., 1 to 3) C 1~6 It is alkyl, or Where applicable, G A and G B These atoms are bonded together to form a 4- to 7-membered heterocyclic ring, and each of these 4- to 7-membered heterocyclic rings may be independently substituted with a halogen, oxo, OH, and F. 1~4 C may be substituted with alkyl or fluorine. 1~4 A compound according to any one of Embodiments A1 to 28, or a pharmaceutically acceptable salt thereof, which may be substituted with one or more (e.g., 1 to 3) substituents that are alkoxy. Embodiment A30. The compound of Embodiment A29 or a pharmaceutically acceptable salt thereof, wherein m is 0. Embodiment A31. A compound of Embodiment A29 or a pharmaceutically acceptable salt thereof, wherein m is 1. Embodiment A32. The compound described in Embodiment A31 or a pharmaceutically acceptable salt thereof, characterized in that the compound has a structure according to formula A1a or A2a: [ka] Embodiment A33.R 2 However, C may be substituted with deuterium, F, and / or OH. 1~4 A compound according to Embodiment A31 or 32, or a pharmaceutically acceptable salt thereof, which is alkyl, for example, methyl, difluoromethyl, or hydroxymethyl. Embodiment A34.R 2 However, these are 5-membered or 6-membered heteroaryl compounds, and these are independently halogen, OH, CN, and C. 1~4 Alkyl, C 1~4 It may be substituted with 1 to 3 substituents that are alkoxy or 3 to 5 membered carboncyclic or heterocyclic rings, C 1~4 Alkyl or C 1~4 Each alkoxy independently contains deuterium, halogen (e.g., F), OH, and C. 1~4 The compound described in Embodiment A31 or 32, or a pharmaceutically acceptable salt thereof, may be substituted with one or more substituents (e.g., 1 to 3) which are alkoxy or 3- to 5-membered carbocyclic or heterocyclic rings, and each of the 3- to 5-membered carbocyclic or heterocyclic rings may, if present, be independently substituted with deuterium, F, OH, and / or methyl. Embodiment A35.R 2 However, -(C 1~4 Alkylene)-C(O)NHG A ,-(C 1~4 Alkylene)-C(O)N(G) A )(G B ), or -(C 1~4 It is alkylene)-CN, preferably G A and G BHowever, each C may be independently substituted with deuterium, F, and / or OH. 1~4 A compound described in Embodiment A31 or 32, or a pharmaceutically acceptable salt thereof, which is alkyl. Embodiment A36.R 1 The compound described in any one of Embodiments A1 to 35 or a pharmaceutically acceptable salt thereof is phenyl, pyridinyl, pyrimidinyl, benzopyrazolyl, benzimidazolyl, imidazolyl, pyridazyl, imidazo[1,2-a]pyrimidinyl, oxazolo[4,5-b]pyrimidinyl, oxazolo[5,4-b]pyrimidinyl, thiazolo[4,5-b]pyrimidinyl, benzo[d]thiazole, indazol, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-b]pyrimidinyl, or tetrazolo[1,5-a]pyrimidinyl, each of which may be substituted. Embodiment A37.R 1 However, these are phenyl or pyridinyl, and each of these is deuterium, halogen, CN, OH, NH2, COOH, CONH2, (C 1~4 Alkylene)-CN, G C , or X c -X d -G C It may also be substituted with 1 to 3 substituents independently selected from the above. X c However, each existence is independent of non-existence, C 1~4 Alkylene, or C 1~4 It is a heteroalkylene; X d However, each existence is independent of non-existence, O, NH, N(G) D ), C(O), C(O)O, C(O)NH, C(O)N(G D ), NHC(O), N(G D )C(O), P(O)(G D ), SO2, SO2NH, or SO2N(G D ) and; G C However, each entity exists independently: (i) Deuterium, halogen, OH, C 1~4C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. 1~6 alkyl; (ii) Deuterium, halogen, C 1~4 Alkyl, C 1~4 C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. 1~6 Heteroalkyl; (iii) Each independently: deuterium, halogen, oxo, OH, CN, C 1~4 Alkyl, C 1~4 An alkoxy, or a 3- to 6-membered ring, which may be substituted with one or more (e.g., 1 to 3) substituents, a 3- to 7-membered carbocyclic or heterocyclic ring; or (iv) Deuterium, halogen, OH, CN, C 1~4 Alkyl, C 1~4 An alkoxy, or a 5-membered or 6-membered heteroaryl which is a 3- to 6-membered ring (preferably a carbocyclic or heterocyclic ring), may be substituted with one or more substituents (e.g., 1 to 3), C in each of (i) to (iv) 1~4 Alkyl or C 1~4 Each alkoxy independently contains deuterium, halogen, OH, and C. 1~4 It may be independently substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3-4 membered carbon-cyclic or heterocyclic rings. Each of the 3-6 member rings in (i) to (iv) may be substituted with oxo, deuterium, halogen, OH, CN, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 They may also be independently substituted with alkoxy compounds; G D However, each C may be independently substituted with deuterium, halogen, OH, deuterium, or F. 1~4 C may be substituted with alkoxy, oxo, deuterium, halogen, OH, CN, deuterium, or F. 1~4C may be substituted with alkyl, deuterium, or fluorine. 1~4 A 3- to 6-membered ring which may be substituted with an alkoxy, and which may be substituted with one or more substituents (e.g., 1 to 3) C 1~6 It is alkyl, or Where applicable, G C and G D However, both of these are bonded together with the heteroatom to form a 4- to 7-membered heterocyclic ring, and each of these 4- to 7-membered heterocyclic rings may be independently substituted with a halogen, oxo, OH, deuterium, or F. 1~4 C may be substituted with alkyl, deuterium, or fluorine. 1~4 It may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy. A compound described in any one of Embodiments A1 to A35, or a pharmaceutically acceptable salt thereof. Embodiment A38.R 1 However, these are phenyl or pyridinyl, and each of these may be substituted with a halogen, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkyl, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkoxy, deuterium, F, CN, methyl, and / or OH. 3~6 Cycloalkyl, NH2, NH(C 1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 A compound according to any one of Embodiments A1 to 35 or a pharmaceutically acceptable salt thereof, which may be substituted with one or more substituents (e.g., 1 to 3) independently selected from alkyl groups. Embodiment A39.R 1 C is phenyl or pyridinyl, and each of these may be substituted with a halogen, deuterium, F, and / or OH. 1~4 C may be substituted with alkyl, deuterium, or F. 1~4 C may be substituted with alkoxy, deuterium, F, CN, methyl, and / or OH. 3~4Cycloalkyl, NH2, NH(C 1~3 Alkyl), or N(C 1~3 Alkyl)(C 1~3 A compound according to any one of Embodiments A1 to 35 or a pharmaceutically acceptable salt thereof, which may be substituted with one or more substituents (e.g., 1 to 3) independently selected from alkyl groups. Embodiment A40.R 1 The compound described in any one of Embodiments A1 to 35 or a pharmaceutically acceptable salt thereof is phenyl or pyridinyl, and each of these may be substituted with 1 to 3 substituents independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, -NH2, hydroxymethyl, and 1-hydroxyethyl, preferably the substituents are independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, and cyclopropyl. Embodiment A41. A compound according to any one of Embodiments A1 to 35, or a pharmaceutically acceptable salt thereof, characterized by having a structure according to formula A1b, A1c, A2b, or A2c: [ka] (In the formula, R 1a and R 1b Each of these may be independently substituted with a halogen, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkyl, deuterium, F, CN, and / or OH. 1~6 C may be substituted with alkoxy, deuterium, F, CN, methyl, and / or OH. 3~6 Cycloalkyl, NH2, NH(C 1~4 Alkyl), or N(C 1~4 Alkyl)(C 1~4 It is alkyl. Embodiment A42.R 1a and R 1bHowever, each is independently selected from methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, -NH2, hydroxymethyl, and 1-hydroxyethyl, and more preferably R 1a and R 1b The compounds described in Embodiment A41 or pharmaceutically acceptable salts thereof, each independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, and cyclopropyl. Embodiment A43.R 1b However, C may be substituted with 1 to 3 deuterium atoms or F atoms. 1~2 It is an alkoxy, preferably R 1b The compound described in Embodiment A41 or a pharmaceutically acceptable salt thereof, wherein the compound is methoxy, ethoxy, or difluoromethoxy. Embodiment A44.R 1a However, C may be substituted with a halogen, 1 to 3 deuterium atoms, or F. 1~3 It is alkyl or cyclopropyl, preferably R 1a The compound described in any one of Embodiments A41 to A43 or a pharmaceutically acceptable salt thereof, wherein the compound is methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, or cyclopropyl.

[0171]

[0171] In some embodiments, the disclosure also provides compounds selected from Table 1 below, their deuterated analogs, their stereoisomers, or pharmaceutically acceptable salts thereof: [Table 1] TIFF2026522322000110.tif206149TIFF2026522322000111.tif200149TIFF2026522322000112.tif205149TIFF2026522322000113.tif23149

[0172]

[0172] In some embodiments, to the extent applicable, the genera of compounds described herein will exclude any specific known single compound prior to this disclosure. In some embodiments, to the extent applicable, any subgenus or species of prior to this disclosure that is within the full scope of the genera of compounds described herein may be excluded from such genera herein.

[0173] Synthesis method

[0173] The compounds of this disclosure can be readily synthesized by those skilled in the art in consideration of this disclosure. Exemplary synthesis is also shown in the Examples section.

[0174]

[0174] As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent undesirable reactions from occurring in certain functional groups. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in "Protective Groups in Organic Synthesis," 4th edition, PGMWuts;TW Greene, John Wiley, 2007 and the literature cited herein. The reagents for the reactions described herein are generally known compounds or may be prepared by known procedures or obvious modifications thereof. For example, many of the reagents are available from commercial suppliers, such as Sigma-Aldrich (Milwaukee, Wisconsin, USA). Other preparations may be made by following the procedures described in any of the standard reference texts, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplement (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (Wiley, 7th edition), and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), or any updated editions available at the time of this application, or obvious modifications thereof.

[0175] Pharmaceutical composition

[0175] Certain embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0176]

[0176] The pharmaceutical composition may optionally contain pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is a compound of the Disclosure (e.g., formula A (e.g., formula I, I-1, I-1a, I-1b, I-1c, I-1d, I-1e, I-1f, I-1g, II, II-1, III, III-1, A1, A2, A3, A1a, A1b, A1c, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6)), The compound comprises a compound of formula K (e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, K-1b-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1 to 145, any of the compounds listed in Table 1 of this specification, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipients are known in the art. Suitable non-limiting excipients include, for example, encapsulating materials or additives such as antioxidants, binders, buffers, carriers, coatings, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, release agents, sterilizers, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st edition, ARGennaro (Lippincott, Williams & Wilkins, Baltimore, Maryland, 2005; incorporated herein by reference), which discloses a variety of excipients used in the formulation of pharmaceutical compositions and known techniques for preparing them.

[0177]

[0177] The pharmaceutical composition may contain one or more of the compounds of the Disclosure. For example, in some embodiments, the pharmaceutical composition may contain, for example, a therapeutically effective amount of the compound of formula A or a pharmaceutically acceptable salt thereof. In any of the embodiments described herein, the pharmaceutical composition may contain a therapeutically effective amount (for example, a therapeutically effective amount for treating cancer as described herein) of any of Examples 1 to 145, or any of the specific compounds disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof. In some preferred embodiments, the pharmaceutical composition may contain an IC50 of less than 100 nM when measured according to Biological Example 1. 50 The value, more preferably, is less than 50 nM for ICs. 50 The compound may be selected from the compounds of Examples 1 to 145 that have a value.

[0178]

[0178] The pharmaceutical compositions described herein may be formulated for delivery via any known delivery route, which are not limited to, oral, nasal, dermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral administration.

[0179]

[0179] In some embodiments, the pharmaceutical composition may be formulated for oral administration. The oral formulation may be provided as individual units, each containing a predetermined amount of the active compound, for example, as capsules, pills, cachets, lozenges, or tablets; as powders or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for preparing compositions for oral administration are known in the art. Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethylcellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, peanut oil, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactol The ingredients include magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0180]

[0180] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous or intramuscular injection). Parenteral formulations may be, for example, aqueous solutions, suspensions, or emulsions. Excipients for preparing parenteral formulations are known in the art. Non-limiting suitable excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water, and mixtures thereof.

[0181]

[0181] The compounds of this disclosure may be used alone, in combination with each other, or in combination with one or more additional therapeutic agents, for example, additional anticancer therapeutic agents, such as PARP inhibitors, signaling inhibitors, chemotherapeutic agents, and / or immune checkpoint inhibitors.

[0182]

[0182] When used in combination with one or more additional therapeutic agents, the compounds of the Disclosure or the pharmaceutical compositions herein may be administered to a subject simultaneously or sequentially to such additional therapeutic agents in any order. In some embodiments, a pharmaceutical composition may contain one or more compounds of the Disclosure and one or more additional therapeutic agents in a single composition. In some embodiments, a pharmaceutical composition containing one or more compounds of the Disclosure may be contained in a kit, which also contains individual pharmaceutical compositions containing one or more additional therapeutic agents.

[0183]

[0183] A pharmaceutical composition may contain varying amounts of the compound of the Disclosure depending on various factors, such as the intended use, efficacy, and selectivity of the compound. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the compound of the Disclosure. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the compound of the Disclosure and a pharmaceutically acceptable excipient. When used herein, the therapeutically effective amount of the compound of the Disclosure is an amount effective to treat the disease or disorder described herein, such as cancer herein, and may depend on the recipient of the treatment, the disorder, condition, or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether or not another drug is administered concurrently.

[0184] Treatment / Usage

[0184] The compounds of the Disclosure have a variety of uses. For example, the compounds of the Disclosure may be used as therapeutic active substances for treating and / or preventing diseases or disorders associated with Polθ, such as Polθ overexpression. Accordingly, some embodiments of the Disclosure also relate to methods of using one or more compounds of the Disclosure or pharmaceutical compositions herein for treating or preventing diseases or disorders associated with Polθ in subjects where it is needed, such as treating cancer in subjects where it is needed.

[0185]

[0185] In some embodiments, the present disclosure is a method for inhibiting Polθ enzyme activity in cells, for example, Polθ-mediated DNA repair activity, comprising cells and an effective amount of the compound of the present disclosure (e.g., formula A (e.g., formula I, I-1, I-1a, I-1b, I-1c, I-1d, I-1e, I-1f, I-1g, II, II-1, III, III-1, A1, A2, A3, A1a, A1b, A1c, A2a, A2b, A2c, A2b-1, A2b-2, A The present invention provides a method comprising the step of contacting a compound of formula K (e.g., formula K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, K-1b-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1 to 145, any of the compounds listed in Table 1 herein, or pharmaceutically acceptable salts thereof. In some embodiments, the contact of cells is performed in vitro. In some embodiments, the contact of cells is performed in vivo. In some embodiments, the cells are cancer cells. In some embodiments, the cells are HR-deficient cells. In some embodiments, the cancer cells have overexpression of Polθ. The cancer cells may be any of the cancers described herein.

[0186]

[0186] In some embodiments, the present disclosure is a method for inhibiting cell proliferation in vitro or in vivo, comprising cells and an effective amount of the compound of the present disclosure (e.g., formula A (e.g., formula I, I-1, I-1a, I-1b, I-1c, I-1d, I-1e, I-1f, I-1g, II, II-1, III, III-1, A1, A2, A3, A1a, A1b, A1c, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, or A2b-6) The present invention provides a method comprising the step of contacting a compound of formula K (for example, formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, K-1b-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1 to 145, any of the compounds listed in Table 1 of this specification, or a pharmaceutically acceptable salt thereof. In some embodiments, the cells are cancer cells. In some embodiments, the cells are HR-deficient cells. In some embodiments, the cancer cells have overexpression of Polθ. The cancer cells may be cells of any of the cancers described herein.

[0187]

[0187] In some embodiments, the Disclosure relates to a method for treating a disease or disorder associated with Polθ in a subject requiring such treatment, comprising a therapeutically effective amount of the compound of the Disclosure (e.g., formula A (e.g., formula I, I-1, I-1a, I-1b, I-1c, I-1d, I-1e, I-1f, I-1g, II, II-1, III, III-1, A1, A2, A3, A1a, A1b, A1c, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5 The present invention provides a method comprising the step of administering a compound of formula K (e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, K-1b-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1 to 145, any of the compounds listed in Table 1 herein, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as defined herein. In some embodiments, the disease or disorder associated with Polθ is the cancer described herein. In some embodiments, the disease or disorder associated with Polθ is characterized by overexpression of Polθ. In some embodiments, the cancer is homologous recombination (HR) deficiency cancer. In some embodiments, the cancer is characterized by reduced or absent BRCA gene expression, absence of the BRAC gene, or impaired BRCA protein function. In some embodiments, the cancer is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy. In some embodiments, the cancer is selected from lymphoma, rhabdoid tumor, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblastic cancer, central nervous system cancer, urinary tract cancer, upper respiratory tract and gastrointestinal cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer.

[0188]

[0188] In some embodiments, the present disclosure is a method for treating homologous recombination (HR)-deficient cancer in a subject requiring such treatment, comprising a therapeutically effective amount of the compound of the present disclosure (e.g., formula A (e.g., formula I, I-1, I-1a, I-1b, I-1c, I-1d, I-1e, I-1f, I-1g, II, II-1, III, III-1, A1, A2, A3, A1a, A1b, A1c, A2a, A2b, A2c, A2b-1, A2b-2, A2b-3, A2b-4, A2b-5, The present invention provides a method comprising the step of administering a compound of formula K (e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, K-1b-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1 to 145, any of the compounds listed in Table 1 herein, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as defined herein. In some embodiments, the HR-deficient cancer is breast cancer. Breast cancers include, but are not limited to, intralobular carcinoma (LCIS), intraductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget's disease of the nipple, phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, or, but are not limited to, triple-negative, HER-positive, estrogen receptor-positive, progesterone receptor-positive, HER and estrogen receptor-positive, HER and progesterone receptor-positive, estrogen and progesterone receptor-positive, and HER, estrogen and progesterone receptor-positive. In some embodiments, HR-deficient cancer is ovarian cancer. Ovarian cancers, though not limited to these, include epithelial ovarian carcinoma (EOC), mature teratoma, undifferentiated germ cell tumor, endodermal sinus tumor, granulosa-follicular tumor, Sertli-Leydig cell tumor, and primary peritoneal carcinoma.

[0189]

[0189] In some embodiments, the present disclosure is a method for treating cancer in a subject requiring such treatment, wherein the cancer is characterized by reduced or absent BRCA gene expression, absence of BRCA genes, and / or reduced function of the BRCA protein, and the method is a therapeutically effective amount of the compound of the present disclosure (e.g., formula A (e.g., formula I, I-1, I-1a, I-1b, I-1c, I-1d, I-1e, I-1f, I-1g, II, II-1, III, III-1, A1, A2, A3, A1a, A1b, The present invention provides a method comprising the step of administering a compound of formula K (e.g., formula K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, K-1b-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1 to 145, any of the compounds listed in Table 1 herein, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as defined herein.

[0190]

[0190] In some embodiments, the present disclosure is a method for treating cancer in a subject requiring it, wherein the cancer is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy, and the method is a therapeutically effective amount of a compound of the present disclosure (e.g., formula A (e.g., formula I, I-1, I-1a, I-1b, I-1c, I-1d, I-1e, I-1f, I-1g, II, II-1, III, III-1, A1, A2, A3, A1a, A1b, A1c, A2a, A2b, A2c, A2b-1, A2b-2 The present invention provides a method comprising the step of administering a compound of formula K (e.g., formula K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, K-1b-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1 to 145, any of the compounds listed in Table 1 herein, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as defined herein. In some embodiments, cancers resistant to PARP inhibitor therapy are selected from breast cancer, ovarian cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, pancreatic cancer, gastrointestinal cancer, and colorectal cancer. As used herein and unless otherwise specified, the phrase "cancer resistant to PARP inhibitor therapy" means that the cancer is not responding to the PARP inhibitor, is not responding adequately to the PARP inhibitor, or has progressed during or after treatment with the PARP inhibitor. For example, in some cases, a subject with cancer may have responded to the PARP inhibitor once but is no longer responding to the treatment, or is no longer responding adequately to the treatment.

[0191]

[0191] The compounds of the present disclosure may be used alone, in combination with another Polθ inhibitor, or in combination with other active agents or other prophylactic or therapeutic modalities. In some embodiments, the compounds of the present disclosure may be used in combination therapy, for example, with one or more active therapeutic agents (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modalities (e.g., radiation). In such combination therapy, the various active agents often have separate complementary mechanisms of action. Such combination therapy may be particularly advantageous in that it allows for a reduction in the dose of one or more of the agents, and therefore reduces or eliminates the adverse effects associated with one or more of the agents.

