Bicyclic heteroaryl-containing compounds as IKZF2 degraders

Abstract

Described herein are compounds of formula II, and their pharma- ceutically acceptable salts, solvates, or stereoisomers, and their uses in the treatment or prevention of diseases or disorders (eg, as IKZF2 degraders).

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 323,656, filed March 25, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] background IKAROS family zinc finger 2 (IKZF2) (also known as Helios) is one of five members of the Ikaros family of transcription factors found in mammals. IKZF2 contains four zinc finger domains near its N-terminus involved in DNA binding and two zinc finger domains at its C-terminus involved in protein dimerization. IKZF2 is approximately 50% identical to the Ikaros family members Ikaros (IKZF1), Aiolos (IKZF3), and Eos (IKZF4), with the highest homology (80%+ identity) in the zinc finger region. These four Ikaros family transcription factors bind to the same DNA consensus site and can heterodimerize with each other when coexpressed in cells. The fifth Ikaros family protein, Pegasus (IKZF5), is only 25% identical to IKZF2, binds to DNA sites distinct from other Ikaros family members, and does not readily heterodimerize with other Ikaros family proteins. IKZF2, IKZF1, and IKZF3 are primarily expressed in hematopoietic cells, whereas IKZF4 and IKZF5 are expressed in a wide variety of tissues.

[0003] IKZF2 is a key regulator of T cell activity and function. Genetic deletion of Helios resulted in enhanced antitumor immune responses. In particular, Helios is highly expressed in regulatory T cells, a subpopulation of T cells that limits the activity of effector T cells. Selective deletion of Helios in regulatory T cells resulted in both loss of suppressive activity and acquisition of effector T cell function. Thus, Helios is an important factor in limiting T cell effector function in Tregs. Anti-CTLA4 antibodies are currently used in the clinic to target Tregs within tumors. However, targeting CTLA4 often leads to systemic activation of T effector cells, resulting in excessive toxicity and limiting therapeutic utility. Up to three-quarters of patients treated with the combination of anti-PD-1 and anti-CTLA4 reported grade 3 or higher adverse events. Therefore, there is a strong need for compounds that target Tregs in tumors without causing systemic activation of T effector cells. IKZF2-specific degraders have the potential to focus an enhanced immune response to areas within or near the tumor, potentially providing a better tolerated and less toxic therapeutic agent for the treatment of cancer.

[0004] Helios expression has also been reported to be upregulated in "exhausted" T cells in both chronic viral infections and dysfunctional chimeric antigen receptor (CAR) T cells. Overexpression or aberrant expression of Helios and various splice isoforms has been reported in several hematologic malignancies, including T-cell leukemia and lymphoma. Furthermore, knockdown of Helios in a model of mixed lineage leukemia (MLL)-driven myeloid leukemia strongly suppressed proliferation and increased cell death. Consistent with these results, genomic profiling and chromatin accessibility analysis demonstrated that loss of IKZF2 resulted in increased myeloid differentiation. These data suggest that IKZF2 is differentially required in myeloid leukemia cells compared to normal cells. Thus, ablation of IKZF2 has preferential effects in leukemic stem cells compared to normal hematopoietic stem cells, providing a novel strategy for targeting leukemic stem cells. Summary of the Invention

[0005] overview In certain aspects, the present disclosure provides a compound of formula II: TIFF2025510834000001.tif28128 and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein each of the variables of Formula II is as described, embodied, and exemplified herein.

[0006] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0007] In certain aspects, the present disclosure further provides a method for degrading IKZF2 protein in a subject or biological sample, comprising administering to the subject a compound disclosed herein or contacting the biological sample with a compound disclosed herein.

[0008] In certain aspects, the present disclosure further provides the use of a compound disclosed herein in the manufacture of a medicament for degrading IKZF2 protein in a subject or biological sample.

[0009] In certain aspects, the present disclosure provides a compound disclosed herein for use in degrading IKZF2 protein in a subject or biological sample.

[0010] In certain aspects, the present disclosure provides a method of treating an IKZF2-mediated disease or disorder, comprising administering to a subject in need thereof a compound disclosed herein.

[0011] In certain aspects, the present disclosure provides the use of a compound disclosed herein in the manufacture of a medicament for treating an IKZF2-mediated disease or disorder.

[0012] In certain aspects, the present disclosure provides a compound disclosed herein for use in treating an IKZF2-mediated disease or disorder.

[0013] In certain aspects, the present disclosure provides methods of (a) increasing IL-2 production, (b) suppressing regulatory T cells, (c) enhancing effector T cells, (d) inhibiting tumor growth, and / or (e) enhancing tumor regression in a subject, comprising administering to a subject in need thereof a compound disclosed herein.

[0014] In certain aspects, the present disclosure provides for the use of a compound disclosed herein in the manufacture of a medicament for (a) increasing IL-2 production, (b) suppressing regulatory T cells, (c) enhancing effector T cells, (d) inhibiting tumor growth, and / or (e) enhancing tumor regression in a subject. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description The present disclosure relates to compounds and methods for degrading IKZF2 protein, comprising contacting the IKZF2 protein with an IKZF2 degrading agent. The present invention also relates to methods for treating an IKZF2 protein-mediated disease or disorder in a patient in need thereof by administering an IKZF2 degrading agent to the patient. The present invention further relates to a method for treating an IKZF2 protein-mediated disease or disorder in a patient, comprising administering to the patient in need thereof a pharmaceutical composition comprising an IKZF2 degrading agent.

[0016] Compounds of the Disclosure The present disclosure provides a compound of formula II: TIFF2025510834000002.tif28128 and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: W is -N(R 1 ) 2, 3 to 12-membered heterocyclyl, or 5 to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is selected from the group consisting of one or more R 1b may be substituted with The Two R's 1 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl, and the heterocyclyl or heteroaryl is 1b may be substituted with Each R 1b are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c Rd , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u or Two Vicinal R 1b together with the intervening atom, C 6~10 Form an aryl or a 5- to 10-membered heteroaryl, and the aryl or heteroaryl is one or more R u or Each R 1 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -(C 1~6 alkylene)-(C 6~10 aryl), -(C1~6 alkylene)-(5-10 membered heteroaryl), -(C 1~6 alkylene)-(C 3~12 carbocyclyl), -(C 1~6 alkylene)-(3-12 membered heterocyclyl), S(=O)R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R 1a may be substituted with Each R 1a are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)ORb , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with X is -[C(R 2 )2]- m , O, or NR X and X is O or NR X When W is a 3- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl, the heterocyclyl or heteroaryl may be selected from the group consisting of one or more R 1b may be substituted with Each R 2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b, -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with Two Germinal R 2 together to form an oxo, or Two Germinal R 2 together with the carbon atoms to which they are attached, form C 3~6 Form a carbocyclyl or a 3- to 6-membered heterocyclyl, and the carbocyclyl or heterocyclyl is one or more R u may be substituted with m is an integer from 0 to 5, R X is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(O)Ra , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with Ring A is a 9- or 10-membered bicyclic fused ring system containing at least one 5- or 6-membered heteroaryl; Each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR cR d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with n is an integer from 0 to 10, valence permitting, or Two Vicinal R A together with the intervening atom, C 3~12 Form a carbocyclyl or a 3- to 12-membered heterocyclyl, and the carbocyclyl or heterocyclyl is one or more R u may be substituted with Each R B are independently halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)ORb , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with p is an integer from 0 to 3, U is -C(R 4 )2- or -C(=O)-, Each R 4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u or The Two R's 4 together with the carbon atoms to which they are attached, form C 3~6 Form a carbocyclyl or a 3- to 6-membered heterocyclyl, and the carbocyclyl or heterocyclyl is one or more R u may be substituted with Each R D are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with d is an integer selected from 0 to 4, R 3 are hydrogen, deuterium, and C 1~6 Haloalkyl, or C 1~6 is alkyl, q is an integer from 0 to 2, Each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2-6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c Rd , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 optionally substituted with one or more substituents selected from carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, and 5- to 6-membered heteroaryl; The Two R's u together with one or more intervening atoms form a C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 forming a carbocyclyl or a 3- to 12-membered heterocyclyl; Each R a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; Each R b are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; Each R c and R d are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; or R c and R d together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is selected from the group consisting of oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 optionally substituted with one or more substituents selected from carbocyclyl and 3- to 6-membered heterocyclyl; R a , R b , R c , and R d each independently represents one or more R z may be substituted with Each R z are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0017] In certain embodiments, when ring A is a 10-membered bicyclic heteroaryl, ring A is not isoquinolinyl.

[0018] In certain embodiments, i) Ring A is: If the file is TIFF2025510834000003.tif14128, m is not 0, ii) Each R 1 are independently hydrogen, C 1~6 Alkyl, C 3~12 Carbocyclyl, or -C(=O)(C 1~6alkyl), 1) m is not 0, and 2) two geminal R 2 do not combine to form oxo, and iii) The compound is: Not TIFF2025510834000004.tif30128.

[0019] In certain embodiments, ring A is not pyrido[2,3-d]pyrimidinyl.

[0020] In certain embodiments, two R 1 together with the nitrogen atoms to which they are attached, form one or more R 1b and ring A is not pyrido[2,3-d]pyrimidinyl.

[0021] In certain embodiments, the compound is a compound of formula II-1: TIFF2025510834000005.tif30128 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0022] In certain embodiments, the compound is a compound of formula II-2: TIFF2025510834000006.tif31128 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0023] In certain embodiments, W is —N(R 1 ) 2, 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), or 5- to 10-membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S), wherein the heterocyclyl or heteroaryl is selected from one or more R 1b may be substituted with.

[0024] In certain embodiments, two R 1are, together with the nitrogen atom to which they are attached, a 3- to 12-membered heterocyclyl (e.g., a heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), or a 5- to 10-membered heteroaryl (e.g., a heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S), and the heterocyclyl or heteroaryl can be selected from one or more R 1b may be substituted with.

[0025] In certain embodiments, each R 1 are independently hydrogen, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 2~6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2~6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S), -(C 1~6 alkylene)-(C 6~10 aryl), -(C 1~6 alkylene)-(5-10 membered heteroaryl), -(C 1~6 alkylene)-(C 3~12 carbocyclyl), -(C 1~6 alkylene)-(3-12 membered heterocyclyl), -S(=O)R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R 1a may be substituted with.

[0026] In certain embodiments, each R 1 are independently hydrogen, C 1~6 Alkyl, -(C 1~6 alkylene)-(C 6~10 aryl), or -(C 1~6 alkylene)-(5- to 10-membered heteroaryl), wherein the alkyl, alkylene, aryl, or heteroaryl is selected from one or more R 1a may be substituted with.

[0027] In certain embodiments, each R 1aare independently oxo, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1~6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1~6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino amino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C 2~6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2~6Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S), -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c Rd , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0028] In certain embodiments, each R 1a are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be one or more R u may be substituted with.

[0029] In certain embodiments, each R 1a are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0030] In certain embodiments, each R 1a are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0031] In certain embodiments, each R 1a are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0032] In certain embodiments, each R 1a are independently halogen, C 1~6 Alkyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, and the alkyl, aryl, or heteroaryl may be one or more R u may be substituted with.

[0033] In certain embodiments, each R 1bare independently oxo, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1~6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1~6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino amino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C 2~6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2~6Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S), -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c Rd , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0034] In certain embodiments, each R 1b are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be one or more R u may be substituted with.

[0035] In certain embodiments, each R 1b are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0036] In certain embodiments, each R 1b are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0037] In certain embodiments, each R 1b are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0038] In certain embodiments, each R 1b are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 Carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, or -S(=O)2R aand the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from one or more R u may be substituted with.

[0039] In certain embodiments, each R 1b are independently oxo, halogen, -CN, -OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C6 aryl, 5-6 membered heteroaryl, or -S(=O)2R a and the alkyl, alkoxy, alkylamino, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0040] In certain embodiments, two vicinal R 1b together with the intervening atom, C 6~10 aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the aryl or heteroaryl is joined to one or more R u may be substituted with.

[0041] In certain embodiments, X is —[C(R 2 )2]- m , O, or NR X is.

[0042] In certain embodiments, X is —[C(R 2 )2] -m In certain embodiments, X is O. In certain embodiments, X is NR X In certain embodiments, X is O or NR X where W is a 3- to 12-membered heterocyclyl or a 5- to 10-membered heteroaryl, and the heterocyclyl or heteroaryl is selected from the group consisting of one or more R 1b may be substituted with.

[0043] In certain embodiments, each R2 are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1~6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1~6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino amino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C 2~6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2~6Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S), -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c Rd , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0044] In certain embodiments, each R 2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be one or more R u may be substituted with.

[0045] In certain embodiments, each R 2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0046] In certain embodiments, each R 2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0047] In certain embodiments, each R 2 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0048] In certain embodiments, each R 2 are independently hydrogen or C 1~6 In certain embodiments, each R 2 is hydrogen.

[0049] In certain embodiments, two geminal R 2 together to form oxo.

[0050] In certain embodiments, two geminal R 2 together with the carbon atoms to which they are attached, form C 3~6 forming a carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or a 3- to 6-membered heterocyclyl (e.g., a heterocyclyl containing one 3- to 6-membered ring and one to three heteroatoms selected from N, O, and S), wherein the carbocyclyl or heterocyclyl is selected from one or more R u may be substituted with.

[0051] In certain embodiments, m is an integer from 0 to 5. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5.

[0052] In certain embodiments, R X is hydrogen, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 2~6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2~6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), C 6~10 Aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S), -S(=O)R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0053] In certain embodiments, R X is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6Carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0054] In certain embodiments, R X is hydrogen, C 1~6 Alkyl, C 3~6 Carbocyclyl, 3-6 membered heterocyclyl, -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0055] In certain embodiments, ring A is a 9- or 10-membered bicyclic fused ring system containing at least one 5- or 6-membered heteroaryl (e.g., a heteroaryl containing one 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S).

[0056] In certain embodiments, ring A is selected from the group consisting of one 5- or 6-membered heteroaryl (e.g., a heteroaryl containing one 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S) and one C 5~6and 9- or 10-membered bicyclic fused ring systems, including carbocyclyl (e.g., cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or 5- to 6-membered heterocyclyl (e.g., heterocyclyl containing one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S).

[0057] In certain embodiments, ring A is a 9- or 10-membered bicyclic heteroaryl (e.g., a bicyclic heteroaryl containing two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S).

[0058] In certain embodiments, ring A is a 9-membered bicyclic heteroaryl (e.g., a bicyclic heteroaryl containing one 5-membered ring and one 6-membered ring and 1-5 heteroatoms selected from N, O, and S, wherein at least one of the 5-membered ring and the 6-membered ring is a heteroaryl).

[0059] In certain embodiments, ring A is a 9-membered bicyclic heteroaryl containing 1 to 4 nitrogen atoms.

[0060] In certain embodiments, Ring A is imidazo[1,5-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, indolyl, benzo[d]imidazolyl, indazolyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, benzo[d]isothiazolyl, benzo[d]thiazolyl, benzo[b]thiophenyl, or benzofuranyl.

[0061] In certain embodiments, TIFF2025510834000007.tif23128 is TIFF2025510834000008.tif177147, R 3a is hydrogen, C 1~6 Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -S(=O)2R a , S(=O)2OR b , -S(=O)2NR c R d , -C(O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0062] In certain embodiments, TIFF2025510834000009.tif23128 is The file is TIFF2025510834000010.tif126142.

[0063] In certain embodiments, TIFF2025510834000011.tif23128 is The file is TIFF2025510834000012.tif100157.

[0064] In certain embodiments, R 3a is hydrogen, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1~6 Heteroalkyl (e.g., C containing 1 to 3 heteroatoms selected from O, N, and S) 1~6 alkyl), C 2~6alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2~6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S), -(C 1~3 alkylene)-(C 3~6 carbocyclyl), -(C 1~3 alkylene)-(3- to 6-membered heterocyclyl), -(C 1~3 alkylene)-(C aryl), -(C 1~3 alkylene)-(5-6 membered heteroaryl), -S(=O)R a , -S(=O)2OR b, -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0065] In certain embodiments, R 3a is hydrogen, C 1~6 Alkyl, C 1~6 Heteroalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0066] In certain embodiments, R 3a is hydrogen, C 1~6 Alkyl, C 1~6 Heteroalkyl, C 3~6 Carbocyclyl, 3-6 membered heterocyclyl, -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R dand the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0067] In certain embodiments, R 3a is hydrogen, C 1~6 Alkyl, C 1~6 Heteroalkyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or -(C 1~3 alkylene)-(C aryl), and the alkyl, alkylene, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0068] In certain embodiments, ring A is a 10-membered bicyclic heteroaryl (e.g., a bicyclic heteroaryl comprising two 6-membered rings and 1-5 heteroatoms selected from N, O, and S, wherein at least one of the two 6-membered rings is a heteroaryl).

[0069] In certain embodiments, ring A is a 10-membered bicyclic heteroaryl containing 1-3 nitrogen atoms.

[0070] In certain embodiments, TIFF2025510834000013.tif23128 is The file is TIFF2025510834000014.tif43147.

[0071] In certain embodiments, ring A is selected from one 5- or 6-membered heteroaryl and one 5- to 6-membered heterocyclyl or C 5~6 It is a 9- or 10-membered bicyclic fused ring system containing a carbocyclyl.

[0072] In certain embodiments, ring A is selected from the group consisting of one 5- or 6-membered heteroaryl and one C5~6 It is a 9- or 10-membered bicyclic fused ring system containing a carbocyclyl.

[0073] In certain embodiments, TIFF2025510834000015.tif22128 is TIFF2025510834000016.tif20128.

[0074] In certain embodiments, each R A are independently oxo, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1~6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1~6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino amino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C 2~6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2~6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S), -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a, -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0075] In certain embodiments, each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be one or more R u may be substituted with.

[0076] In certain embodiments, each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0077] In certain embodiments, each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0078] In certain embodiments, each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0079] In certain embodiments, each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 Carbocyclyl, or 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, or -NR c S(=O)R aand the alkyl, alkoxy, alkylamino, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0080] In certain embodiments, each R A are independently oxo, halogen, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkynyl, C 3~6 Carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, or -NR c S(=O)R a and the alkyl, alkoxy, alkylamino, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0081] In certain embodiments, n is an integer from 0 to 10, valence permitting.

[0082] In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4, where valence allows. In certain embodiments, n is 5, where valence allows. In certain embodiments, n is 6, where valence allows. In certain embodiments, n is 7, where valence allows. In certain embodiments, n is 8. In certain embodiments, n is 9, where valence allows. In certain embodiments, n is 10, where valence allows.

[0083] In certain embodiments, two vicinal R A together with the intervening atom, C 3~12Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), forming a 3- to 12-membered heterocyclyl (e.g., a heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), and the carbocyclyl or heterocyclyl may be formed by one or more R u may be substituted with.

[0084] In certain embodiments, each R B are independently selected from halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1~6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1~6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino amino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C 2~6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2~6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S), -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a, OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0085] In certain embodiments, each R B are independently halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be one or more R u may be substituted with.

[0086] In certain embodiments, each R B are independently halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more Ru may be substituted with.

[0087] In certain embodiments, each R B are independently halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0088] In certain embodiments, each R B are independently halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0089] In certain embodiments, each R B are independently halogen, C 1~6 Alkyl or C 1~6 It is an alkoxy.

[0090] In certain embodiments, p is an integer from 0 to 3.

[0091] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.

[0092] In certain embodiments, U is —C(R 4 )2- or -C(=O)-.

[0093] In certain embodiments, each R 4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1~6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino amino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C 3~6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or 3- to 6-membered heterocyclyl (e.g., a heterocyclyl containing one 3- to 6-membered ring and one to three heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from one or more R u may be substituted with.

[0094] In certain embodiments, each R 4 are independently hydrogen or C 1~6 In certain embodiments, each R 4 is hydrogen.

[0095] In certain embodiments, two R 4 together with the carbon atoms to which they are attached, form C 3~6 forming a carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or a 3- to 6-membered heterocyclyl (e.g., a heterocyclyl containing one 3- to 6-membered ring and one to three heteroatoms selected from N, O, and S), wherein the carbocyclyl or heterocyclyl is selected from one or more R u may be substituted with.

[0096] In certain embodiments, each R D are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1~6Alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1~6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino amino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C 2~6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2~6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S); alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from one or more R u may be substituted with.

[0097] In certain embodiments, each R D are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R umay be substituted with.

[0098] In certain embodiments, each R D are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0099] In certain embodiments, each R D are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0100] In certain embodiments, d is an integer selected from 0-4.

[0101] In certain embodiments, d is 0. In certain embodiments, d is 1. In certain embodiments, d is 2. In certain embodiments, d is 3. In certain embodiments, d is 4.

[0102] In certain embodiments, R 3 are hydrogen, deuterium, and C 1~6 Haloalkyl (e.g., C containing 1 to 8 halogen atoms selected from -F, -Cl, and -Br) 1~6 alkyl), or C 1~6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)).

[0103] In certain embodiments, R 3 is hydrogen.

[0104] In certain embodiments, q is an integer from 0 to 2. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.

[0105] In certain embodiments, the compound is a compound of formula II-2: TIFF2025510834000017.tif29128 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: The Two R's 1 together with the nitrogen atoms to which they are attached, form one or more R 1b forming an optionally substituted 3- to 12-membered heterocyclyl; Each R 1b are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2ORb , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u or Two Vicinal R 1b together with the intervening atoms form a C6 aryl or a 5- to 6-membered heteroaryl, and the aryl or heteroaryl is u may be substituted with Each R 2 is hydrogen, m is 1, Ring A is a 9- or 10-membered bicyclic fused heteroaryl or one 5- or 6-membered heteroaryl and one C 5~6 a 9- or 10-membered bicyclic fused ring system containing a carbocyclyl; Each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is present in one or more R u may be substituted with n is an integer from 0 to 2, Each R B are independently halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is present in one or more R u may be substituted with p is an integer from 0 to 3, U is -CH2-, Each R D are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with d is an integer selected from 0 to 4, R 3 are hydrogen, deuterium, and C 1~6 Haloalkyl, or C 1~6 is alkyl, q is 1.

[0106] In certain embodiments, the compound is a compound of Formula I: TIFF2025510834000018.tif33128 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Each R 1 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, -(C 1~6 alkyl)-(C 6~14 aryl), -(C 1~6 alkyl)-(5- to 14-membered heteroaryl), -(C 1~6 alkyl)-(C 3~10 carbocyclyl), -(C 1~6 alkyl)-(3- to 10-membered heterocyclyl), where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R 1a may be substituted with Each R 1a are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10Carbocyclyl, 3- to 10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u or The Two R's 1 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl, the heterocyclyl being one or more R 1b may be substituted with Each R 1b are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with Each R 2 are independently hydrogen, halogen, -CN, NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a ,-OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with The Two R's 2 together to form an oxo, or The Two R's 2 together with the intervening atom, C 3~10Form a carbocyclyl or a 3- to 10-membered heterocyclyl, and the carbocyclyl or heterocyclyl is one or more R u may be substituted with m is an integer from 1 to 5, Ring A is a 9- or 10-membered bicyclic heteroaryl; Each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NRc R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with n is an integer from 0 to 10, as permitted by atomic valence; Each R B are independently halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b, or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with p is an integer from 0 to 3, U is -CH2- or -C(=O)-; R 3 are hydrogen, deuterium, and C 1~6 Haloalkyl, or C 1~6 is alkyl, q is an integer from 0 to 2, Here, each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NRc R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~10 optionally substituted with one or more substituents selected from carbocyclyl and 3- to 6-membered heterocyclyl; The Two R's u together with one or more intervening atoms form a C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 forming a carbocyclyl or a 3- to 10-membered heterocyclyl; Each R a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; Each R b are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; Each R c and R d are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; or R c and R d together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl; R a , R b , R c , and R d each independently represents one or more R z may be substituted with Each R z are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl or 3- to 6-membered heterocyclyl, with the proviso that when ring A is a 10-membered bicyclic heteroaryl, then ring A is not isoquinolinyl. A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0107] In certain embodiments, each R 1 are independently hydrogen, C 1~6 Alkyl, C 3~6 Carbocyclyl, 3- to 6-membered heterocyclyl, -(C 1~6 alkyl)-(C 6~10 aryl), -(C 1~6 alkyl)-(5-10 membered heteroaryl), -(C 1~6 alkyl)-(C 3~6 carbocyclyl), or -(C 1~6 alkyl)-(3- to 6-membered heterocyclyl), where the alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from one or more R 1a may be substituted with.

[0108] In certain embodiments, each R 1 are independently hydrogen, C 1~6 Alkyl, -(C1~6 alkyl)-(C 6~14 aryl), or -(C 1~6 alkyl)-(5- to 14-membered heteroaryl), where the alkyl, aryl, or heteroaryl is selected from one or more R 1a may be substituted with.

[0109] In certain embodiments, each R 1a are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0110] In certain embodiments, each R 1a are independently halogen, C 1~6 Alkyl, C 6~14 aryl, or 5- to 14-membered heteroaryl, and the alkyl, aryl, or heteroaryl may be one or more R u may be substituted with.

[0111] In certain embodiments, two R 1 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl, the heterocyclyl being one or more R 1b may be substituted with.

[0112] In certain embodiments, each R 1b are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 Carbocyclyl, 3- to 6-membered heterocyclyl, or -S(=O)2R aand the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from one or more R u may be substituted with.

[0113] In certain embodiments, each R 1b are independently halogen, C 1~6 Alkyl, C 6~14 Aryl, or -S(=O)R a and the alkyl or aryl is one or more R u may be substituted with.

[0114] In certain embodiments, each R 2 is hydrogen.

[0115] In certain embodiments, two R 2 together to form oxo.

[0116] In certain embodiments, two R 2 together with the carbon atoms to which they are attached, form C 3~10 It forms a carbocyclyl or a 3- to 10-membered heterocyclyl.

[0117] In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5.

[0118] In certain embodiments, Ring A is a 9-membered bicyclic heteroaryl containing 1-4 nitrogen atoms, and optionally 0-2 sulfur atoms, or 0-2 oxygen atoms.

[0119] In certain embodiments, Ring A is imidazo[1,5-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, indolyl, benzo[d]imidazolyl, indazolyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, benzo[d]isothiazolyl, benzo[d]thiazolyl, benzo[b]thiophenyl, or benzofuranyl.

[0120] In certain embodiments, ring A is a 9-membered bicyclic heteroaryl containing 1-3 nitrogen atoms.

[0121] In certain embodiments, TIFF2025510834000019.tif22128 is The file is TIFF2025510834000020.tif178162.

[0122] In certain embodiments, TIFF2025510834000021.tif22128 is The file is TIFF2025510834000022.tif24150.

[0123] In certain embodiments, Ring A is a 10-membered bicyclic heteroaryl containing 1-3 nitrogen atoms, and optionally 0-2 sulfur atoms, or 0-2 oxygen atoms.

[0124] In certain embodiments, ring A is a 10-membered bicyclic heteroaryl containing 1-3 nitrogen atoms.

[0125] In certain embodiments, TIFF2025510834000023.tif22128 is The file is TIFF2025510834000024.tif44159.

[0126] In certain embodiments, ring A is 5-6 membered heterocyclyl or C 5~6 It is a 6-membered heteroaryl fused to a carbocyclyl.

[0127] In certain embodiments, TIFF2025510834000025.tif22128 is TIFF2025510834000026.tif20128.

[0128] In certain embodiments, the compound is a compound of formula Ia, Ib, Ic, Id, Ie, or If: TIFF2025510834000027.tif119154 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0129] In certain embodiments, the compound is a compound of the following formula Ia-1, Ib-1, Ic-1, Id-1, Ie-1, or If-1: TIFF2025510834000028.tif123157 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0130] In certain embodiments, each R A are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0131] In certain embodiments, each R A independently, C 1~6 alkyl, which is one or more R u may be substituted with.

[0132] In certain embodiments, n is an integer from 0 to 8, as permitted by valence. In certain embodiments, n is an integer from 0 to 6, as permitted by valence. In certain embodiments, n is an integer from 0 to 5, as permitted by valence. In certain embodiments, n is an integer from 0 to 4, as permitted by valence. In certain embodiments, n is an integer from 0 to 3, as permitted by valence. In certain embodiments, n is an integer of 0 or 1, as permitted by valence. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8. In certain embodiments, n is 9. In certain embodiments, n is 10.

[0133] In certain embodiments, each R B are independently halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0134] In certain embodiments, each R B are independently halogen or C 1~6 alkoxy, which is one or more R u may be substituted with.

[0135] In certain embodiments, p is 0 or 1. In certain embodiments, p is 0. In certain embodiments, p is 1.

[0136] In certain embodiments, U is -CH2-. In certain embodiments, U is -C(=O)-.

[0137] In certain embodiments, R 3 are hydrogen, deuterium, halogens, C 1~6 Haloalkyl, or C 1~6 In certain embodiments, R 3 is hydrogen, deuterium, or C 1~6 In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is deuterium. In certain embodiments, R 3 is C 1~6 It is alkyl.

[0138] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.

[0139] In certain embodiments, each R a independently, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 2~6 Alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), or 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S), where the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0140] In certain embodiments, each R a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 It is carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl.

[0141] In certain embodiments, each R a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6It is a carbocyclyl or a 3- to 6-membered heterocyclyl.

[0142] In certain embodiments, each R a independently, C 1~6 Alkyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, carbocyclyl, or heterocyclyl may be one or more R u may be substituted with.

[0143] In certain embodiments, each R b are independently hydrogen, C 1~6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 2~6 Alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), or 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S), where the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0144] In certain embodiments, each R b are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 It is carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl.

[0145] In certain embodiments, each R b are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 It is a carbocyclyl or a 3- to 6-membered heterocyclyl.

[0146] In certain embodiments, each R b are independently hydrogen, C 1~6 Alkyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, or C 2~6 alkynyl, alkyl, carbocyclyl, or heterocyclyl may be one or more R u may be substituted with.

[0147] In certain embodiments, each R c and each R d are independently hydrogen, C 1~6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 2~6 Alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C 2~6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), or 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R umay be substituted with.

[0148] In certain embodiments, each R c and R d are independently hydrogen, C 1~6 Alkyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, carbocyclyl, or heterocyclyl may be one or more R u may be substituted with.

[0149] In certain embodiments, R c and R d together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl (e.g., a heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), and the heterocyclyl may be selected from one or more R u may be substituted with.

[0150] In certain embodiments, R a , R b , R c , and R d may independently be one or more R z may be substituted with.

[0151] In certain embodiments, R z are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 It is carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl.

[0152] In certain embodiments, each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1~6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1~6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino amino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C 2~6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2~6Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and one to five heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and one to five heteroatoms selected from N, O, and S), -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c Rd , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d , alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 It may be substituted with one or more substituents selected from carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, and 5- to 6-membered heteroaryl.

[0153] In certain embodiments, each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5-10 membered heteroaryl, and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 It may be substituted with one or more substituents selected from carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, and 5- to 6-membered heteroaryl.

[0154] In certain embodiments, each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 It may be substituted with one or more substituents selected from carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, and 5- to 6-membered heteroaryl.

[0155] In certain embodiments, each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is oxo, halogen, -CN, -NO2, -OH, -NH2, C1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 It may be substituted with one or more substituents selected from carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, and 5- to 6-membered heteroaryl.

[0156] In certain embodiments, each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 It may be substituted with one or more substituents selected from carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, and 5- to 6-membered heteroaryl.

[0157] In certain embodiments, two R u together with the carbon atoms to which they are attached, form C 3~6Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), 3- to 6-membered heterocyclyl (e.g., heterocyclyl containing one 3- to 6-membered ring and one to three heteroatoms selected from N, O, and S), C6 aryl (i.e., phenyl), or 5- to 6-membered heteroaryl (e.g., heteroaryl containing one 5- or 6-membered ring and one to three heteroatoms selected from N, O, and S), carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from one or more R z may be substituted with.

[0158] In certain embodiments, two R u together with the carbon atoms to which they are attached, form C 3~6 forming a carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or a 3- to 6-membered heterocyclyl (e.g., a heterocyclyl containing one 3- to 6-membered ring and one to three heteroatoms selected from N, O, and S), wherein the carbocyclyl or heterocyclyl is selected from one or more R z may be substituted with.

[0159] In certain embodiments, two geminal R u together with the carbon atoms to which they are attached, form C 3~6forming a carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or a 3- to 6-membered heterocyclyl (e.g., a heterocyclyl containing one 3- to 6-membered ring and one to three heteroatoms selected from N, O, and S), wherein the carbocyclyl or heterocyclyl is selected from one or more R z may be substituted with.

[0160] Where appropriate, embodiments of the variables in any of the formulas described herein are described above. Any of the variables can be any moiety described in the above embodiments. Furthermore, where appropriate, combinations of any moiety described for any of the variables with any moiety described for any of the remaining variables are also contemplated.

[0161] When a range of values ​​is listed, each discrete value and subrange within the range is also contemplated. For example, "C 1~6 "Alkyl" refers to 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 Alkyl is intended to be included.

[0162] In certain embodiments, the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof.

[0163] [Table 1] TIFF2025510834000030.tif210150TIFF2025510834000031.tif231154TIFF2025510834000032.tif215152TIFF2025510834000033.tif207152TIFF2025510834000034.tif225151TIFF2025510834000035.tif202151TIFF2025510834000036.tif217151TIFF2025510834000037.tif214152TIFF2025510834000038.tif214152TIFF2025510834000039.tif218152TIFF2025510834000040.tif213153TIFF2025510834000041.tif207151TIFF2025510834000042.tif211151TIFF2025510834000043.tif231152TIFF2025510834000044.tif220152TIFF2025510834000045.tif220153TIFF2025510834000046.tif211152TIFF2025510834000047.tif220150TIFF2025510834000048.tif198154TIFF2025510834000049.tif213151TIFF2025510834000050.tif204152TIFF2025510834000051.tif206152TIFF2025510834000052.tif198152TIFF2025510834000053.tif231152TIFF2025510834000054.tif199152TIFF2025510834000055.tif221151TIFF2025510834000056.tif231152TIFF2025510834000057.tif203151TIFF2025510834000058.tif230156TIFF2025510834000059.tif221151TIFF2025510834000060.tif208151TIFF2025510834000061.tif208152TIFF2025510834000062.tif213152TIFF2025510834000063.tif186152TIFF2025510834000064.tif218154TIFF2025510834000065.tif22015 3TIFF2025510834000066.tif211152TIFF2025510834000067.tif224152TIFF2025510834000068.tif217152TIFF2025 510834000069.tif213152TIFF2025510834000070.tif220151TIFF2025510834000071.tif204152TIFF2025510834000 072.tif209152TIFF2025510834000073.tif205151TIFF2025510834000074.tif212152TIFF2025510834000075.tif21 2151TIFF2025510834000076.tif232150TIFF2025510834000077.tif209152TIFF2025510834000078.tif219152TIFF 2025510834000079.tif219152TIFF2025510834000080.tif231155TIFF2025510834000081.tif208151TIFF202551083 4000082.tif212152TIFF2025510834000083.tif217152TIFF2025510834000084.tif232154TIFF2025510834000085.t if218152TIFF2025510834000086.tif215152TIFF2025510834000087.tif230152TIFF2025510834000088.tif239151.

[0164] The compounds of the present disclosure may have advantageous characteristics compared to known compounds, such as known IKZF2 degraders. For example, the compounds of the present disclosure may have more potent IKZF2 activity, more favorable pharmacokinetic properties (e.g., C max , T maxand / or AUC) and / or less interaction with other cellular targets (e.g., hepatocyte transporters such as OATP1B1), and correspondingly improved safety (e.g., drug-drug interactions). These beneficial properties of compounds of the present disclosure can be measured according to methods commonly available in the art, such as those exemplified herein.

[0165] The compounds of the present disclosure may have advantageous characteristics compared to other p300 degrading agents. For example, the compounds of the present disclosure may potentially exhibit selectivity for IKZF2 over IKZF1, such as stronger degrading activity against IKZF2, more favorable pharmacokinetic properties (e.g., C max , T max , and / or AUC) and / or may exhibit fewer interactions with other cellular targets (e.g., hepatocyte transporters such as OATP1B1) and correspondingly improved safety (e.g., drug-drug interactions).

[0166] In certain embodiments, a compound disclosed herein is "selective" or "exhibits selectivity" for IKZF2 if it selectively degrades or exhibits selective degradation of IKZF2 relative to IKZF1. For example, a compound may selectively degrade or exhibit selective degradation of IKZF2 relative to IKZF1. 50 DC of IKZF2 is lower than 50 In certain embodiments, the compounds disclosed herein are selective for IKZF2 if they have the D max D of IKZF2 is larger than max In certain embodiments, the compounds disclosed herein exhibit selective degradation of IKZF2 relative to IKZF1 if they have a smaller DC for IKZF2 compared to IKZF1. 50 and larger D max In certain embodiments, the compounds disclosed herein exhibit selective degradation of IKZF2 relative to IKZF1. 50 DC of IKZF2 is at least 10 times smaller than 50 , and / or IKZF2 Dmax From IKZF1 D max minus the value (ΔD max ) is at least 30, at least 35, at least 40, or at least 45 percentage points. In certain preferred embodiments, the compounds disclosed herein exhibit selectivity when the DC 50 DC of IKZF2 is at least 30 times smaller than 50 , and / or IKZF2 D max From IKZF1 D max minus the value (ΔD max ) is at least 50, at least 55, at least 60, or at least 65 percentage points. In certain more preferred embodiments, the compounds disclosed herein exhibit selectivity when their DC 50 DC of IKZF2 is at least about 100 times smaller than that of 50 , and / or IKZF2 D max From IKZF1 D max minus the value (ΔD max ) is at least 70, at least 75, at least 80, at least 85, or at least 90 percentage points, indicating selectivity. These beneficial properties of the compounds of the present disclosure can be measured according to methods generally available in the art, such as those exemplified herein.

[0167] Due to the presence of double bonds, compounds of the present disclosure may be in the cis or trans, or Z or E configuration. It is understood that while one configuration may be depicted in the structure of a compound or formula of the present disclosure, the present disclosure encompasses other configurations. For example, compounds or formulas of the present disclosure may be depicted in the cis or trans, or Z or E configuration.

[0168] In one embodiment, a compound of the present disclosure (e.g., a compound of any of the formulas disclosed herein or any individual compound) is a pharmaceutically acceptable salt. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulas disclosed herein or any individual compound) is a solvate. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulas disclosed herein or any individual compound) is a hydrate.

[0169] Details of the present disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods and materials are described. Other features, objects, and advantages of the present disclosure will be apparent from the specification and claims. As used herein and in the appended claims, the singular also includes the plural unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference in their entirety.

[0170] Further forms of the compounds disclosed herein pharmaceutically acceptable salts In certain embodiments, the compounds disclosed herein are present as their pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0171] In certain embodiments, the compounds described herein possess acidic or basic groups and thus react with any of a number of inorganic or organic bases and acids to form pharmaceutically acceptable salts. In certain embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting the purified compound, in its free form, with a suitable acid or base and isolating the salt thus formed.

[0172] Examples of pharmaceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, benzoyl ... Etate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, odor Hydrogen chloride, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenanthate Examples of suitable amines include phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undecanoate, and xylenesulfonate.

[0173] Additionally, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like, and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, and the like. These include, but are not limited to, benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0174] In certain embodiments, compounds described herein containing free acid groups are reacted with a suitable base, such as a hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1~4 alkyl)4.

[0175] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In certain embodiments, aqueous or oil-soluble or dispersible products are obtained by such quaternization.

[0176] solvate Those skilled in the art of organic chemistry will recognize that many organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are known as "solvates." For example, a complex with water is known as a "hydrate." Solvates are within the scope of the present invention.

[0177] It will also be appreciated by those skilled in the art of organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline forms may vary as solvates. Accordingly, all crystalline forms or their pharmaceutically acceptable solvates are contemplated and within the scope of the present invention.

[0178] In certain embodiments, the compounds described herein exist as solvates. The present disclosure provides methods of treating diseases by administering such solvates. The present disclosure further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0179] Solvates contain either stoichiometric or non-stoichiometric amounts of solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein can exist in unsolvated and solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0180] Isomers / stereoisomers It should also be understood that compounds that have the same molecular formula but that differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0181] In certain embodiments, the compounds described herein exist as geometric isomers. In certain embodiments, the compounds described herein have one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as all corresponding mixtures thereof. All geometric forms of the compounds disclosed herein are contemplated and are within the scope of the present invention.

[0182] In certain embodiments, the compounds disclosed herein have one or more chiral centers, and each center exists in the R or S configuration. The compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms, and their corresponding mixtures. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the present invention.

[0183] In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and collecting the optically pure enantiomers. In certain embodiments, dissociable complexes are preferred. In certain embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by exploiting these differences. In certain embodiments, diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In certain embodiments, the optically pure enantiomers are then collected with a resolving agent.

[0184] tautomers In certain embodiments, the compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulae described herein.

[0185] Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, accompanied by the switching of a single bond and an adjacent double bond. In bond configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated and within the scope of the present invention. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0186] Pharmaceutical Composition In certain embodiments, the compounds described herein are administered as pure chemicals. In certain embodiments, the compounds described herein are administered as pure chemicals, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 2011). stThe compositions are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the chosen route of administration and standard pharmaceutical practice, as described in Ed. Mack Pub. Co., Easton, PA (2005).

[0187] Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0188] In certain embodiments, the compounds provided herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1%, of other small organic molecules, such as, for example, unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic method.

[0189] The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dose and the suitable duration and frequency of administration are determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., improved clinical outcomes such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced severity of symptoms). The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body weight, weight, or blood volume.

[0190] In certain embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, pulmonary, intradermal, intrathecal, epidural, and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, intranasal administration, topical administration, or ocular administration. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for intravenous injection. In certain embodiments, the pharmaceutical composition is formulated as a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, suspension, gel, colloid, dispersion, suspension, solution, emulsion, ointment, lotion, eye drop, or ear drop. In certain embodiments, the pharmaceutical composition is formulated as a tablet.

[0191] Appropriate doses and administration regimens are determined by conventional range-finding techniques known to those skilled in the art. Generally, treatment is initiated with a small dose less than the optimal dose of the compounds disclosed herein. Thereafter, the dosage is increased by small increments until the optimal effect under the circumstances is reached. In certain embodiments, the method involves administering about 0.1 μg to about 50 mg of at least one compound described herein per kg of subject body weight. For a 70 kg patient, a dose of about 10 μg to about 200 mg of the compounds disclosed herein would be more commonly used, depending on the subject's physiological response.

[0192] By way of example only, the dose of a compound described herein for a method of treating a disease described herein is about 0.001 to about 1 mg per kg of subject body weight per day / kg of subject body weight, e.g., about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg per kg of subject body weight per day. In certain embodiments, the dose of a compound described herein for the described methods is from about 1 to about 1000 mg per kg of body weight of the subject being treated per day, e.g., about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per kg of body weight of the subject being treated per day.

[0193] Preparation of compounds The compounds of the present disclosure can be prepared in several ways known to those skilled in the art of organic synthesis. As an example, the compounds of the present disclosure can be synthesized using the methods described below, along with synthetic methods known in the art of synthetic organic chemistry, or variations thereof, as will be understood by those skilled in the art. The compounds of the present disclosure (i.e., compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound)) can be synthesized by following the steps outlined in the following general synthetic schemes, as well as the examples, schemes, procedures, and / or syntheses described herein (e.g., in the Examples).

[0194] General synthetic scheme Exemplary compounds can be prepared according to general synthetic procedures as outlined in the schemes below. TIFF2025510834000089.tif93134

[0195] According to Scheme 1, the compound of formula (II) wherein R is C 1~6and X is a halogen), with a radical initiator such as dibenzoyl peroxide (BPO), azobisisobutyronitrile (AIBN), etc., in the presence of a halogen source such as N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), etc., in a suitable solvent such as CCl4, benzene, etc., at a temperature ranging from 60°C to 100°C, to give a compound of formula (III, where R is C 1~6 wherein X is alkyl and X is halogen. Treatment of the halogenated substituted phenyl carboxylate of formula III with a commercially available or synthetically accessible aminoglutarimide of formula IV in the presence of a suitable base such as DIPEA or TEA in an aprotic solvent such as MeCN or DMF at a temperature ranging from 0° C. to 25° C., preferably 10° C., provides a compound of formula (V). Cyclization of the compound of formula (V) in the presence of a suitable acid such as AcOH or TFA in a suitable solvent such as dichloromethane (DCM) or dichloroethane (DCE) at a temperature ranging from 25° C. to 80° C., preferably 60° C., provides the cyclized compound of formula (VI). Compounds of formula (VI) can be coupled under palladium catalyzed boronation conditions with commercially available 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) with a suitable catalyst such as Pd(dppf)Cl, Pd(OAc), and a suitable base such as KPO, CsCO, or KOAc in a suitable solvent such as dioxane, DMF, or THF at temperatures ranging from 60°C to about 120°C to provide boronic ester compounds of formula (VII).