[0192]

[0192] In some embodiments, the compounds of the present disclosure are administered in combination with at least one additional therapeutic agent, such as a PARP inhibitor, a signaling inhibitor, a chemotherapeutic agent, and / or an immune checkpoint inhibitor.

[0193]

[0193] In some embodiments, additional therapeutic agents are signaling inhibitors (STIs) or chemotherapeutic agents. As used herein, the term “signaling inhibitor” refers to an agent that selectively inhibits one or more steps in a signaling pathway. In some embodiments, chemotherapeutic agents include antihormone agents that act to modulate or inhibit hormonal action on tumors, such as antiestrogens. In certain embodiments, combination therapy involves the administration of hormones or related hormonal agents. Agents involved in immunomodulation may also be used in combination with one or more compounds of the present disclosure.

[0194]

[0194] In some embodiments, the compounds of the Disclosure are administered in combination with one or more poly-ADP-ribose polymerase (PARP) inhibitors. For example, in some embodiments, the methods described herein are for treating cancer in subjects that are unresponsive to PARP inhibitor therapy or have developed resistance to PARP inhibitors, and may include the step of administering one or more compounds of the Disclosure in combination with a PARP inhibitor to the subject. While we do not wish to be bound by theory, in such embodiments, it is thought that the administration of Polθ sensitizes or resensitizes the cancer to PARP inhibitor treatment. Suitable PARP inhibitors include any of those known in the Art, for example, those approved for sale by the U.S. Food and Drug Administration or a corresponding agency outside the United States. In some embodiments, the methods include the step of administering a PARP inhibitor selected from niraparib, lucaparib, olaparib, talazoparib, veliparib, and fluzoparib to the subject.

[0195]

[0195] In some embodiments, the compounds of the present disclosure are administered in combination with immune checkpoint inhibitors. The vast number of genetic and epigenetic alterations characteristic of all cancers provide a diverse range of antigens that the immune system can use to distinguish tumor cells from their normal counterparts. In the case of T cells, the final variability (e.g., the level of cytokine production or proliferation) and quality (e.g., the type of immune response produced, e.g., the pattern of cytokine production) of the response initiated via antigen recognition by the T cell receptor (TCR) is regulated by a balance between co-stimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are important for the prevention of autoimmunity (i.e., maintaining self-tolerance) and for the protection of tissues from damage when the immune system responds to pathogenic infections. The expression of immune checkpoint proteins as an important mechanism of immune resistance may be dysregulated by tumors. Examples of immune checkpoint inhibitors, but not limited to those listed above, include those targeting CTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, OX40, 4IBB, VISTA, CD96, TGFp, CD73, CD39, A2AR, A2BR, IDO1, TDO2, arginase, B7-H3, and / or B7-H4. For example, in some embodiments, the method includes the step of administering an anti-PD-1 antibody, e.g., pembrolizumab or nivolumab, and / or an anti-PD-L1 antibody, e.g., avelumab or atezolizumab. In some embodiments, the method includes the step of administering an anti-CTLA-4 antibody, e.g., ipilimumab. Cell-based anti-cancer immunomodulators are also being investigated. Drugs that may be used in combination with Polθ inhibitors include those listed in International Publication Nos. 2020243459A1, 2022118210A1, 2022259204A1, and 2023067515A1.

[0196]

[0196] As understood herein, the term “combination” refers to simultaneous, individual, or sequential administration. In one aspect of the present invention, “combination” refers to simultaneous administration. In another aspect of the present invention, “combination” refers to individual administration. In a further aspect of the present invention, “combination” refers to sequential administration. When administration is sequential or individual, delays in the administration of the second component should not result in the loss of the beneficial effect of the combination.

[0197]

[0197] Dosages and other applications of the methods described herein may be modified and adjusted depending on the recipient of the treatment, the disorder, condition or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether or not other drugs are being administered concurrently.

[0198] definition

[0198] It is intended that the appropriate valence is maintained for all parts and combinations thereof.

[0199]

[0199] It is also intended to be understood that certain embodiments of the variable symbol portion in this specification may be the same as or different from other particular embodiments having the same identifier.

[0200]

[0200] Suitable groups for the variable symbols in compounds of formula A, formula K, or their subformulas are selected independently, where applicable. Useful groups not limited to the variable symbols in compounds of formula A, formula K, or their subformulas include, where applicable, any of the respective groups, individually or in any combination, as shown in the examples or in the specific compounds listed in Table 1 herein. Furthermore, it should be understood that the definition of the variable symbol in formula A or formula K may have the same definition as the definition of the variable symbol defined in the subformula of formula A or formula K, respectively. Similarly, unless otherwise specified or contrary to the context, the definition of a subformula of formula I or formula K may have the same definition as the definition of the variable symbol defined in relation to formula I or formula K, or another subformula of formula I or formula K, respectively.

[0201]

[0201] The embodiments described herein may be combined. Such combinations have been considered and are within the scope of this disclosure. For example, where applicable, Z, J of formula A 1 , J 2 , J 3 , R 1 , R 2 The definitions of one or more of rings A, B, and m are Z, J 1 , J 2 , J 3 , R 1 , R 2 The definitions of ring A, ring B, and m may be combined with one or more other definitions, and compounds obtained from such combinations may be examined and may fall within the scope of this disclosure.

[0202]

[0202] Symbol [ka] When shown perpendicular to (or especially intersecting) the bond, it indicates the point where the shown portion is bonded to the rest of the molecule. For divalent (or polyvalent) structures, the directly bonded group shown in the formula or the appropriate variable symbol indicates the direction of the bond. [ka] It should be noted that this may be shown in the outer divalent (or polyvalent) structure. Unless otherwise specified or clearly contrary to the context, if a directly linked group or variable symbol is not shown with respect to either of the two bond sites in the divalent structure, it should be assumed that bonding to the rest of the molecule is possible in either direction.

[0203]

[0203] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition, inside front cover, and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional parts and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987. This disclosure is not intended to be limited in any way by the exemplary enumeration of substituents described herein.

[0204]

[0204] The compounds described herein may contain one or more chiral centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of stereoisomeric mixtures, including racemic mixtures and mixtures containing many of one or more stereoisomers. The isomers may be isolated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC), chiral supercritical fluid chromatography (SFC), and chiral salt formation and crystallization; preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron Vol. 33: p. 2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (edited by ELEliel, Univ. of Notre Dame Press, Notre Dame, 1972). This disclosure further encompasses the compounds described herein as individual isomers substantially free from other isomers, or as mixtures of various isomers, including racemic mixtures. Where stereochemistry is specifically described, unless otherwise inconsistent with the context, the compound may primarily exist as the stereoisomer shown in the illustration with respect to its particular chiral center or axial chirality, and may contain other stereoisomers in amounts less than 20% by weight, less than 10% by weight, less than 5% by weight, less than 1% by weight, or undetectable amounts, for example, by HPLC area or SFC area or both. It should be understood that the compound may have an enantiomer excess of more than 60%, more than 80%, more than 90%, more than 95%, more than 98%, or more than 99%.The presence and / or amount of stereoisomers, including those obtained by the use of chiral HPLC or chiral SFC, may be determined by a person skilled in the art in consideration of this disclosure. As will be understood by a person skilled in the art, where “*” is shown in a chemical structure herein, unless particularly inconsistent with the context, it indicates that the corresponding chiral center is either enantiomerically pure or contains a large proportion of either the enantiomerically pure or the configuration as depicted, for example, by HPLC area or SFC area or both, in amounts less than 20% by weight, less than 10% by weight, less than 5% by weight, less than 1% by weight, or in amounts in which other stereoisomers are undetectable. Furthermore, where stereochemistry is not specifically depicted and “*” is not used in a chemical structure, unless particularly inconsistent with the context, it should be understood that such a structure includes the corresponding compound as any stereoisomerized form containing individual isomers substantially free of other isomers, and as a mixture of various isomers, including racemic mixtures.

[0205]

[0205] When a range of values ​​is listed, it is intended to encompass each value and subranges within that range. For example, "C 1~6 ” is C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 It is intended to include

[0206]

[0206] When used herein, the term “compounds of the disclosure” means formula A (for example, formula I, I-1, I-1a, I-1b, I-1c, I-1d, I-1e, I-1f, I-1g, II, II-1, III, III-1, A1, A2, A3, A1a, A1b, A1c, A2a, A2b, A2c, A2b-1, A2 Compounds of formula K (e.g., formulas K-1, K-2, K-3, K-4, K-5, K-6, K-1a, K-1b, K-1c, K-1b-1, K-1b-2, K-1b-3, K-1b-4, K-3a, K-3b, K-5a, or K-5b), any of Examples 1 to 145 or any of the specific compounds disclosed in Table 1 of this Specification, their isotopically labeled compounds (e.g., deuterated analogs in which one or more of the hydrogen atoms are substituted with deuterium atoms in amounts exceeding their natural abundance, e.g., CD3 analogs if the compound has a CH3 group), their possible positional isomers, possible geometric isomers, possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures), their tautomers, their conformational isomers, their pharmaceutically acceptable esters, and / or their possible pharmaceutically acceptable salts (e.g., acid adduct salts, e.g., HCl salts, or base adduct salts, e.g., Na salts). Hydrates and solvates of the compounds of this Disclosure are considered to be compositions of this Disclosure in which the compounds are associated with water or a solvent, respectively.

[0207]

[0207] The compounds of this disclosure may exist in an isotope-labeled or isotope-enriched form containing one or more atoms having atomic masses or mass numbers different from those most abundantly found in nature. The isotopes may be radioactive or non-radioactive. The isotopes of atoms, for example, hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine, are not limited to these, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F,36 Cl, and 125 There is I. Compounds containing other isotopes of these and / or other atoms are within the scope of the present invention.

[0208]

[0208] As used herein, the phrases “administer” the compound, “administer” the compound, or other variations thereof, mean to provide the compound or a prodrug of the compound to an individual in need of treatment.

[0209]

[0209] As used herein, the term "alkyl" refers to a linear or branched aliphatic saturated hydrocarbon, either by itself or as part of another group. In some embodiments, alkyl consists of 1 to 12 carbon atoms (i.e., C 1~12 It may contain alkyl groups or a specified number of carbon atoms. In one embodiment, the alkyl group is a linear C 1~10 It is an alkyl group. In another embodiment, the alkyl group is a branched chain C 3~10 It is an alkyl group. In another embodiment, the alkyl group is a linear C 1~6 It is an alkyl group. In another embodiment, the alkyl group is a branched chain C 3~6 It is an alkyl group. In another embodiment, the alkyl group is a linear C 1~4 It is an alkyl group. For example, C 1~4 Alkyl groups include methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and iso-butyl. As used herein, the term "alkylene," whether used alone or as part of another group, refers to a divalent radical derived from an alkyl group. Examples of non-restrictive linear alkylene groups include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, and -CH2-CH2-.

[0210]

[0210] As used herein, the term "alkenyl" refers to a linear or branched aliphatic hydrocarbon containing one or more carbon-carbon double bonds, for example, one, two, or three, either by itself or as part of another group. In one embodiment, the alkenyl group is C 2~6 It is an alkenyl group. In another embodiment, the alkenyl group is C 2~4 These are alkenyl groups. Non-exclusive exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0211]

[0211] As used herein, the term "alkynyl" refers to a linear or branched aliphatic hydrocarbon containing one or more, for example, one to three carbon-carbon triple bonds, when used by itself or as part of another group. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is C 2~6 In another embodiment, the alkynyl group is C 2~4 These are alkynyl groups. Non-exclusive exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0212]

[0212] As used herein, the term "alkoxy" means, when used by itself or as part of another group, the formula OR a1 This refers to the radical of the expression, where R is located in the formula. a1 It is alkyl.

[0213]

[0213] In use herein, the term "cycloalkoxy" means, when used by itself or as part of another group, the formula OR a1 This refers to the radical of the expression, where R is located in the formula. a1 It is a cycloalkyl group.

[0214]

[0214] As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms, either by itself or as part of another group. In preferred embodiments, a haloalkyl group is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is C 1~10 It is a haloalkyl group. In one embodiment, the haloalkyl group is C 1~6 It is a haloalkyl group. In one embodiment, the haloalkyl group is C 1~4 It is a haloalkyl group.

[0215]

[0215] As used herein, the term "heteroalkyl," either by itself or in combination with other terms, means, unless otherwise specified, a stable linear or branched alkyl group, for example, having 2 to 14 carbon atoms in the chain, for example, 2 to 10 carbon atoms, one or more of which are S, O 、 It is replaced by a heteroatom selected from P and N, and the nitrogen, phosphine, and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. S, O of the heteroatom 、 P and N may be replaced at any internal position of the heteroalkyl group or at positions where the alkyl group is bonded to the rest of the molecule. When a heteroalkyl group is said to be substituted, the substituents may replace one or more hydrogen atoms bonded to the carbon atom and / or the heteroatom of the heteroalkyl group. In some embodiments, the heteroalkyl group is C 1~4 This refers to a heteroalkyl group, which is a heteroalkyl group as defined herein having 1 to 4 carbon atoms. 1~4Examples of heteroalkyls, but not limited to these, include C4 heteroalkyls, e.g., -CH2-CH2-N(CH3)-CH3; C3 heteroalkyls, e.g., -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3; C2 heteroalkyls, e.g., -CH2-CH2-OH, -CH2-CH2-NH2, -CH2-NH(CH3), -O-CH2-CH3; and C1 heteroalkyls, e.g., -CH2-OH, -CH2-NH2, -O-CH3. Preferably, C in this specification 1~4 Heteroalkyl (or C 1~4 A heteroalkylene contains one or two heteroatoms, e.g., one oxygen, one nitrogen, two oxygens, two nitrogens, or one oxygen and one nitrogen. Similarly, the term “heteroalkylene” means a divalent radical derived from a heteroalkyl group, either by itself or as part of another substituent, as exemplified by -CH2-CH2-O-CH2-CH2- and -O-CH2-CH2-NH-CH2-. With respect to heteroalkylene groups, the heteroatoms may occupy either or both of the chain ends (e.g., alkylene oxy, alkylenedioxy, alkylene amino, alkylenediamino, etc.). Furthermore, with respect to alkylene and heteroalkylene bonding groups, the orientation of the bonding group is not implied by the direction in which the formula of the bonding group is written. When “heteroalkyl” is mentioned, followed by a specific heteroalkyl group, e.g., -NR'R”” it will be understood that the terms heteroalkyl and -NR'R” are neither redundant nor mutually exclusive. Rather, the specific heteroalkyl group is mentioned for clarity. Therefore, the term "heteroalkyl" refers to a specific heteroalkyl group, e.g., -NR'R ” This specification should not be interpreted as excluding such things.

[0216]

[0216] In some preferred embodiments, unless otherwise specified or contrary to the context, C in this specification 1~6Heteroalkyls are C 1~6 Alkoxy, NH(C 1~6 Alkyl), N(C 1~4 Alkyl)(C 1~4 Alkyl), -(C 1~5 Alkylene)-O-(C 1~5 Alkyl), -(C 1~5 Alkylene)-NH(C) 1~5 Alkyl), -(C 1~4 Alkylene)-N(C) 1~4 Alkyl)(C 1~4 Alkyl), -(C 1~5 Alkilen)-S-(C 1~5 Alkyl), -(C 1~5 Alkylene)-SO2-(C 1~5 Alkyl), SO2(C 1~6 Alkyl), P(O)(C 1~4 Alkyl)(C 1~4 Alkyl), SO2NH(C 1~6 Alkyl), SO2N(C 1~4 Alkyl)(C 1~4 Alkyl), -(C 1~5 Alkylene)-SO2NH-(C 1~5 Alkyl), or -(C 1~4 Alkylene)-SO2N(C) 1~4 Alkyl)(C 1~4 It may be an alkyl group, however, the total number of carbon atoms shall not exceed 6, excluding any optional substituents.

[0217]

[0217] In some preferred embodiments, unless otherwise specified or contrary to the context, C in this specification 1~4 Heteroalkyls are C 1~4 Alkoxy, NH(C 1~4 Alkyl), N(C 1~3 Alkyl)(C 1~3 Alkyl), -(C 1~3 Alkylene)-O-(C 1~3 Alkyl), -(C 1~3 Alkylene)-NH(C) 1~3 Alkyl), -(C 1~2 Alkylene)-N(C) 1~2 Alkyl)(C 1~2 Alkyl), -(C1~3 Alkilen)-S-(C 1~3 Alkyl), -(C 1~3 Alkylene)-SO2-(C 1~3 Alkyl), SO2(C 1~4 Alkyl), P(O)(C 1~3 Alkyl)(C 1~3 Alkyl), SO2NH(C 1~4 Alkyl), SO2N(C 1~3 Alkyl)(C 1~3 Alkyl), -(C 1~3 Alkylene)-SO2NH-(C 1~3 Alkyl), or -(C 1~2 Alkylene)-SO2N(C) 1~2 Alkyl)(C 1~2 It may be an alkyl group, however, the total number of carbon atoms shall not exceed 4, excluding any optional substituents.

[0218]

[0218] When used by itself or as part of another group, "carbocyrill" or "carbocyclic" must have at least three carbon atoms, for example, 3 to 10 ring carbon atoms ("C"). 3~10 The term "carbocyclyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having zero heteroatoms in the non-aromatic ring system. Carbocyclyl groups may be monocyclic ("monocyclic carbocyclyl"), condensed, cross-linked, or spirocyclic systems, such as bicyclic systems ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl. As used herein, the term "carbocyclylene," whether used by itself or as part of another group, refers to a divalent radical derived from a carbocyclyl group as defined herein.

[0219]

[0219] In some embodiments, the "carbocykyl" is fully saturated and is also called a cycloalkyl. In some embodiments, the cycloalkyl may have 3 to 10 ring carbon atoms ("C3~10 (Cycloalkyl). In preferred embodiments, the cycloalkyl is a monocyclic ring. As used herein, the term "cycloalkylene" refers to a divalent radical derived from a cycloalkyl group, whether used by itself or as part of another group, for example, [ka] This refers to things like that.

[0220]

[0220] Unless otherwise defined or contrary to the context, heteroatoms as used herein refer to atoms selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon.

[0221]

[0221] "Heterocyclyl" or "heterocyclic" means a 3-membered or greater, e.g., 3-14-membered non-aromatic cyclic radical having a ring carbon atom and at least one ring heteroatom, e.g., 1-4 ring heteroatoms, when used by itself or as part of another group, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the bond sites may be carbon or nitrogen atoms, as long as the valence allows. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl"), condensed, bridged, or spirocyclic systems, e.g., bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. When all ring carbon atoms in a heterocyclyl as defined herein are saturated carbons, the heterocyclyl may also be called a heterocycloalkyl. A heterocyclyl bicyclic ring system may contain one or more heteroatoms in one or both rings, and the bonding site may be located on either ring. As used herein, the term "heterocyclylene," when used by itself or as part of another group, refers to a divalent radical derived from a heterocyclyl group as defined herein. The heterocyclyl or heterocyclylene may optionally be bonded to the rest of the molecule via carbon or nitrogen atoms.

[0222]

[0222] Exemplary three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azildinyl, oxyranil, and thiranil. Exemplary four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil. Exemplary five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanil, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Exemplary five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinil, dithianyl, and dioxanil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Examples of five-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as examples of 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Examples of six-membered heterocyclyl groups fused to an aryl ring (also referred to herein as examples of 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0223]

[0223] When used by itself or as part of another group, "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., one having 6, 10, or 14 pi electrons shared in the cyclic arrangement) that has 6 to 14 ring carbon atoms in the aromatic ring system and no heteroatoms ("C"). 6~14 In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group consists of 14 ring carbon atoms ("C"). 14 Having an aryl group (for example, anthracyl). As used herein, the term "arylene," whether used by itself or as part of another group, refers to a divalent radical derived from an aryl group as defined herein.

[0224]

[0224] When used by itself or as part of another group, "aralkyl" refers to an alkyl group that is substituted with one or more aryl groups, preferably one aryl group substituted. Examples of aralkyls include benzyl and phenethyl. When it is said that an aralkyl may be substituted, either the alkyl or aryl portion of the aralkyl may be optionally substituted.