[0196] TIFF2025510834000090.tif38133

[0197] According to Scheme 2, a commercially available or synthetically accessible aldehyde or ketone of formula (VIII, X = halogen) is coupled with a commercially available or synthetically accessible amine compound of formula (IX) in the presence of a suitable reducing agent such as NaBCNH3, NaBH(OAc)3, in an alcoholic solvent such as MeOH, EtOH, at a temperature ranging from 0°C to about 50°C, preferably 25°C, to provide a compound of formula (Xa).

[0198] TIFF2025510834000091.tif82128

[0199] According to Scheme 3, a commercially available or synthetically accessible aldehyde or ketone of formula (VIII, X = halogen) is reacted with a commercially available or synthetically accessible Grignard reagent of formula (XI) in a solvent such as diethyl ether or THF at a temperature ranging from -20°C to about 25°C, preferably 0°C, to provide an alcohol compound of formula (XII). The compound of formula (XII) is reacted with a mesylating agent such as MsCl in a solvent such as DCM or THF in the presence of a suitable base such as DIPEA or TEA at a temperature ranging from -10°C to about 30°C, preferably 0°C, to provide a compound of formula (XIII). The compound of formula (XIII) is reacted with a commercially available or synthetically accessible amine of formula (IX) in a solvent such as DMF or DMSO in the presence of a suitable base such as CsCO or KCO at a temperature ranging from 25°C to about 100°C, preferably 80°C, to provide a compound of formula (Xb).

[0200] TIFF2025510834000092.tif82128

[0201] According to Scheme 4, the brominated ester compound of formula (VII) is reacted with either the halogenated compound of formula (Xa) or (Xb) under Suzuki coupling conditions using a suitable catalyst such as Pd(PhP), Pd(dba), Pd(ddpf)Cl, and a suitable base such as KPO, CsCO in a suitable solvent such as dioxane, DMF, and a co-solvent such as water at a temperature ranging from 60° C. to about 120° C., preferably 80° C., to provide the claimed compound of formula (I).

[0202] Those skilled in the art will recognize if a stereocenter exists in a compound of the present disclosure (e.g., in any compound of the formulas disclosed herein or in any individual compound). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis), including not only racemates but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material can be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds," E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

[0203] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" include Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0204] Suitable references and papers detailing the synthesis of reactants useful in preparing the compounds described herein or providing references to articles describing the preparation include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions", 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L.G. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Further suitable references and papers detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to articles describing the preparation include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons, ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J.“Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2, Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1, Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9, Solomons, TWG “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0, Stowell, JC, “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2, "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X (8 volumes), "Organic Reactions (1942-2000)" John Wiley & Sons (over 55 volumes), and "Chemistry of Functional Groups" John Wiley & Sons (73 volumes).

[0205] Specific and similar reactants are optionally identified through an index of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries and online. Known but not commercially available chemicals in catalogs are optionally prepared by custom chemical synthesis companies, and many standard chemical supply companies (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is PH Stahl & CG Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0206] Analytical methods, materials, and equipment Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either a 400 MHz Bruker or Varian spectrometer. Spectra are reported in ppm (δ), and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Liquid chromatography-mass spectrometry (LC / MS) was collected using a SHIMADZU LCMS-2020EV or an Agilent 1260-6125B LCMS. Purity and low-resolution mass spectral data were measured using an Agilent 1260-6125B LCMS system (equipped with a Diode Array Detector and an Agilent G6125BA Mass Spectrometer) or a Waters Acquity UPLC system (equipped with a Diode Array Detector and a Waters 3100 Mass Detector). Purity was characterized by UV wavelengths of 214 nm, 220 nm, and 254 nm, and by ESI. Column: Poroshell 120EC-C18 2.7 μm 4.6 x 100 mm, flow rate 0.8 mL / min, solvent A (100 / 0.1 water / formic acid), solvent B (100 acetonitrile), gradient: 5% B until 0.3 min, 5 to 95% B from 0.3 to 2 min, 95% B until 4.8 min, 95 to 5% B from 4.8 to 5.4 min, then 5% B until 6.5 min. Alternatively, column: Acquity UPLC BEH C18 1.7 μm 2.1 × 50 mm, flow rate 0.5 mL / min, solvent A (0.1% formic acid in water), solvent B (acetonitrile), gradient: hold 5% B for 0.2 min, 5 to 95% B from 0.2 to 2.0 min, hold 95% B until 3.1 min, then hold 5% B for 3.5 min.

[0207] Biological assays The biological activity of the compounds of the present application can be evaluated using methods and assays known in the art.

[0208] The binding ability of compounds to CRBN / DDB1 is determined using HTRF assay technology. HTRF signals are measured by displacing Cy5-labeled thalidomide with test compounds against His-tagged CRBN / DDB1. Data are analyzed using XLfit using a four-parameter dose-response curve to determine IC 50 Determine.

[0209] The cytolytic activity of IKZF2 in Jurkat cells is measured by FACS at test compound concentrations of 0.001, 0.01, 0.1, 1-10 μM for 24 hours. Protein concentration is assessed by PVDF membrane and immunoblotting with an antibody against IKZF2. Band intensity is quantified and analyzed using XLfit.

[0210] Alternatively, the cytolytic activity of IKZF2 in Jurkat cells is measured by FACS at test compound concentrations ranging from 0.05 to 10 µM for 24 h. Cells are stained with IKZF2 primary and secondary antibodies, then imaged on an iQue flow cytometer, and IKZF2 levels are quantified using iQue software.

[0211] Alternatively, the cytolytic activity of IKZF2 is measured by the HiBit IKZF2 assay using the HiBiT protein tagging system applied to modified HEK293T Flp-in-HiBiT cells. Test compounds and reference compounds are diluted over 11 three-fold dilutions starting from 1 μM. The Nano-Glo® HiBiT lysis detection system is used to detect the bioluminescence of the HiBiT tag in treated cells, determining that the amount of tag present is proportional to the level of luminescence. After normalization to DMSO, dose-response curves are plotted (GraphPad Prism) to determine the concentration at which each compound achieves 50% HiBiT-Helios degradation.

[0212] Alternatively, the cytolytic activity of IKZF1 is measured by the HiBit IKZF1 assay using the HiBiT protein tagging system applied to modified HEK293T Flp-in-HiBiT cells. Test compounds and reference compounds are diluted over 11 three-fold dilutions starting from 1 μM. The Nano-Glo® HiBiT lysis detection system is used to detect the bioluminescence of the HiBiT tag in treated cells, determining that the amount of tag present is proportional to the level of luminescence. After normalization to DMSO, dose-response curves are plotted (GraphPad Prism) to determine the concentration at which each compound achieves 50% of HiBiT-Ikaros degradation.

[0213] How to use In certain aspects, the present disclosure provides a method of degrading IKZF2 protein in a subject, comprising administering to the subject a compound disclosed herein.

[0214] In certain aspects, the present disclosure provides for the use of a compound disclosed herein in the manufacture of a medicament for degrading IKZF2 protein in a subject.

[0215] In certain aspects, the present disclosure provides a compound disclosed herein for use in degrading IKZF2 protein in a subject.

[0216] In certain aspects, the present disclosure provides methods for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount).

[0217] In certain aspects, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount).

[0218] In certain aspects, the disclosure provides for the use of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0219] In certain aspects, the disclosure provides for the use of a compound disclosed herein in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof.

[0220] In certain aspects, the present disclosure provides a compound disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.

[0221] In certain aspects, the present disclosure provides a compound disclosed herein for use in treating a disease or disorder in a subject in need thereof.

[0222] In certain embodiments, the disease or disorder is an IKZF2-mediated disease or disorder.

[0223] In certain embodiments, the disease or disorder is selected from T-cell leukemia, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).

[0224] In certain aspects, the present disclosure provides methods of (a) increasing IL-2 production, (b) suppressing regulatory T cells, (c) enhancing effector T cells, (d) inhibiting tumor growth, and / or (e) enhancing tumor regression in a subject, comprising administering to a subject in need thereof a compound disclosed herein.

[0225] In certain aspects, the present disclosure provides for the use of a compound disclosed herein in the manufacture of a medicament for (a) increasing IL-2 production, (b) suppressing regulatory T cells, (c) enhancing effector T cells, (d) inhibiting tumor growth, and / or (e) enhancing tumor regression in a subject.

[0226] In certain embodiments, the subject is a mammal.

[0227] In certain embodiments, the subject is a human.

[0228] definition As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated below.

[0229] chemical definition Definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Organic compounds are generally identified according to the principles of organic chemistry, and specific functional groups are generally defined as described therein, Ed. (inside cover). Further, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th 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, 3. rdEdition, Cambridge University Press, Cambridge, 1987.

[0230] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.F. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972).

[0231] The present invention further includes the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0232] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C1~2 , 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 Alkyl is intended to be included.

[0233] The following terms are intended to have the meanings indicated therewith below and are useful in describing and understanding the intended scope of the present invention. In describing the present invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. It should also be understood that, as described herein, any of the moieties defined below may be substituted with various substituents, and that each definition is intended to include such substituted moieties within its scope as described below. Unless otherwise indicated, the term "substituted" is as defined below. It should further be understood that, as used herein, the terms "group" and "radical" can be considered interchangeable. The articles "a" and "an" can be used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. As an example, "an analog" means one analog or more than one analog.

[0234] As used herein, "alkyl" refers to an alkyl group having 1 to 20 carbon atoms ("C 1~20 In certain embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1~12 In certain embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In certain embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9In certain embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8 In certain embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1~7 In certain embodiments, an alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl" or "C 1~6 In certain embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In certain embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In certain embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In certain embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In certain embodiments, the alkyl group has one carbon atom ("C alkyl"). 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group may be independently substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10Common alkyl abbreviations include Me(-CH), Et(-CHCH), i-Pr(-CH(CH)), n-Pr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0235] As used herein, "alkylene" refers to an alkyl group from which two hydrogens have been removed to provide a divalent group. When a range or number of carbons is provided for a particular "alkylene" group, it is understood that the range or number refers to the range or number of carbons in a linear divalent chain of carbons. An "alkylene" group can be unsubstituted or substituted with one or more substituents described herein. Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCHCH-), and the like. For example, exemplary substituted divalent alkylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0236] As used herein, "alkenyl" refers to an alkyl group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20In certain embodiments, alkenyl groups have 2 to 10 carbon atoms ("C"). In certain embodiments, alkenyl groups do not contain any triple bonds. In certain embodiments, alkenyl groups have 2 to 10 carbon atoms ("C"). 2~10 In certain embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In certain embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8 In certain embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In certain embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In certain embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In certain embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In certain embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2~3 In certain embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group can be independently substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0237] As used herein, "alkenylene" refers to an alkenyl group from which two hydrogens have been removed to provide a divalent group. When a range or number of carbons for a particular "alkenylene" group is provided, it is understood that the range or number refers to the range or number of carbons in a linear divalent carbon chain. An "alkenylene" group may be substituted or unsubstituted with one or more substituents described herein. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH-, -CH-CH=CH-). For example, exemplary substituted divalent alkenylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0238] As used herein, "alkynyl" refers to an alkyl group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2~20 In certain embodiments, alkynyl groups have 2 to 10 carbon atoms ("C"). In certain embodiments, alkynyl groups do not contain any double bonds. In certain embodiments, alkynyl groups have 2 to 10 carbon atoms ("C"). 2~10 In certain embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In certain embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8In certain embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In certain embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In certain embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In certain embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4 In certain embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In certain embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted ("substituted alkynyl") with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0239] As used herein, "alkynylene" refers to a straight-chain alkynyl group in which two hydrogens have been removed to provide a divalent group. When a range or number of carbons for a particular "alkynylene" group is provided, it is understood that the range or number refers to the range or number of carbons in a straight-chain divalent carbon chain. An "alkynylene" group may be substituted or unsubstituted with one or more substituents described herein. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0240] As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, where one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, heteroalkyl groups have 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC"). 1~10 In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~9 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~8 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~7 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1~6 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~5In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and / or 2 heteroatoms ("heteroC 1~4 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1~3 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1~2 In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is alkyl.

[0241] As used herein, the term "heteroalkenyl" refers to an alkenyl group, as defined herein, that further contains one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), where one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or where one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkenyl"). 2~10 In certain embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~9In certain embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~8 In certain embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~7 In certain embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (hetero"C 2~6 In certain embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~5 In certain embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and / or two heteroatoms ("heteroC 2~4 In certain embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom ("heteroC 2~3 In certain embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2~10 It is alkenyl.

[0242] As used herein, the term "heteroalkynyl" refers to an alkynyl group, as defined herein, that further contains one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), where one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or where one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkynyl groups"). 2~10 In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~9 In certain embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~8 In certain embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~7 In certain embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroC"). 2~6 In certain embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~5 In certain embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~4 In certain embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom ("heteroC 2~3 In certain embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~6Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2~10 It is alkynyl.

[0243] As used herein, analogous to "alkylene," "alkenylene," and "alkynylene" defined above, "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" refer to divalent radicals of heteroalkyl, heteroalkenyl, and heteroalkynyl groups, respectively. When a range or number of carbons is provided for a particular "heteroalkylene," "heteroalkynylene," or "heteroalkynylene" group, it is understood that the range or number refers to the range or number of carbons in a linear divalent chain. "Heteroalkylene," "heteroalkenylene," and "heteroalkynylene" groups can be substituted or unsubstituted with one or more substituents described herein.

[0244] "Aryl" means an aromatic ring system ("C 6~14 "C6 aryl" refers to a group of monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aryl group. In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl," e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C6 aryl," e.g., phenyl). 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 aryl" (e.g., anthracyl).

[0245] Typical aryl groups include, but are not limited to, groups derived from acentrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, obolene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Specific aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each example of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0246] As used herein, "arylene" refers to an aryl group in which two hydrogens have been removed to provide a divalent group. When a range or number of carbon atoms for a particular "arylene" group is provided, it is understood that the range or number refers to the range or number of carbon atoms in the aryl group. An "arylene" group may be substituted or unsubstituted with one or more substituents described herein.

[0247] "Heteroaryl" refers to a group of 5-14 membered monocyclic or polycyclic 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 pi electrons shared by the cyclic array) having ring carbon atoms and 1 to 8 ring heteroatoms provided to the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings.

[0248] "Heteroaryl" also includes ring systems in which the heteroaryl group is fused to one or more aryl groups, as defined above, and the point of attachment is on either the heteroaryl group or the one or more aryl groups; in such cases, the number of ring members refers to the total number of ring members in the fused (aryl / heteroaryl) ring system. If substitution is indicated in such cases, unless otherwise specified, the substitution can occur on either the heteroaryl group or the one or more aryl groups. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring containing a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl).

[0249] In certain embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heteroaryl"). In certain embodiments, a heteroaryl group is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur (a "5- to 9-membered heteroaryl"). In certain embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heteroaryl"). In certain embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In certain embodiments, a 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0250] Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryls containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryls containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0251] As used herein, "heteroarylene" refers to a heteroaryl group in which two hydrogen atoms have been removed to provide a divalent group. When a range or number of carbon atoms for a particular "heteroarylene" group is provided, it is understood that the range or number refers to the range or number of ring members in the aryl group. "Heteroarylene" groups may be substituted or unsubstituted with one or more substituents described herein.

[0252] "Carbocyclyl" means a non-aromatic ring system containing 3 to 12 ring carbon atoms (C 3~12 In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3~10 In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms ("C 5~12 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms ("C 5~8 In certain embodiments, the carbocyclyl group has 5 or 6 ring carbon atoms ("C 5~6 carbocyclyl). Exemplary C 3~6 Carbocyclyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3~8 As for carbocyclyl, the aforementioned C 3~6Examples of carbocyclyl groups include, but are not limited to, cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3~10 As for carbocyclyl, the aforementioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and the like, but are not limited to these.

[0253] In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 12 ring carbon atoms ("C 3~12 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 8 ring carbon atoms ("C 3~8 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 6 ring carbon atoms ("C 3~6 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 5 to 12 ring carbon atoms ("C 5~12 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms ("C 5~8 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 5 or 6 ring carbon atoms ("C 5~6Carbocyclyl). C 5~6 Examples of carbocyclyl include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of carbocyclyls include the aforementioned C 5~6 Examples include carbocyclyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of carbocyclyls include the aforementioned C 3~6 Examples of carbocyclyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~12 In certain embodiments, the carbocyclyl group is a substituted C 3~12 It is a carbocyclyl.

[0254] As the foregoing examples illustrate, in certain embodiments, carbocyclyl groups contain fused, bridged, or spiro ring systems and are either monocyclic ("monocyclic carbocyclyl") or polycyclic ("polycyclic carbocyclyl"), which may be saturated or partially unsaturated. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~12 In certain embodiments, the carbocyclyl group is a substituted C 3~12 It is a carbocyclyl.

[0255] "Fused carbocyclyl" or "fused carbocycle" refers to a ring system in which a carbocyclyl group, as defined above, is fused to one or more carbocyclyl groups, as defined above, i.e., they share two common atoms (and thus one common bond), and the point of attachment is on either of the fused rings. In such instances, the number of carbons indicates the total number of carbons in the fused ring system. If substitution is indicated, unless otherwise specified, the substitution can occur on either of the fused rings.

[0256] "Spirocarbocyclyl" or "spirocarbocycle" refers to a ring system in which a carbocyclyl group, as defined above, forms a spiro structure, i.e., shares one common atom with one or more carbocyclyl groups, as defined above, and the point of attachment is on the carbocyclyl ring in which the spiro structure is embedded. In such instances, the number of carbons indicates the total number of carbons in the carbocyclyl ring in which the spiro structure is embedded. If substitution is indicated, unless otherwise specified, the substitution can occur on the carbocyclyl ring in which the spiro structure is embedded.

[0257] "Bridged carbocyclyl" or "bridged carbocycle" refers to a ring system in which a carbocyclyl group, as defined above, forms a bridged structure with one or more carbocyclyl groups, as defined above, i.e., shares three or more common atoms (and thus two or more bonds) therewith, and the point of attachment is on either of the carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of carbons indicates the total number of carbons in the carbocyclyl ring in which the bridged structure is embedded. If substitution is indicated, unless otherwise specified, the substitution can occur on either of the carbocyclyl rings in which the bridged structure is embedded.

[0258] As used herein, "carbocyclylene" refers to a carbocyclyl group in which two hydrogens have been removed to provide a divalent group. The divalent groups can be on different atoms or the same atom of the carbocyclylene group. When a range or number of carbons for a particular "carbocyclyl" group is provided, it is understood that the range or number refers to the range or number of carbons in the carbocyclyl group. A "carbocyclyl group" can be substituted or unsubstituted with one or more substituents described herein.

[0259] "Heterocyclyl" refers to a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 12-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, valence permitting. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6 bicyclic heterocycle) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0260] In certain embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 12-membered heterocyclyl"). In certain embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In certain embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In certain embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In certain embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0261] As the foregoing examples illustrate, in certain embodiments, heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic ("polycyclic heterocyclyl"), which contain fused, bridged, or spiro ring systems and may be saturated or partially unsaturated. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl group is fused to one or more carbocyclyl groups, as defined above, and the point of attachment is on either the carbocyclyl or the heterocyclyl ring; in such cases, the number of ring members indicates the total number of ring members in the entire ring system. Where substitution is indicated in such examples, unless otherwise specified, the substitution can occur on either the heterocyclyl group or the one or more carbocyclyl groups. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 12-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 12-membered heterocyclyl.

[0262] "Fused heterocyclyl" or "fused heterocycle" refers to a ring system in which a heterocyclyl group, as defined above, is fused with one or more heterocyclyl or carbocyclyl groups, as defined above, i.e., they share two common atoms (and thus one common bond), and the point of attachment is on either of the fused rings. In such instances, the ring number indicates the total number of ring members in the fused ring system. If substitution is indicated, unless otherwise specified, the substitution can occur on either of the fused rings.

[0263] "Spiroheterocyclyl" or "spiroheterocycle" refers to a ring system in which a heterocyclyl group, as defined above, forms a spiro structure, i.e., shares one common atom with one or more heterocyclyl or carbocyclyl groups, as defined above, and the point of attachment is on the heterocyclyl or carbocyclyl ring in which the spiro structure is embedded. In such instances, the number of ring members indicates the total number of ring members of the heterocyclyl or carbocyclyl ring in which the spiro structure is embedded. If substitution is indicated, unless otherwise specified, the substitution may occur on either the heterocyclyl or carbocyclyl ring in which the spiro structure is embedded.

[0264] "Bridged heterocyclyl" or "bridged heterocycle" refers to a ring system in which a heterocyclyl group, as defined above, forms a bridged structure, i.e., shares three or more common atoms (and thus two or more bonds) with one or more heterocyclyl or carbocyclyl groups, as defined above, and the point of attachment is on either the heterocyclyl or carbocyclyl ring in which the bridged structure is embedded. In such instances, the number of ring members indicates the total number of ring members of the heterocyclyl or carbocyclyl ring in which the bridged structure is embedded. If substitution is indicated, unless otherwise specified, the substitution may occur on either the heterocyclyl or carbocyclyl ring in which the bridged structure is embedded.

[0265] As used herein, "heterocyclylene" refers to a heterocyclyl group in which two hydrogens have been removed to provide a divalent group. The divalent groups can be on different atoms or the same atom of the heterocyclylene group. When a range or number of carbon atoms for a particular "heterocyclylene" group is provided, it is understood that the range or number refers to the range or number of ring members in the heterocyclylene group. A "heterocyclylene group" can be substituted or unsubstituted with one or more substituents described herein.

[0266] As used herein, "alkoxy" refers to the group -OR, where R is alkyl as defined herein.1~6 Alkoxy refers to an —OR group, where each R is a C as defined herein. 1~6 Alkyl, C 3~4 carbocyclyl, or 3- to 4-membered heterocyclyl. 1~6 Alkyl is described above.

[0267] As used herein, "alkylamino" refers to the group -NHR or -NR2, where each R is independently alkyl as defined herein. 1~6 Alkylamino refers to the group -NHR or -NR, where each R is independently a C as defined herein. 1~6 Alkyl, C 3~4 carbocyclyl, or 3- to 4-membered heterocyclyl. 1~6 Alkyl is described above.

[0268] "Oxo" refers to =O. When a group or atom other than aryl or heteroaryl is substituted with oxo, it is meant to indicate that two geminal radicals on that group or atom form a double bond with an oxygen radical. When a heteroaryl is substituted with oxo, it is meant to indicate that a resonance structure / tautomer involving the heteroatom provides a carbon atom that can form two geminal radicals that form a double bond with an oxygen radical.

[0269] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

[0270] As used herein, "protecting group" is art-recognized and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction. Common functional groups that need to be protected include, but are not limited to, hydroxyl, amino, thiol, and carboxylic acid. Accordingly, protecting groups are referred to as hydroxyl-protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid-protecting groups, respectively.

[0271] Common types of hydroxyl protecting groups include, but are not limited to, ethers (e.g., methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p-methoxyphenyl (PMP), t-butyl, triphenylmethyl (trityl), allyl, and benzyl ethers (Bn)), silyl ethers (e.g., t-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), tri-isopropylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalate (Piv) and benzoate (benzoate; Bz)).

[0272] Common types of amino-protecting groups include, but are not limited to, carbamates (e.g., t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzylcarbonyl (Moz or MeOZ), 2,2,2-trichloroethoxycarbonyl (Troc), and benzyl carbamate (Cbz)), esters (e.g., acetyl (Ac), benzoyl (Bz), trifluoroacetyl, and phthalimide), amines (e.g., benzyl (Bn), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), and triphenylmethyl (trityl)), and sulfonamides (e.g., tosyl (Ts), N-alkylnitrobenzenesulfonamide (nosyl), and 2-nitrophenylsulfenyl (Nps)).

[0273] Common types of thiol protecting groups include, but are not limited to, sulfides (e.g., p-methylbenzyl (Meb), t-butyl, acetamidomethyl (Acm), and triphenylmethyl (trityl)).

[0274] Common types of carboxylic acid protecting groups include, but are not limited to, esters (e.g., methyl esters, triphenylmethyl (trityl), t-butyl esters, benzyl esters (Bn), St-butyl esters, silyl esters, and orthoesters), and oxazolines.

[0275] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the above exemplary list of substituents.

[0276] Other definitions "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government, or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, and more particularly in humans.

[0277] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. In particular, such salts include (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, and camphorsulfonic acid. or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinates with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Further salts include, by way of example only, salts of non-toxic organic or inorganic acids such as sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the compound contains a basic functional group, hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc.

[0278] The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like (see, e.g., Berge, et al., J. Pharm. Sci. 66(1):1-79 (January 77)).

[0279] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is administered.

[0280] A pharmaceutically acceptable metabolically cleavable group refers to a group that is cleaved in vivo to yield a parent molecule of the structural formula shown herein. Examples of metabolically cleavable groups include -COR, -COOR, -CONR, and -CHOR groups, where R is independently selected in each occurrence from alkyl, trialkylsilyl, carbocyclic aryl, or carbocyclic aryl substituted with one or more of alkyl, halogen, hydroxy, or alkoxy. Specific examples of representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl, and trimethylsilyl groups.

[0281] "Solvate" refers to a form of a compound associated with a solvent or water (also referred to as a "hydrate"), usually by a solvolysis reaction. This physical association involves hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the present invention may be prepared, for example, in crystalline form, and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In certain instances, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0282] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0283] An "effective amount" refers to the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to effect such treatment or prevention. The "effective amount" may vary depending on the compound, the disease and its severity, as well as the age, weight, etc., of the subject being treated. A "therapeutically effective amount" refers to an amount effective for therapeutic treatment. A "prophylactically effective amount" refers to an amount effective for prophylactic treatment.

[0284] "Preventing," "prevention," or "prophylactic treatment" refers to a reduction in the risk of acquiring or developing a disease or disorder (i.e., not developing at least one clinical symptom of the disease in a subject who has not yet been exposed to a pathogen or who is susceptible to the disease prior to the onset of the disease).

[0285] The term "prophylaxis" is related to "prevention" and refers to a measure or procedure whose purpose is to prevent, rather than treat or cure, a disease. Non-limiting examples of prophylactic measures may include the administration of a vaccine, the administration of low molecular weight heparin to hospital patients at risk of thrombosis, for example, due to immobilization, and the administration of an antimalarial agent such as chloroquine before visiting a geographic area where malaria is endemic or where there is an increased risk of contracting malaria.

[0286] "Treating" or "treatment" or "therapeutic treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., halting the disease or reducing the onset, extent, or severity of at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.

[0287] It should also be understood that compounds that have the same molecular formula but that differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0288] Stereoisomers that are not mirror images of one another are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, if it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0289] "Tautomers" refer to interchangeable forms of a particular compound structure, differing in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the shifting of electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci and nitro forms of phenylnitromethane, similarly formed by treatment with acid or base. Tautomeric forms can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0290] As used herein, a pure enantiomer is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, the S form of a compound is substantially free of the R form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" indicate that a compound contains greater than 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0291] As used herein, and unless otherwise indicated, the term "enantiomerically pure (R)-compound" refers to at least about 95% by weight of the (R)-compound and at most about 5% by weight of the (S)-compound, at least about 99% by weight of the (R)-compound and at most about 1% by weight of the (S)-compound, or at least about 99.9% by weight of the (R)-compound and at most about 0.1% by weight of the (S)-compound. In certain embodiments, the weights are based on the total weight of the compound.

[0292] As used herein, and unless otherwise indicated, the term "enantiomerically pure (S)-compound" or "(S)-compound" refers to at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, at least about 99% by weight (S)-compound and at most about 1% by weight (R)-compound, or at least about 99.9% by weight (S)-compound and at most about 0.1% by weight (R)-compound. In certain embodiments, the weights are based on the total weight of the compound.

[0293] In the compositions provided herein, the enantiomerically pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure (R)-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such a composition may contain, for example, at least about 95% by weight of the (R)-compound and up to about 5% by weight of the (S)-compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure (S)-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions may comprise, for example, at least about 95% by weight of the (S)-compound and up to about 5% by weight of the (R)-compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated with few or no excipients or carriers.

[0294] The compounds of the present invention may possess one or more asymmetric centers and such compounds may therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.

[0295] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, racemic or otherwise. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0296] When referring to a numerical value or numerical range, the term "about" means that the stated numerical value or numerical range is approximate within experimental variability (or within statistical experimental error), and thus, in some instances, the numerical value or numerical range may vary by 1% to 15% of the stated numerical value or numerical range.

[0297] The term "comprising" (and related terms, e.g., "comprise" or "comprises," or "having" or "including") is not intended to exclude that in other particular embodiments, any embodiment of the material, composition, method, or process described herein, "consists of" or "consists essentially of" the recited features.

[0298] As used herein in the specification and claims, the term "and / or" should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are present conjunctively in some cases and separately in other cases. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and / or" clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended terminology such as "comprising," may refer in one embodiment to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements), etc.

[0299] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as being inclusive, i.e., including at least one of a number or list of elements, but also including two or more, and optionally additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of," or when used in the claims, "consisting of" refers to the inclusion of exactly one element of a number or list of elements. Generally, as used herein, the term "or" should only be interpreted as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." When used in the claims, "consisting essentially of" shall have its ordinary meaning as used in the field of patent law.

[0300] As used herein in the specification and claims, the phrase "at least one" in connection with a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of every element specifically listed in the list of elements, and not excluding any combinations of elements in the list of elements. This definition also allows for elements, whether related or unrelated to those specifically identified elements, optionally being present other than the elements specifically identified in the list of elements to which the phrase "at least one" refers. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") can refer in one embodiment to at least one A, optionally including more than one, and no B (and optionally including elements other than B); in another embodiment to at least one B, optionally including more than one, and no A (and optionally including elements other than A); in yet another embodiment to at least one A, optionally including more than one, and at least one B, optionally including more than one (and optionally including other elements);

[0301] While the present teachings have been described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those skilled in the art.

[0302] While various inventive embodiments have been described and illustrated herein, those skilled in the art will readily envision various other means and / or structures for performing the functions and / or obtaining one or more of the results and / or advantages described herein, and each such variation and / or modification is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are intended to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the particular application for which the teachings of the present invention are used. Those skilled in the art will recognize many equivalents to the specific inventive embodiments described herein. Accordingly, it should be understood that the foregoing embodiments are presented by way of example only, and that, within the scope of the appended claims and their equivalents, inventive embodiments may be practiced otherwise than as specifically described and claimed. The inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and / or method described herein. Furthermore, any combination of two or more such features, systems, articles, materials, kits, and / or methods is included within the inventive scope of the present disclosure, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent.

[0303] The claims should not be construed as limited to the described order or elements unless expressly stated to that effect. It should be understood that various changes in form and detail may be made by those skilled in the art without departing from the spirit and scope of the appended claims. All embodiments that come within the spirit and scope of the following claims, and equivalents thereto, are claimed. [Example]

[0304] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed in any way as limiting the scope thereof.

[0305] I. Synthesis and Characterization of Intermediates and Compounds 1-318 In the following examples, chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company) and used without further purification.

[0306] To obtain the compounds described in the following examples and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

[0307] Unless otherwise noted, reaction mixtures were magnetically stirred under a nitrogen atmosphere at room temperature (rt). When solutions were "dried," they were typically dried over a desiccant such as NaSO or MgSO. When mixtures, solutions, and extracts were "concentrated," they were typically concentrated on a rotary evaporator under reduced pressure.

[0308] Compound purification was performed as needed using a variety of conventional methods, including, but not limited to, normal-phase or reverse-phase HPLC, or preparative chromatography under acidic, neutral, or basic conditions using either flash columns or preparative TLC plates.

[0309] Flash chromatography was performed on a Biotage Isolera One using columns with 200-300 mesh silica gel particles. Analytical and preparative thin-layer chromatography was performed using silica gel 60 GF254 plates. Normal-phase silica gel chromatography (FCC) was also performed on silica gel (SiO2) using prepacked cartridges.

[0310] Preparative reversed-phase high performance liquid chromatography (RP HPLC) was performed either: Method A Preparative HPLC using a YMC-Actus Triart 18C (5 μm, 20 × 250 mm) and a mobile phase of 5 to 99% ACN in water (0.1% HCOOH) over 10 min, followed by a 2 min hold at 100% ACN, at a flow rate of 25 mL / min; or Method B Preparative supercritical fluid high-performance liquid chromatography (SFC) was performed on either a Thar 80 Prep-SFC system or a Waters 80Q Prep-SFC system. The ABPR was set at 100 bar to maintain CO2 at SF conditions, and flow rates ranged from 50 g / min to 70 g / min, depending on compound characteristics. Column temperature was ambient.

[0311] Unless otherwise specified, nuclear magnetic resonance (NMR) spectra were recorded using a Brucker AVANCE NEO 400 MHz at approximately 20-30°C. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet; ddd, double of doublet; dt, double of triplet; bs, broad signal. Chemical shifts are reported in parts per million (ppm, δ) downfield from tetramethylsilane. It will be understood that for compounds containing exchangeable protons, the protons may or may not be visible on the NMR spectrum, depending on the choice of solvent used to run the NMR spectrum and the concentration of the compound in solution.

[0312] Mass spectra (MS) were obtained on a SHIMADZU LCMS-2020MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) masses correspond to exact masses.

[0313] Chemical names were generated using ChemDraw Ultra 12.0, ChemDraw Ultra 14.0 (CambridgeSoft Corp., Cambridge, MA), or ACD / Name Version 10.01 (Advanced Chemistry).

[0314] Compounds designated as R* or S* are enantiopure compounds where the absolute configuration has not been determined.

[0315] Intermediate 1: 5-chloroimidazo[1,5-a]pyridine-7-carbaldehyde TIFF2025510834000093.tif26128Step A: Methyl 2-(bromomethyl)-6-chloropyridine-4-carboxylate A solution of methyl 2-chloro-6-methylpyridine-4-carboxylate (9 g, 48.489 mmol, 1.0 equiv.), NBS (11.22 g, 63.036 mmol, 1.3 equiv.), and AIBN (0.717 mL, 4.849 mmol, 0.1 equiv.) in CCl4 (180 mL) was stirred at 90 °C for 12 h under nitrogen. After cooling to room temperature, the mixture was diluted with cold water (300 mL) and extracted with DCM (300 mL × 3). The combined organic extracts were washed with water (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA in PE, 0–10%) to give a mixture (20 g). To a solution of the mixture (20 g) in THF (300 mL) were added DIPEA (25.3 mL, 145.467 mmol, 3.0 equiv.) and diethyl phosphite (18.7 mL, 145.467 mmol, 3.0 equiv.) at 0 °C, and the resulting mixture was stirred at room temperature for 4 h. The mixture was diluted with EA (300 mL × 3) and extracted with EA (300 mL × 3). The organic layer was washed with water (300 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA in PE, 0-4%) to give methyl 2-(bromomethyl)-6-chloroisonicotinate (10 g, 78% yield) as a white solid.

[0316] LC-MS (ESI): calculated mass for C8H7BrClNO2 262.93, observed m / z 264.3 [M+H] + .

[0317] Step B: Methyl 2-(azidomethyl)-6-chloropyridine-4-carboxylate A solution of methyl 2-(bromomethyl)-6-chloropyridine-4-carboxylate (8 g, 30.245 mmol, 1.0 equiv.) and sodium azide (3.93 g, 60.489 mmol, 2.0 equiv.) in DMF (80 mL) was stirred at room temperature for 12 hours. The mixture was diluted with cold water (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic extracts were washed with brine (150 mL × 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude product, methyl 2-(azidomethyl)-6-chloropyridine-4-carboxylate (6 g, 87% yield), as a yellow oil.

[0318] LC-MS (ESI): calculated mass for C8H7ClN4O2 226.03, observed m / z 227.1 [M+H] + .

[0319] Step C: Methyl 2-(aminomethyl)-6-chloropyridine-4-carboxylate A solution of methyl 2-(azidomethyl)-6-chloropyridine-4-carboxylate (6 g, 26.476 mmol, 1.0 equiv.) and PPh (10.42 g, 39.714 mmol, 1.5 equiv.) in THF (80 mL) and HO (8 mL) was heated at 50 °C for 1 h. After evaporation, the mixture was dissolved in aqueous HCl solution (2 N) (50 mL) and extracted with DCM (50 mL × 3). The organic layer was discarded, and the aqueous layer was concentrated under reduced pressure to give methyl 2-(aminomethyl)-6-chloropyridine-4-carboxylate hydrochloride (4.4 g, 70% yield) as a white solid.

[0320] LC-MS (ESI): calculated mass for C8H9ClN2O2 200.04, observed m / z 201.1 [M+H] + .

[0321] Step D: Methyl 2-chloro-6-(formamidomethyl)pyridine-4-carboxylate To a solution of methyl 2-(aminomethyl)-6-chloropyridine-4-carboxylate hydrochloride (1.5 g, 7.476 mmol, 1.0 equiv.) in ethyl formate (30 mL) was added NaHCO (0.31 g, 3.738 mmol, 0.5 equiv.) and triethylamine (1.6 mL, 11.214 mmol, 1.5 equiv.), and the mixture was refluxed for 10 h. After filtration, the filtrate was concentrated to give crude methyl 2-chloro-6-(formamidomethyl)pyridine-4-carboxylate (1.20 g, 70% yield) as a brown oil. The crude product was used in the next step without further purification.

[0322] LC-MS (ESI): calculated mass for C9H9ClN2O3 228.03, observed m / z 229.2 [M+H] + .

[0323] Step E: Methyl 5-chloroimidazo[1,5-a]pyridine-7-carboxylate To a solution of methyl 2-chloro-6-(formamidomethyl)pyridine-4-carboxylate (1.2 g, 5.249 mmol, 1.0 equiv.) in dioxane (20 mL) was added POCl (0.978 mL, 10.497 mmol, 2.0 equiv.), and the mixture was refluxed for 3 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO solution (50 mL) at 0 °C, and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (EtOAc in petroleum ether, 30%) to give methyl 5-chloroimidazo[1,5-a]pyridine-7-carboxylate (340 mg, 28% yield) as a yellow solid.

[0324] LC-MS (ESI): calculated mass for C9H7ClN2O2 210.02, observed m / z 211.2 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ8.69(s,1H), 8.41(s,1H), 7.94(s,1H), 7.25(s,1H), 3.87(s,3H).

[0325] Step F: {5-chloroimidazo[1,5-a]pyridin-7-yl}methanol To a solution of methyl 5-chloroimidazo[1,5-a]pyridine-7-carboxylate (340 mg, 1.614 mmol, 1.0 equiv.) in dry THF (15 mL) was added DIBAL-H (1N in THF) (2.4 mL, 2.421 mmol, 1.5 equiv.) dropwise under N at −78° C., and the mixture was stirred at room temperature for 30 min. The mixture was diluted with THF (30 mL) and added with NaSO. . The mixture was slowly quenched with 10H2O and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (EtOAc in petroleum ether, 50%) to give {5-chloroimidazo[1,5-a]pyridin-7-yl}methanol (250 mg, yield 76.33%) as a yellow solid.

[0326] LC-MS (ESI): calculated mass for C8H7ClNO 182.02, observed m / z 183.2 [M+H] + .

[0327] Step G: 5-chloroimidazo[1,5-a]pyridine-7-carbaldehyde To a solution of {5-chloroimidazo[1,5-a]pyridin-7-yl}methanol (250 mg, 1.369 mmol, 1.0 equiv.) in DCM (5 mL) was added Dess-Martin periodinane (1.279 mL, 4.107 mmol, 3.0 equiv.), and the reaction was stirred at room temperature for 1 h. The reaction mixture was quenched with aqueous NaSO (20 mL) and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (50% EtOAc in petroleum ether) to give 5-chloroimidazo[1,5-a]pyridine-7-carbaldehyde (200 mg, 73% yield) as a yellow solid.

[0328] LC-MS (ESI): calculated mass for C8H5ClN2O 180.01, observed m / z 181.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ9.82 (s, 1H), 8.71 (s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 7.15 (d, J = 1.0hz, 1H).

[0329] Intermediate 2: 8-Bromoimidazo[1,2-a]pyridine-6-carbaldehyde TIFF2025510834000094.tif24128Step A: Methyl 8-bromoimidazo[1,2-a]pyridine-6-carboxylate A solution of methyl 6-amino-5-bromopyridine-3-carboxylate (2 g, 8.656 mmol, 1.0 equiv.), 2-chloroacetaldehyde (2.062 mL, 12.984 mmol, 1.5 equiv.), and NaHCO3 (1.09 g, 12.984 mmol, 1.5 equiv.) in EtOH (40 mL) was stirred at 80 °C under nitrogen for 12 h. After evaporation, the mixture was diluted with cold water (100 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic extracts were washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA / PE = 1 / 2) to give methyl 8-bromoimidazo[1,2-a]pyridine-6-carboxylate (1.5 g, 61% yield) as a yellow solid.

[0330] LC-MS (ESI): calculated mass for C9H7BrN2O2 253.97, observed m / z 254.4 [M+H] + . 1 HNMR (400MHz, CDCl3) δ8.90 (s, 1H), 8.01 (s, 1H), 7.76 (d, J = 6.8Hz, 2H), 3.96 (s, 3H).

[0331] Step B: {8-bromoimidazo[1,2-a]pyridin-6-yl}methanol To a solution of methyl 8-bromoimidazo[1,2-a]pyridine-6-carboxylate (15 g, 58.807 mmol, 1.0 equiv.) in THF (300 mL) was added DIBAL-H (1N in THF) (88.2 mL, 88.210 mmol, 1.5 equiv.) dropwise at −78° C. under N. The mixture was then warmed to 0° C. and stirred for 1 h. The reaction mixture was diluted with THF (150 mL) and added with NaSO. . 10H O. After filtration, the filtrate was concentrated and purified by flash column chromatography on silica gel (EA / PE=1 / 1) to give {8-bromoimidazo[1,2-a]pyridin-6-yl}methanol (10 g, yield 67.4%) as a white solid.

[0332] LC-MS (ESI): calculated mass for C8H7BrN2O 225.97, observed m / z 227.4 [M+H] + .

[0333] Step C: 8-Bromoimidazo[1,2-a]pyridine-6-carbaldehyde To a solution of {8-bromoimidazo[1,2-a]pyridin-6-yl}methanol (10 g, 44.041 mmol, 1.0 equiv.) in DCM (100 mL) was added Dess-Martin periodinane (41.145 mL, 132.124 mmol, 3.0 equiv.), and the mixture was stirred at room temperature for 1 h. The residue was poured into water (60 mL) and extracted with EtOAc (60 mL × 4). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA / PE = 1 / 1) to afford 8-bromoimidazo[1,2-a]pyridine-6-carbaldehyde (8 g, 73% yield) as a yellow solid.

[0334] LC-MS (ESI): calculated mass for C8H5BrN2O 223.96, observed m / z 225.5 [M+H] + .

[0335] Intermediate 3: 5-Chloro-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde TIFF2025510834000095.tif26128Step A: tert-Butyl 2-chloro-6-hydrazinylpyridine-4-carboxylate To a solution of tert-butyl 2,6-dichloropyridine-4-carboxylate (3.912 mL, 20.152 mmol, 1.0 equiv) in EtOH (20 mL) was added hydrazine (3.23 g, 100.762 mmol, 5.0 equiv). The mixture was stirred at 75° C. for 18 hours. The mixture was cooled to room temperature and concentrated to half its volume under reduced pressure, causing a solid to precipitate. The solid was filtered, and the filtrate was concentrated to dryness to give crude tert-butyl 2-chloro-6-hydrazinylpyridine-4-carboxylate (4.1 g, 83% yield) as a yellow solid.

[0336] LC-MS(ESI):C 10 H 14 Calculated mass of ClN3O2: 243.08, measured m / z: 244.0 [M+H] + .

[0337] Step B: tert-Butyl 7-chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate A mixture of tert-butyl 2-chloro-6-hydrazinylpyridine-4-carboxylate (4.1 g, 16.825 mmol, 1.0 equiv) in trimethyl orthoformate (15 mL) was stirred at 85° C. for 5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ethyl acetate in petroleum ether, 0-50%) to provide tert-butyl 7-chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (1.8 g, 42% yield).

[0338] LC-MS(ESI):C 11 H 12 ClN3O2 253.06, m / z 254.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.61 (s, 1H), 8.33 (s, 1H), 7.47 (d, J = 1.0Hz, 1H), 1.59 (s, 9H).

[0339] Step C: 7-chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic acid TFA (20 mL) was added to a solution of tert-butyl 7-chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (4.2 g, 16.556 mmol, 1.0 equiv.) in DCM (20 mL). The reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure to give 7-chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic acid (1.8 g, 55% yield) as a crude yellow solid.

[0340] LC-MS (ESI): calculated mass for C7H4ClN3O2 197.00, observed m / z 198.1 [M+H] + .