[0225]

[0225] When used by itself or as part of another group, “heteroaryl” refers to a radical of a 5-14 member monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., one having 6 or 10 pi electrons shared in the cyclic arrangement) having a ring carbon atom and at least one, preferably 1-4, ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 member heteroaryl"). When used herein, for clarity, pyridone (e.g., pyridine-2-one) is used. [ka] (wherein R may be a hydrogen or nitrogen atom substituent), pyrimidinone, for example, pyridone condensed with an aryl or heteroaryl (e.g., [ka] (wherein R may be a hydrogen atom or a nitrogen atom substituent) is considered a heteroaryl ring as used herein. In heteroaryl groups containing one or more nitrogen atoms, the bond site may be a carbon atom or a nitrogen atom, as long as the valence allows. A heteroaryl bicyclic ring system may contain one or more heteroatoms in one or both rings. In bicyclic heteroaryl groups that do not contain a heteroatom in one ring (e.g., indolyl, quinolinyl, etc.), the bond site may be on either ring, i.e., either ring containing a heteroatom (e.g., 2-indolyl) or ring not containing a heteroatom (e.g., 5-indolyl). As used herein, the term "heteroarylene," when used by itself or as part of another group, refers to a divalent radical derived from a heteroaryl group as defined herein.

[0226]

[0226] Exemplary five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl. Examples of seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolidinyl, and prinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinyl, isoquinolinyl, cinolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0227]

[0227] When used by itself or as part of another group, "heteroaralkyl" refers to an alkyl group substituted with one or more heteroaryl groups, preferably one heteroaryl group substituted. When it is said that a heteroaralkyl may be substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl may be optionally substituted.

[0228]

[0228] In use herein, unless otherwise specified or specifically indicated to the contrary, “ring structure,” “cyclic structure,” or simply “ring,” e.g., “3-10 membered ring structure,” “3-12 membered ring structure,” or “5 or 6 membered ring,” having a specified number of ring members should be understood to encompass any ring structure having a specified number of ring members (e.g., carbocyclic, heterocyclic, aryl, heteroaryl, etc.), and ring structures include (1) monocyclic or polycyclic (to the extent chemically feasible), e.g., monocyclic rings or bicyclic rings (condensed, spiro, and bridging bicyclic rings). (1) The ring may be a ring system in which two monocyclic rings are linked by a single or double bond; (2) It may be aromatic, partially unsaturated, or fully saturated; in the case of a polycyclic structure, each ring may independently be aromatic, partially unsaturated, or fully saturated; (3) It may contain no heteroatoms (i.e., all ring members are carbon atoms) or it may contain 1 to 4 heteroatoms; or in the case of a polycyclic structure, each ring may independently have no ring heteroatoms or 1 to 4 ring heteroatoms (e.g., O, N, S). Where a ring is said to contain a ring sulfur or nitrogen atom, the sulfur or nitrogen atom may optionally be oxidized. One or more ring carbon atoms in a ring structure may exist as C(=O). A fully saturated ring means a ring in which neither the ring carbon atoms nor any present ring heteroatoms (e.g., nitrogen) form double or triple bonds with any other atoms. The ring structure may optionally be substituted with one or more substituents as described herein. The substituents of the cyclic structure in this specification may also have a cyclic structure, and in some cases, it can be said that two substituents of the cyclic structure are bonded together to form a cyclic structure.

[0229]

[0229] For clarity, as is generally understood in the art, if a structure can be characterized in multiple ways, then the structure can be said to be a suitable definition for the variable symbol, insofar as one such characterization falls within the scope of the definition of the variable symbol as herein. For example, if a monovalent variable symbol is defined as a six-membered ring which may be substituted, then the variable symbol can be considered, in particular, as a six-membered monocyclic or bicyclic ring substituted with a phenyl group. [ka] (b) The structure of (b) can be considered as a six-membered ring in which two substituents are bonded to form a cyclopropyl ring. [ka] The structure includes (unless an optional substituent on the 6-membered ring is specified and this is not included as an option); however, since the connecting ring is not a 6-membered ring under any structural characterization, the variable symbol is [ka] This would mean that it does not include. For further explanation, instead, if it is defined as a monoring 6-membered ring in which the variable symbol may be substituted, then the variable symbol is [ka] It does not include, [ka] The structure includes (unless an optional substituent for the 6-membered ring is specified and this is not included as an option). If the variable symbol is defined as a 6-membered ring that may be substituted with a halogen, then each of these can be considered as an unsubstituted or 6-membered ring substituted with one or two fluorine atoms, so the variable symbol is a structure, for example, [ka] It may include.

[0230]

[0230] As is commonly understood in the art, alkylene, alkenylene, alkynylene, heteroalkylene, carbocyrylene, heterocyclylene, arylene, and heteroarylene refer to the corresponding divalent radicals of alkyl, alkenyl, alkynyl, heteroalkyl, carbocyryl, heterocyclyl, aryl, and heteroaryl groups, respectively.

[0231]

[0231] The "optionally substituted" groups, e.g., optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyryl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refer to the unsubstituted or substituted respective groups. Generally, the term "substituted" means, whether preceded by the term "optionally," that at least one hydrogen (e.g., carbon or nitrogen atom) present on the group is replaced by an acceptable substituent, e.g., a substituent that results in a stable compound upon substitution, e.g., a compound that is not spontaneously converted by rearrangement, cyclization, disappearance, or other reaction. Unless otherwise indicated, an "substituted" group has substituents at one or more substituted positions on the group, and if more than one position is substituted in any given structure, the substituents may be the same or different at each position. Typically, when substituted, the optionally substituted groups as herein may be substituted with 1 to 5 substituents. Substituents may, where applicable, be carbon atom substituents, nitrogen atom substituents, oxygen atom substituents, or sulfur atom substituents, each of which may optionally be isotopically labeled or, for example, deuterated. Two of the optional substituents may bond to form a ring structure, such as an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl ring. Substitutions may occur on any available carbon, oxygen, or nitrogen atom and may form a spiro ring. Typically, substitutions as used herein do not result in OO, ON, SS, SN (except SO2-N bonds), heteroatom-halogens, or -C(O)-S bonds except O-SO2-O, O-SO2-N, and N-SO2-N, or three or more consecutive heteroatoms, although this may be possible if some of such bonds or linkages are present in a stable aromatic system.

[0232]

[0232] In a broad range of embodiments, the substituents permitted herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permitted substituents may be one or more, and may be the same or different, with respect to a suitable organic compound. For the purposes of this disclosure, a heteroatom, for example, nitrogen, may have any permitted substituent of the organic compound described herein that satisfies the valence of the hydrogen substituent and / or the heteroatom. Substituents may be any substituents described herein, such as halogens, hydroxyls, carbonyls (e.g., carboxyls, alkoxycarbonyls, formyls, or acyls), thiocarbonyls (e.g., thioesters, thioacetates, or thioformates), alkoxys, cycloalkoxys, phosphoryls, phosphates, phosphonates, phosphinates, aminos, amides, amidines, imines, cyanos, nitros, azides, sulfhydryls, alkylthios, sulfates, sulfonates, sulfamoyls, sulfonamides, sulfonyls, heterocyclyls, alkyls, alkenyls, alkynyls, cycloalkyls, heterocyclyls, aralkyls, aryls, or heteroaryls, each of which may be substituted as appropriate.

[0233]

[0233] Exemplary substituents, but not limited to these, include alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkyline-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, -O-heteroaryl, -O-alkylene-heteroaryl, -O-cycloalkyl, -O- Terocycloalkyl, acyl, -C(O)-alkyl, -C(O)-haloalkyl, -C(O)-aryl, -C(O)-alkylene-aryl, -C(O)-heteroaryl, -C(O)-alkylene-heteroaryl, -C(O)-cycloalkyl, -C(O)-heterocycloalkyl, halo, -NO2, -CN, -SF5, -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-alkylene-aryl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)-haloalkyl, -S(O)2-haloalkyl, -S (O)-aryl, -S(O)2-aryl, -S(O)-heteroaryl, -S(O)2-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, -S(O)2-alkylene-aryl, -S(O)2-alkylene-heteroaryl, -S-cycloalkyl, -S-heterocycloalkyl, -S(O)-cycloalkyl, -S(O)-heterocycloalkyl, -S(O)2-cycloalkyl, -S(O)2-heterocycloalkyl, -S(O)(=NH)-aryl Kill, -S(O)(=NH)-haloalkyl, -S(O)(=NH)-aryl, -S(O)(=NH)-alkylene-aryl, -S(O)(=NH)-heteroaryl, -S(O)(=NH)-alkylene-heteroaryl, -S(O)(=NH)-cycloalkyl, -S(O)(=NH)-heterocycloalkyl, -S(O)(=Nalkyl)-alkyl, -S(O)(=Nalkyl)-haloalkyl, -S(O)(=Nalkyl)-aryl, -S(O)(=Nalkyl)-alkylene-aryl, -S(O)(=Nalkyl)-heteroaryl,-S(O)(=Nalkyl)-alkylene-heteroaryl, -S(O)(=Nalkyl)-cycloalkyl, -S(O)(=Nalkyl)-heterocycloalkyl, cycloalkyl, heterocycloalkyl, -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(=N-CN)-NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), -N(Y1)(Y2), -alkylene-N(Y 1) There are (Y2), -C(O)N(Y1)(Y2), and -S(O)2N(Y1)(Y2), where Y1 and Y2 may be the same or different, and are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, -alkylene-aryl, heteroaryl, -alkylene-heteroaryl, cycloalkyl, and heterocycloalkyl. Y1 and Y2 can form heterocyclic rings together with the nitrogen to which they are bonded.

[0234]

[0234] Some examples of preferred substituents, but not limited to these, include (C1-C8) alkyl groups, (C2-C8) alkenyl groups, (C2-C8) alkynyl groups, (C3-C 10)Cycloalkyl groups, halogens (F, Cl, Br or I), halogenated (C1~C8) alkyl groups (e.g., -CF3, but not limited to these), -O-(C1~C8) alkyl groups, -OH, -S-(C1~C8) alkyl groups, -SH, -NH(C1~C8) alkyl groups, -N((C1~C8)alkyl)2 groups, -NH2, -C(O)NH2, -C(O)NH(C1~C8) alkyl groups, -C(O)N((C1~C8)alkyl)2, -NHC(O)H, -NHC(O)(C1~C8) alkyl groups, -NHC(O)(C3~C8) cycloalkyl groups, -N ((C1~C8)alkyl)C(O)H, -N((C1~C8)alkyl)C(O)(C1~C8)alkyl group, -NHC(O)NH2, -NHC(O)NH(C1~C8)alkyl group, -N((C1~C8)alkyl)C(O)NH2 group, -NHC(O)N((C1~C8)alkyl)2 group, -N((C1~C8)alkyl)C(O)N((C1~C8)alkyl)2 group, -N((C1~C8)alkyl)C(O)NH((C1~C8)alkyl), -C(O)H, -C(O)(C1~C8)alkyl group, -CN, -NO2, -S(O)(C1~C8) HCl group, -S(O)2(C1~C8)alkyl group, -S(O)2N((C1~C8)alkyl)2 group, -S(O)2NH(C1~C8)alkyl group, -S(O)2NH(C3~C8)cycloalkyl group, -S(O)2NH2 group, -NHS(O)2(C1~C8)alkyl group, -N((C1~C8)alkyl)S(O)2(C1~C8)alkyl group, -(C1~C8)alkyl-O-(C1~C8)alkyl group, -O-(C1~C8)alkyl-O-(C1~C8)alkyl group, -C(O)OH, -C(O)O(C1~C8)alkyl group, NHOH, NHO (C1~C8) alkyl groups, -O-halogenated (C1~C8) alkyl groups (e.g., -OCF3, but not limited to these), -S(O)2-halogenated (C1~C8) alkyl groups (e.g., -S(O)2CF3, but not limited to these), -S-halogenated (C1~C8) alkyl groups (e.g., -SCF3, but not limited to these), -(C1~C6) heterocyclic groups (e.g., pyrrolidine, tetrahydrofuran, pyran, or morpholine, but not limited to these), -(C1~C6) heteroaryl groups (e.g., tetrazole, imidazole, but not limited to these),These include furan, pyrazine, or pyrazole, -phenyl, -NHC(O)O-(C1~C6)alkyl, -N((C1~C6)alkyl)C(O)O-(C1~C6)alkyl, -C(=NH)-(C1~C6)alkyl, -C(=NOH)-(C1~C6)alkyl, or -C(=NO-(C1~C6)alkyl)-(C1~C6)alkyl.

[0235]

[0235] Exemplary carbon atom substituents include, but are not limited to, deuterium, halogens, -CN, -NO2, -N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkylamino, dialkylamino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C 3~10 Carbocyclyl, C 6~10 Examples include aryls, 3-10 membered heterocyclines, and 5-10 membered heteroaryls. For example, exemplary carbon atom substituents include F, Cl, -CN, -SO2H, -SO3H, -OH, and -OC. 1~6 Alkyl, -NH2, -N(C 1~6 Alkyl)2,-NH(C 1~6 Alkyl), -SH, -SC 1~6 Alkyl, -C(=O)(C 1~6 Alkyl), -CO2H, -CO2(C 1~6 Alkyl), -OC(=O)(C 1~6 Alkyl), -OCO2(C 1~6 Alkyl), -C(=O)NH2, -C(=O)N(C 1~6 Alkyl)2,-OC(=O)NH(C 1~6 Alkyl), -NHC(=O)(C 1~6 Alkyl), -N(C 1~6 Alkyl)C(=O)(C 1~6 Alkyl), -NHCO2(C 1~6 Alkyl), -NHC(=O)N(C 1~6 Alkyl)2,-NHC(=O)NH(C 1~6 Alkyl), -NHC(=O)NH2, -NHSO2(C 1~6 Alkyl), -SO2N(C1~6 Alkyl)2,-SO2NH(C 1~6 Alkyl), -SO2NH2,-SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, C 6~10 The substituents may be aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; or two geminal substituents may be bonded to form =O.

[0236]

[0236] Nitrogen atoms may be substituted or unsubstituted as long as their valence allows, and nitrogen atoms can be primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents, but are not limited to these, include acyl groups, esters, sulfones, sulfoxides, and C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14The rings may consist of an aryl group and a 5- to 14-membered heteroaryl group, or two substituents bonded to the nitrogen atom to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, and heteroaryl group may be further substituted as defined herein. In certain embodiments, the substituents on the nitrogen atom are nitrogen protecting groups (also known as amino protecting groups). Nitrogen protecting groups are well known in the art, and some are described in detail in Protective Groups in Organic Synthesis, 4th edition, PGMWuts;TW Greene, John Wiley, 2007, which are incorporated herein by reference. Examples of nitrogen protecting groups include, but are not limited to, those that form carbamates, such as carbobenzyloxy (Cbz) group, p-methoxybenzylcarbonyl (Moz or MeOZ) group, tert-butyloxycarbonyl (BOC) group, Troc, 9-fluorenylmethyloxycarbonyl (Fmoc) group, etc.; those that form amides, such as acetyl, benzoyl, etc.; those that form benzylamines, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc.; those that form sulfonamides, such as tosyl, nosyl, etc.; and others, such as p-methoxyphenyl.

[0237]

[0237] Examples of oxygen atom substituents include, but are not limited to, acyl groups, esters, sulfonates, and C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14There are aryl and 5- to 14-membered heteroaryl groups, each alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl group may be further substituted as defined herein. In certain embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art, and some oxygen protecting groups are described in detail in Protective Groups in Organic Synthesis, 4th edition, PGMWuts;TW Greene, John Wiley, 2007, which are incorporated herein by reference. Examples of oxygen protecting groups include, but are not limited to, those forming alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyl, such as 4-methoxybenzyl, methoxylmethyl (MOM), benzyloxymethyl (BOM), and 2-methoxyethoxymethyl (MEM); those forming silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), and t-butyldimethylsilyl (TBDMS); those forming acetals or ketals, such as tetrahydropyranyl (THP); those forming esters, such as formates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, and methoxyacetates; and those forming carbonates or sulfonates, such as methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0238]

[0238] Unless otherwise expressly provided, combinations of substituents and / or variable symbols are acceptable only if such combinations are chemically possible and result in a stable compound. A “stable” compound is one that can be prepared and isolated, and whose structure and properties remain substantially unchanged or can be kept substantially unchanged for a sufficient period of time to enable the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

[0239]

[0239] Unless otherwise specified or contrary to the context, the optionally substituted groups referred to herein are (A) unsubstituted or (B) deuterium, halogen, CN, or Q 1 -Q 2 -Q 3 -Q 4 Q 1 Q 2 , and Q 3 These are, independently, non-existence, O, and NQ. 4 , C(O), S, SO, SO2, S(O)(=NQ 4 ), C which may be substituted with deuterium, F, and / or OH. 1~4 Alkylene, or P(O)Q 4 Q 4 Each entity independently contains hydrogen, one or more Q atoms. 10 Even if replaced by C 1~6 Alkyl, one or more Q 10 Even if replaced by C 2~6 Alkenyl, one or more Q 10 Even if replaced by C 2~6 Alkinyl, one or more Q 10 Even if replaced by C 1~6 Heteroalkyl, or one or more Q 10 It is a 3- to 14-membered ring which may be substituted with Q 10 Each element present independently contains deuterium, halogens, oxo (where applicable), CN, or Q 20 -Q21 -Q 22 -Q 23 Q 20 Q 21 , and Q 22 These are, independently, non-existence, O, and NQ. 23 , C(O), S, SO, SO2, S(O)(=NQ 23 ), C which may be substituted with deuterium, F, and / or OH. 1~4 Alkylene, or P(O)Q 23 Q 23 Each entity independently contains hydrogen, one or more Q atoms. 30 Even if replaced by C 1~6 Alkyl, one or more Q 30 Even if replaced by C 2~6 Alkenyl, one or more Q 30 Even if replaced by C 2~6 Alkinyl, one or more Q 30 Even if replaced by C 1~6 Heteroalkyl, or one or more Q 30 It is a 3- to 8-membered ring which may be substituted with Q 30 Each element independently contains deuterium, halogens, oxo (where applicable), CN, OH, NH2, and one or more Q atoms. 31 Even if replaced by C 1~4 Alkyl, one or more Q 31 Even if replaced by C 1~4 Heteroalkyl, or one or more Q 31 It is a 3- to 5-membered ring which may be substituted with Q 31 Each C may be independently substituted with deuterium, F, OH, deuterium and / or F. 1~4 C may be substituted with alkyl, or deuterium and / or F. 1~4It is heteroalkyl; or (C) two or more substituents of each optionally substituted group and / or one substituent of each optionally substituted group are bonded to another variable group as defined herein to form a ring (e.g., a spiro ring, a fused ring, or a bridging ring), the ring may be substituted with one or more substituents as defined in (B), and any remaining substituents of each optionally substituted group are as defined in (B). In some preferred embodiments, the optionally substituted groups as defined herein in relation to the formula may be unsubstituted or substituted with one or more substituents as defined in (B). Q 1 Q 2 , and Q 3 The combination is not particularly limited, and the combination is preferably (a)Q 1 Q 2 , and Q 3 If two of them are not present, O, NQ 4 C(O), S, SO, SO2, or P(O)Q 4 Even with the linker, (b)Q 1 Q 2 , and Q 3 If one of them is absent, then amide (C(O)NQ 4 ), ester (C(O)O), sulfonamide (SO2NQ 4 Even with linkers such as (c)Q 1 Q 2 , and Q 3 If none of them are absent, then carbamate (OC(O)NQ 4 ), urea (NQ 4 C(O)NQ 4 ), sulfamoylamino(NQ 4 SO2NQ 4 ) or other linkers may also be used. Q 20 Q 21 , and Q 22 The combinations should be understood similarly.

[0240]

[0240] Unless otherwise specified or contrary to the context, where a group in this specification is defined as a group which may be substituted with one or more substituents selected from a defined list of substituents or simply a defined list, the group is typically unsubstituted or substituted with one, two, three, or four substituents as defined, although in some embodiments the group may also be substituted with more than four substituents. For example, an alkyl group which may be substituted with one or more substituents independently selected from deuterium, F, and OH is typically unsubstituted or substituted with 1 to 4 substituents which are each independently deuterium, F, or OH. Similarly, an alkyl group which may be substituted with deuterium and / or F is typically unsubstituted or substituted with 1 to 4 substituents which are each independently deuterium or F.

[0241]

[0241] Unless otherwise specified or contrary to the context, a 3-x membered ring (wherein x is an integer of 6 or more, e.g., a 3-14 membered ring, a 3-8 membered ring, etc.) as used herein may mean (i) a 3-x membered carbocyclic ring, (ii) a 4-x membered heterocyclic ring having 1-3 ring heteroatoms, each independently being O, S, and N, wherein the sulfur atom may, if present, be oxidized; (iii) a phenyl ring, or a phenyl or naphthyl ring if x is 10 or greater; (iv) a 5- or 6-membered heteroaryl ring having 1-4 ring heteroatoms, each independently being O, S, and N, or, if x is 9 or greater, a 5- or 6-membered heteroaryl ring or a bicyclic heteroaryl ring having 1-4 ring heteroatoms, each independently being O, S, and N.