[0341] Step D: (5-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol To a solution of 7-chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic acid (1.8 g, 9.110 mmol, 1.0 equiv.) in THF (20 mL) was added borane-tetrahydrofuran complex (1 N) (45.5 mL, 45.551 mmol, 5.0 equiv.) dropwise at 0 °C. The reaction mixture was warmed to room temperature for 24 h. After cooling to 0 °C, the mixture was slowly quenched with methanol (50 mL) and refluxed for 1 h. After evaporation, the residue was partitioned between ethyl acetate (200 mL) and aqueous NaOH solution (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (methanol in chloroform, 0–5%) to give {7-chloro-[1,2,4]triazolo[4,3-a]pyridin-5-yl}methanol (760 mg, 45% yield) as a yellow solid.

[0342] LC-MS (ESI): calculated mass for C7H6ClN3O: 183.02, observed m / z: 184.1 [M+H] + .

[0343] Step E: 7-chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carbaldehyde To a solution of {7-chloro-[1,2,4]triazolo[4,3-a]pyridin-5-yl}methanol (620 mg, 3.377 mmol, 1.0 equiv.) in DCM (20 mL) was added Dess-Martin periodinane (2.15 g, 5.065 mmol, 1.5 equiv.), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (60 mL) and washed with saturated aqueous NaSO solution (30 mL), saturated aqueous NaHCO solution (20 mL), and brine (20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (petroleum ether / EtOAc = 50 / 1) to afford 7-chloro-[1,2,4]triazolo[4,3-a]pyridine-5-carbaldehyde (350 mg, 57% yield) as a yellow oil.

[0344] LC-MS (ESI): calculated mass for C7H4ClN3O 181.02, observed m / z 182.1 [M+H] + .

[0345] Intermediate 4: 4-Bromo-1-methyl-1H-benzo[d]imidazole-6-carbaldehyde TIFF2025510834000096.tif27128Step A: 4-Bromo-1-methyl-1H-1,3-benzodiazole-6-carbonitrile To a solution of 4-bromo-1H-1,3-benzodiazole-6-carbonitrile (1.0 g, 4.504 mmol, 1.0 equiv) in DMF (20 mL) was added NaH (60% suspension in oil) (0.27 g, 6.756 mmol, 1.5 equiv) under nitrogen at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, and then iodomethane (0.83 g, 5.855 mmol, 1.3 equiv) was added dropwise to the above mixture, and the mixture was stirred at 0 °C for 1 h. The mixture was diluted with cold water (40 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with brine (30 mL × 4), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The combined organic extracts and brine residue were purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10%) to give 4-bromo-1-methyl-1H-benzo[d]imidazole-6-carbonitrile (0.314 g, 29% yield) as a white solid.

[0346] LC-MS (ESI): calculated mass for C9H6BrN3 234.97, observed m / z 235.98 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.56 (s, 1H), 8.31 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H), 3.92 (s, 3H).

[0347] Step B: 4-Bromo-1-methyl-1H-1,3-benzodiazole-6-carbaldehyde To a solution of 4-bromo-1-methyl-1H-1,3-benzodiazole-6-carbonitrile (150 mg, 0.635 mmol, 1.0 equiv.) in toluene (10 mL) was added DIBAL-H (1.5 N in THF) (0.63 mL, 0.953 mmol, 1.5 equiv.) dropwise at 0 °C under nitrogen. The reaction mixture was stirred at room temperature for 1 h, diluted with aqueous NH4Cl solution (20 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give 4-bromo-1-methyl-1H-1,3-benzodiazole-6-carbaldehyde (45 mg, 29% yield) as a white solid.

[0348] LC-MS (ESI): calculated mass for C9H7BrN2O 237.97, observed m / z 238.98 [M+H] + .

[0349] Intermediate 5: 3-iodo-7-(pyrrolidin-1-ylmethyl)imidazo[1,5-a]pyridine TIFF2025510834000097.tif37128Step A: Imidazo[1,5-a]pyridin-7-yl(pyrrolidin-1-yl)methanone To a solution of imidazo[1,5-a]pyridine-7-carboxylic acid (1 g, 6.167 mmol, 1.0 equiv.) and pyrrolidine (0.608 mL, 7.400 mmol, 1.2 equiv.) in DMF (25 mL) was added HATU (3.52 g, 9.251 mmol, 1.5 equiv.) and TEA (2.572 mL, 18.501 mmol, 3.0 equiv.). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (50 mL × 3). The combined organic layer was washed with brine (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (methanol in dichloromethane, 0% to 10%) to afford imidazo[1,5-a]pyridin-7-yl(pyrrolidin-1-yl)methanone (1.3 g, 98% yield) as a yellow oil.

[0350] LC-MS(ESI):C 12 H 13 Calculated mass of NO: 215.11, measured m / z: 216 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.35(d,J=7.2Hz,1H),7.81(s,1H),7.50(s,1H),6.78(d,J=7.2Hz,1H),3.52-3.47(m,4H),1.85(s,4H)

[0351] Step B: 7-(pyrrolidin-1-ylmethyl)imidazo[1,5-a]pyridine A solution of imidazo[1,5-a]pyridin-7-yl(pyrrolidin-1-yl)methanone (1 g, 4.646 mmol, 1.0 equiv.) and BH solution (2N in THF) (11.614 mL, 23.228 mmol, 5.0 equiv.) in THF (20 mL) was stirred overnight at 70 °C under N. The reaction mixture was cooled to 0 °C, quenched with MeOH (20 mL), and the solution was stirred at 70 °C under N for 1 h. The reaction mixture was cooled to room temperature, concentrated, diluted with water (10 mL), and extracted with dichloromethane (50 mL × 3). The combined organic layer was washed with brine (20 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (methanol in dichloromethane, 0% to 10%) to afford 7-(pyrrolidin-1-ylmethyl)imidazo[1,5-a]pyridine (800 mg, 85% yield) as a yellow oil.

[0352] LC-MS(ESI):C 12 H 15 Calculated mass of N3: 201.13, measured m / z: 202.3 [M+H] + .

[0353] Step C: 3-iodo-7-(pyrrolidin-1-ylmethyl)imidazo[1,5-a]pyridine To a solution of 7-(pyrrolidin-1-ylmethyl)imidazo[1,5-a]pyridine (800 mg, 3.97 mmol, 1.0 equiv.) in THF (20 mL) was added nBuLi (2N in n-hexane) (2.385 mL, 5.96 mmol, 1.5 equiv.) at −78° C. The mixture was stirred under N at −78° C. for 0.5 h. Then, a solution of iodine (1010 mg, 3.97 mmol, 1.0 equiv.) in THF (5 mL) was added dropwise to the above solution. The resulting mixture was stirred at room temperature for 0.5 h at −78° C. The mixture was quenched with saturated aqueous NH4Cl solution (20 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to afford 3-iodo-7-(pyrrolidin-1-ylmethyl)imidazo[1,5-a]pyridine (500 mg, yield 38%) as a yellow oil.

[0354] LC-MS(ESI):C 12 H 14 Calculated mass of IN3: 327.02, measured m / z: 328 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.2Hz,1H),7.42(d,J=5.0Hz,2H),6.78(d,J=7.2Hz,1H),3.53(s,2H),2.45(s,4H),1.70(s,4H).

[0355] Intermediate 6: 3-iodo-6-(pyrrolidin-1-ylmethyl)imidazo[1,5-a]pyridine TIFF2025510834000098.tif33128Step A: Imidazo[1,5-a]pyridin-6-yl(pyrrolidin-1-yl)methanone To a solution of imidazo[1,5-a]pyridine-6-carboxylic acid (1 g, 6.2 mmol, 1.0 equiv.) and HATU (3.5 g, 9.3 mmol, 1.5 equiv.) in DMF (15 mL) was added TEA (2.6 mL, 18.5 mmol, 3.0 equiv.) and pyrrolidine (0.76 mL, 9.3 mmol, 1.5 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL × 3). The organic layer was washed with brine (40 mL × 4), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EA=1 / 1) to afford 1-{imidazo[1,5-a]pyridine-6-carbonyl}pyrrolidine (900 mg, 68% yield) as a yellow solid.

[0356] LC-MS(ESI):C 12 H 13 Calculated mass of NO: 215.11, measured m / z: 216.12 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),8.42(s,1H),7.57(d,J=9.4Hz,1H),7.40(s,1H),6.90(d,J=9.4Hz,1H),3.53-3.47(m,4H),1.88-1.83(m,4H).

[0357] Step B: 6-(pyrrolidin-1-ylmethyl)imidazo[1,5-a]pyridine To a solution of 1-{imidazo[1,5-a]pyridine-6-carbonyl}pyrrolidine (600 mg, 2.8 mmol, 1.0 equiv.) in THF (5 mL) was added BH-MeS complex (2 M in THF) (7 mL, 14.0 mmol, 5.0 equiv.) at room temperature. The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was cooled to room temperature, quenched with MeOH (5 mL), and then stirred at 70° C. for 30 min. The reaction mixture was diluted with dilute aqueous HCl solution (1 N) (10 mL), stirred for 30 min, adjusted to pH 8 with saturated NaHCO solution, and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM / MeOH=5 / 1) to give 1-({imidazo[1,5-a]pyridin-6-yl}methyl)pyrrolidine (300 mg, 53% yield) as a yellow solid.

[0358] LC-MS(ESI):C 12 H 15 Calculated mass of N3: 201.13, measured m / z: 202.13 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.38(s,1H),8.35(s,1H),7.56(d,J=9.4Hz,1H),7.35(s,1 H),6.83(d,J=9.0Hz,1H),3.88-3.78(m,2H),2.93-2.74(m,4H),1.86-1.79(m,4H).

[0359] Step C: 3-iodo-6-(pyrrolidin-1-ylmethyl)imidazo[1,5-a]pyridine To a solution of 1-({imidazo[1,5-a]pyridin-6-yl}methyl)pyrrolidine (300 mg, 1.5 mmol, 1.0 equiv) in anhydrous THF (5 mL) was added n-BuLi (1.6 M in hexanes) (0.894 mL, 2.3 mmol, 1.5 equiv) dropwise at −78° C. under N. The reaction mixture was stirred at −78° C. for 1 h. A stirred solution of I (661.2 mg, 1.5 mmol, 1.0 equiv) in THF (5 mL) was added dropwise to the above mixture, and the resulting reaction mixture was stirred at −78° C. for 0.5 h. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL × 3). The organic layer was washed with brine (40 mL × 4), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM / MeOH=5 / 1) to give 1-({3-iodoimidazo[1,5-a]pyridin-6-yl}methyl)pyrrolidine (150 mg, 31% yield) as a yellow solid.

[0360] LC-MS(ESI):C 12 H 14 Calculated mass of IN3: 327.02, measured m / z: 328.03 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ7.90(s,1H),7.53(d,J=9.4Hz,1H),7.48(s,1H),6.8 5(d,J=9.0Hz,1H),3.61(s,2H),3.42(s,2H),3.04-2.89(m,2H),1.72(s,4H).

[0361] Intermediate 7: 5-Chloroimidazo[1,5-a]pyridine-8-carbaldehyde TIFF2025510834000099.tif21128Step A: 3-Bromo-2-(bromomethyl)-6-chloropyridine To a solution of 3-bromo-6-chloro-2-methylpyridine (8 g, 38.747 mmol, 1.0 equiv.) in carbon tetrachloride (130 mL) was added BPO (0.94 g, 3.875 mmol, 0.1 equiv.) and NBS (8.97 g, 50.371 mmol, 1.3 equiv.) at room temperature. The reaction mixture was heated to 95 °C overnight. After cooling to room temperature, the reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic extracts were washed with water (200 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EA = 80 / 1) to provide 3-bromo-2-(bromomethyl)-6-chloropyridine (7.1 g, 55% yield) as a yellow oil.

[0362] LC-MS (ESI): calculated mass for C6H4Br2ClN 282.84, observed m / z 283.85 [M+H] + .

[0363] Step B: 2-(azidomethyl)-3-bromo-6-chloropyridine To a solution of 3-bromo-2-(bromomethyl)-6-chloropyridine (7.1 g, 24.880 mmol, 1.0 equiv.) in DMF (100 mL) was added sodium azide (3.23 g, 49.760 mmol, 2.0 equiv.) at room temperature. The reaction mixture was stirred at 30° C. for 1 hour. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (150 mL×3). The combined organic extracts were washed with brine (100 mL×4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(azidomethyl)-3-bromo-6-chloropyridine (6.0 g, 83% yield) as a yellow oil. The oil was used directly in the next step without further purification.

[0364] LC-MS (ESI): calculated mass for C6H4BrClN4 245.93, observed m / z 246.94 [M+H] + .

[0365] Step C: (3-Bromo-6-chloropyridin-2-yl)methanamine To a solution of 2-(azidomethyl)-3-bromo-6-chloropyridine (6.0 g, 24.244 mmol, 1.0 equiv.) in THF (70 mL) and HO (8 mL) was added PPh (9.54 g, 36.366 mmol, 1.5 equiv.) at room temperature. The reaction mixture was stirred at 50 °C for 2 h. After evaporation, the residue was diluted with water (30 mL), acidified to pH 2-3 with aqueous HCl solution (2 N), and extracted with DCM (50 mL × 2). After discarding the organic layer, the aqueous phase was concentrated under reduced pressure to give (3-bromo-6-chloropyridin-2-yl)methanamine hydrochloride (3.35 g, 56% yield) as a red oil.

[0366] LC-MS (ESI): calculated mass for C6H6BrClN2 219.94, observed m / z 220.95 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.61(s,3H),8.24(d,J=8.4Hz,1H),7.56(d,J=8.4Hz,1H),4.24(s,2H).

[0367] Step D: N-[(3-bromo-6-chloropyridin-2-yl)methyl]formamide To a solution of (3-bromo-6-chloropyridin-2-yl)methanamine (3.35 g, 15.125 mmol, 1.0 equiv) in ethyl formate (80 mL) was added NaHCO (2.54 g, 30.250 mmol, 2.0 equiv) and triethylamine (10.5 mL, 75.624 mmol, 5.0 equiv) at room temperature. The reaction mixture was stirred at 70 °C overnight. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give N-[(3-bromo-6-chloropyridin-2-yl)methyl]formamide (3.0 g, 64% yield) as a pink solid, which was used directly in the next step.

[0368] LC-MS (ESI): calculated mass for C7H6BrClNO 247.94, observed m / z 248.94 [M+H] + .

[0369] Step E: 8-Bromo-5-chloroimidazo[1,5-a]pyridine To a solution of N-[(3-bromo-6-chloropyridin-2-yl)methyl]formamide (3.0 g, 12.024 mmol, 1.0 equiv.) in dioxane (60 mL) was added POCl (2.2 mL, 24.048 mmol, 2.0 equiv.) at room temperature. The reaction mixture was stirred at 115 °C for 3 hours. After cooling to room temperature, the mixture was slowly quenched with aqueous NaHCO and extracted with EtOAc (50 mL × 2). The organic layer was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (PE / EA = 10 / 1) to provide 8-bromo-5-chloroimidazo[1,5-a]pyridine (1.57 g, 56% yield) as a yellow solid.

[0370] LC-MS (ESI): calculated mass for C7H4BrClN2 229.92, observed m / z 230.93 [M+H] + .

[0371] Step F: Methyl 5-chloroimidazo[1,5-a]pyridine-8-carboxylate To a solution of 8-bromo-5-chloroimidazo[1,5-a]pyridine (0.5 g, 2.160 mmol, 1.0 equiv.) in DMF (20 mL) and MeOH (20 mL) was added triethylamine (1.5 mL, 10.800 mmol, 5 equiv.) and Pd(dppf)Cl (0.16 g, 0.216 mmol, 0.1 equiv.) at room temperature. The reaction mixture was stirred at 80 °C under CO (1 atm.) for 6 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic extracts were washed with water (30 mL × 2) and brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EA=6 / 1) to give methyl 5-chloroimidazo[1,5-a]pyridine-8-carboxylate (0.21 g, yield 46%) as a yellow solid.

[0372] LC-MS (ESI): calculated mass for C9H7ClN2O2 210.02, observed m / z 211.03 [M+H] + .

[0373] Step G: {5-chloroimidazo[1,5-a]pyridin-8-yl}methanol To a solution of methyl 5-chloroimidazo[1,5-a]pyridine-8-carboxylate (210 mg, 0.997 mmol, 1.0 equiv.) in THF (8 mL) was added DIBAL-H (1 M) (3 mL, 2.991 mmol, 3 equiv.) dropwise at −70° C. under nitrogen. The reaction mixture was then stirred at 0° C. for 1 h, slowly diluted with saturated aqueous NH4Cl solution (10 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (100% EA) to afford {5-chloroimidazo[1,5-a]pyridin-8-ylmethanol (100 mg, 55% yield) as a yellow solid.

[0374] LC-MS (ESI): calculated mass for C8H7ClNO 182.02, observed m / z 183.03 [M+H] + .

[0375] Step H: 5-chloroimidazo[1,5-a]pyridine-8-carbaldehyde To a solution of {5-chloroimidazo[1,5-a]pyridin-8-yl}methanol (100 mg, 0.548 mmol, 1.0 equiv) in DCM (8 mL) was added Dess-Martin periodinane (302.16 mg, 0.712 mmol, 1.5 equiv) at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (30 mL), washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (100% EA) to give 5-chloroimidazo[1,5-a]pyridine-8-carbaldehyde (90 mg, 87% yield) as a yellow solid.

[0376] LC-MS (ESI): calculated mass for C8H5ClN2O: 180.01, observed m / z: 181.02 [M+H] + .

[0377] Intermediate 8: 6-Chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde TIFF2025510834000100.tif24128Step A: Methyl 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate To a solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (800 mg, 3.8 mmol, 1.0 equiv) in DMF (10 mL) was added NaH (60% suspension in oil) (341.8 mg, 5.7 mmol, 1.5 equiv) and CHCl (0.36 mL, 5.7 mmol, 1.5 equiv) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL×3). The organic layer was washed with brine (40 mL×3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EA=10 / 1) to afford methyl 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (700 mg, 82% yield) as a yellow solid.

[0378] LC-MS (ESI, m / z): C 10 Calculated mass of H9ClN2O2: 224.04, Measured mass: 224.9 [M+H] + .

[0379] Step B: (6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol To a solution of methyl 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (700 mg, 3.1 mmol, 1.0 equiv.) in anhydrous THF (10 mL) was added LiAlH (118.3 mg, 3.1 mmol, 1.0 equiv.) in portions at 0 °C. The reaction mixture was stirred at 0 °C for 20 minutes. The reaction mixture was slowly quenched with aqueous NaOH solution (1 N) (40 mL) and extracted with EtOAc (40 mL × 3). The organic layer was washed with brine (40 mL × 4), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EA = 1 / 1) to afford {6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl}methanol (500 mg, 82% yield) as a yellow solid.

[0380] LC-MS (ESI, m / z): calculated mass for C9H9ClNO 196.04, found mass 196.9 [M+H] + .

[0381] Step C: 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde To a solution of {6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl}methanol (500 mg, 2.5 mmol, 1.0 equiv.) in DMSO (15 mL) was added IBX (2.1 g, 7.5 mmol, 3.0 equiv.) in several portions at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL × 3). The organic layer was washed with brine (40 mL × 4), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EA = 2 / 1) to afford 6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (350 mg, 71% yield) as a yellow solid.

[0382] LC-MS (ESI, m / z): calculated mass for C9H7ClNO 194.02, found mass 195.2 [M+H] + .

[0383] Intermediate 9: 6-Chloro-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde TIFF2025510834000101.tif21128Step A: (6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol To a solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (120 mg, 570 μmol, 1.0 equiv.) in THF (5.0 mL) was added LiAlH (21.6 mg, 570 μmol, 1.0 equiv.) in portions at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes. The reaction mixture was slowly quenched with aqueous NaOH solution (1 N) (5 mL) and extracted with EtOAc (5 mL×3). The organic layer was washed with brine (5 mL×2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EA=1 / 1) to afford (6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (100 mg, 96% yield) as a yellow solid.

[0384] LC-MS (ESI): calculated mass for C8H7ClNO 182.02, observed m / z 183.02 [M+H] + .

[0385] Step B: 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde To a solution of (6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (100 mg, 548 μmol, 1.0 equiv.) in DMSO (5.0 mL) was added IBX (383 mg, 1.4 mmol, 2.5 equiv.) in several portions at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL×3). The organic layer was washed with brine (10 mL×4), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EA=2 / 1) to afford 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (80 mg, 81% yield).

[0386] LC-MS (ESI): calculated mass for C8H5ClN2O: 180.01, observed m / z: 181.01 [M+H] + .

[0387] Intermediate 10: 6-Chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde TIFF2025510834000102.tif26128Step A: Methyl 6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate To a stirred solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (500 mg, 2.37 mmol, 1.0 equiv.) in DMF (6.00 mL) was added sodium hydride (60% suspension in oil) (0.19 g, 4.75 mmol, 2.0 equiv.) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. Iodoethane (444 mg, 2.85 mmol, 1.2 equiv.) was then added to the above mixture, and the reaction mixture was stirred at 25 °C for 30 min under a nitrogen atmosphere. The reaction mixture was quenched with saturated aqueous NH4Cl solution (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine (30 mL × 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=10 / 1) to give methyl 6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (215 mg, 38% yield) as a white solid.

[0388] LC-MS(ESI):C 11 H 11 Calculated mass of ClN2O2: 238.05, measured m / z: 239.05 [M+H] + .

[0389] Step B: (6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol To a solution of methyl 6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (215 mg, 901 μmol, 1.0 equiv.) in THF (4.00 mL) was added lithium aluminum hydride (34.2 mg, 901 μmol, 1.0 equiv.) at 0° C., and the reaction mixture was stirred at 0° C. for 5 minutes under a nitrogen atmosphere. The reaction mixture was quenched with saturated NaOH solution (5 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were concentrated under reduced pressure to give (6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (170 mg, 89.6% yield) as a red oil. LC-MS (ESI): C 10 H 11 Calculated mass of ClNO: 210.06, measured m / z: 211.06 [M+H] + .

[0390] Step C: 6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde To a stirred solution of (6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (170 mg, 807 μmol, 1.0 equiv.) in DMSO (4.00 mL), IBX (678 mg, 2.42 mmol, 3.0 equiv.) was added, and the reaction mixture was stirred at 30° C. under a nitrogen atmosphere for 20 minutes. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (20 mL×4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=10 / 1) to afford 6-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (110 mg, 65% yield) as a yellow solid.

[0391] LC-MS(ESI):C 10 Calculated mass of H9ClNO: 208.04, measured m / z: 209.04 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.28(s,1H),7.90(d,J=3.4Hz,1H),7.70(s,1H),7.00(d,J=3.4Hz,1H),4.31(q,J=7.2Hz,2H),1.39(t,J=7.2Hz,3H).

[0392] Intermediate 11: 5-Chloro-1H-pyrrolo[3,2-b]pyridine-7-carbaldehyde TIFF2025510834000103.tif18128Step A: (5-chloro-1H-pyrrolo[3,2-b]pyridin-7-yl)methanol To a solution of methyl 5-chloro-1H-pyrrolo[3,2-b]pyridine-7-carboxylate (350 mg, 1.66 mmol, 1.0 equiv.) in THF (10.0 mL) was added LiAlH (94.6 mg, 2.49 mmol, 1.5 equiv.) at 0 °C, and the mixture was stirred at 0 °C for 30 min. The mixture was cooled to 0 °C with NaSO . The mixture was quenched with 10H2O and filtered. The filtrate was concentrated under reduced pressure to give (5-chloro-1H-pyrrolo[3,2-b]pyridin-7-yl)methanol (250 mg, 82% yield) as a pale yellow solid.

[0393] LC-MS (ESI): calculated mass for C8H7ClN2O 182.6, observed m / z 183.2 [M+H] +

[0394] Step B: 5-chloro-1H-pyrrolo[3,2-b]pyridine-7-carbaldehyde To a solution of (5-chloro-1H-pyrrolo[3,2-b]pyridin-7-yl)methanol (250 mg, 1.37 mmol, 1.0 equiv) in DMSO (5.00 mL) was added IBX (575 mg, 2.05 mmol, 1.5 equiv). The mixture was stirred at 30 °C for 3 h. The reaction mixture was quenched with ice water (20 mL) and extracted with EA (15 mL × 3). The organic layer was washed with brine (10 mL × 4), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0-30%) to afford 5-chloro-1H-pyrrolo[3,2-b]pyridine-7-carbaldehyde (180 mg, 73% yield) as a pale yellow solid.

[0395] LC-MS (ESI): calculated mass for C8H5ClN2O 180.01, observed m / z 181.1 [M+H] +

[0396] Intermediate 12: 5-Chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine-7-carbaldehyde TIFF2025510834000104.tif18128Step A: Methyl 5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylate To a mixture of methyl 5-chloro-1H-pyrrolo[3,2-b]pyridine-7-carboxylate (150 mg, 0.71 mmol, 1.0 equiv.) in DMF (3.00 mL), NaH (60% suspension in oil) (51 mg, 2.14 mmol, 3.0 equiv.) was added at 0 °C, and the mixture was stirred under a N atmosphere for 1 h. Then, MeI (355 mg, 2.14 mmol, 3.0 equiv.) was added to the above mixture, and the resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated aqueous NH Cl solution (20 mL) and extracted with EtOAc (15 mL × 3). The organic layer was washed with brine (20 mL × 4), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc in PE, 0-50%) to afford methyl 5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylate (50.0 mg, 30% yield) as a white solid.

[0397] LC-MS(ESI):C 10 Calculated mass of H9ClN2O2: 223.2, measured m / z: 225.2 [M+H] +

[0398] Step B: (5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-7-yl)methanol To a solution of methyl 5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine-7-carboxylate (370 mg, 1.65 mmol, 1.0 equiv.) in THF (10.0 mL) was added LiAlH (93.8 mg, 2.47 mmol, 1.5 equiv.) at 0° C. The mixture was stirred at 0° C. for 30 min, then added NaSO . The mixture was quenched with 10H2O and stirred at room temperature for 10 minutes. After filtration, the filtrate was concentrated under reduced pressure to give (5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-7-yl)methanol (280 mg, 1.42 mmol, 86.5%) as a pale yellow solid.

[0399] LC-MS (ESI): calculated mass for C9H9ClNO 196.6, observed m / z 197 [M+H]+ 。

[0400] Step C: 5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine-7-carbaldehyde To a solution of (5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-7-yl)methanol (280 mg, 1.42 mmol, 1.0 equiv) in DMSO (8.00 mL) was added IBX (598 mg, 2.14 mmol, 1.5 equiv) at 0 °C. The mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with water (10 mL) and extracted with EA (15 mL × 3). The organic layer was washed with brine (10 mL × 4), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA in PE, 0-30%) to afford 5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine-7-carbaldehyde (160 mg, 58% yield) as a pale yellow solid.

[0401] LC-MS (ESI): calculated mass for C9H7ClNO 194.02, observed m / z 195.2 [M+H] + 。 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),7.86(d,J=3.4Hz,1H),7.60(s,1H),6.70(d, J=3.4Hz,1H),4.11(s,3H)

[0402] Intermediate 13: 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione TIFF2025510834000105.tif28128Step A: 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione To a solution of methyl 4-bromo-2-(bromomethyl)benzoate (20 g, 65.1 mmol, 1.0 equiv.) in ACN (500 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (10.7 g, 65.1 mmol, 1.0 equiv.) and DIPEA (25.2 g, 195.3 mmol, 3.0 equiv.) at room temperature. The reaction mixture was stirred at 85° C. for 12 hours. After evaporation, the residue was diluted with a mixture of ACN and HO (160 mL, 3 / 1 v / v) and filtered to give a blue solid. The solid was dried to give 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (10.5 g, 50% yield).

[0403] LC-MS(ESI):C 13 H 11 Calculated mass of BrN2O3: 322.00, measured m / z: 323.00 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),7.89(s,1H),7.73-7.66(m,2H),5.14-5.09(m,1H),4.47(d,J=16.8H) z,1H),4.34(d,J=16.8Hz,1H),3.02-2.77(m,1H),2.62-2.58(m,1H),2.45-2.36(m,1H),2.13-1.92(m,1H).

[0404] Step B: 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione To a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (10.5 g, 32.5 mmol, 1.0 equiv.) in anhydrous dioxane (150 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (9.9 g, 39.0 mmol, 1.2 equiv.), Pd(dppf)Cl (1.2 g, 1.62 mmol, 0.05 equiv.), and KOAc (9.5 g, 97.5 mmol, 3.0 equiv.) at room temperature. The reaction mixture was stirred at 100 °C under N for 12 h. After evaporation, the residue was diluted with HO (150 mL) and filtered to give a blue solid. The blue solid was washed with EA (50 mL × 3) and dried to give 3-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (9.2 g, 71% yield) as a blue solid.

[0405] LC-MS(ESI):C 19 H 23 Calculated mass of BN2O5: 370.17, measured m / z: 371.21 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),7.90(s,1H),7.80(d,J=7.6Hz,1H),7.73(d,J=7.6Hz,1H),5.15-5.10(m,1H),4.47(d,J= 16.8Hz,1H),4.35(d,J=16.8Hz,1H),3.08-2.80(m,1H),2.62-2.58(m,1H),2.45-2.33(m,1H),2.18-1.94(m,1H),1.24(s,12H).

[0406] Intermediate 14: 3-(4-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione TIFF2025510834000106.tif27128 The title compound was prepared in a manner similar to intermediate 13 by bromination of methyl 4-bromo-3-fluoro-2-methylbenzoate, coupling with 3-aminopiperidine-2,6-dione, cyclization, and then boronation with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane).

[0407] LC-MS(ESI):C 19 H 22 Calculated mass of BFN2O5: 388.16, measured m / z: 389.3 [M+H] + .

[0408] Intermediate 15: 3-(6-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione TIFF2025510834000107.tif28128 The title compound was prepared in a manner similar to intermediate 13 by brominating methyl 4-bromo-5-fluoro-2-methylbenzoate, coupling with 3-aminopiperidine-2,6-dione, cyclization, and then boronation with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane).

[0409] LC-MS(ESI):C 19 H 22 Calculated mass of BFN2O5: 388.20, measured m / z: 389.1 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ11.02(s,1H),7.89(d,J=4.0Hz,1H),7.45(d,J=8.0Hz,1H),5.15-5.11(m,1H),4.45(d,J=17.6H) z,1H),4.33(d,J=17.6Hz,1H),2.93-2.91(m,1H),2.62-2.58(m,1H),2.41-2.36(m,1H),2.03-1.99(m,1H),1.32(s,12H).

[0410] Intermediate 16: 3-(7-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione TIFF2025510834000108.tif31128 The title compound was prepared in a manner similar to intermediate 13 by bromination of methyl 4-bromo-6-fluoro-2-methylbenzoate, coupling with 3-aminopiperidine-2,6-dione, cyclization, and then boronation with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane).

[0411] LC-MS(ESI):C 19 H 22 Calculated mass of BFN2O5: 388.20, measured m / z: 389.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.71(s,1H),7.39(d,J=8.0Hz,1H),5.12-5.07(m,1H),4.49(d,J=17.6Hz,1H) ,4.37(d,J=17.6Hz,1H),2.94-2.91(m,1H),2.62-2.59(m,1H),2.50-2.48(m,1H),2.01-1.99(m,1H),1.32(s,12H).

[0412] Intermediate 17: 3-(4-methoxy-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione TIFF2025510834000109.tif28128 The title compound was prepared in a similar manner to intermediate 13 by bromination of methyl 4-bromo-3-methoxy-2-methylbenzoate, coupling with 3-aminopiperidine-2,6-dione, cyclization, and then boronation with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane).

[0413] Intermediate 18: 3-(6-methoxy-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione TIFF2025510834000110.tif28128 The title compound was prepared in a manner similar to intermediate 13 by brominating methyl 4-bromo-5-methoxy-2-methylbenzoate, coupling with 3-aminopiperidine-2,6-dione, cyclization, and then boronation with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane).

[0414] Intermediate 19: 3-(7-methoxy-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione TIFF2025510834000111.tif32128 The title compound was prepared in a similar manner to intermediate 13 by bromination of methyl 4-bromo-6-methoxy-2-methylbenzoate, coupling with 3-aminopiperidine-2,6-dione, cyclization, and then boronation with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane).

[0415] Intermediate 20: 2-(3-chloro-4-methylphenyl)ethan-1-amine TIFF2025510834000112.tif27128Step A: (3-chloro-4-methylphenyl)methyl methanesulfonate To a solution of (3-chloro-4-methylphenyl)methanol (1 g, 6.385 mmol, 1.0 equiv) and TEA (1.8 mL, 12.77 mmol, 2.0 equiv) in DCM (15 mL) was added MsCl (0.741 mL, 9.578 mmol, 1.5 equiv) dropwise at 0 °C. The mixture was stirred at room temperature for 2 h. The residue was poured into water (30 mL) and extracted with DCM (30 mL × 3). The organic layer was washed with brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10%) to give (3-chloro-4-methylphenyl)methyl methanesulfonate (0.6 g, 36% yield) as a yellow oil.

[0416] Step B: 2-(3-chloro-4-methylphenyl)acetonitrile To a solution of (3-chloro-4-methylphenyl)methyl methanesulfonate (500 mg, 2.130 mmol, 1.0 equiv) in DMF (1 mL) was added NaCN (0.131 mL, 4.261 mmol, 2.0 equiv), and the mixture was stirred at 50 °C overnight. The mixture was poured into water (6 mL) and extracted with DCM (15 mL × 3). The organic layer was washed with brine (15 mL × 4), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10%) to give 2-(3-chloro-4-methylphenyl)acetonitrile (300 mg, 76% yield) as a yellow oil.

[0417] Step C: 2-(3-chloro-4-methylphenyl)ethan-1-amine To a solution of 2-(3-chloro-4-methylphenyl)acetonitrile (300 mg, 1.811 mmol, 1.0 equiv.) in THF (5 mL), BH3-THF (1 M in THF) (5.4 mL, 5.433 mmol, 3.0 equiv.) was added, and the mixture was stirred at 40 °C overnight. The residue was quenched with MeOH (6 mL) and stirred for 30 min. Then, concentrated HCl (3 mL) was added to the above mixture and stirred for 30 min. After evaporation, the residue was diluted with HO (10 mL), adjusted to pH 9–10, and extracted with DCM (15 mL × 3). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 40%) to give 2-(3-chloro-4-methylphenyl)ethan-1-amine (100 mg, 29.3% yield) as a yellow oil.

[0418] LC-MS(ESI):CH 12 Calculated mass of ClN: 169.07, measured m / z: 170.3 [M+H] + .

[0419] Intermediate 21: (1-methyl-1H-indol-7-yl)methanamine TIFF2025510834000113.tif25128Step A: 1-Methyl-1H-indole-7-carbaldehyde To a solution of 1H-indole-7-carbaldehyde (1.4 g, 9.645 mmol, 1.0 equiv.) in DMF (10 mL), NaH (60% suspension in oil) (0.46 g, 11.574 mmol, 1.2 equiv.) was added, and the mixture was stirred for 20 min. Then, iodomethane (1.64 g, 11.574 mmol, 1.2 equiv.) was added dropwise to the above mixture, and the mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (30 mL) and extracted with EA (40 mL × 3). The combined organic phase was washed with brine (30 mL × 4), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by fluff column chromatography on silica gel (MeOH / DCM=1 / 10) to give 1-methyl-1H-indole-7-carbaldehyde (700 mg, yield 46%) as a yellow oil.

[0420] LC-MS(ESI):C 10 H9NO 159.07, m / z measured value 160.10 [M+H] + .

[0421] Step B: 2-methyl-N-((1-methyl-1H-indol-7-yl)methyl)propane-2-sulfinamide To a solution of 1-methyl-1H-indole-7-carbaldehyde (700 mg, 4.397 mmol, 1.0 equiv) and 2-methylpropane-2-sulfinamide (1065.83 mg, 8.794 mmol, 2.0 equiv) in THF (20 mL) was added Ti(OEt) (0.922 mL, 4.397 mmol, 1.0 equiv), and the mixture was stirred at 70 °C for 30 min. After cooling to room temperature, NaBH (250 mg, 6.596 mmol, 1.5 equiv) was added to the above mixture at 0 °C, and the mixture was stirred at 50 °C for 24 h. After cooling to room temperature, the mixture was quenched with saturated aqueous NH Cl solution (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with 5% aqueous KH2PO4 solution (50 mL, pH 5 to destroy the borane complex) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) under reflux and cooled to 22 °C while heptane (50 mL) was added in one portion. The solution was stirred at 22 °C for 30 min, during which time crystallization began. It was then cooled to 5 °C and stirred for 30 min. The solid was filtered, washed with EtOAc / Hep (20 mL, 1 / 1) and pentane (20 mL), and dried to give 2-methyl-N-[(1-methyl-1H-indol-7-yl)methyl]propane-2-sulfinamide (800 mg, 68.81% yield) as a white solid.

[0422] LC-MS (ESI): calculated mass for CHNOS: 264.13, observed m / z: 265.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.46(dd,J=7.8,0.8Hz,1H),7.22(d,J=3.2Hz,1H),7.06(d,J=7.0Hz,1H),6.94(t,J=7.4Hz,1H),6.39 (d,J=3.2Hz,1H),5.64(t,J=5.2Hz,1H),4.63(dd,J=13.8,4.6Hz,1H),4.52(dd,J=13.8,5.6Hz,1H),4.05(s,3H),1.36(s,9H).

[0423] Step C: (1-methyl-1H-indol-7-yl)methanamine To a solution of 2-methyl-N[(1-methyl-1H-indol-7-yl)methyl]propane-2-sulfinamide (800 mg, 3.026 mmol, 1.0 equiv.) in dioxane (5 mL) was added hydrogen chloride (4N in dioxane) (3.1 mL, 12.500 mmol, 4.0 equiv.) at 0° C., and the resulting reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give (1-methyl-1H-indol-7-yl)methanamine hydrochloride (460 mg, 95% yield) as an off-white solid.

[0424] LC-MS(ESI):Chemical formula:C 10 H 12 Calculated mass of N2: 160.10, measured m / z: 161.0 [M+H] + .

[0425] Intermediate 22: 2-Chloroquinoline-4-carbaldehyde TIFF2025510834000114.tif27128Step A: (2-chloroquinolin-4-yl)(pyrrolidin-1-yl)methanone To a mixture of 2-chloroquinoline-4-carboxylic acid (1.00 g, 1.0 equivalent, 4.82 mmol) in dry DMF (10 mL) was added HATU (2.20 g, 1.2 equivalent, 5.78 mmol), DIEA (2.52 mL, 3.0 equivalent, 14.5 mmol), and pyrrolidine (603 μL, 1.5 equivalent, 7.23 mmol) at 20 °C. The mixture was stirred at 20 °C for 30 minutes to give a yellow solution. The reaction solution was poured into saturated NH Cl and extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-67% EtOAc in PE) to afford (2-chloroquinolin-4-yl)(pyrrolidin-1-yl)methanone (1.20 g, 95.6%) as a yellow solid.

[0426] LC-MS(ESI):Chemical formula:C 14 H 13Calculated mass of ClNO: 260.7, measured m / z: 261.5 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.03(d,J=8.4Hz,1H),7.91-7.83(m,2H),7.72(dd,J=11.2,4.0Hz,1H),7. 66(s,1H),3.62(t,J=7.0Hz,2H),3.10(t,J=6.7Hz,2H),1.96-1.88(m,2H),1.80(p,J=6.7Hz,2H).

[0427] Step B: 2-chloroquinoline-4-carbaldehyde To a mixture of (2-chloroquinolin-4-yl)(pyrrolidin-1-yl)methanone (400 mg, 1.0 equiv., 1.53 mmol) in THF (6 mL) was added LAH (116 mg, 2.0 equiv., 3.07 mmol) under an ice-water bath. The reaction was stirred at 0 °C for 5 min. The reaction solution was poured into saturated NH Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-30% EtOAc in PE) to afford 2-chloroquinoline-4-carbaldehyde (150 mg, 51.0%) as a yellow solid.

[0428] LC-MS(ESI):Chemical formula:C 10 Calculated mass of H6ClNO: 191.0, measured m / z: 192.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.55(s,1H),8.99(d,J=8.4Hz,1H),8.21(s,1H),8.16(d,J=8.1Hz,1H),8.03-7.97(m,1H),7.93-7.86(m,1H).

[0429] Intermediate 23: 2-chloro-4-(pyrrolidin-1-ylmethyl)-5,6,7,8-tetrahydroquinoline TIFF2025510834000115.tif35128Step A: Ethyl 3-cyano-2-oxo-1,2,5,6,7,8-hexahydroquinoline-4-carboxylate To a mixture of sodium ethanolate (26.6 g, 25 wt%, 1.2 equiv., 97.8 mmol) and diethyl oxalate (11.9 g, 1.0 equiv., 81.5 mmol) in EtOH (30 mL) was added cyclohexanone (8.0 g, 1.0 equiv., 81.5 mmol) dropwise. The mixture was stirred at 25° C. for 3 hours, and then 2-cyanoacetamide (6.85 g, 1.0 equiv., 81.5 mmol) was added. The reaction was stirred at 80° C. for 2 hours and then concentrated in vacuo. The residue was taken up in 150 mL of boiling water and 12 mL of acetic acid and stirred at 0° C. for 10 minutes. A precipitate occurred and the solid was isolated by filtration and dried in vacuo to give ethyl 3-cyano-2-oxo-1,2,5,6,7,8-hexahydroquinoline-4-carboxylate (12.6 g, 62.8% yield) as a brown solid.

[0430] LC-MS(ESI):Chemical formula:C 13 H 14 Calculated mass of N2O3: 246.3, measured m / z: 247.2 [M+H] + .

[0431] Step B: 2-oxo-1,2,5,6,7,8-hexahydroquinoline-4-carboxylic acid A mixture of ethyl 3-cyano-2-oxo-1,2,5,6,7,8-hexahydroquinoline-4-carboxylate (12.5 g, 1 equivalent, 50.8 mmol) and 36% aqueous hydrochloric acid solution (34.5 mL, 10 equivalents, 508 mmol) was stirred at 115° C. overnight. An additional 2 mL of 6 M hydrochloric acid was added to the mixture, and the reaction was further heated to 115° C. overnight. The hot reaction solution was poured onto ice to form a precipitate, and the solid was filtered. The solid was dried in vacuo at 65° C. to give 2-oxo-1,2,5,6,7,8-hexahydroquinoline-4-carboxylic acid (8.60 g, 44% yield).

[0432] LC-MS(ESI):Chemical formula:C10 H 11 Calculated mass of NO3: 193.2, measured m / z: 194.1 [M+H] + .

[0433] Step C: (2-chloro-5,6,7,8-tetrahydroquinolin-4-yl)(pyrrolidin-1-yl)methanone A solution of 2-oxo-1,2,5,6,7,8-hexahydroquinoline-4-carboxylic acid (4.0 g, 1.0 equiv., 10.4 mmol) in POCl (18.2 mL, 18.9 equiv., 196 mmol) was stirred at 100° C. for 2 hours. The reaction mixture was concentrated under vacuum to give the crude product. This was then added to DCM (50 mL) followed by TEA (2.89 mL, 2.0 equiv., 20.7 mmol) at 0° C. The mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with water (15 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was then purified by flash with EA / PE=48% to afford (2-chloro-5,6,7,8-tetrahydroquinolin-4-yl)(pyrrolidin-1-yl)methanone (1.00 g, 36.5% yield) as a yellow oil.

[0434] LC-MS(ESI):Chemical formula:C 14 H 17 Calculated mass of ClNO: 264.1, measured m / z: 265.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.23(s,1H),3.45(t,J=6.7Hz,2H),3.08(t,J=6.3Hz,2H),2.81(t,J=6.3Hz,2H),2.55(t,J=6.0Hz,2H),1.91-1.68(m,9H).

[0435] Step D: 2-chloro-4-(pyrrolidin-1-ylmethyl)-5,6,7,8-tetrahydroquinoline To a solution of (2-chloro-5,6,7,8-tetrahydroquinolin-4-yl)(pyrrolidin-1-yl)methanone (500 mg, 1.0 equiv., 1.89 mmol) in THF (10 mL) was added LAH (143 mg, 2.0 equiv., 3.78 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes. The reaction solution was added to saturated NH4Cl at 0° C. The mixture was filtered, and the filtrate was partitioned between water (3 mL) and EA (5 mL × 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, and purified by preparative TLC (PE:EA = 1:1) to give 2-chloro-4-(pyrrolidin-1-ylmethyl)-5,6,7,8-tetrahydroquinoline (40 mg, yield 8.45%) as a yellow solid.

[0436] LC-MS(ESI):Chemical formula:C 14 H 19 Calculated mass of ClN: 193.2, measured m / z: 251 [M+H] + .