[0242]

[0242] Unless otherwise specified or contrary to the context, the 3-6 membered rings herein may be (i) 3-6 membered carbocyclic rings, e.g., cyclopropyl, cyclobutyl, etc.; (ii) 4-6 membered heterocyclic rings having 1-2 ring heteroatoms, each independently being O, S, and N, and where the sulfur atom may be oxidized if present, e.g., oxetane, azetidine, etc.; (iii) 5 membered heteroaryl rings having 1-4 ring heteroatoms, each independently being O, S, and N; (iv) 6 membered heteroaryl rings having 1 or 2 ring nitrogen atoms; or (v) phenyl rings.

[0243]

[0243] Unless otherwise specified or contrary to the context, a 3- to 5-membered ring as used herein means (i) a 3- to 5-membered carbocyclic ring, e.g., cyclopropyl, cyclobutyl, etc.; (ii) a 4- to 5-membered heterocyclic ring having 1-2 ring heteroatoms, each independently being O, S, and N, and where the sulfur atom may be oxidized if present, e.g., oxetane, azetidine, etc.; or (iii) a 5-membered heteroaryl ring having 1-4 ring heteroatoms, each independently being O, S, and N.

[0244]

[0244] In some embodiments, the "may be substituted" alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, carbocyclic, carbocyclylene, cycloalkyl, cycloalkylene, alkoxy, cycloalkoxy, heterocyclyl, or heterocyclene as used herein may be independently substituted with deuterium, F, Cl, -OH, CN, protected hydroxyl, oxo (where applicable), NH2, protected amino, NH(C 1~4 Alkyl) or its protected derivatives, N(C 1~4 Alkyl)(C 1~4 Alkyl), C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Alkoxy, C 3~6 Cycloalkyl, C 3~6The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxyphenyl, heteroaryl, and heterocyclyl compounds may be substituted with one, two, three, or four substituents independently selected from cycloalkoxy, phenyl, O, S, and N, 5- or 6-membered heteroaryl compounds containing one, two, or three ring heteroatoms independently selected from O, S, and N, each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxyphenyl, heteroaryl, and heterocyclyl compounds may be substituted with deuterium, F, -OH, oxo (where applicable), C 1~4 Alkyl, fluorosubstituted C 1~4 Alkyl (e.g., CF3), C 1~4 Alkoxy and fluorosubstituted C 1~4 The alkoxy may be substituted with one, two, or three substituents independently selected. In some embodiments, the "may be substituted" aryl group, arylene group, heteroaryl group, or heteroarylene group as used herein may not be independently substituted with deuterium, F, Cl, -OH, -CN, NH2, protected amino, NH(C) 1~4 Alkyl) or its protected derivatives, N(C 1~4 Alkyl)(C 1~4 Alkyl), -S(=O)(C 1~4 Alkyl), -SO2(C 1~4 Alkyl), C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Alkoxy, C 3~6 Cycloalkyl, C 3~6 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, oxo (where applicable), and heterocyclyl may be substituted with one, two, three, or four substituents independently selected from cycloalkoxy, phenyl, O, S, and N, 5- or 6-membered heteroaryls containing one, two, or three ring heteroatoms independently selected from O, S, and N, each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl may be substituted with deuterium, F, -OH, oxo (where applicable), C 1~4Alkyl, fluorosubstituted C 1~4 Alkyl, C 1~4 Alkoxy and fluorosubstituted C 1~4 It may be substituted with one, two, or three substituents independently selected from the alkoxy.

[0245]

[0245] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iod, -I).

[0246]

[0246] The term "pharmaceutically acceptable salt" refers to a salt that, within the bounds of sound medical judgment, does not exhibit excessive toxicity, irritation, or allergic reactions, is suitable for use in contact with human and lower animal tissues, and has a reasonable benefit-to-risk ratio. pharmaceutically acceptable salts are well known in the art.

[0247]

[0247] The terms “tautomer” or “tautomerous” refer to two or more interconvertible compounds resulting from tautomerization. The exact ratio of tautomers depends on several factors, including, for example, temperature, solvent, and pH. Tautomerization is known to those skilled in the art. Exemplary tautomerizations include tautomerization from keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine).

[0248]

[0248] The term “subject” (or “patient” as used herein) means, as used herein, an animal, preferably a mammal, most preferably a human being, that is being treated, observed or experimented on.

[0249]

[0249] The terms “inhibit,” “reduce,” or any variation thereof relating to Polθ include any measurable reduction or complete inhibition to achieve the desired result. For example, a reduction in Polθ activity may be a reduction of approximately, at most approximately, or at least approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more than these percentages, or any range derived from these.

[0250]

[0250] The term "homologous recombination" refers to an intracellular process of genetic recombination in which nucleotide sequences are exchanged between two similar or identical DNA molecules.

[0251]

[0251] The term “homologous recombination (HR) deficiency cancer,” or any of these variants, refers to cancer characterized by a reduction or absence of the functional HR repair pathway. HR deficiency may result from the absence of one or more HR-related genes or from the presence of one or more mutations in one or more HR-related genes. Examples of HR-related genes include BRCA1, BRCA2, RAD54, RAD51B, CtlP (choline transport-like protein), PALB2 (BRCA2 partner and localizer), XRCC2 (X-ray damage repair complement / deficiency repair in Chinese hamster cells), RECQL4 (RecQ protein-like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome, one or more HR-related genes), Nbs1 (Nibnn), and genes encoding Fanconi anemia (FA) proteins or FA-like genes, such as FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANCP (SLX4), FANCS (BRCA1), RAD51C, and XPF.

[0252]

[0252] The term "Polθ overexpression," or any variation thereof, refers to an increase in the expression or activity of Polθ in diseased cells, such as cancerous cells, compared to the expression or activity of Polθ in normal cells (e.g., non-disease cells of the same species). The amount of Polθ may be at least twice, at least three times, at least four times, at least five times, at least ten times, or more than the amount of Polθ expression in normal cells. Examples of cancers with Polθ overexpression include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, lung cancer, colorectal cancer, gastric cancer, bladder cancer, and prostate cancer.

[0253]

[0253] As used herein, terms such as “to treat,” “to treat,” and “treatment” mean to eliminate, reduce, or improve a disease or condition and / or symptoms associated therewith. Treating a disease or condition does not mean eliminating it, but does not require the complete disappearance of the disease, condition, or symptoms associated therewith. As used herein, terms such as “to treat,” “to treat,” and “treatment” may include “preventive treatment,” which means reducing the probability of recurrence of a disease or condition or a previously controlled disease or condition in subjects who do not have a disease or condition but are at risk of recurring or are highly susceptible to recurrence of a disease or condition or condition. The term “to treat” and its synonyms are intended to mean administering a therapeutically effective amount of the compound described herein to subjects requiring such treatment.

[0254]

[0254] The term “effective dose” refers to the amount of any compound or combination of compounds described herein that is sufficient to produce the intended application, including the prevention or treatment of a disease. The therapeutic effective dose may vary depending on the intended application (in vitro or in vivo), or the subject and disease state being treated (e.g., the subject’s weight, age, and sex), the severity of the disease state, the mode of administration, etc., and can be readily determined by those skilled in the art. The term also applies to doses that will induce a particular response in target cells and / or tissues. The specific dose will vary depending on the specific compound selected, the dosage to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system through which the compound is delivered.

[0255]

[0255] In this specification, the singular forms "a," "an," and "the" include plural referents unless expressly provided otherwise or unless it is entirely clear from the context that this is not the intended meaning.

[0256]

[0256] When the term “and / or” is used herein in a phrase, for example, “A and / or B,” it is intended to include both A and B; A or B; A (alone); and B (alone). Similarly, when the term “and / or” is used in a phrase, for example, “A, B, and / or C,” it is intended to include the following embodiments, respectively: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0257]

[0257] Headings and subheadings are used for convenience and / or formal compliance only and are not intended to limit the scientific and technological subject matter, nor are they to be referenced in connection with the interpretation of the description of the scientific and technological subject matter. Features described under one heading or subheading of the disclosure may be combined in various embodiments with features described under other headings or subheadings. Furthermore, it is not necessarily required that all features under a single heading or subheading be used together in an embodiment. [Examples]

[0258] Abbreviation CMPI 2-chloro-1-methylpyridinium iodide DCM Dichloromethane DIAD (Diisopropyl Azodicarboxylate) DIPEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) hrs time LCMS Liquid Chromatography-Mass Spectrometry NBS N-bromosuccinimide NMI (N-methylimidazole) PE (Petroleum Ether) SFC supercritical fluid TCFH N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate TEA (Triethylamine) X-Phos Dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine

[0258] Various starting materials, intermediates, and compounds of the embodiments herein may be isolated and purified, where appropriate, using the prior art, e.g., precipitation, filtration, crystallization, evaporation, distillation, and chromatography. These compounds may be characterized using conventional methods, e.g., by melting point, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses. Abbreviations used in the Examples section should be understood to have their ordinary meanings in the art unless otherwise indicated or obviously contrary to the context. The examples are illustrative and do not in any way limit the claimed invention.

[0259]

[0259] Exemplary embodiments of the steps for synthesizing the products described herein are described in further detail below.

[0260] Intermediate A 6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-amine [ka]

[0260] Thiourea (390.9 mg, 5.14 mmol) was added to a solution of 2-bromo-4-phenyl-cyclohexanone (1.3 g, 5.14 mmol) in THF (15 mL). The mixture was stirred at room temperature for 24 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was treated with water and extracted with RINKAN. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain crude intermediate A (1.3 g), which was used without further purification. LC-MS (ESI, m / z): [M+H] + = 231.1.

[0261] Intermediate B 6-(4-chlorophenyl)-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine [ka] Step 1: 2-Bromo-4-(4-chlorophenyl)cyclohexanone (B-1)

[0261] A mixture of 4-(4-chlorophenyl)cyclohexanone (340 mg, 1.63 mmol), NBS (290 mg, 1.63 mmol), and p-toluenesulfonic acid (28.1 mg, 0.163 mmol) in CCl4 (5 mL) was stirred at 80°C for 4 hours. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 1-5% ethyl acetate in PE) to obtain 2-bromo-4-(4-chlorophenyl)cyclohexanone (210 mg). 1 H NMR (400 MHz, DMSO-d6) δ 7.43-7.30 (m, 4H), 4.63-4.57 (m, 1H), 3.43-3.33 (m, 1H), 3.22-3.12 (m, 1H), 2.68-2.58 (m, 1H), 2.34-2.18 (m, 2H), 2.09-1.93 (m, 2H).

[0262] Step 2: 6-(4-chlorophenyl)-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine (B)

[0262] A solution of 2-bromo-4-(4-chlorophenyl)cyclohexanone (210 mg, 0.73 mmol) and thiourea (133 mg, 1.75 mmol) in THF (10 mL) was stirred at room temperature under an N2 atmosphere for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was treated with water and extracted with SiO2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain intermediate B (180 mg). LC-MS (ESI, m / z): [M+H] + = 265.0.

[0263] Intermediate C 2-amino-5-(4-chlorophenyl)-6,7-dihydrothiazolo[5,4-c]pyridine-4(5H)-one [ka] Step 1: Ethyl 3-((4-chlorophenyl)amino)propanoate (C-1)

[0263] Ethyl acrylate (13.0 g, 0.130 mol) was added to a solution of 4-chloroaniline (13.8 g, 0.108 mol) in acetic acid (8 mL). The mixture was stirred at 100 °C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was cooled to room temperature and poured into saturated sodium bicarbonate aqueous solution. The resulting mixture was extracted with HCl. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (eluted with 5% HCl in PE) to obtain ethyl 3-((4-chlorophenyl)amino)propanoate (13 g). LC-MS (ESI, m / z): [M+H] + = 228.1.

[0264] Step 2: Ethyl 3-((4-chlorophenyl)(3-ethoxy-3-oxopropyl)amino)-3-oxopropanoate(C-2)

[0264] DIPEA (14.7 g, 0.114 mol) was added to a solution of ethyl 3-((4-chlorophenyl)amino)propanoate (13.0 g, 0.057 mol) in DCM (40 mL). After cooling to 0°C, ethyl 3-chloro-3-oxopropanoate (10.2 g, 0.068 mol) was added under N2. The mixture was stirred at room temperature for 18 hours. LC-MS indicated that the reaction was complete. The reaction mixture was poured into ice-cooled water and extracted with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (eluted with 25% HCl in PE) to obtain ethyl 3-((4-chlorophenyl)(3-ethoxy-3-oxopropyl)amino)-3-oxopropanoate (10.0 g). LCMS (ESI, m / z): [M+H] + = 342.2.

[0265] Step 3: Ethyl 1-(4-chlorophenyl)-2,4-dioxopiperidine-3-carboxylate (C-3)

[0265] Sodium ethoxide (21% of ethanol, 19.1 g, 0.059 mol) was added to a mixture of ethyl 3-((4-chlorophenyl)(3-ethoxy-3-oxopropyl)amino)-3-oxopropanoate (10.0 g, 0.029 mol) in ethanol (20 mL). The resulting mixture was stirred under reflux under N2 for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under vacuum. The residue was dispersed in chloroform, acidified to pH=3.0 with 1N HCl aqueous solution, and extracted with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product, which was used without purification. LC-MS (ESI, m / z): [M+H] + = 296.1.

[0266] Step 4: 1-(4-chlorophenyl)piperidine-2,4-dione(C-4)

[0266] Ethyl 1-(4-chlorophenyl)-2,4-dioxopiperidine-3-carboxylate (6.5 g, 0.022 mol), acetic acid (50 mL), and water (10 mL) were added to a round-bottom flask. The mixture was stirred at 100°C for 4 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was dispersed in water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product, which was used without purification. LC-MS (ESI, m / z): [M+H] + = 224.0.

[0267] Step 5: 3-Bromo-1-(4-chlorophenyl)piperidine-2,4-dione(C-5)

[0267] NBS (0.952 g, 5.34 mmol) was added at 0°C to a solution of 1-(4-chlorophenyl)piperidine-2,4-dione (1.0 g, 4.47 mmol) in CH2Cl2 (25 mL). The mixture was warmed to room temperature and stirred for 18 hours. LC-MS indicated that the reaction was complete. The reaction mixture was treated with water and extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was used without further purification. LC-MS (ESI, m / z): [M+H] + = 301.7.

[0268] Step 6: 2-amino-5-(4-chlorophenyl)-6,7-dihydrothiazolo[5,4-c]pyridine-4(5H)-one(C)

[0268] Thiourea (291 mg, 3.82 mmol) was added to a mixture of 3-bromo-1-(4-chlorophenyl)piperidine-2,4-dione (1.045 g, 3.45 mmol) and sodium bicarbonate (320 mg, 3.81 mmol) in ethanol (20 mL). The mixture was stirred under reflux for 2.5 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under vacuum. The residue was dispersed in water and extracted with RINKAN. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (0.05% NH4HCO3) to obtain intermediate C (0.45 g). LC-MS (ESI, m / z): [M+H] + = 280.1.

[0269] Intermediate D 2-amino-5-(4-chlorophenyl)thiazolo[5,4-c]pyridine-4(5H)-one [ka]

[0269] 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (536 mg, 2.36 mmol) was added to a solution of intermediate C (220 mg, 0.79 mmol) in 1,4-dioxane at room temperature. The mixture was stirred at 100°C for 6 hours. LC-MS indicated that the reaction was complete. The reaction mixture was treated with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (eluted with 5% ethyl acetate in PE) to obtain intermediate D (65.0 mg). LC-MS (ESI, m / z): [M+H] + = 278.1.

[0270] Intermediate E 6-(4-chlorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-amine [ka] Step 1: Ethyl 1-(2-(4-chlorophenyl)-2-oxoethyl)-3-nitro-1H-pyrazole-5-carboxylate (E-1)

[0270] To a solution of ethyl 3-nitro-1H-pyrazole-5-carboxylate (1.00 g, 5.40 mmol) in MeCN (60 mL), 2-bromo-1-(4-chlorophenyl)ethanone (1.39 g, 5.95 mmol) and K2CO3 (1.49 g, 10.8 mmol) were added. The mixture was stirred under reflux for 5 hours. LC-MS indicated that the reaction was complete. The reaction mixture was treated with water and extracted with ethyl. The combined organic layers were washed with 5% aqueous citrate solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 30% ethyl in PE) to obtain ethyl 2-[2-(4-chlorophenyl)-2-oxoethyl]-5-nitropyrazole-3-carboxylate (1.59 g). LC-MS (ESI, m / z): [M+H] + = 336.0.

[0271] Step 2: 1-(4-chlorophenyl)-2-(5-(hydroxymethyl)-3-nitro-1H-pyrazole-1-yl)ethane-1-ol(E-2)

[0271] To a solution of ethyl 2-[2-(4-chlorophenyl)-2-oxoethyl]-5-nitropyrazole-3-carboxylate (1.59 g, 4.71 mmol) in MeOH (59.5 mL), sodium borohydride (0.53 g, 14.1 mmol) was added at 0°C. The mixture was stirred at 0°C for 4 hours. LC-MS indicated that the reaction was complete. The reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layers were washed with 5% aqueous citric acid solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 20-60% ethyl acetate in PE) to obtain 1-(4-chlorophenyl)-2-[5-(hydroxymethyl)-3-nitropyrazole-1-yl]ethanol (861.0 mg). LC-MS (ESI, m / z): [M+H] + = 296.2.

[0272] Step 3: 6-(4-chlorophenyl)-2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine(E-3)

[0272] A degassed solution of 1-(4-chlorophenyl)-2-[5-(hydroxymethyl)-3-nitropyrazole-1-yl]ethanol (340.0 mg, 1.14 mmol) in DCM (4 mL) was mixed with PPh3 (898.7 mg, 3.43 mmol) and DIAD (692.8 mg, 3.43 mmol) under N2. The mixture was stirred at room temperature for 3 hours. After completion, the mixture was treated with water and extracted with DCM. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 25% ethyl acetate in PE) to obtain 6-(4-chlorophenyl)-2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (184.0 mg). LCMS (ESI, m / z): [M+H] + = 280.1.

[0273] Step 4: 6-(4-chlorophenyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-amine(E)

[0273] To a solution of 6-(4-chlorophenyl)-2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (180.0 mg, 0.64 mmol) in THF (3 mL), Raney nickel (37.8 mg) was added under N2 at room temperature. Hydrazine (85% of the volume in water, 379 mg, 6.44 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 3 hours. LC-MS indicated that the reaction was complete. The mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (0.05% NH4HCO3) to obtain intermediate E (125.0 mg). LC-MS (ESI, m / z): [M+H] + = 250.2.

[0274] Intermediate F 5-(4-chlorophenyl)thiazolo[5,4-b]pyridine-2-amine [ka] Step 1: tert-butyl(5-(4-chlorophenyl)thiazolo[5,4-b]pyridine-2-yl)carbamate(F-1)

[0274] A mixture of tert-butyl(5-bromothiazolo[5,4-b]pyridine-2-yl)carbamate (700 mg, 2.12 mmol), (4-chlorophenyl)boronic acid (497 mg, 3.18 mmol), Pd(PPh3)2Cl2 (298 mg, 0.424 mmol), and Cs2CO3 (1.45 g, 4.45 mmol) in DMF (36 mL) and water (9 mL) was degassed and stirred at 116 °C for 4 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was treated with water and extracted with RINKAN. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (eluted with 10-50% ethyl acetate in PE) to obtain tert-butyl (5-(4-chlorophenyl)thiazolo[5,4-b]pyridine-2-yl)carbamate (450 mg). LCMS (ESI, m / z): [M+H] + = 362.1.

[0275] Step 2: 5-(4-chlorophenyl)thiazolo[5,4-b]pyridine-2-amine(F)

[0275] A solution of tert-butyl(5-(4-chlorophenyl)thiazolo[5,4-b]pyridine-2-yl)carbamate (450 mg, 1.24 mmol) and HCl (4 M in 1,4-dioxane, 10 mL) in MeOH (10 mL) was stirred at 50°C for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under vacuum to obtain crude intermediate F (400 mg). LC-MS (ESI, m / z): [M+H] + = 261.9.