[0437] Intermediate 24: 2-Chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carbaldehyde TIFF2025510834000116.tif28128Step A: 3-Cyano-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-4-carboxylate To a mixture of sodium ethoxide (20%, 27.9 mL, 1.2 equiv., 71.3 mmol) in ethanol and cyclopentanone (5.00 g, 1.0 equiv., 59.4 mmol), diethyl oxalate (8.69 g, 1.0 equiv., 59.4 mmol) was added dropwise. The mixture was stirred at 25° C. for 3 hours. 2-Cyanoacetamide (5.00 g, 1.0 equiv., 59.4 mmol) was then added. The reaction was stirred at 80° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in 250 mL of boiling water and 20 mL of acetic acid at 0° C. The solid was precipitated and isolated by filtration, and the collected solid was dried in vacuo to give ethyl 3-cyano-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-4-carboxylate (4.90 g, 35.5% yield) as a green solid.

[0438] LC-MS(ESI):Chemical formula:C 12 H 12 Calculated mass of N2O3: 232.2, measured m / z: 233.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.22(s,1H),4.38(q,J=7.1Hz,2H),2.87(t,J=7.7Hz,2H),2.79(t,J=7.3Hz,2H),2.09-1.99(m,2H),1.32(t,J=7.1Hz,3H).

[0439] Step B: 2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-4-carboxylic acid To a solution of ethyl 3-cyano-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-4-carboxylate (4.90 g, 1.0 equivalent, 21.1 mmol) in an aqueous solution of 6 N HCl (35.2 mL, 211 mmol). The mixture was stirred at 115 °C for 16 hours. The hot reaction solution was poured into ice to precipitate a solid. The solid was then filtered. The filter cake was dried in vacuo at 45 °C to give 2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-4-carboxylic acid (3.00 g, 79.4%) as a red solid.

[0440] LC-MS (ESI): Formula: C9H9NO3, calculated mass 179.2, observed m / z 180.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ6.64 (s, 1H), 2.89 (t, J = 7.4Hz, 2H), 2.76 (t, J = 7.7Hz, 2H), 2.05-1.95 (m, 2H).

[0441] Step C: Methyl 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carboxylate To a solution of 2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-4-carboxylic acid (600 mg, 1.0 equiv., 3.35 mmol) in POCl (6.00 mL, 64.4 mmol). The mixture was stirred at 90 °C for 16 h. The reaction mixture was concentrated in vacuo to give crude 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carbonyl chloride (600 mg, 82.9%) as a brown oil.

[0442] To a solution of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carbonyl chloride (600 mg, 1.85 mmol) in DCM (3.0 mL) was added methanol (600 mL, 18.5 mmol) at −40° C. The mixture was stirred at room temperature for 20 minutes. The reaction mixture was quenched with water (15 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine solution, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was then purified by flash with EA / PE=20% to give methyl 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carboxylate (300 mg, 76.6%) as a yellow solid.

[0443] LC-MS(ESI):Chemical formula:C 10 H 10 Calculated mass of ClNO2: 211.6, measured m / z: 198.4 (M-19)+ . 1 H NMR (400MHz, DMSO-d6) δ7.57(s,1H),3.88(s,3H),3.16(t,J=7.6Hz,2H),2.97(t,J=7.8Hz,2H),2.09(p,J=7.7Hz,2H).

[0444] Step D: (2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methanol To a solution of methyl 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carboxylate (300 mg, 1.0 equiv., 1.42 mmol) in THF (5.0 mL) was added LiAlH (53.8 mg, 1.0 equiv., 1.42 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. NaSO.10H0 was added to the mixture at 0 °C. The mixture was filtered, and the filtrate was partitioned between water (3 mL) and EA (5 mL × 3). The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give (2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methanol (250 mg, 96.0%) as a yellow solid.

[0445] LC-MS(ESI):Chemical formula:C9H 10 ClNO, 183.6, m / z measured, 184.5 [M+1] + .

[0446] Step E: 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carbaldehyde To a solution of (2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methanol (250 mg, 1 eq., 1.36 mmol) in DCM (10 mL) was added DMP (866 mg, 1.5 eq., 2.04 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenched by dropwise addition of saturated aqueous NaHCO (20 mL). The mixture was filtered through a pad of Celite, and the filtrate was extracted with DCM (15 mL × 3). The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The crude product was then purified by preparative TLC using PE / EA = 2.5:1 to give 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carbaldehyde (150 mg, 60.7% yield) as a yellow solid.

[0447] LC-MS (ESI): calculated mass for C9H8ClNO 181.0, observed m / z 182.1 [M+H] + .

[0448] Intermediate 25: 5-chloro-3-(isopropylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde TIFF2025510834000117.tif24128Step A: 4-Bromo-6-chloro-2-methylpyrazin-3-amine To a solution of 6-chloro-2-methylpyridin-3-amine (40 g, 0.28 mol, 1.0 equiv.) and AcOH (30.4 mL, 0.53 mol, 1.9 equiv.) in MeOH (400 mL) was added Br (26 mL, 0.504 mol, 1.8 equiv.) dropwise at 0 °C, and the mixture was stirred at 0 °C for 6 h. After evaporation, the reaction mixture was diluted with EA (1 L), washed with saturated aqueous sodium thiosulfate solution (500 mL × 2), saturated aqueous NaHCO solution (500 mL × 2), and brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EA = 10 / 1 v / v) to afford 4-bromo-6-chloro-2-methylpyrazin-3-amine (55 g, 90% yield) as a yellow solid. LC-MS (ESI): calculated mass for C6H6BrClN2 219.94, observed m / z 221.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.41 (s, 1H), 5.39 (s, 2H), 2.33 (s, 3H).

[0449] Step B: 7-Bromo-5-chloro-1H-pyrazolo[4,3-b]pyridine To a solution of 4-bromo-6-chloro-2-methylpyrazin-3-amine (25 g, 113 mmol, 1.0 equiv) in toluene (625 mL) were added potassium acetate (22.2 g, 226 mmol, 2.0 equiv) and AcOH (210 mL) at 0 °C. Then, isoamyl nitrite (19.8 g, 22.7 mL, 169 mmol, 1.5 equiv) was added dropwise to the above mixture at 0 °C. The resulting mixture was stirred at 0 °C for 6 h. After evaporation, the mixture was poured into ice water (300 mL), adjusted to pH 7-8 with solid NaHCO3, and extracted with EA (300 mL × 3). The organic layer was washed with water (300 mL) and brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 2% to 15% v / v) to give 7-bromo-5-chloro-1H-pyrazolo[4,3-b]pyridine (8.4 g, 32% yield) as a yellow solid. LC-MS (ESI): mass calculated for CHBrClN 230.92, m / z found 232.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 14.14 (s, 1H), 8.43 (s, 1H), 7.87 (s, 1H).

[0450] Step C: 7-Bromo-5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine To a solution of 7-bromo-5-chloro-1H-pyrazolo[4,3-b]pyridine (15.0 g, 64.5 mmol, 1.0 equiv) in concentrated HSO (48 mL) was added HSO / concentrated HNO (96 mL, 1 / 1 v / v) (concentrated HSO was added to concentrated HNO at 0 °C) dropwise at 0 °C. The mixture was stirred at 110 °C for 2 h. After cooling to room temperature, the mixture was poured into ice water (300 mL) and stirred for 0.5 h. The mixture was extracted with EA (200 mL × 3). The organic layer was washed with HO (300 mL × 4) and brine (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 7-bromo-5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine (17.9 g, 100% yield) as a yellow solid. LC-MS (ESI): mass calculated for CHBrClNO 275.90, m / z found 276.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),8.13(s,1H).

[0451] Step D: 7-bromo-5-chloro-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine (4a) and 7-bromo-5-chloro-3-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine To a solution of 7-bromo-5-chloro-3-nitro-1H-pyrazolo[4,3-b]pyridine (35.8 g, 129 mmol, 1.0 equiv) in anhydrous DMF (500 mL) was added sodium hydride (60% suspension in oil) (9.29 g, 232 mmol, 1.8 equiv) in portions at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then, 2-(trimethylsilyl)ethoxymethyl chloride (25.8 g, 27.4 mL, 155 mmol, 1.2 equiv) was added dropwise to the above mixture, and the resulting mixture was stirred at 0 °C for 30 min. The mixture was quenched with saturated aqueous NH Cl solution (1000 mL) at 0 °C and extracted with EA (800 mL × 3). The organic layer was washed with HO (500 mL × 4) and brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 10%) to give 7-bromo-5-chloro-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine (28.2 g, 54% yield) as a yellow solid and 7-bromo-5-chloro-3-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine (14.8 g, 28% yield) as a yellow solid.

[0452] 7-Bromo-5-chloro-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine: LC-MS(ESI):C 12 H 16 Calculated mass of BrClN4O3Si: 405.99, measured m / z: 407.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.35(s,1H),6.16(s,2H),3.71(t,J=7.8Hz,2H),0.93(t,J=7.8Hz,2H),-0.00(s,9H).

[0453] 7-Bromo-5-chloro-3-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine: LC-MS(ESI):C12 H 16 Calculated mass of BrClN4O3Si: 405.99, measured m / z: 407.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.24(s,1H),6.26(s,2H),3.77(dd,J=16.7,8.9Hz,2H),0.94(t,J=8.1Hz,2H),-0.00(s,9H).

[0454] Step E: 7-Bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-amine To a solution of 7-bromo-5-chloro-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine (28.0 g, 68.7 mmol, 1.0 equiv) and ammonium chloride (18.4 g, 343 mmol, 5.0 equiv) in EtOH (400 mL), THF (400 mL), and water (200 mL) was added iron powder (19.2 g, 343 mmol, 5.0 equiv) at room temperature. The mixture was stirred at 70° C. for 2 h. After cooling to room temperature, the mixture was filtered, and the cake was washed with EA (200 mL × 3). The filtrate was concentrated under reduced pressure, and the residue was diluted with EA (1200 mL). The organic layer was washed with water (500 mL) and brine (500 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 7-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (26.0 g, 100% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI): C 12 H 18 Calculated mass of BrClN4OSi: 376.01, measured m / z: 377.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.96(s,1H),6.02(s,2H),5.78(s,2H),3.64(t,J=7.8Hz,2H),0.89(t,J=7.8Hz,2H),0.00(s,9H).

[0455] Step F: 7-Bromo-5-chloro-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-amine To a solution of 7-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (5.00 g, 13.2 mmol, 1.0 equiv) in acetone (150 mL) was added acetic acid (5.23 g, 5.00 mL, 87.0 mmol, 6.57 equiv) at room temperature, and the mixture was stirred at 50° C. for 4 h. Then, sodium cyanoborohydride (4.16 g, 66.2 mmol, 5.0 equiv) was added portionwise to the above mixture, and the reaction mixture was stirred at 50° C. overnight. After evaporation, the residue was diluted with EA (200 mL), washed with saturated aqueous NaHCO solution (200 mL × 3), water (200 mL), and brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel (PE / EA = 15 / 1 to 10 / 1 v / v) to give 7-bromo-5-chloro-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (3.20 g, 58%) as a yellow solid. LC-MS (ESI): C 15 H 24 Calculated mass of BrClN4OSi: 418.06, measured m / z: 419.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.98(s,1H),6.32(d,J=7.6Hz,1H),5.83(s,2H),4.02-3.98(m, 1H),3.67(t,J=7.6Hz,2H),1.35(d,J=6.0Hz,6H),0.90(t,J=7.64Hz,2H),-0.00(s,9H).

[0456] Step G: 5-chloro-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-7-vinyl-1H-pyrazolo[4,3-b]pyridin-3-amine To a solution of 7-bromo-5-chloro-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (2.30 g, 5.48 mmol, 1.0 equiv.), potassium trifluoroborate (1.10 g, 8.22 mmol, 1.5 equiv.), and tripotassium phosphate (3.49 g, 16.4 mmol, 3.0 equiv.) in 1,4-dioxane (50.00 mL) and water (5.00 mL) was added Pd(dppf)Cl (401 mg, 548 μmol, 0.1 equiv.) at room temperature. The reaction mixture was stirred at 85 °C for 2.5–3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EA (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 6% v / v) to give 5-chloro-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-7-vinyl-1H-pyrazolo[4,3-b]pyridin-3-amine (1.63 g, 81% yield) as a red oil. LC-MS (ESI): C 17 H 27 Calculated mass of ClN4OSi: 366.16, measured m / z: 367.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.66(s,1H),7.37(dd,J=17.4,11.2Hz,1H),6.32(d,J=17.4Hz,1H),6.09(d,J=8.0Hz,1H),5.83(d,J=11.8Hz, 1H),5.66(s,2H),4.05-3.96(m,1H),3.68-3.58(m,2H),1.35(d,J=6.4Hz,6H),0.96-0.84(m,2H),0.00(s,9H).

[0457] Step H: 1-(5-chloro-3-(isopropylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)ethane-1,2-diol To a solution of 5-chloro-N-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-7-vinyl-1H-pyrazolo[4,3-b]pyridin-3-amine (6.10 g, 16.6 mmol, 1.0 equiv)) in acetone (120.00 mL) and water (60.0 mL) was added NMO (3.89 g, 33.2 mmol, 2.0 equiv) and potassium osmate(VI) dihydrate (612 mg, 1.66 mmol, 0.1 equiv). The reaction was stirred at 15 °C for 16 h. After filtration, the filtrate was evaporated under reduced pressure. The residue was diluted with EA (250 mL), washed with water (150 mL) and brine (150 mL), dried over anhydrous MgSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 36% v / v) to yield 1-(5-chloro-3-(isopropylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)ethane-1,2-diol (4.78 g, 72% yield) as a black oil. LC-MS (ESI): C 17 H 29 Calculated mass of ClN4O3Si: 400.17, measured m / z: 401.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.53(s,1H),6.01(d,J=8.0Hz,1H),5.93(d,J=5.0Hz,1H),5.77(d,J=11.8Hz,1H),5.59(d,J=11.8Hz,1H),5.23(q,J=5.6Hz,1H) ),5.13(t,J=5.6Hz,1H),3.98(dq,J=13.0,6.4Hz,1H),3.72(t,J=5.6Hz,2H ),3.67-3.51(m,2H),1.32(d,J=6.4Hz,6H),0.95-0.82(m,2H),0.00(s,9H).

[0458] Step I: 5-chloro-3-(isopropylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde To a solution of 1-(5-chloro-3-(isopropylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)ethane-1,2-diol (2.10 g, 5.24 mmol, 1.0 equiv) in THF (20 mL) and water (10 mL) was added NaIO (2.24 g, 10.5 mmol, 2.0 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by adding saturated aqueous sodium thiosulfate solution (30 mL) and extracted with EA (40 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 15% v / v) to give 5-chloro-3-(isopropylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde (1.70 g, 88% yield) as a red solid. LC-MS (ESI): C 16 H 25 Calculated mass of ClN4O2Si: 368.14, measured m / z: 387.2 [M+18+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.08(s,1H),6.46(d,J=8.0Hz,1H),5.94(s,2H),4.12- 3.98(m,1H),3.59(t,J=8.0Hz,2H),1.39(d,J=6.4Hz,6H),0.88(t,J=8.0Hz,2H),0.00(s,9H).

[0459] Intermediate 26: 3-Amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-7-carbaldehyde TIFF2025510834000118.tif21128 Step A: 7-Bromo-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-3-amine To a solution of 7-bromo-5-chloro-3-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine (14.8 g, 36.3 mmol, 1.0 equiv) and ammonium chloride (9.71 g, 181 mmol, 5.0 equiv) in EtOH (200 mL), THF (200 mL), and water (100 mL) was added iron powder (10.1 g, 181 mmol, 5.0 equiv) at room temperature. The mixture was stirred at 70 °C for 1 h. After cooling to room temperature, the mixture was filtered, and the cake was washed with EA (150 mL × 3). The filtrate was concentrated under reduced pressure, and the residue was diluted with EA (500 mL). The organic layer was washed with water (200 mL) and brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 7-bromo-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-3-amine (13.7 g, 100% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI): C 12 H 18 Calculated mass of BrClN4OSi: 376.01, measured m / z: 377.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.63(s,1H),6.89(s,2H),5.63(s,2H),3.68(t,J=7.8Hz,2H),0.91(t,J=7.8Hz,2H),-0.00(s,9H).

[0460] Step B: Methyl 3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-7-carboxylate To a solution of 7-bromo-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-3-amine (5.00 g, 13.2 mmol, 1.0 equiv) and triethylamine (4.02 g, 5.52 mL, 39.7 mmol, 3.0 equiv) in DMF (60.0 mL) and MeOH (60.0 mL) was added Pd(dppf)Cl (969 mg, 1.32 mmol, 0.1 equiv). The mixture was stirred at 70 °C under CO (balloon) for 6 h. After cooling to room temperature, MeOH was removed under reduced pressure and the solution was extracted with EA (100 mL × 3). The organic layer was washed with brine (80 mL × 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA / PE=1 / 1 v / v) to give methyl 3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-7-carboxylate (3.3 g, 72% yield) as a red solid. LC-MS (ESI): C 14 H 21 Calculated mass of ClN4O3Si: 356.11, measured m / z: 357.1 [M+H] + .

[0461] 1 H NMR (400MHz, DMSO-d6) δ7.61(s,1H),6.98(s,2H),5.64(s,2H),3.95(s,3H),3.68(t,J=7.8Hz,2H),0.91(t,J=7.8Hz,2H),-0.00(s,9H).

[0462] Step C: (3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-7-yl)methanol To a solution of methyl 3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-7-carboxylate (1.00 g, 2.80 mmol, 1.0 equiv.) in THF (40.0 mL) was added lithium aluminum hydride (213 mg, 5.60 mmol, 2.0 equiv.) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with NaSO . 10H2O and stirred for 30 minutes. After filtration, the filtrate was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-7-yl)methanol (600 mg, 65% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI): C 13 H 21 Calculated mass of ClN4O2Si: 328.11, measured m / z: 329.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.15(s,1H),6.61(s,2H),5.59(s,2H),5.56(d,J=5.6H z,1H),4.88-4.76(m,2H),3.72-3.63(m,2H),0.95-0.87(m,2H),-0.01(s,9H).

[0463] Step D: 3-Amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-7-carbaldehyde To a solution of (3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridin-7-yl)methanol (315 mg, 958 μmol, 1.0 equiv) in DMSO (20.0 mL) was added IBX (536 mg, 1.92 mmol, 2.0 equiv) at room temperature (10 °C). The reaction mixture was stirred at 27 °C for 1 hour. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic extracts were washed with saturated aqueous NaSO solution (40 mL × 2), saturated aqueous NaHCO solution (40 mL), and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EA=6 / 1) to give 3-amino-5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-7-carbaldehyde (50.0 mg, 16% yield) as a red solid. LC-MS (ESI): C 13 H 19 Calculated mass of ClN4O2Si: 326.10, measured m / z: 327.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,2H),7.70(s,1H),7.10(s,2H),5.65(s,2H),3.70-3.61(m,2H),0.94-0.85(m,2H),-0.00(s,9H).

[0464] Intermediate 27: 3-Amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde TIFF2025510834000119.tif24128 Step A: Methyl 3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylate To a stirred solution of 7-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (18.0 g, 47.7 mmol, 1.0 equiv.) in DMF (50.0 mL) and MeOH (50.0 mL), Pd(dppf)Cl (3.49 g, 4.77 mmol, 0.1 equiv.) and TEA (14.5 g, 19.9 mL, 143 mmol, 3.0 equiv.) were added. The reaction mixture was stirred at 70 °C under a CO atmosphere (balloon) for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was diluted with EtOAc (600 mL). The organic layer was washed with brine (200 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1 v / v) to give methyl 3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylate (14.0 g, 82% yield, 50% purity) as a brown oil. LC-MS (ESI): C 14 H 21 Calculated mass of ClN4O3Si: 356.11, measured m / z: 357.1 [M+H] + .

[0465] Step B: (3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)methanol To a solution of methyl 3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylate (4.00 g, 11.2 mmol, 1.0 equiv) in THF (20.0 mL) was added LiAlH (638 mg, 16.8 mmol, 1.5 equiv) in several portions at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched with sodium sulfate decahydrate and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1 v / v) to give (3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)methanol (1.40 g, 38% yield) as a pale yellow solid. LC-MS(ESI):C 13 H 21 Calculated mass of ClN4O2Si: 328.11, measured m / z: 329.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.35(s,1H),5.62(s,2H),5.07(s,2H),4.69(s,2H),4.63-4.44(m,1H),3.60-3.52(m,2H),0.94-0.84(m,2H),-0.00(s,9H).

[0466] Step C: 3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde To a stirred mixture of (3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridin-7-yl)methanol (1.40 g, 4.26 mmol, 1.0 equiv) in DMSO (20.0 mL) was added IBX (1.79 g, 6.39 mmol, 1.5 equiv). The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated aqueous NaSO solution (30 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine (100 mL × 4), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v / v) to give 3-amino-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde (900 mg, 64% yield) as a red solid. LC-MS (ESI): C 13 H 19 Calculated mass of ClN4O2Si: 326.10, measured m / z: 327.1 [M+H] + .

[0467] Intermediate 28: 3-(3-methyl-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione TIFF2025510834000120.tif23128Step A: Methyl 4-bromo-2-ethylbenzoate To a solution of 4-bromo-2-ethylbenzoic acid (5.0 g, 21.8 mmol, 1.0 equiv) in DMF (25.0 mL) was added potassium carbonate (6.03 g, 43.7 mmol, 2.0 equiv) and iodomethane (4.65 g, 2.04 mL, 32.7 mmol, 1.5 equiv). The mixture was stirred at room temperature for 16 h. After filtration, the cake was washed with EA (50 mL). The filtrate was diluted with EA (200 mL), washed with brine (100 mL × 4), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give methyl 4-bromo-2-ethylbenzoate (4.4 g, 83% yield) as a yellow solid. LC-MS (ESI): C10 H 11 Calculated mass of BrO2: 241.99, observed m / z, no mass value [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.71(d,J=8.4Hz,1H),7.59(s,1H),7.53(d,J=8.4Hz,1H),3.84(s,3H),2.89(q,J=7.4Hz,2H),1.15(t,J=7.4Hz,3H)

[0468] Step B: Methyl 4-bromo-2-(1-bromoethyl)benzoate To a stirred mixture of methyl 4-bromo-2-ethylbenzoate (4.3 g, 17.7 mmol, 1.0 equiv) in CCl (40 mL) was added BPO (857 mg, 3.54 mmol, 0.2 equiv) and NBS (3.46 g, 19.5 mmol, 1.1 equiv). The resulting mixture was stirred at 80 °C under N for 3 h. After evaporation, the residue was diluted with EA (200 mL), washed with saturated aqueous NaSO solution (100 mL × 2), saturated aqueous NaHCO solution (100 mL × 2), and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 5 / 1 v / v) to give methyl 4-bromo-2-(1-bromoethyl)benzoate (4.2 g, 74% yield) as a yellow oil. LC-MS(ESI):C 10 H 10 Calculated mass of Br2O2: 319.90, observed m / z, no mass value [M+H] + .