[0276] intermediate G 5-(6-methoxy-3-pyridyl)thiazolo[5,4-d]pyrimidine-2-amine [ka] Step 1: tert-butyl(5-chlorothiazolo[5,4-d]pyrimidine-2-yl)carbamate (G-1)

[0276] Boc2O (1.75 g, 8.02 mmol) was added to a solution of 5-chlorothiazolo[5,4-d]pyrimidine-2-amine (500 mg, 2.68 mmol), DMAP (33 mg, 0.27 mmol), and TEA (542 mg, 5.36 mmol) in THF (10 mL). The mixture was stirred at room temperature for 8 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 30% Â in PE) to obtain tert-butyl(5-chlorothiazolo[5,4-d]pyrimidine-2-yl)carbamate (500 mg). LC-MS (ESI, m / z): [M+H] + = 287.1.

[0277] Step 2: tert-butyl(5-(6-methoxypyridine-3-yl)thiazolo[5,4-d]pyrimidine-2-yl)carbamate(G-2)

[0277] To a mixture of tert-butyl(5-chlorothiazolo[5,4-d]pyrimidine-2-yl)carbamate (220 mg, 0.767 mmol) and (6-methoxy-3-pyridyl)boronic acid (141 mg, 0.921 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL), Pd(dppf)Cl2·CH2Cl2 complex (125 mg, 0.154 mmol) and Cs2CO3 (750 mg, 2.30 mmol) were added under N2. The mixture was degassed and stirred at 100°C for 12 hours under an N2 atmosphere. LCMS indicated that the reaction was complete. The mixture was treated with water and extracted with siRNA. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (eluted with 20-50% ethyl acetate in PE) to obtain tert-butyl(5-(6-methoxypyridine-3-yl)thiazolo[5,4-d]pyrimidine-2-yl)carbamate (270 mg). LCMS (ESI, m / z): [M+H] + = 360.3.

[0278] Step 3: 5-(6-methoxy-3-pyridyl)thiazolo[5,4-d]pyrimidine-2-amine(G)

[0278] A solution of tert-butyl N-[5-(6-methoxy-3-pyridyl)thiazolo[5,4-d]pyrimidine-2-yl]carbamate (260 mg, 0.723 mmol) in HCl (4 M, 5 mL in 1,4-dioxane) was stirred at 50°C for 12 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated under vacuum to obtain crude intermediate G, which was used without further purification. LC-MS (ESI, m / z): [M+H] + = 260.1.

[0279] Intermediate H 6-[4-(difluoromethoxy)phenyl]thiazolo[4,5-b]pyrazine-2-amine [ka] Step 1: tert-butyl N-[6-[4-(difluoromethoxy)phenyl]thiazolo[4,5-b]pyrazine-2-yl]carbamate(H-1)

[0279] A solution of tert-butyl N-(6-bromothiazolo[4,5-b]pyrazine-2-yl)carbamate (500 mg, 1.51 mmol), 2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (530 mg, 1.96 mmol), Pd(PPh3)2Cl2 (212 mg, 0.30 mmol), and Cs2CO3 (984 mg, 3.02 mmol) in DMF (8 mL) and water (2 mL) was degassed and stirred at 116 °C for 4 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (eluted with 30% ethyl acetate in PE) to obtain tert-butyl N-[6-[4-(difluoromethoxy)phenyl]thiazolo[4,5-b]pyrazine-2-yl]carbamate (550 mg). LCMS (ESI, m / z): [M+H] + = 394.9.

[0280] Step 2: 6-[4-(difluoromethoxy)phenyl]thiazolo[4,5-b]pyrazine-2-amine(H)

[0280] A mixture of tert-butyl N-[6-[4-(difluoromethoxy)phenyl]thiazolo[4,5-b]pyrazine-2-yl]carbamate (400 mg, 1.01 mmol) in MeOH (4 mL) was mixed with HCl (4.0 M in 1,4-dioxane, 4 mL). The mixture was stirred at 50°C for 2 hours. LC-MS indicated that the reaction was complete. The mixture was treated with saturated NaHCO3 aqueous solution and extracted by DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude intermediate H was used without further purification. LC-MS (ESI, m / z): [M+H] + = 295.2.

[0281] Intermediate I 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid [ka] Step 1: Methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (I-1)

[0281] To a solution of methyl 4-bromo-6-methylnicotinate (10 g, 43.5 mmol) and (2-chloro-5-methoxypyridine-4-yl)boronic acid (8.96 g, 47.8 mmol) in 1,4-dioxane (100 mL) and H2O (25 mL), K2CO3 (18.0 g, 130.2 mmol) and Pd(dppf)Cl2·CH2Cl2 complex (3.18 g, 4.3 mmol) were added under N2. The mixture was degassed and stirred at 80°C for 2 hours under an N2 atmosphere. LCMS indicated that the reaction was complete. The reaction mixture was treated with water and extracted with siRNA. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (eluted with 10-50% ethyl acetate in PE) to obtain methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (10.1 g). LCMS (ESI, m / z): [M+H] + = 293.3.

[0282] Step 2: 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (I)

[0282] LiOH·H2O (5.79 g, 138.0 mmol) was added to a solution of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (10.1 g, 34.5 mmol) in THF (50 mL) and H2O (50 mL). The mixture was stirred at room temperature for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under vacuum to remove most of the THF. The resulting mixture was acidified to pH 4-5 with HCl aqueous solution (2N). The mixture was extracted with 10% MeOH in DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (eluted with 10% MeOH in DCM) to obtain intermediate I (8.7 g). LC-MS (ESI, m / z): [M+H] + = 278.9. 1H NMR (400 MHz, DMSO-d6) δ 13.05 (br s, 1H), 8.89 (s, 1H), 8.21 (s, 1H), 7.44(s, 1H), 7.30 (s, 1H), 3.78 (s, 3H), 2.56 (s, 3H).

[0283] Intermediate J 5'-Methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid [ka] Step 1: Methyl 5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylate (J-1)

[0283] To a solution of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (8.0 g, 27.3 mmol) in DME (100 mL), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (3.5 M in THF, 25 mL, 87.5 mmol), Pd(dppf)Cl2·CH2Cl2 complex (3.96 g, 5.41 mmol), and K2CO3 (11.3 g, 81.8 mmol) were added under N2. The mixture was degassed and stirred under reflux for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was treated with water and extracted with siRNA. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (eluted with 10-50% ethyl acetate in PE) to obtain methyl 5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylate (6.0 g). LCMS (ESI, m / z): [M+H] + = 273.2.

[0284] Step 2: 5'-Methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid (J)

[0284] To a solution of methyl 5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylate (6.0 g, 22.0 mmol) in THF (30 mL), methanol (10 mL), and water (10 mL), LiOH (1.05 g, 43.8 mmol) was added. The mixture was stirred at room temperature for 3 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under vacuum to remove most of the solvent. The remaining aqueous phase was acidified to pH=4-5 with aqueous HCl (2N). The mixture was purified by preparative HPLC (0.05% FA) to obtain intermediate J (3.0 g). LC-MS (ESI, m / z): [M+H] + = 259.1; 1 H NMR (400 MHz, CD3OD) δ 8.88 (s, 1H), 8.12 (s, 1H), 7.28 (s, 1H), 7.23 (s, 1H), 3.84 (s, 3H), 2.63 (s, 3H), 2.54 (s, 3H).

[0285] Intermediate K N-(5-chlorothiazolo[5,4-d]pyrimidine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide [ka]

[0285] To a solution of intermediate J (1.00 g, 3.87 mmol) in MeCN (10 mL), 5-chlorothiazolo[5,4-d]pyrimidine-2-amine (0.86 g, 4.61 mmol), CMPI (1.98 g, 7.75 mmol), and Et3N (1.96 g, 19.4 mmol) were added. The mixture was stirred under N2 at 40°C for 3 hours. LC-MS indicated that the reaction was complete. The mixture was treated with water and extracted with SiO2. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was ground with SiO2 and PE(2 / 1), filtered, and intermediate K (0.98 g) was obtained. LC-MS (ESI, m / z): [M+H] + = 427.2.

[0286] Intermediate L N-(5-bromothiazolo[5,4-b]pyridine-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide [ka]

[0286] Intermediate I (1.00 g, 3.59 mmol) and 5-bromothiazolo[5,4-b]pyridine-2-amine (2.48 g, 10.8 mmol) were stirred in DMF (40 mL). TCFH (3.02 g, 10.8 mmol) and NMI (1.77 g, 21.6 mmol) were added at room temperature. The mixture was stirred under N2 at room temperature for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was treated with water and extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (eluted at 50-80% EA in PE) to obtain intermediate L (860 mg). LC-MS (ESI, m / z): [M+H] + = 490.0.

[0287] Intermediate M N-(6-bromothiazolo[4,5-b]pyridine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide [ka]

[0287] To a solution of intermediate J (1 g, 3.87 mmol) in MeCN (10 mL), 6-bromothiazolo[4,5-b]pyridine-2-amine (1.66 g, 7.21 mmol), CMPI (1.98 g, 7.75 mmol), and Et3N (1.96 g, 19.4 mmol) were added. The mixture was stirred under N2 at 40°C for 2 hours. LC-MS indicated that the reaction was complete. The mixture was treated with water and extracted with SiO2. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (eluted with 5% MeOH in DCM) to obtain intermediate M (600 mg). LC-MS (ESI, m / z): [M+H] + = 470.1.

[0288] Intermediate N N-(3-bromothiazolo[4,5-c]pyridazine-6-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide [ka] Step 1: Ethyl (3-bromothiazolo[4,5-c]pyridazin-6-yl)carbamate (N-1)

[0288] O-ethyl carboisothiocyanate (9.10 g, 69.4 mmol) was added to a solution of 4,6-dibromopyridazine-3-amine (2 g, 7.91 mmol) in acetone (20 mL). The mixture was stirred under reflux under N2 for 16 hours. LC-MS indicated that the reaction was complete. The mixture was treated with water and extracted with MeOH / DCM(1 / 3). The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product, which was used without further purification. LC-MS (ESI, m / z): [M+H] + = 303.0.

[0289] Step 2: 3-Bromothiazolo[4,5-c]pyridazine-6-amine(N-2)

[0289] To a solution of crude ethyl N-(3-bromothiazolo[4,5-c]pyridazin-6-yl)carbamate from Step 1 in MeOH (20 mL), an aqueous solution of NaOH (2N, 20 mL, 40 mmol) was added. The mixture was stirred at 100°C for 4 hours. LC-MS indicated that the reaction was complete. The reaction mixture was neutralized with an aqueous solution of HCl (1N). The precipitate was collected, washed with water, and dried under vacuum to obtain 3-bromothiazolo[4,5-c]pyridazin-6-amine (600 mg). LC-MS (ESI, m / z): [M+H] + = 231.0.

[0290] Step 3: N-(3-bromothiazolo[4,5-c]pyridazine-6-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide(N)

[0290] TCFH (680 mg, 2.42 mmol) was added to a solution of 3-bromothiazolo[4,5-c]pyridazine-6-amine (280 mg, 1.21 mmol), intermediate J (344 mg, 1.33 mmol), and NMI (497 mg, 6.05 mmol) in DMF (10 mL). The mixture was stirred at 40°C for 24 hours. LC-MS indicated that the reaction was complete. The mixture was treated with water and extracted with RINKAN. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (eluted with 5% MeOH in DCM) to obtain intermediate N (60 mg). LC-MS (ESI, m / z): [M+H] + = 471.1.

[0291] Intermediate O N-(6-chlorothiazolo[4,5-c]pyridine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide [ka]

[0291] A mixture of 6-chlorothiazolo[4,5-c]pyridine-2-amine (600 mg, 3.23 mmol) and intermediate J (557 mg, 2.16 mmol) in MeCN (15 mL) was mixed with CMPI (550 mg, 2.15 mmol) and TEA (218 mg, 2.15 mmol). After stirring at room temperature under N2 for 16 hours, LC-MS indicated that the reaction was complete. The mixture was treated with water and extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (eluted with 5% MeOH in DCM) to obtain intermediate O (590 mg). LC-MS (ESI, m / z): [M+H] + = 426.2.

[0292] Intermediate P 2-(difluoromethyl)-5-methoxypyridine-4-yltrifluoromethanesulfonate [ka]

[0292] Intermediate P was synthesized according to the procedure reported in the literature (WO202350007).

[0293] Intermediate Q 2-Bromo-4-(difluoromethyl)-1-methoxybenzene [ka]

[0293] To a stirred solution of 3-bromo-4-methoxybenzaldehyde (4.3 g, 20.5 mmol) in DCM (10 mL), DAST (5.61 g, 4.60 mL, 34.8 mmol) was added at 0°C. After stirring at room temperature for 16 hours, the reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE / siRNA (20:1) to obtain intermediate Q (2.69 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.57 (t, J = 56.8 Hz, 1H), 3.93 (s, 3H).

[0294] Intermediate R 2-Chloro-5-(difluoromethoxy)-4-iodopyridine [ka]

[0294] A mixture of 6-chloro-4-iodopyridine-3-ol (15 g, 58.7 mmol), sodium chlorodifluoroacetate (17.9 g, 117.4 mmol), and Cs2CO3 (38.3 g, 117.4 mmol) in DMF (200 mL) was stirred at 100°C for 16 hours. After completion, the reaction mixture was treated with saturated saline and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography eluted with PE / ethyl acetate (10:1) to obtain intermediate R (12 g). 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.24 (s, 1H), 7.40 (t, J = 72.6 Hz, 1H).

[0295] Intermediate S Methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate [ka]

[0295] Methyl iodide (1.84 g, 13.0 mmol) was added to a stirred solution of methyl 5-bromo-2-oxo-1,2-dihydropyridine-4-carboxylate (2 g, 8.62 mmol) and Cs2CO3 (8.44 g, 25.9 mmol) in DMF (30 mL) at 0°C under an N2 atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain intermediate S (1.5 g). LCMS (ESI, m / z): [M+H] + = 246.0.

[0296] Intermediate T Ethyl 4-chloro-6-(1-(difluoromethyl)-1H-pyrazole-4-yl)nicotinate [ka]

[0296] A mixture of ethyl 4,6-dichloronicotinate (700 mg, 3.18 mmol), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (698 mg, 2.86 mmol), Pd(dppf)Cl2 (234 mg, 0.32 mmol), and Cs2CO3 (2.07 g, 6.36 mmol) in 1,4-dioxane (10 mL) and H2O (2.5 mL) was degassed and stirred at 80°C for 2 hours under an N2 atmosphere. After completion, the reaction mixture was treated with H2O and extracted with ethyl. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography eluted with PE / ethyl (10:1) to obtain intermediate T (400 mg). LCMS (ESI, m / z): [M+H] + = 301.9.

[0297] Intermediate U 1-Bromo-5-(difluoromethyl)-4-fluoro-2-methoxybenzene [ka] Step 1: 5-Bromo-2-fluoro-4-methoxybenzaldehyde (U-1)

[0297] To a stirred solution of Br2 (10.37 g, 64.8 mmol) in MeOH (50 mL), 2-fluoro-4-methoxybenzaldehyde (5 g, 32.4 mmol) in MeOH (10 mL) was added dropwise at -20°C. After stirring at -20°C, the reaction mixture was quenched with saturated sodium sulfite aqueous solution and water. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain 5-bromo-2-fluoro-4-methoxybenzaldehyde (U-1, 6 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 12.4 Hz, 1H), 3.98 (s, 3H).

[0298] Step 2: 1-Bromo-5-(difluoromethyl)-4-fluoro-2-methoxybenzene(U)

[0298] To a stirred solution of 5-bromo-2-fluoro-4-methoxybenzaldehyde (5.9 g, 25.3 mmol) in 6 mL of DCM at 0°C, DAST (8.16 g, 50.6 mmol) was added under an N2 atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was quenched with MeOH, followed by water, and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE / siRNA (20:1) to obtain intermediate U (3.12 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 12.4 Hz, 1H), 7.10 (t, J = 54.0 Hz, 1H), 3.92 (s, 3H).

[0299] Intermediate V Methyl 5-bromo-1-(2-(dimethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-4-carboxylate [ka]

[0299] To a stirred solution of methyl 5-bromo-2-oxo-1,2-dihydropyridine-4-carboxylate (2 g, 8.62 mmol) in DMF (20 mL), Cs2CO3 (8.43 g, 25.9 mmol) and 2-bromo-N,N-dimethylacetamide (2.15 g, 13.0 mmol) were added under an N2 atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was treated with water and extracted with siRNA. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain intermediate V (800 mg). LCMS (ESI, m / z): [M+H] + = 316.9.

[0300] Intermediate W Methyl 4-bromo-6-(dimethylcarbamoyl)nicotinate [ka] Step 1: Methyl(E)-4-bromo-6-(2-(dimethylamino)vinyl)nicotinate(W-1)

[0300] A solution of methyl 4-bromo-6-methylnicotinate (2.3 g, 10 mmol) and DMF-DMA (3.57 g, 30 mmol) in DMF (10 mL) was stirred at 120 °C for 18 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE / SiO(10:1) to obtain methyl(E)-4-bromo-6-(2-(dimethylamino)vinyl)nicotinate (W-1, 1.1 g). LC-MS (ESI, m / z): [M+H] + = 284.9.

[0301] Step 2: 4-Bromo-5-(methoxycarbonyl)picolinic acid (W-2)

[0301] To a solution of methyl(E)-4-bromo-6-(2-(dimethylamino)vinyl)nicotinate (W-1, 1 g, 3.51 mmol) and K2CO3 (969 mg, 7.01 mmol) in t-BuOH (17 mL) and water (17 mL), KMnO4 (1.66 g, 10.5 mmol) was gradually added. After stirring at room temperature for 1 hour, the reaction mixture was filtered. The filtrate was purified by reverse-phase column chromatography (0.1% FA) to obtain 4-bromo-5-(methoxycarbonyl)picolinic acid (W-2, 550 mg). LCMS (ESI, m / z): [M+H] + = 260.0.

[0302] Step 3: Methyl 4-bromo-6-(dimethylcarbamoyl)nicotinate (W)

[0302] To a stirred solution of 4-bromo-5-(methoxycarbonyl)picolinic acid (W-2, 600 mg, 2.31 mmol) and dimethylamine hydrochloride (282 mg, 3.46 mmol) in MeCN (30 mL), CMPI (884 mg, 3.46 mmol) and TEA (934 mg, 1.29 mL, 9.23 mmol) were added under N2. After stirring at room temperature for 1 hour, the reaction mixture was treated with water and extracted with DCM. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE / Âi (10:1~1:1) to obtain intermediate W (135 mg). LCMS (ESI, m / z): [M+H] + = 286.9.

[0303] Intermediate X 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinic acid [ka] Step 1: Methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinate (X-1)

[0303] A mixture of 2-bromo-4-(difluoromethyl)-1-methoxybenzene (2.68 g, 11.3 mmol), B2pin2 (4.32 g, 17.0 mmol), Pd(dppf)Cl2 (827 mg, 1.13 mmol), and KOAc (3.33 g, 33.9 mmol) in 1,4-dioxane (100 mL) was degassed and stirred at 100 °C for 3 hours under an N2 atmosphere. After cooling to room temperature, methyl 4-bromo-6-methylnicotinate (2.17 g, 9.43 mmol), Pd(dppf)Cl2 (690 mg, 0.943 mmol), Cs2CO3 (6.16 g, 18.9 mmol), and water (25 mL) were added to the mixture. The resulting mixture was degassed and stirred for a further 2 hours at 80 °C under an N2 atmosphere. LC-MS confirmed the completion of the reaction. The reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / ethyl acetate (10:1-2:1) to obtain methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinate (X-1, 2g). LC-MS (ESI, m / z): [M+H] + = 308.2.

[0304] Step 2: 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinic acid (X)

[0304] To a stirred solution of methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinate (1.8 g, 5.86 mmol) in MeOH (10 mL), LiOH·H2O (1.23 g, 29.3 mmol) in water (20 mL) was added. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under vacuum to remove most of the MeOH and water. The residue was acidified to pH=5-6 using HCl aqueous solution (1N). The mixture was purified by reverse-phase column chromatography (0.1% FA) to obtain intermediate X (1.3 g). LCMS (ESI, m / z): [M+H] + = 294.1.

[0305]

[0305] The intermediates in the table below were synthesized by using conditions similar to those used to synthesize intermediate X, converting appropriate aromatic halides or triflates to the corresponding boronic acid reagents, and then performing Suzuki coupling and hydrolysis. [Table 2] TIFF2026522322000150.tif102149

[0306] Intermediate AL Methyl 3-(5-chloro-2-methoxyphenyl) isonicotinate [ka]

[0306] To a solution of (5-chloro-2-methoxyphenyl)boronic acid (3 g, 16.1 mmol) and methyl 3-bromoisonicotinate (3.47 g, 16.1 mmol) in 1,4-dioxane (50 mL) and water (15 mL), Pd(dppf)Cl2.DCM (1.29 g, 1.58 mmol) and K2CO3 (5.55 g, 40.2 mmol) were added under N2. The mixture was degassed and stirred at 100°C for 4 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE / ethyl acetate (1:1) to obtain intermediate AL (2.5 g). LCMS (ESI, m / z): [M+H] + = 278.3.

[0307] Intermediate AM [ka] Step 1: Methyl 2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (AM-1)

[0307] To a solution of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (I-1, 2.2 g, 7.52 mmol) in 1,4-dioxane (40 mL) and water (10 mL), cyclopropylboronic acid (6.46 g, 75.2 mmol), Cs2CO3 (7.35 g, 22.6 mmol), and Pd(dppf)Cl2 (1.10 g, 1.50 mmol) were added under N2. The mixture was degassed and stirred at 90°C for 6 hours under an N2 atmosphere. After completion, the reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with ethyl elution to obtain methyl 2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (AM-1, 2g) as a brown oily substance. LCMS (ESI, m / z): [M+H] + = 299.2.

[0308] Step 2: 2'-Cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (AM)

[0308] To a solution of methyl 2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (AM-1, 2g, 6.70 mmol) in THF (30 mL) and water (15 mL), LiOH.H2O (1.41 g, 33.6 mmol) was added. After stirring at room temperature for 16 hours, the reaction mixture was concentrated under vacuum to remove most of the THF and water. The residue was acidified to pH=5-6 using HCl aqueous solution (1N). The mixture was purified by reverse-phase column chromatography (0.1% FA) to obtain intermediate AL (1.6 g). LCMS (ESI, m / z): [M+H] + = 285.2.

[0309]

[0309] The intermediates in the table below were synthesized by reacting the synthesized hetero-biaryl chloride with a commercially available boronic acid derivative via Suzuki coupling, using conditions similar to those used to synthesize intermediate AL, followed by hydrolysis. [Table 3]

[0310] Intermediate AQ 2-(2-(difluoromethyl)-5-methoxypyridine-4-yl)-4-(1-methyl-1H-pyrazole-3-yl)benzoic acid [ka] Step 1: Methyl 2-(2-(difluoromethyl)-5-methoxypyridine-4-yl)-4-(1-methyl-1H-pyrazole-3-yl)benzoate (AQ-1)

[0310] A solution of methyl 4-bromo-2-(2-(difluoromethyl)-5-methoxypyridine-4-yl)benzoate (precursor of intermediate AD) (100 mg, 0.27 mmol) in 1,4-dioxane (3 mL) and water (1 mL), to which 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (84 mg, 0.40 mmol), Pd(dppf)Cl2 . CH2Cl2 (24 mg, 0.029 mmol) and Cs2CO3 (263 mg, 0.80 mmol) were added under N2 conditions. The mixture was degassed and stirred at 100°C for 3 hours under an N2 atmosphere. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / siRNA (5:1) to obtain methyl 2-(2-(difluoromethyl)-5-methoxypyridine-4-yl)-4-(1-methyl-1H-pyrazole-3-yl)benzoate (AQ-1, 80 mg). LCMS (ESI, m / z): [M+H] + = 374.3.

[0311] Step 2: 2-(2-(difluoromethyl)-5-methoxypyridine-4-yl)-4-(1-methyl-1H-pyrazole-3-yl)benzoic acid (AQ)

[0311] To a solution of methylmethyl 2-(2-(difluoromethyl)-5-methoxypyridine-4-yl)-4-(1-methyl-1H-pyrazole-3-yl)benzoate (AQ-1, 80 mg, 0.21 mmol) in THF (2 mL) and H2O (2 mL), LiOH·H2O (13.5 mg, 0.32 mmol) was added. After stirring at room temperature for 12 hours, the reaction mixture was concentrated to remove most of the THF. The mixture was acidified to pH=6 with aqueous HCl (1N). The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to obtain intermediate AQ (70 mg). LCMS (ESI, m / z): [M+H] + = 360.2. The intermediates in the table below were synthesized via the Suzuki coupling reaction using conditions similar to those used to synthesize intermediate AQ. [Table 4]

[0312] Intermediate AS N-(6-bromothiazolo[4,5-b]pyrazine-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide [ka]

[0312] To a solution of intermediate AJ (180 mg, 0.61 mmol) in MeCN (2.0 mL), 6-bromothiazolo[4,5-b]pyrazine-2-amine (141 mg, 0.61 mmol), Et3N (257 mg, 2.54 mmol), and CMPI (258 mg, 1.01 mmol) were added under N2 conditions. After stirring at room temperature for 4 hours, the reaction mixture was concentrated to dryness under vacuum. The residue was purified by preparative HPLC (0.05% NH4HCO3) to obtain intermediate AS (150 mg). LCMS (ESI, m / z): [M+H]+ = 507.2.

[0313]

[0313] The intermediates in the table below were synthesized via amide coupling reactions using conditions similar to those used to synthesize intermediate AS from the corresponding acids. [Table 5]

[0314] Intermediate AW 6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazine-2-amine [ka] Step 1: tert-butyl(6-bromothiazolo[4,5-b]pyrazine-2-yl)carbamate (AW-1)

[0314] A mixture of 6-bromothiazolo[4,5-b]pyrazine-2-amine (5 g, 21.6 mmol), (Boc)2O (7.09 g, 32.5 mmol), DMAP (794 mg, 6.5 mmol), and TEA (4.38 g, 43.3 mmol) in acetone (150 mL) was stirred at 60°C for 4 hours. After completion, the reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / ethyl acetate (8:1~1:1) to obtain tert-butyl(6-bromothiazolo[4,5-b]pyrazine-2-yl)carbamate (AW-1, 4 g). LCMS (ESI, m / z): [M+H] + = 331.0.

[0315] Step 2: tert-butyl(6-(cyclopropylethinyl)thiazolo[4,5-b]pyrazine-2-yl)carbamate (AW-2)

[0315] To a stirred mixture of tert-butyl(6-bromothiazolo[4,5-b]pyrazine-2-yl)carbamate (AW-1, 4g, 12.1 mmol), ethinylcyclopropane (2.40 g, 36.3 mmol), and TEA (3.67 g, 36.3 mmol) in DMF (40 mL), CuI (230 mg, 1.21 mmol) and Pd(PPh3)4 (1.40 g, 1.21 mmol) were added under N2 atmosphere. The mixture was degassed and stirred at 90°C for 2 hours under an N2 atmosphere. The mixture was treated with water and extracted with SiO2. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE / ELISA (3:1) to obtain tert-butyl(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazine-2-yl)carbamate (AW-2, 3g). LCMS (ESI, m / z): [M+H]+ = 317.2.

[0316] Step 3: 6-(cyclopropylethinyl)thiazolo[4,5-b]pyrazine-2-amine (AW)

[0316] To a stirred solution of tert-butyl(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazine-2-yl)carbamate (AW-2, 3g, 9.48 mmol) in DCM (25 ml), TFA (12.5 ml) was added. After stirring at room temperature for 2 hours, the reaction mixture was concentrated to dryness under vacuum. The residue was purified by polishing with a mixture of aqueous ammonia and methanol to obtain intermediate AV (1.8 g). LCMS (ESI, m / z): [M+H] + = 217.2.

[0317] Intermediate AX 5-(cyclopropylethinyl)thiazolo[5,4-d]pyrimidine-2-amine [ka] Step 1: tert-butyl(5-(cyclopropylethinyl)thiazolo[5,4-d]pyrimidine-2-yl)carbamate (AX-1)

[0317] To a solution of tert-butyl(5-chlorothiazolo[5,4-d]pyrimidine-2-yl)carbamate (G-1, 200 mg, 0.70 mmol) in 1,4-dioxane (3 mL), 2-(cyclopropylethynyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (201 mg, 1.05 mmol), Pd(dppf)Cl2 (51 mg, 0.07 mmol), and Cs2CO3 (683 mg, 2.09 mmol) were added under N2 conditions. The mixture was degassed and stirred at 100°C for 12 hours under an N2 atmosphere. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (0.05% NH4HCO3) to obtain tert-butyl(5-(cyclopropylethynyl)thiazolo[5,4-d]pyrimidine-2-yl)carbamate (AX-1, 50 mg). LCMS (ESI, m / z): [M+H] + = 317.2.

[0318] Step 2: 5-(cyclopropylethinyl)thiazolo[5,4-d]pyrimidine-2-amine (AX)

[0318] To a solution of tert-butyl(5-(cyclopropylethynyl)thiazolo[5,4-d]pyrimidine-2-yl)carbamate (AX-1, 50 mg, 0.174 mmol) in THF (2 mL), TFA (1 mL) was added. After stirring at room temperature for 2 hours, the reaction mixture was concentrated to dryness under vacuum to obtain intermediate AX, which was used in the next step without purification. LCMS (ESI, m / z): [M+H] + = 217.1.

[0319] Example 1 2'-Chloro-5'-methoxy-6-methyl-N-(6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2-yl)-[4,4'-bipyridine]-3-carboxamide [ka]

[0319] To a solution of intermediate I (100.0 mg, 0.36 mmol) in DMF (2 mL), TCFH (151.5 mg, 0.54 mmol) and NMI (147.8 mg, 1.80 mmol) were added, followed by intermediate A (92.0 mg, 0.40 mmol). The resulting mixture was stirred at room temperature for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was directly purified by preparative HPLC (0.05% NH4HCO3) to obtain Example 1. LC-MS (ESI, m / z): [M+H] + = 491.5; 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (br s, 1H), 8.78 (s, 1H), 8.17 (s, 1H), 7.51 (s, 1H), 7.41 (s, 1H), 7.35-7.30 (m, 4H), 7.24-7.20 (m, 1H), 3.62 (s, 3H), 3.05-2.99 (m, 1H), 2.95-2.90 (m, 1H), 2.81-2.69 (m, 3H), 2.58 (s, 3H), 2.07-1.97 (m, 2H).

[0320] Examples 2 and 3 (S)-2'-chloro-N-(6-(4-chlorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide and (R)-2'-chloro-N-(6-(4-chlorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide [ka]

[0320] Intermediate I (170 mg, 0.642 mmol) and intermediate B (268 mg, 0.962 mmol) were coupled under conditions similar to those of the synthesis in Example 1 to obtain 2'-chloro-N-(6-(4-chlorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (100 mg). The racemic mixture was purified by SFC under the following conditions (OJ column, 0.05% DEA) to obtain two distinct enantiomers: (S)-2'-chloro-N-(6-(4-chlorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide and (R)-2'-chloro-N-(6-(4-chlorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide. Example 2 (Peak 1): LCMS (ESI, m / z): [M+H] + = 525.2; Retention time 11.6 minutes in UPCC (YMC Triart C18); 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (br s, 1H), 8.78 (s, 1H), 8.17 (s, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 7.38-7.34 (m, 4H), 3.62 (s, Example 3 (Peak 2): LCMS (ESI, m / z): [M+H] + = 525.2, retention time 8.8 minutes in UPCC (YMC Triart C18); 1H NMR (400 MHz, DMSO-d6) δ 12.41 (br s, 1H), 8.78 (s, 1H), 8.17 (s, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 7.38-7.34 (m, 4H), 3.62 (s, 3H), 3.09-3.01 (m, 1H), 2.95-2.87 (m, 1H), 2.77-2.66 (m, 3H), 2.58 (s, 3H), 2.05-1.95 (m, 2H).

[0321]

[0321] Examples 4-10 were synthesized by reacting acid intermediate I with a suitable aminothiazole from the intermediate list or a commercial supplier, using conditions similar to those used to synthesize Example 1. [Table 6] TIFF2026522322000163.tif177149TIFF2026522322000164.tif52149

[0322] Example 11 5'-Methoxy-2',6-dimethyl-N-(6-methylthiazolo[4,5-b]pyrazine-2-yl)-[4,4'-bipyridine]-3-carboxamide [ka]

[0322] To a stirred solution of intermediate J (100 mg, 0.387 mmol) in MeCN (3 mL), 6-methylthiazolo[4,5-b]pyrazine-2-amine (96.5 mg, 0.581 mmol), CMPI (197.8 mg, 0.774 mmol), and TEA (195.9 mg, 1.94 mmol) were added. The mixture was stirred under N2 at 40°C for 2 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (0.1% FA) to obtain Example 11. LC-MS (ESI, m / z): [M+H] + = 407.2; 1H NMR (400 MHz, DMSO-d6) δ 13.29 (br s, 1H), 8.84 (s, 1H), 8.50 (s, 1H), 8.18 (s, 1H), 7.39 (s, 1H), 7.29 (s, 1H), 3.57 (s, 3H), 2.60 (s, 3H), 2.59 (s, 3H), 2.49 (s, 3H).

[0323]

[0323] Examples 12-14 were synthesized by reacting acid intermediate J with a suitable aminothiazole from the intermediate list or a commercial supplier, using conditions similar to those used to synthesize Example 11. [Table 7]

[0324] Example 15 N-(6-(1-(2,2-difluoroethyl)-1H-pyrazole-4-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide [ka]

[0324] A solution of Example 13 (100 mg, 0.212 mmol) in 1,4-dioxane (3 ml) and water (1 mL) is prepared by adding 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (65.7 mg, 0.255 mmol) and Pd(dppf)Cl2 . DCM complex (17 mg, 0.021 mmol) and Cs2CO3 (207 mg, 0.637 mmol) were added under N2 conditions. The mixture was degassed and stirred at 100°C for 5 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (0.05% FA) to obtain Example 15. LC-MS (ESI, m / z): [M+H] + = 523.3; 1H NMR (400 MHz, DMSO-d6) δ 13.35 (br s, 1H), 9.01 (s, 1H), 8.83 (s, 1H), 8.55 (s, 1H), 8.26 (s, 1H), 8.19 (s, 1H), 7.41 (s, 1H), 7.31 (s, 1H), 6.57-6.30(m, 1H), 4.78-4.65 (m, 2H), 3.59 (s, 3H), 2.61 (s, 3H), 2.53 (s, 3H).

[0325]

[0325] Examples 16-32 were synthesized by reacting intermediate M, Example 10, or Example 13 with a suitable boronic acid or boronic acid ester from a commercial supplier, using conditions similar to those used to synthesize Example 15. [Table 8] TIFF2026522322000169.tif194149TIFF2026522322000170.tif197149TIFF20265223220 00171.tif184149TIFF2026522322000172.tif190149TIFF2026522322000173.tif181149

[0326] Example 33 2'-Chloro-5'-Methoxy-N-(5-(5-methoxypyridine-2-yl)thiazolo[5,4-b]pyridine-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide [ka] Step 1: 5-Methoxy-2-(tributylstannyl)pyridine (33-1)

[0326] A mixture of 2-bromo-5-methoxypyridine (500 mg, 2.66 mmol), Sn2(n-Bu)6 (4.63 g, 7.98 mmol), Pd2(dba)3 (244 mg, 0.266 mmol), tricyclohexylphosphine (149 mg, 0.531 mmol), and LiCl (564 mg, 13.3 mmol) in 1,4-dioxane (30 mL) was degassed and stirred at 110 °C for 4 hours under N2. LC-MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with petroleum ether) to obtain 5-methoxy-2-(tributylstannyl)pyridine (550 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.8 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.23 (dd, J = 8.0 Hz, 2.8 Hz, 1H), 3.79 (s, 3H), 1.58-1.42 (m, 6H), 1.32-1.23 (m, 6H), 1.10-0.98 (m, 6H), 0.83 (t, J = 7.2, 9H).

[0327] Step 2: 2'-Chloro-5'-Methoxy-N-(5-(5-methoxypyridine-2-yl)thiazolo[5,4-b]pyridine-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide(33-2)

[0327] A mixture of intermediate L (100 mg, 0.204 mmol), 5-methoxy-2-(tributylstannyl)pyridine (121.7 mg, 0.306 mmol), CuCl (40.4 mg, 0.408 mmol), LiCl (43.2 mg, 1.02 mmol), and Pd(PPh3)4 (47.1 mg, 0.041 mmol) in 1,4-dioxane (5 mL) was degassed and stirred at 110°C for 16 hours under N2. LC-MS indicated that the reaction was complete. The mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure and purified by preparative HPLC (0.1% NH4OH) to obtain Example 33. LC-MS (ESI, m / z): [M+H] + = 519.3; 1H NMR (400 MHz, DMSO-d6) δ 13.13 (br s, 1H), 8.87 (s, 1H), 8.44-8.37 (m, 3H), 8.21 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 7.60 (s, 1H), 7.55 (dd, J = 8.4 Hz, 3.2 Hz, 1H), 7.48 (s, 1H), 3.91 (s, 3H), 3.63 (s, 3H), 2.61 (s, 3H).

[0328] Example 34 5'-Methoxy-N-(5-(5-methoxypyridine-2-yl)thiazolo[5,4-d]pyrimidine-2-yl)-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide [ka]

[0328] To a solution of 2-bromo-5-methoxypyridine (110 mg, 0.59 mmol) in 1,4-dioxane (4 mL), hexamethyltin (231 mg, 0.71 mmol) and Pd(PPh3)4 (67 mg, 0.058 mmol) were added under N2. The mixture was degassed and then stirred under N2 at 100°C for 2 hours. After cooling to room temperature, intermediate K (124 mg, 0.29 mmol) and Pd(PPh3)2Cl2 (41 mg, 0.058 mmol) were added. The mixture was degassed and stirred under N2 at 100°C for 2 hours. LCMS indicated that the reaction was complete. After concentration under vacuum, the residue was purified by preparative HPLC (0.05% NH4HCO3) to obtain Example 34. LCMS (ESI, m / z): [M+H] + = 500.3; 1 H NMR (400 MHz, DMSO-d6): δ 13.34 (br s, 1H), 9.22 (s, 1H), 8.85 (s, 1H), 8.46-8.41 (m, 2H), 8.19 (s, 1H), 7.55 (dd, J = 8.4 Hz, 3.2 Hz, 1H), 7.40 (s, 1H), 7.30 (s, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 2.61 (s, 3H), 2.51 (s, 3H).

[0329]

[0329] Examples 35 to 46 were synthesized using conditions similar to those used to synthesize Examples 33 and 34, by converting appropriate commercially available heteroaryl halides to the corresponding tin reagents and then performing Still coupling. [Table 9] TIFF2026522322000177.tif184149TIFF2026522322000178.tif203149TIFF2026522322000179.tif184149

[0330] Example 47 5'-Methoxy-2',6-dimethyl-N-(thiazolo[4,5-b]pyrazine-2-yl)-[4,4'-bipyridine]-3-carboxamide [ka]

[0330] To a stirred solution of Example 13 (70.0 mg, 0.149 mmol) in DMF (2 ml) and water (0.5 mL), NaOAc (40.3 mg, 0.492 mmol) and Pd / C (containing 55% water, 17.3 mg) were added. The reaction mixture was stirred at 80°C for 14 hours. LC-MS indicated that the reaction was complete. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (0.05% FA) to obtain Example 47. LC-MS (ESI, m / z): [M+H] + = 393.2; 1 H NMR (400 MHz, DMSO-d6) δ 13.42 (br s, 1H), 8.84 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.18 (s, 1H), 7.40 (s, 1H), 7.31 (s, 1H), 3.58 (s, 3H), 2.60 (s, 3H), 2.49 (s, 3H).

[0331] Example 48 5'-Methoxy-2',6-dimethyl-N-(6-(tetrahydro-2H-pyran-3-yl)thiazolo[4,5-b]pyrazine-2-yl)-[4,4'-bipyridine]-3-carboxamide [ka] Step 1: N-(6-(5,6-dihydro-2H-pyran-3-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide(48-1)

[0331] A solution of Example 13 (100 mg, 0.212 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) contains 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (44.6 mg, 0.212 mmol) and Pd(dppf)Cl2 . CH2Cl2 complex (17 mg, 0.021 mmol) and Cs2CO3 (207 mg, 0.635 mmol) were added under N2 conditions. The mixture was degassed and stirred at 100°C for 3 hours under N2 conditions. LC-MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (0.1% FA) to obtain N-(6-(5,6-dihydro-2H-pyran-3-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (22 mg). LC-MS (ESI, m / z): [M+H] + = 475.2.

[0332] Step 2: 5'-Methoxy-2',6-dimethyl-N-(6-(tetrahydro-2H-pyran-3-yl)thiazolo[4,5-b]pyrazine-2-yl)-[4,4'-bipyridine]-3-carboxamide(48)

[0332] To a solution of N-(6-(5,6-dihydro-2H-pyran-3-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (22 mg, 0.046 mmol) in MeOH (3 mL), PtO2 (2.3 mg, 0.010 mmol) was added under N2. The mixture was purged with H2 and then stirred at room temperature under an H2 atmosphere (1 atm) for 16 hours. LC-MS indicated that the reaction was complete. The mixture was filtered. The filtrate was concentrated under vacuum and purified by preparative HPLC (0.1% NH4HCO3) to obtain Example 48. LC-MS (ESI, m / z): [M+H] + = 477.3; 1H NMR (400 MHz, DMSO-d6) δ 13.34 (br s, 1H), 8.86 (s, 1H), 8.53 (s, 1H), 8.17 (s, 1H), 7.36 (s, 1H), 7.27 (s, 1H), 3.98 (dd, J = 8.8 Hz, 3.2 Hz, 1H), 3.88 (d, J = 7.2 Hz, 1H), 3.57 (s, 3H), 3.52 (t, J = 10.8 Hz, 1H), 3.41 (m, 1H), 3.11 (m, 1H), 2.59 (s, 3H), 2.48 (s, 3H), 2.01 (m, 1H), 1.90 (m, 1H), 1.68 (m, 2H).

[0333] Example 49 N-(6-(1H-pyrazole-1-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide [ka]

[0333] To a solution of Example 13 (100 mg, 0.212 mmol) in DMSO (4 mL), 1H-pyrazole (43 mg, 0.632 mmol), CuI (8.1 mg, 0.043 mmol), L-proline (4.9 mg, 0.043 mmol), and K2CO3 (58.6 mg, 0.424 mmol) were added under N2. The mixture was degassed and stirred under N2 at 100°C for 18 hours. LC-MS indicated that the reaction was complete. The mixture was directly purified by preparative HPLC (0.05% FA) to obtain Example 49. LC-MS (ESI, m / z): [M+H] + = 459.3; 1 H NMR (400 MHz, DMSO-d6) δ 13.54 (br s, 1H), 9.21 (s, 1H), 8.89 (s, 1H), 8.68 (d, J = 2.8 Hz, 1H), 8.28 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 6.66 (dd, J = 2.8 Hz, 2.0 Hz 1H), 3.63 (s, 3H), 2.63 (s, 3H), 2.56 (s, 3H).

[0334] Example 50 2'-Chloro-5'-Methoxy-N-(6-(5-methoxypyridine-2-yl)thiazolo[4,5-b]pyrazine-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide [ka] Step 1: 2'-Chloro-N-(6-(3,6-dihydro-2H-pyran-4-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide(50-1)

[0334] A mixture of Example 10 (150 mg, 0.305 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (96.1 mg, 0.458 mmol), Pd(PPh3)2Cl2 (42.8 mg, 0.061 mmol), and Cs2CO3 (248 mg, 0.763 mmol) in DMF (8 mL) and water (2 mL) was degassed and stirred at 110°C for 4 hours under N2. LC-MS indicated that the reaction was complete. The mixture was concentrated under vacuum. The residue was purified by silica gel flash column chromatography (eluted with 1-5% MeOH in DCM) to obtain 2'-chloro-N-(6-(3,6-dihydro-2H-pyran-4-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (110 mg). LCMS (ESI, m / z): [M+H] + = 495.1.

[0335] Step 2: 2'-Chloro-5'-methoxy-6-methyl-N-(6-(tetrahydro-2H-pyran-4-yl)thiazolo[4,5-b]pyrazine-2-yl)-[4,4'-bipyridine]-3-carboxamide(50)

[0335] A mixture of 2'-chloro-N-(6-(3,6-dihydro-2H-pyran-4-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (70.0 mg, 0.141 mmol) in MeOH (20 mL) was mixed with PtO2 (64.2 mg, 0.283 mmol) under N2. The mixture was purged with H2 and stirred under H2 (1 atm) at room temperature for 16 hours. LC-MS indicated that the reaction was complete. The mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (0.1% FA) to obtain Example 50. LC-MS (ESI, m / z): [M+H] + = 497.3;1 H NMR (400 MHz, DMSO-d6) δ 13.36 (br s, 1H), 8.89 (s, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 4.01-3.95 (m, 2H), 3.62 (s, 3H), 3.51-3.44 (m, 2H), 3.18-3.10 (m, 1H), 2.61 (s, 3H), 1.87-1.79 (m, 4H).

[0336] Example 51 2'-Chloro-N-(6-(1-(2,2-difluoroethyl)piperidine-4-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide [ka] Step 1: 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(51-1)

[0336] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (1.5 g, 6.11 mmol) in DMF (6 mL), 2,2-difluoroethyl trifluoromethanesulfonate (2.2 g, 10.3 mmol) and DIPEA (1.85 g, 14.2 mmol) were added. The mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.0 g). 1 H NMR (400 MHz, DMSO-d6) δ 6.36-6.32 (m, 1H), 6.11 (tt, J = 55.6 Hz, 4.4 Hz, 1H), 3.10 (m, 2H), 2.76 (td, J =15.6 Hz, 4.4 Hz, 2H), 2.57 (t, J = 5.6 Hz, 2H), 2.12-2.07 (m, 2H), 1.19 (s, 12H).

[0337] Step 2: 2'-Chloro-N-(6-(1-(2,2-difluoroethyl)-1,2,3,6-tetrahydropyridine-4-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide(51-2)

[0337] A solution of Example 10 (100 mg, 0.203 mmol) in 1,4-dioxane (4 mL) contains 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (66.7 mg, 0.244 mmol), Pd(dppf)Cl2 . DCM complex (16.2 mg, 0.020 mmol) and Cs2CO3 (199 mg, 0.61 mmol) were added under N2 conditions. The mixture was degassed and stirred at 100°C for 2 hours under N2 conditions. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (0.05% FA) to obtain 2'-chloro-N-(6-(1-(2,2-difluoroethyl)-1,2,3,6-tetrahydropyridine-4-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (50 mg). LC-MS (ESI, m / z): [M+H] + = 558.2.

[0338] Step 3: 2'-Chloro-N-(6-(1-(2,2-difluoroethyl)piperidine-4-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide(51)

[0338] To a solution of 2'-chloro-N-(6-(1-(2,2-difluoroethyl)-1,2,3,6-tetrahydropyridine-4-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (50 mg, 0.90 mmol) in methanol (2 mL), PtO2 (5 mg, 0.02 mmol) was added under N2. The mixture was purged with H2 and stirred under H2 (1 atm) at room temperature for 2 hours. LC-MS indicated that the reaction was complete. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (0.05% FA) to obtain Example 51. LC-MS (ESI, m / z): [M+H] + = 560.3; 1H NMR (400 MHz, DMSO-d6): δ 13.32 (br s, 1H), 8.90 (s, 1H), 8.55 (s, 1H), 8.16 (s, 1H), 7.57 (s, 1H), 7.44 (s, 1H), 6.16 (tt, J = 56.0 Hz, 4.0 Hz, 1H), 3.62 (s, 3H), 3.03 (m, 2H), 2.89-2.72 (m, 3H), 2.60 (s, 3H), 2.35-2.27 (m, 2H), 1.88-1.77 (m, 4H).

[0339] Example 52 2'-Chloro-5'-methoxy-6-methyl-N-(6-morpholinothiazolo[4,5-b]pyrazine-2-yl)-[4,4'-bipyridine]-3-carboxamide [ka]

[0339] Morpholine (124 mg, 1.42 mmol) and DIPEA (185 mg, 1.43 mmol) were added to a solution of Example 10 (70.0 mg, 0.14 mmol) in NMP (2 mL). The mixture was stirred under N2 at 120°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was purified by preparative HPLC (0.05% NH4HCO3) to obtain Example 52. LC-MS (ESI, m / z): [M+H] + = 498.2; 1 H NMR (400 MHz, DMSO-d6) δ 13.00 (br s, 1H), 8.87 (s, 1H), 8.31 (s, 1H), 8.16 (s, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 3.77-3.70 (m, 4H), 3.62 (s, 3H), 3.57-3.51 (m, 4H), 2.59 (s, 3H).

[0340] Example 53 5'-Methoxy-N-(6-(4-methoxyphenyl)thiazolo[4,5-c]pyridine-2-yl)-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide [ka]

[0340] A mixture of intermediate O (200 mg, 0.470 mmol), (4-methoxyphenyl)boronic acid (286 mg, 1.88 mmol), X-Phos (45 mg, 0.094 mmol), Pd2(dba)3 (43 mg, 0.047 mmol), and Na2CO3 (149 mg, 1.41 mmol) in 1,4-dioxane (7.5 mL) and water (2.5 mL) was degassed. The mixture was stirred under N2 at 110°C for 1 hour. LC-MS indicated that the reaction was complete. The mixture was treated with water and extracted with DCM / MeOH (10:1). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (0.1% FA) to obtain Example 53. LC-MS (ESI, m / z): [M+H] + = 498.3; 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.85 (s, 1H), 8.49 (s, 1H), 8.18 (s, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.36 (s, 1H), 7.27 (s, 1H), 7.05 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 3.57 (s, 3H), 2.59 (s, 3H), 2.48 (s, 3H).

[0341] Example 54 (E)-N-(6-(2-cyclopropylvinyl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide [ka]

[0341] A mixture of Example 13 (150 mg, 0.318 mmol), (E)-2-(2-cyclopropyl vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (92.6 mg, 0.477 mmol), Pd(dppf)Cl2 (23.3 mg, 0.032 mmol), and Cs2CO3 (207 mg, 0.636 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was degassed and stirred at 80°C for 2 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under vacuum. The residue was purified by reverse-phase column chromatography (0.1% FA) to obtain Example 54 (110 mg). LC-MS (ESI, m / z): [M+H] + = 459.3; 1 H NMR (400 MHz, DMSO-d6) δ 13.32 (brs, 1H), 8.82 (s, 1H), 8.57 (s, 1H), 8.18 (s, 1H), 7.40 (s, 1H), 7.31 (s, 1H), 6.72 (d, J = 15.6 Hz, 1H), 6.43 (dd, J = 15.6 Hz, 9.6 Hz, 1H), 3.58 (s, 3H), 2.60 (s, 3H), 2.49 (s, 3H), 1.71-1.68 (m, 1H), 0.92-0.82 (m, 2H), 0.70-0.62 (m, 2H).

[0342] Example 55 N-(6-(2-cyclopropylethyl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide [ka]

[0342] To a mixture of Example 54 (90 mg, 0.196 mmol) in MeOH (10 mL), Pd / C (palladium on 10% carbon, moistened with approximately 55% water for safety, 90 mg) was added under an N2 atmosphere. The mixture was purged with H2 and then stirred at room temperature under an H2 atmosphere (1 atm) for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (0.1% FA) to obtain Example 55. LC-MS (ESI, m / z): [M+H] + = 461.4; 1 H NMR (400 MHz, DMSO-d6) δ 13.29 (brs, 1H), 8.83 (s, 1H), 8.53 (s, 1H), 8.18 (s, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 3.57 (s, 3H), 2.95 (t, J = 7.6 Hz, 2H), 2.60 (s, 3H), 2.49 (s, 3H), 1.63 (m, 2H), 0.73 (m, 1H), 0.41-0.36 (m, 2H), 0.06-0.01 (m, 2H).

[0343] Example 56 N-(6-(3-hydroxypropyl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide [ka] Step 1: Ethyl(E)-3-(2-(5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide)thiazolo[4,5-b]pyrazine-6-yl)acrylate(56-1)

[0343] A solution of Example 13 (203 mg, 0.43 mmol) in 1,4-dioxane (5 mL) and water (1 mL) is prepared by adding ethyl(E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (117.6 mg, 0.52 mmol) and Pd(dppf)Cl2 .CH2Cl2 (32.4 mg, 0.04 mmol) and Cs2CO3 (277 mg, 0.85 mmol) were added under N2 conditions. The mixture was degassed and stirred at 100°C for 3 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with PE / Â(1:1) to obtain ethyl(E)-3-(2-(5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide)thiazolo[4,5-b]pyrazine-6-yl)acrylate (56-1, 150 mg). LC-MS (ESI, m / z): [M+H] + = 491.3.

[0344] Step 2: Ethyl 3-(2-(5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide)thiazolo[4,5-b]pyrazine-6-yl)propanoate(56-2)

[0344] NaBH4 (11 mg, 0.306 mmol) was added at 0°C to a solution of ethyl(E)-3-(2-(5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide)thiazolo[4,5-b]pyrazine-6-yl)acrylate (56-1, 150 mg, 0.306 mmol) and NiCl2 (4 mg, 0.031 mmol) in MeOH (5 mL). After stirring at room temperature for 2 hours, the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (0.1% FA) to obtain ethyl 3-(2-(5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide)thiazolo[4,5-b]pyrazine-6-yl)propanoate (56-2, 90 mg). LCMS (ESI, m / z): [M+H] + = 493.2.

[0345] Step 3: N-(6-(3-hydroxypropyl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide(56)

[0345] To a solution of ethyl 3-(2-(5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide)thiazolo[4,5-b]pyrazine-6-yl)propanoate (56-2, 90 mg, 0.182 mmol) in dry THF (5 mL), LiAlH4 (7 mg, 0.182 mmol) and NaBH4 (11 mg, 0.306 mmol) were added under N2 at -70°C. After stirring at -70°C for 1 hour, the reaction mixture was quenched with water and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (0.05% NH4HCO3) to obtain Example 56. LCMS (ESI, m / z): [M+H] + = 451.3; 1 H NMR (400 MHz, DMSO-d6): δ 13.31 (brs, 1H), 8.83 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 7.42 (s, 1H), 7.34 (s, 1H), 4.50 (brs, 1H), 3.58 (s, 3H), 3.46 (t, J = 6.4 Hz, 2H), 2.92 (t, J = 6.4 Hz, 2H), 2.61 (s, 3H), 2.49 (s, 3H), 1.89 (m, 2H).

[0346] Example 57 N-(6-(cyclohexylethinyl)thiazolo[4,5-b]pyrazine-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide [ka]

[0346] To a solution of intermediate AS (80.0 mg, 0.16 mmol) in DMF (2 mL), ethynylcyclohexane (85.3 mg, 0.79 mmol), CuI (3.8 mg, 0.020 mmol), Et3N (81 mg, 0.80 mmol), and Pd(PPh3)2Cl2 (14.1 mg, 0.020 mmol) were added under N2 conditions. The mixture was degassed and stirred at 55°C for 16 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was purified by preparative HPLC (0.1% FA) to obtain Example 57. LC-MS (ESI, m / z): [M+H] + = 535.4; 1H NMR (400 MHz, DMSO-d6): δ 13.56 (brs, 1H), 8.93 (s, 1H), 8.58 (s, 1H), 8.46 (s, 1H), 7.71 (s, 1H), 7.43 (s, 1H), 6.99 (t, J = 55.2 Hz, 1H), 3.70 (s, 3H), 2.73 (m, 1H), 2.61 (s, 3H), 1.88-1.85 (m, 2H), 1.72-1.68 (m, 2H), 1.52-1.48 (m, 3H), 1.38-1.34 (m, 3H).

[0347]

[0347] The examples in the following table were synthesized via Sonogashira coupling reaction from the corresponding bromides and commercially available alkynes, using conditions similar to those used to synthesize Example 57. [Table 10] TIFF2026522322000192.tif204149TIFF2026522322000193.tif204149TIFF2026522322000194.tif195149TIFF20265223220 00195.tif197149TIFF2026522322000196.tif180149TIFF2026522322000197.tif194149TIFF2026522322000198.tif123149

[0348] Example 81 N-(6-(3,3-difluoropropane-1-in-1-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide [ka] Step 1: N-(6-(3,3-diethoxypropane-1-in-1-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide(81-1)

[0348] To a solution of Example 13 (2.0 g, 4.24 mmol) in DMF (10 mL), 3,3-diethoxypropane-1-yne (1.63 g, 12.6 mmol), Pd(PPh3)2Cl2 (0.30 g, 0.43 mmol), CuI (81 mg, 0.43 mmol), and Et3N (2.15 g, 21.3 mmol) were added under N2 conditions. The mixture was degassed and stirred at 45°C for 2 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (0.05% NH4HCO3) to obtain N-(6-(3,3-diethoxypropane-1-in-1-yl)thiazolo[4,5-b]pyrazine-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (81-1, 1.50 g). LCMS (ESI, m / z): [M+H] + = 519.2.

[0349] Step 2: 5'-Methoxy-2',6-dimethyl-N-(6-(3-oxopropa-1-in-1-yl)thiazolo[4,5-b]pyrazine-2-yl)-[4,4'-bipyridine]-3-carboxamide(81-2)

[0349] A solution of N-(6-(3,3-diethoxypropa-1-in-1...

Claims

1. Compounds of formula K or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula: Ring A is either a phenyl ring or a 5-10 membered heteroaryl ring having 1-4 ring heteroatoms independently selected from N, O, and S; R １ is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 3-10 membered carbocyclic, or optionally substituted 5-10 membered heterocyclic or heteroaryl, preferably R １ It is located in the ortho position relative to the amide group (-C(O)-NH-) shown in formula K; The subscript m is an integer between 0 and 4, as far as the valence allows; R ２ is, independently for each occurrence, deuterium, halogen, OH, NH ２ , CN, SF ５ , COOH, CONH ２ , SO ２ NH ２ , R ２０ , OR ２０ , SR ２０ , N(R ２０ )(R ２１ ), SO ２ R ２０ , S(=O)(=NR ２１ )R ２０ , SO ２ N(R ２０ )(R ２１ ), N(R ２１ )SO ２ R ２０ , COR ２０ , COOR ２０ , OC(O)R ２０ , CON(R ２０ )(R ２１ ), or N(R ２１ )COR ２０ ; and R ２０ is, independently for each occurrence, optionally substituted C １～６ alkyl, optionally substituted C ２～６ alkenyl, optionally substituted C ２～６ alkynyl, optionally substituted C １～６ heteroalkyl, or an optionally substituted 3- to 10-membered ring structure; and R ２１ is, independently for each occurrence, hydrogen, optionally substituted C １～６ alkyl, optionally substituted C ３～６ alkenyl, optionally substituted C ３～６ alkynyl, optionally substituted C １～６ heteroalkyl, or an optionally substituted 3- to 10-membered ring structure; or, where applicable, R ２０ and R ２１ are joined together with one or more intervening atoms (e.g., nitrogen atoms) to form an optionally substituted 4- to 8-membered heterocyclic ring? or R ２ Two of these are bonded together to form a 4- to 7-membered ring, which may be substituted; R Ｊ C may be hydrogen, halogen, or substituted C １～６ Alkyl, optionally substituted C ２～６ Alkenyl, C may be substituted. ２～６ Alkynyl, C may be substituted. １～６ It is a heteroalkyl or possibly substituted 3- to 10-membered ring structure; L is C １～４ Alkylene, C ２～４ Alkenylene, C ２～４ Alkynylene, or C １～４ These are heteroalkylenes, each of which may be substituted with deuterium and / or F. R Ｋ C may be hydrogen, deuterium, or substituted. １～６ Alkyl, optionally substituted C １～６ (It is a heteroalkyl or possibly substituted 3- to 10-membered ring structure.)

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by having a structure according to formula K-1. 【Chemistry 2】

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized by having a structure according to formula K-2. 【Transformation 3】

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized by having a structure according to formula K-3. 【Chemistry 4】

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized by having a structure according to formula K-4. 【Transformation 5】

6. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized by having a structure according to formula K-5. 【Transformation 6】

7. A compound according to any one of claims 1 to 3 or 6, or a pharmaceutically acceptable salt thereof, characterized by having a structure according to formula K-6. 【Transformation 7】

8. L is C ２～４ Alkilen, 【Transformation 8】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. R Ｋ However, C may be substituted. ３～８ A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl compound.

10. R Ｋ However, the C is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and each of these may be substituted with deuterium, F, OH, CN, or F. １～４ C may be substituted with alkyl or F. １～４ C may be substituted with heteroalkyl, deuterium, halogen, CN, OH, oxo, or F. １～４ C which may be substituted with alkyl and F １～４ A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, which may be substituted with one or more substituents independently selected from a 3- to 6-membered ring that may be independently substituted with one or more substituents independently selected from a heteroalkyl group, for example, one to five substituents.

11. R Ｋ but: 【Chemistry 9】 A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from among.

12. R Ｋ The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein the compound is a substituted 4 to 8-membered heterocycline.

13. R Ｋ However, the C is a 4-6 membered heterocycline having one or two ring heteroatoms, each independently being O, S, or N, and if a sulfur atom is present, it may be oxidized, and the 4-6 membered heterocycline may be substituted with deuterium, F, oxo, OH, CN, deuterium and / or F. １～４ C may be substituted with alkyl, deuterium, and / or F. １～４ Heteroalkyl, 3-6 membered ring, (C １～４ Alkylene)-(3-6 membered ring), or (C) １～４ The heteroalkylene may be substituted with one or more substituents (e.g., 1 to 3) independently selected from a (3- to 6-membered ring), and the C １～４ Alkylene or C １～４ The heteroalkylene may be substituted with deuterium and / or fluorine, and each of the 3- to 6-membered rings may be substituted with deuterium, halogen, CN, OH, oxo, or fluorine. １～４ C which may be substituted with alkyl and F １～４ The compound according to claim 12 or a pharmaceutically acceptable salt thereof, which may be substituted with one or more substituents independently selected from heteroalkyl groups.

14. R Ｋ but: 【Chemistry 10】 A compound according to claim 12 or 13, or a pharmaceutically acceptable salt thereof, selected from the above.

15. R Ｋ The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein the compound is a substituted five-membered or six-membered heteroaryl.

16. R Ｋ However, it is a five-membered heteroaryl having 1 to 4 ring heteroatoms, each independently being O, S, or N, and the five-membered heteroaryl may be substituted with F, Cl, OH, CN, deuterium and / or F. １～４ C may be substituted with alkyl, deuterium, and / or F. １～４ Heteroalkyl, 3-6 membered ring, (C １～４ Alkylene)-(3-6 membered ring), or (C) １～４ The heteroalkylene may be substituted with 1 to 3 substituents independently selected from a (3-6 membered ring), and the C １～４ Alkylene or C １～４ The heteroalkylene may be substituted with deuterium and / or fluorine, and each of the 3- to 6-membered rings may be substituted with deuterium, halogen, CN, OH, oxo, or fluorine. １～４ C which may be substituted with alkyl and F １～４ The compound according to claim 15 or a pharmaceutically acceptable salt thereof, which may be substituted with one or more substituents independently selected from heteroalkyl groups.

17. R Ｋ is a 5-membered heteroaryl selected from pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and the 5-membered heteroaryl is optionally substituted with F, Cl, OH, CN, deuterium, and / or F, C １～４ alkyl, optionally substituted with deuterium and / or F, C １～４ heteroalkyl, a 3- to 6-membered ring, (C １～２ alkylene)-(3- to 6-membered ring), or (C １～２ heteroalkylene)-(3- to 6-membered ring), and is optionally substituted with 1 to 3 substituents independently selected therefrom, wherein the C １～２ alkylene or C １～２ heteroalkylene is optionally substituted with deuterium and / or F, and preferably, each of the 3- to 6-membered rings is independently selected from (a) C ３～６ cycloalkyl optionally substituted with methyl and / or F; or (b) a 4- to 6-membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O, S, and N, and when a sulfur atom is present, it may be oxidized, and the 4- to 6-membered heterocyclyl is optionally substituted with deuterium, F, OH, oxo, CN, F, C １～４ alkyl, or C １～４ heteroalkyl optionally substituted with 1 to 3 substituents independently selected therefrom, the compound according to claim 15 or 16, or a pharmaceutically acceptable salt thereof.

18. R Ｋ but, 【Chemistry 11】 The compound according to any one of claims 15 to 17 or a pharmaceutically acceptable salt thereof. (In the formula: q is 0, 1, 2, or 3; G １０ is, independently for each occurrence, F, Cl, CN, deuterium and / or C optionally substituted with F １～４ alkyl, deuterium and / or C optionally substituted with F １～４ heteroalkyl, a 3- to 6-membered ring, (C １～２ alkylene)-(3- to 6-membered ring), or (C １～２ heteroalkylene)-(3- to 6-membered ring), wherein the C １～２ alkylene or C １～２ heteroalkylene may be optionally substituted with deuterium and / or F, and preferably, for each occurrence, the 3- to 6-membered ring is independently selected from (a) C optionally substituted with methyl and / or F ３～６ cycloalkyl; or (b) a 4- to 6-membered heterocyclyl having one or two ring heteroatoms independently selected from O, S, and N, wherein the sulfur atom, if present, may be oxidized, and the 4- to 6-membered heterocyclyl is optionally substituted with deuterium, F, OH, oxo, CN, C optionally substituted with F １～４ alkyl, or C optionally substituted with F １～４ heteroalkyl, and may be optionally substituted with 1 to 3 substituents independently selected therefrom).

19. R Ｋ but: 【Chemistry 12】 A compound according to claim 18 or a pharmaceutically acceptable salt thereof, selected from the above. (In the formula: G １０Ａ Each C may be independently substituted with deuterium and / or F. １～４ Alkyl, 3-6 membered ring, or (C １～２ Alkylene)-(3-6 membered ring), and the C １～２ Alkylene or C １～２ The heteroalkylene may be substituted with deuterium and / or fluorine, and preferably, each of the 3- to 6-membered rings may be substituted with (a) methyl and / or fluorine. ３～６ Cycloalkyl; or (b) a 4- to 6-membered heterocycline independently selected from one or two ring heteroatoms independently selected from O, S, and N, wherein the sulfur atom may be oxidized if present, and the 4- to 6-membered heterocycline may be substituted with deuterium, F, OH, oxo, CN, or F. １～４ C may be substituted with alkyl or F. １～４ It may also be substituted with 1 to 3 substituents independently selected from the heteroalkyl group; G １０Ｂ Each instance independently contains F, Cl, CN, or G １０Ａ (That is the case.)

20. G １０Ａ However, each C may be independently substituted with deuterium and / or F. １～４ Alkyl (e.g., methyl), cyclopropyl, cyclobutyl, (C １～２ Alkylene)-(cyclopropyl), or (C) １～２ The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein the compound is alkylene)-(cyclobutyl).

21. G １０Ｂ However, each C may be independently substituted with F, Cl, deuterium and / or F. １～４ Alkyl (e.g., methyl), cyclopropyl, cyclobutyl, (C １～２ Alkylene)-(cyclopropyl), or (C) １～２ The compound according to claim 19 or 20, or a pharmaceutically acceptable salt thereof, wherein the compound is alkylene)-(cyclobutyl).

22. R Ｋ but: 【Chemistry 13】 A compound according to claim 15 or 16, or a pharmaceutically acceptable salt thereof, selected from the above.

23. R Ｋ However, the C is a six-membered heteroaryl having one or two ring nitrogen atoms, for example, pyridyl, pyrimidyl, and the six-membered heteroaryl may be substituted with F, Cl, OH, CN, deuterium and / or F. １～４ C may be substituted with alkyl, deuterium, and / or F. １～４ Heteroalkyl, 3-6 membered ring, (C １～４ Alkylene)-(3-6 membered ring), or (C) １～４ The heteroalkylene may be substituted with 1 to 3 substituents independently selected from a (3-6 membered ring), and the C １～４ Alkylene or C １～４ The heteroalkylene may be substituted with deuterium and / or fluorine, and each of the 3- to 6-membered rings may be substituted with deuterium, halogen, CN, OH, oxo, or fluorine. １～４ C which may be substituted with alkyl and F １～４ The compound according to claim 15 or a pharmaceutically acceptable salt thereof, which may be substituted with one or more substituents independently selected from heteroalkyl groups.

24. R Ｊ A compound according to any one of claims 1, 2, and 8 to 23, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

25. The compound according to any one of claims 1 to 3 and 8 to 24 or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl ring, or a five-membered or six-membered heteroaryl ring having one to three ring heteroatoms independently selected from N, O, and S, for example, a pyridine ring.

26. The compound according to any one of claims 1 to 3 and 8 to 24, or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl, pyridinyl, pyrimidinyl, or imidazo[1,2-a]pyridinyl ring, preferably a phenyl or pyridinyl ring.

27. In formula K 【Chemistry 14】 Part of it: 【Chemistry 15】 A compound according to any one of claims 1 to 3 and 8 to 24, or a pharmaceutically acceptable salt thereof, selected from among.

28. m is 0, 1, or 2, and R ２ However, independently of each presence, deuterium, halogen, CN, OH, (C １～４ Alkylene)-CN, G Ａ , or X ａ -X ｂ -G Ａ And, X ａ However, each existence is independent of non-existence, C １～４ Alkylene, or C １～４ It is a heteroalkylene; X ｂ However, each existence is independent of non-existence, 【Chemistry 16】 , O, NH, N(G Ｂ ), C(O), C(O)O, C(O)NH, C(O)N(G Ｂ ), NHCO, N(G Ｂ ), C(O), SO ２ , S(=O)(=NH), S(=O)(=NG Ｂ ), SO ２ NH, or SO ２ N(G Ｂ ); G Ａ However, each entity exists independently: (i) Deuterium, halogen, OH, C, each independently １～４ Alkoxy, C(O)-NH(C １～４ Alkyl), C(O)-N(C １～４ (Alkyl) (C １～４ C may be substituted with one or more substituents (e.g., 1 to 3) that are alkyl or 3- to 6-membered rings. １～６ Alkyl; (ii) Deuterium, halogen, oxo, C independently １～４ Alkyl, C １～４ C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. １～６ heteroalkyl; (iii) Each independently: deuterium, halogen, oxo, OH, CN, C １～４ Alkyl, C １～４ Alkoxy, C(O)NH ２ , C(O)-NH(C １～４ Alkyl), C(O)-N(C １～４ (Alkyl) (C １～４ Alkyl), 【Chemistry 17】 The nitrogen-containing ring E is a 3-8 membered carbocyclic or heterocyclic ring, which may be substituted with one or more substituents (e.g., 1 to 3), and the nitrogen-containing ring E is a 4-8 membered heterocyclic ring or a 3-6 membered ring; or (iv) Deuterium, halogen, OH, CN, C, each independently １～４ Alkyl, C １～４ Five-membered or six-membered heteroaryls which may be substituted with one or more substituents (e.g., one to three) that are alkoxy or three- to six-membered rings (preferably carbocyclic or heterocyclic rings). And, Each C in (i) to (iv) １～４ Alkyl or C １～４ Alkoxy compounds are each independently composed of deuterium, halogen, OH, and C. １～４ It may be independently substituted with one or more substituents (e.g., 1 to 3) that are alkoxys or 3- to 4-membered carbon-cyclic or heterocyclic rings. Each of the three to six-membered rings in (i) to (iv) or ring E may be independently substituted with oxo, deuterium, halogen, OH, CN, deuterium, or F. １～４ C may be substituted with alkyl, deuterium, or fluorine. １～４ It may be independently substituted with one or more (e.g., 1 to 3) substituents that are alkoxy; G Ｂ However, each C may be independently substituted with deuterium, halogen, OH, deuterium, or F. １～４ C may be substituted with alkoxy, oxo, deuterium, halogen, OH, CN, deuterium, or F. １～４ C may be substituted with alkyl, deuterium, or fluorine. １～４ A 3- to 6-membered ring which may be substituted with an alkoxy, and which may be substituted with one or more substituents (e.g., 1 to 3) C １～６ Alkyl or Where applicable, G Ａ and G Ｂ These atoms are bonded together to form a 4- to 8-membered heterocyclic ring, and each of these heterocyclic rings may be independently substituted with a halogen, oxo, OH, or F. １～４ C may be substituted with alkyl or F. １～４ It is an alkoxy, and may be substituted with one or more substituents (e.g., 1 to 3), A compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein m is 0.

30. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein m is 1.

31. In formula K [Chemistry 18] Some of them 【Chemistry 19】 The compound according to claim 30 or a pharmaceutically acceptable salt thereof.

32. R ２ However, each instance may independently be substituted with (i) deuterium, F, and / or OH. １～４ Alkyl, e.g., methyl, difluoromethyl, or hydroxymethyl; (ii) each independently of halogen, OH, CN, C １～４ Alkyl, C １～４ It may be substituted with 1 to 3 substituents that are alkoxy or 3 to 5-membered carboncyclic or heterocyclic rings, C １～４ Alkyl or C １～４ Each alkoxy independently contains deuterium, halogen (e.g., F), OH, and C. １～４ A five- or six-membered heteroaryl, which may be substituted with one or more substituents (e.g., one to three) that are alkoxy or three- to five-membered carbon-cyclic or heterocyclic rings, and each of the three- to five-membered carbon-cyclic or heterocyclic rings, if present, may be independently substituted with deuterium, F, OH, and / or methyl; or (iii) for example, G Ａ and G Ｂ However, each C may be independently substituted with deuterium, F, and / or OH. １～４ Alkyl or G Ａ and G Ｂ However, they bond together with the nitrogen atoms to which they are bonded to form a 4- to 8-membered heterocyclic ring, and this heterocyclic ring may be substituted (C １～４ Alkylene)-C(O)NHG Ａ , - (C １～４ Alkylene)-C(O)N(G) Ａ ) (G Ｂ ), or -(C １～４ A compound according to any one of claims 1 to 27, 30, and 31, or a pharmaceutically acceptable salt thereof, wherein the compound is alkylene-CN.

33. R １ The compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, wherein the compound is phenyl, pyridinyl, pyrimidinyl, benzopyrazolyl, benzimidazolyl, imidazolyl, pyridazyl, imidazo[1,2-a]pyrimidinyl, oxazolo[4,5-b]pyrimidinyl, oxazolo[5,4-b]pyrimidinyl, thiazolo[4,5-b]pyrimidinyl, benzo[d]thiazole, indazol, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-b]pyrimidinyl, or tetrazolo[1,5-a]pyrimidinyl, and each of these may be substituted.

34. R １ However, these are phenyl or pyridinyl, and each of these is deuterium, halogen, CN, OH, NH ２ , COOH, CONH ２ , (C １～４ Alkylene)-CN, G Ｃ , or X ｃ -X ｄ -G Ｃ It may be substituted with 1 to 3 substituents independently selected from the above, X ｃ However, each existence is independent of non-existence, C １～４ Alkylene, or C １～４ It is a heteroalkylene; X ｄ However, each existence is independent of non-existence, O, NH, N(G) Ｄ ), C(O), C(O)O, C(O)NH, C(O)N(G Ｄ ), NHC(O), N(G Ｄ )C(O), P(O)(G Ｄ ), SO ２ SO ２ NH, or SO ２ N(G) Ｄ ) and; G Ｃ However, each entity exists independently: (i) Deuterium, halogen, OH, C, each independently １～４ C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. １～６ Alkyl; (ii) Deuterium, halogen, C １～４ Alkyl, C １～４ C may be substituted with one or more substituents (e.g., 1 to 3) that are alkoxy or 3- to 6-membered rings. １～６ heteroalkyl; (iii) Each independently: deuterium, halogen, oxo, OH, CN, C １～４ Alkyl, C １～４ An alkoxy, or a 3- to 6-membered ring, which may be substituted with one or more (e.g., 1 to 3) substituents, a 3- to 7-membered carbocyclic or heterocyclic ring; or (iv) Deuterium, halogen, OH, CN, C, each independently １～４ Alkyl, C １～４ Five-membered or six-membered heteroaryls which may be substituted with one or more substituents (e.g., one to three) that are alkoxy or three- to six-membered rings (preferably carbocyclic or heterocyclic rings). And, C in each of (i) to (iv) １～４ Alkyl or C １～４ Each alkoxy independently contains deuterium, halogen, OH, and C. １～４ It may be independently substituted with one or more substituents (e.g., 1 to 3) that are alkoxys or 3- to 4-membered carbon-cyclic or heterocyclic rings. Each of the 3-6 membered rings in (i) to (iv) may be substituted with oxo, deuterium, halogen, OH, CN, deuterium, or F. １～４ C may be substituted with alkyl, deuterium, or fluorine. １～４ They may also be independently substituted with alkoxy compounds; G Ｄ However, each C may be independently substituted with deuterium, halogen, OH, deuterium, or F. １～４ C may be substituted with alkoxy, oxo, deuterium, halogen, OH, CN, deuterium, or F. １～４ C may be substituted with alkyl, deuterium, or fluorine. １～４ A 3- to 6-membered ring which may be substituted with an alkoxy, and which may be substituted with one or more substituents (e.g., 1 to 3) C １～６ Alkyl or Where applicable, G Ｃ and G Ｄ However, both of these can bond together with the heteroatom to form a 4- to 7-membered heterocyclic ring, and each of these 4- to 7-membered heterocyclic rings may be independently substituted with a halogen, oxo, OH, deuterium, or F. １～４ C may be substituted with alkyl, deuterium, or fluorine. １～４ A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, which may be substituted with one or more (e.g., 1 to 3) substituents that are alkoxy.

35. R １ However, C is either phenyl or pyridinyl, and each of these may be substituted with a halogen, deuterium, F, CN, and / or OH. １～６ C may be substituted with alkyl, deuterium, F, CN, and / or OH. １～６ C may be substituted with alkoxy, deuterium, F, CN, methyl, and / or OH. ３～６ Cycloalkyl, NH ２ NH(C １～４ Alkyl), or N(C) １～４ (Alkyl) (C １～４ A compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, which may be substituted with one or more substituents (e.g., 1 to 3) independently selected from alkyl groups.

36. R １ C is phenyl or pyridinyl, and each of these may be substituted with a halogen, deuterium, F, and / or OH. １～４ C may be substituted with alkyl, deuterium, or F. １～４ C may be substituted with alkoxy, deuterium, F, CN, methyl, and / or OH. ３～４ Cycloalkyl, NH ２ NH(C １～３ Alkyl), or N(C) １～３ (Alkyl) (C １～３ A compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, which may be substituted with one or more substituents (e.g., 1 to 3) independently selected from alkyl groups.

37. R １ These are phenyl or pyridinyl, and each of these is methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, -NH ２ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 32, which may be substituted with one to three substituents independently selected from hydroxymethyl and 1-hydroxyethyl, preferably the substituents being independently selected from methyl, fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, ethoxy, difluoromethoxy, and cyclopropyl.

38. R １ but, 【Chemistry 20】 And, R １ａ and R １ｂ However, each C may be independently substituted with a halogen, deuterium, F, CN, and / or OH. １～６ C may be substituted with alkyl, deuterium, F, CN, and / or OH. １～６ C may be substituted with alkoxy, deuterium, F, CN, methyl, and / or OH. ３～６ Cycloalkyl, NH ２ NH(C １～４ Alkyl), or N(C) １～４ (Alkyl) (C １～４ A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, which is alkyl.

39. R １ｂ However, C may be substituted with 1 to 3 deuterium atoms or F atoms. １～４ The compound according to claim 38 or a pharmaceutically acceptable salt thereof, wherein the compound is an alkoxy, for example, methoxy, ethoxy, or difluoromethoxy.

40. R １ａ However, (i) a halogen (e.g., F or Cl); (ii) C which may be substituted with 1 to 3 deuterium atoms or F １～４ The compound according to claim 38 or 39 or a pharmaceutically acceptable salt thereof, wherein the alkyl is, for example, methyl, trifluoromethyl, difluoromethyl, etc.; or (iii) cyclopropyl or cyclobutyl which may be substituted with methyl and / or F.

41. A compound selected from Table 1 or Examples 1 to 145, or a pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, and an optionally pharmaceutically acceptable excipient.

43. A method for treating a disease or disorder in a subject requiring such treatment, wherein the disease or disorder is characterized by overexpression of Polθ, and the method comprises the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 42.

44. The method according to claim 43, wherein the disease or disorder is cancer.

45. A method for treating homologous recombination (HR) deficiency cancer in a subject requiring such treatment, comprising the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 42.

46. A method for treating cancer in a subject requiring such treatment, wherein the cancer is characterized by reduced or absent BRCA gene expression, absence of the BRCA gene, and / or impaired function of the BRCA protein, and the method comprises the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 42.

47. The method according to any one of claims 44 to 46, wherein the cancer is selected from lymphoma, rhabdoid tumor, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblastic carcinoma, central nervous system cancer, urinary tract cancer, upper respiratory tract and gastrointestinal cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer.

48. The method according to any one of claims 43 to 47, further comprising the step of administering to the subject one or more additional therapeutic agents selected from PARP inhibitors, signaling inhibitors, chemotherapeutic agents, and / or immune checkpoint inhibitors.

49. A method for treating cancer in a subject requiring such treatment, wherein the cancer is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy, and the method comprises the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 42.

50. The method according to claim 49, wherein the cancer is breast cancer, ovarian cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, pancreatic cancer, gastrointestinal cancer, or colorectal cancer.

51. The method according to claim 49 or 50, further comprising the step of administering a PARP inhibitor to the subject.

Images