[0469] Step C: 3-(5-bromo-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione To a solution of methyl 4-bromo-2-(1-bromoethyl)benzoate (2.0 g, 6.21 mmol, 10 equiv.) and 3-aminopiperidine-2,6-dione hydrochloride (1.53 g, 9.32 mmol, 1.5 equiv.) in MeCN (20 mL) was added DIPEA (2.41 g, 3.3 mL, 18.6 mmol, 3.0 equiv.). The mixture was stirred at 85 °C under N for 16 h. After evaporation, the residue was purified by flash column chromatography on a silica gel column (100% ethyl acetate) to give 3-(5-bromo-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 48% yield) as a gray solid. LC-MS (ESI): C 14 H 13 Calculated mass of BrN2O3: 336.01, measured m / z: 337.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.00-10.66(m,1H),7.98-7.83(m,1H),7.74-7.56(m,2H),4.96- 4.50(m,2H),2.89-2.69(m,1H),2.68-2.52(m,2H),2.03-1.98(m,1H),1.58-1.39(m,3H).

[0470] Step D: 3-(3-methyl-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione To a solution of 3-(5-bromo-3-methyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.1 g, 3.26 mmol, 1.0 equiv.), anhydrous potassium acetate (961 mg, 9.79 mmol, 3.0 equiv.), and 4,4,4',4',5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.24 g, 4.89 mmol, 1.5 equiv.) in dry dioxane (10 mL) was added Pd(dppf)Cl (239 mg, 326 μmol, 0.1 equiv.). The reaction mixture was stirred at 100 °C under N for 16 h. After evaporation, the residue was washed with water (50 mL) and EA (10 mL) and dried to give 3-(3-methyl-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (900 mg, 72% yield) as a grey solid. LC-MS (ESI): C 20 H 25 Calculated mass of BN2O5: 384.19, measured m / z: 385.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.93(d,J=12.4Hz,1H),7.93-7.87(m,1H),7.83-7.75(m,1H),7.71-7.63(m,1H),4 .86-4.59(m,2H),2.82-2.75(m,1H),2.62-2.56(m,2H),2.03-1.99(m,1H),1.46-1.42(m,3H),1.32(s,12H).

[0471] Intermediate 29: 6-chloro-1-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde TIFF2025510834000121.tif31128Step A: Methyl 6-chloro-1-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate To a solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (1.10 g, 5.22 mmol, 1.0 equiv) in DMF (30 mL) were added CsCO (5.10 g, 15.7 mmol, 3.0 equiv) and 3-iodooxetane (2.40 g, 13.1 mmol, 2.5 equiv), and the reaction mixture was stirred at 80 °C for 16 h under N. After cooling to room temperature, the reaction mixture was filtered, and the cake was washed with EA (100 mL × 2). The combined filtrate was washed with brine (100 mL × 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 20% v / v) to afford methyl 6-chloro-1-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (650 mg, 47% yield) as a yellow solid. LC-MS (ESI): C 12 H 11 Calculated mass of ClN2O3: 266.05, measured m / z: 267.0 [M+H] + . 1 H NMR (DMSO-d6) δ8.26(d,J=3.6Hz,1H),7.62(s,1H),7.01(d,J=3.6Hz,1H),6.01-5.88(m,1H),5.05-4.94(m,4H),3.97(s,3H).

[0472] Step B: (6-chloro-1-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol To a solution of methyl 6-chloro-1-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (2.00 g, 7.50 mmol, 1.0 equiv.) in THF (40.0 mL) was added LiAlH (427 mg, 11.2 mmol, 1.5 equiv.) in portions at 0° C., and the reaction was stirred at 0° C. for 1 h. The reaction was diluted with THF (50 mL), quenched with sodium sulfate decahydrate, and stirred for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford (6-chloro-1-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (1.80 g, 98% yield) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS (ESI): C 11 H 11 Calculated mass of ClN2O2: 238.05, measured m / z: 239.0 [M+H] + .

[0473] Step C: 6-chloro-1-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde To a solution of (6-chloro-1-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (1.80 g, 7.32 mmol, 1.0 equiv.) in DMSO (20.0 mL) was added IBX (8.19 g, 50 wt%, 14.6 mmol, 2.0 equiv.) in several portions, and the reaction mixture was stirred at room temperature for 1 h. The reaction solution was diluted with ethyl acetate (150 mL), washed with saturated aqueous NaSO solution (100 mL × 2), saturated aqueous sodium bicarbonate solution (100 mL), and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% to 20%) to give 6-chloro-1-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (500 mg, 29% yield) as a yellow solid. LC-MS (ESI): C 11 Calculated mass of H9ClN2O2: 236.04, measured m / z: 237.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.30(d,J=3.6Hz,1H),7.78(s,1H),7.14( d,J=3.6Hz,1H),6.00-5.93(m,1H),5.04(t,J=7.4Hz,2H),4.97(t,J=7.4Hz,2H).

[0474] Intermediate 30: 6-Chloro-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde TIFF2025510834000122.tif26128Step A: Methyl 6-chloro-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate To a solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (1.50 g, 7.12 mmol, 1.0 equiv.) in DCM (20.0 mL) and DMF (5 mL) was added cupric acetate monohydrate (2.84 g, 14.2 mmol, 2.0 equiv.), cyclopropylboronic acid (3.06 g, 35.6 mmol, 5.0 equiv.), and TEA (7.21 g, 9.93 mL, 71.2 mmol, 10.0 equiv.). The reaction mixture was stirred at 40 °C under N (containing O) for 16 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was diluted with DCM (150 mL). The filtrate was washed with brine (100 mL × 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 30% v / v) to afford methyl 6-chloro-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (700 mg, 39% yield) as a white solid. LC-MS (ESI): C 12 H 11 Calculated mass of ClN2O2: 250.05, measured m / z: 251.1 [M+H] + .

[0475] Step B: (6-chloro-1-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol To a solution of methyl 6-chloro-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (700 mg, 2.79 mmol, 1.0 equiv) in THF (10.0 mL) was added lithium aluminum(III) hydride (117 mg, 3.07 mmol, 1.1 equiv) in several portions at 0 °C, and the mixture was stirred at 0 °C for 10 min. The reaction mixture was quenched with saturated aqueous NH Cl solution (15 mL) at 0 °C and extracted with EA (15 mL × 3). The organic layer was washed with HO (15 mL × 3) and brine (15 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to give (6-chloro-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (600 mg, 96% yield) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS(ESI):C 11 H 11 Calculated mass of ClNO: 222.06, measured m / z: 223.0 [M+H] + .

[0476] Step C: 6-chloro-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde To a solution of (6-chloro-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (700 mg, 3.14 mmol, 1.0 equiv) in DMSO (20.0 mL) was added IBX (2.64 g, 9.43 mmol, 3.0 equiv) in several portions at room temperature, and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous NaSO solution (50 mL) and extracted with EA (35 mL × 3). The organic layer was washed with saturated aqueous NaHCO solution (40 mL) and brine (40 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM / EA=1 / 3 v / v) to give 6-chloro-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (400 mg, 52% yield) as a yellow solid. LC-MS (ESI): C 11 H9ClNO 220.04, m / z 221.1 [M+H] +. 1 H NMR(400MHz,CDCl3)δ10.26(s,1H),7.51(s,1H),7.39(d,J=3.6Hz,1H),7.0 2(d,J=3.6Hz,1H),3.61-3.55(m,1H),1.19-1.15(m,2H),1.07-1.05(m,1H).

[0477] Intermediate 31: 6-chloro-4-(pyrrolidin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine To a solution of 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (1.50 g, 8.31 mmol, 1.0 equiv) in DCM (30.0 mL), pyrrolidine (886 mg, 12.5 mmol, 1.5 equiv) and AcOH (748 mg, 713 μL, 12.5 mmol, 1.5 equiv) were added at 25 °C under N , and the mixture was stirred at 25 °C for 16 h. Sodium triacetoxyborohydride (3.52 g, 16.6 mmol, 2.0 equiv) was then added to the above mixture, and the resulting mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched with HO (20 mL) and extracted with DCM (30 mL × 3). The organic layer was washed with saturated aqueous NaHCO3 (30 mL x 2) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 20% v / v) to give 6-chloro-4-(pyrrolidin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (1.64 g, 84% yield) as a yellow solid. LC-MS (ESI): C 12 H 14 Calculated mass of ClN3: 235.09, measured m / z: 236.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.82(s,1H),7.45(s,1H),7.07(s,1H),6.59(s,1H),3.86(s,2H),2.50-2.46(m,4H),1.72(s,4H).

[0478] Intermediate 32: 3-(4-chloro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione TIFF2025510834000124.tif19128Step A: Methyl 4-bromo-3-chloro-2-methylbenzoate To a solution of 4-bromo-3-chloro-2-methylbenzoic acid (5.00 g, 20.0 mmol, 1.0 equiv) in DMF (25.0 mL) were added potassium carbonate (5.54 g, 40.1 mmol, 2.0 equiv) and iodomethane (4.27 g, 1.87 mL, 30.1 mmol, 1.5 equiv). The mixture was stirred at room temperature for 16 h. After filtration, the filtrate was diluted with water (100 mL) and EA (100 mL × 4). The organic phase was washed with brine (100 mL × 4), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give methyl 4-bromo-3-chloro-2-methylbenzoate (5.00 g, 95% yield) as a yellow solid. LC-MS (ESI): calculated mass for C9H8BrClO2 261.94, observed m / z, no mass value [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.76 (d, J = 8.4 Hz, 1H), 7.63-7.56 (m, 1H), 3.85 (s, 3H), 2.58 (s, 3H).

[0479] Step B: Methyl 4-bromo-2-(bromomethyl)-3-chlorobenzoate To a solution of methyl 4-bromo-3-chloro-2-methylbenzoate (2.50 g, 9.49 mmol, 1.0 equiv.) and NBS (1.69 g, 9.49 mmol, 1.0 equiv.) in CCl4 (50.0 mL) was added BPO (460 mg, 1.9 mmol, 0.2 equiv.). The reaction mixture was stirred at 90 °C for 16 h. After evaporation, the residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 5% v / v) to give methyl 4-bromo-2-(bromomethyl)-3-chlorobenzoate (3.00 g, 92% yield) as a white solid. LC-MS (ESI): calculated mass for CHBrClO2 339.85, observed m / z, no mass value [M+H]. + .

[0480] Step C: 3-(5-bromo-4-chloro-1-oxoisoindolin-2-yl)piperidine-2,6-dione To a solution of methyl 4-bromo-2-(bromomethyl)-3-chlorobenzoate (4.50 g, 13.1 mmol, 1.0 equiv.) and 3-aminopiperidine-2,6-dione HCl (3.24 g, 19.7 mmol, 1.5 equiv.) in MeCN (40.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (5.10 g, 6.87 mL, 39.4 mmol, 3.0 equiv.). The reaction mixture was stirred at 85° C. for 16 hours. After evaporation, the reaction mixture was slurried with EA (40 mL) and water (10 mL). After filtration, the cake was washed with tert-butyl methyl ether and dried to give 3-(5-bromo-4-chloro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3.00 g, 64% yield) as a blue solid. LC-MS(ESI):C 13 H 10 Calculated mass of BrClN2O3: 355.96, measured m / z: 357.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.95(d,J=8.0Hz,1H),7.65(d,J=8.0Hz,1H),5.16-5.11(m,1H),4.54(d,J=18 .0Hz,1H),4.37(d,J=18.0Hz,1H),2.98-2.85(m,1H),2.60(d,J=17.4Hz,1H),2.47-2.41(m,1H),2.03-1.98(m,1H).

[0481] Step D: 3-(4-chloro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione To a solution of 3-(5-bromo-4-chloro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.40 mmol, 1.0 equiv.) and potassium acetate (412 mg, 4.19 mmol, 3.0 equiv.) in 1,4-dioxane (10.0 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (426 mg, 1.68 mmol, 1.2 equiv.) and Pd(dppf)Cl (102 mg, 140 μmol, 0.1 equiv.) were added. The mixture was stirred at 95 °C under N for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (20 mL × 3). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM / MeOH=10 / 1 v / v) to give 3-(4-chloro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (400 mg, 78% yield, 80% purity) as a brown solid. LC-MS (ESI): C 19 H 22 Calculated mass of BClN2O5: 404.13, measured m / z: 405.1 [M+H] + .

[0482] Intermediate 33: tert-butyl (S)-5-amino-5-oxo-4-(1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)pentanoate TIFF2025510834000125.tif21128Step A: 4-Bromo-2-(hydroxymethyl)benzoic acid To a solution of 5-bromoisobenzofuran-1(3H)-one (20.0 g, 93.9 mmol, 1.0 equiv.) in MeOH (210 mL), THF (210 mL), and water (70.0 mL) was added NaOH (7.5 g, 188 mmol, 2.0 equiv.) at 0 °C, and the mixture was stirred at 40 °C for 2 h. After evaporation to remove THF / MeOH, the residue was diluted with water (50 mL), acidified to pH 5–6 with dilute aqueous HCl (1 N), and extracted with DCM (300 mL × 3). The combined organic layers were washed with brine ...

Claims

1. The compound of formula II below: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the formula, W is -N(R １ ) ２ , 3-12 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the heterocyclyl or heteroaryl is one or more R １ｂ It may also be replaced with Two R's １ However, together with the nitrogen atoms to which they are bonded, they form a 3-12 membered heterocycline or a 5-10 membered heteroaryl, and the heterocycline or heteroaryl contains one or more R １ｂ It may also be replaced with Each R １ｂ is independently oxo, halogen, -CN, -NO ２ , -OH, -NH ２ , C １～６ alkyl, C １～６ alkoxy, C １～６ alkylamino, C ２～６ alkenyl, C ２～６ alkynyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, C ３～１２ carbocyclic, 3- to 12-membered heterocyclic, -SR ｂ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ OR ｂ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ S(=O) ２ R ａ , -NR ｃ S(=O)R ａ , -NR ｃ S(=O) ２ OR ｂ , -NR ｃ S(=O) ２ NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -OS(=O) ２ R ａ , -OS(=O) ２ OR ｂ , -OS(=O) ２ NR ｃ R ｄ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may be replaced with, or, Two Vicinal R １ｂ However, together with the intervening atom, C ６～１０ An aryl or 5-10 membered heteroaryl is formed, and the aryl or heteroaryl is one or more R ｕ It may be replaced with, or, Each R １ However, independently, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, -(C) １～６ Alkylene) - (C ６～１０ Aryl), - (C １～６ Alkylene)-(5-10 membered heteroaryl),-(C) １～６ Alkylene) - (C ３～１２ Carbocyclyl), - (C １～６ Alkilen)-(3-12 member heterocycline), S(=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkylene, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R １ａ It may also be replaced with Each R １ａ is independently oxo, halogen, -CN, -NO ２ , -OH, -NH ２ , C １～６ alkyl, C １～６ alkoxy, C １～６ alkylamino, C ２～６ alkenyl, C ２～６ alkynyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, C ３～１２ carbocyclic, 3- to 12-membered heterocyclic, -SR ｂ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ OR ｂ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ S(=O) ２ R ａ , -NR ｃ ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with X is -[C(R ２ ) ２ ]- ｍ , O, or NR Ｘ And X is O or NR Ｘ In this case, W is a 3- to 12-membered heterocycline or a 5- to 10-membered heteroaryl, and the heterocycline or heteroaryl is one or more R １ｂ It may also be replaced with Each R ２ However, independently, hydrogen, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, -SR ｂ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S(=O)R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -OS (=O) ２ R ａ , -OS (=O) ２ OR ｂ , -OS (=O) ２ NR ｃ R ｄ -OC(=O)R ａ ,-OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with Two Geminal R ２ However, they either combine to form an oxo, or Two Geminal R ２ However, together with the carbon atoms to which they are bonded, C ３～６ It forms a carbocyclyl or a 3-6 membered heterocyclyl, and the carbocyclyl or heterocyclyl is one or more R ｕ It may also be replaced with m is an integer between 0 and 5. R Ｘ However, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, C ６～１０ Aryl, 5-10 member heteroaryl, -S (=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -C(O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with Ring A is a 9 or 10-membered bicyclic fused ring system containing at least one 5 or 6-membered heteroaryl, Each R Ａ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, -SR ｂ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S(=O)R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -OS (=O) ２ R ａ , -OS (=O) ２ OR ｂ , -OS (=O) ２ NR ｃ R ｄ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with n is an integer between 0 and 10, as long as the valence allows, or Two Vicinal R Ａ However, together with the intervening atom, C ３～１２ It forms a carbocyclyl or a 3- to 12-membered heterocyclyl, and the carbocyclyl or heterocyclyl is one or more R ｕ It may also be replaced with Each R Ｂ However, independently, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, -SR ｂ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S(=O)R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -OS (=O) ２ R ａ , -OS (=O) ２ OR ｂ , -OS (=O) ２ NR ｃ R ｄ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with p is an integer between 0 and 3, U is -C(R ４ ) ２ - or -C (=O)-, Each R ４ However, independently, hydrogen, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ３～６ Carbocyclyl or 3-6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocykyl, or heterocyclyl is one or more R ｕ It may be replaced with, or, Two R's ４ However, together with the carbon atoms to which they are bonded, C ３～６ It forms a carbocyclyl or a 3-6 membered heterocyclyl, and the carbocyclyl or heterocyclyl is one or more R ｕ It may also be replaced with Each R Ｄ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, C ６～１０ The aryl or 5-10 membered heteroaryl is one or more alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, or heteroaryl. ｕ It may also be replaced with d is an integer selected from 0 to 4. R ３ However, hydrogen, deuterium, C １～６ Haloalkyl, or C １～６ It is alkyl, q is an integer between 0 and 2, Here, Each R ｕ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, -SR ｂ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S(=O)R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -OS (=O) ２ R ａ , -OS (=O) ２ OR ｂ , -OS (=O) ２ NR ｃ R ｄ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is an oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ３～６ Carbocyclyl, 3-6 member heterocyclyl, C ６ It may be substituted with one or more substituents selected from aryls and 5- to 6-membered heteroaryls, or Two R's ｕ However, together with one or more intervening atoms, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ They form carbocyclils or 3-12 member heterocyclils. Each R ａ However, independently, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, C ６～１０ It is an aryl or a 5- to 10-membered heteroaryl. Each R ｂ However, independently, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, C ６～１０ It is an aryl or a 5- to 10-membered heteroaryl. Each R ｃ and R ｄ However, independently, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, C ６～１０ It is either an aryl, or a 5- to 10-membered heteroaryl, or R ｃ and R ｄ However, together with the nitrogen atoms to which they are bonded, they form 3-12 membered heterocyclines or 5-10 membered heteroaryls, and these heterocyclines or heteroaryls are oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ３～６ It may be substituted with one or more substituents selected from carbocyclyls and 3- to 6-membered heterocyclyls. R ａ , R ｂ , R ｃ , and R ｄ Each of these independently has one or more R ｚ It may also be replaced with Each R ｚ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ３～６ Carbocyclyl, 3-6 member heterocyclyl, C ６ It is an aryl or a 5-6 member heteroaryl, however, i) Ring A is as follows: If m is not 0, ii) Each R １ However, independently, hydrogen, C １～６ Alkyl, C ３～１２ Carbocyclyl, or -C(=O)(C １～６ If it is alkyl, then 1) m is not 0, and 2) there are two geminal R ２ However, they do not form an oxo together, and iii) The compound is as follows: The condition is that it is not A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. The compound is the following formula II-1: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, The compound according to claim 1.

3. X is -[C(R ２ ) ２ ]- ｍ The compound according to claim 1.

4. W is -N(R １ ) ２ The compound according to claim 1.

5. The compound is the following formula II-2: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, The compound according to claim 1.

6. The compound according to claim 1, wherein ring A is a nine-membered bicyclic heteroaryl containing one to four nitrogen atoms.

7. The compound according to claim 1, wherein ring A is imidazo[1,5-a]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, indolyl, benzo[d]imidazolyl, indazolyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, benzo[d]isothiazolyl, benzo[d]thiazolyl, benzo[b]thiophenyl, or benzofuranil.

8. is, And, During the ceremony, R ３ａ However, hydrogen, C １～６ Alkyl, C １～６ Heteroalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, C ６～１０ Aryl, 5-10 member heteroaryl, -(C １～３ Alkylene) - (C ３～６ Carbocyclyl), - (C １～３ Alkilen) - (3-6 member heterocyclyl), - (C) １～３ Alkylene) - (C ６ Aryl), - (C １～３ Alkylene)-(5-6 member heteroaryl),-S(=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkylene, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ The compound according to claim 1, which may be substituted with

9. is, The compound according to claim 8.

10. R ３ａ However, hydrogen, C １～６ Alkyl, C １～６ Heteroalkyl, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, C ６～１０ Aryl, 5-10 member heteroaryl, or -(C) １～３ Alkylene) - (C ６ The alkyl, alkylene, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ The compound according to claim 8, which may be substituted with

11. The compound according to claim 1, wherein ring A is a 10-membered bicyclic heteroaryl containing 1 to 3 nitrogen atoms.

12. is, The compound according to claim 1.

13. Ring A consists of one 5- or 6-membered heteroaryl and one C ５～６ The compound according to claim 1, which is a 9 or 10-membered bicyclic condensed ring system containing a carbocyclyl.

14. However, The compound according to claim 1.

15. Each R １ However, independently, hydrogen, C １～６ Alkyl, -(C １～６ Alkylene) - (C ６～１０ Aryl), or -(C １～６ Alkylene)-(5-10 membered heteroaryl), wherein the alkyl, alkylene, aryl, or heteroaryl is one or more R １ａ The compound according to claim 1, which may be substituted with

16. Two R's １ The compound according to claim 1, wherein these atoms, together with the nitrogen atoms to which they are bonded, form a 5-10 membered heterocycline or a 5-10 membered heteroaryl, and the heterocycline or heteroaryl may be substituted with one or more R1b atoms.

17. Each R １ｂ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ３～６ Carbocyclyl, 3-6 member heterocyclyl, C ６ Aryl, 5-6 member heteroaryl, or -S (=O) ２ R ａ The alkyl, alkoxy, alkylamino, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ The compound according to claim 1, which may be substituted with

18. Each R ２ However, independently, hydrogen or C １～６ It is alkyl, or two R2 groups combine to form an oxo; The compound according to claim 1, wherein m is 1.

19. Each R Ａ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ３～６ Carbocyclyl, or 3-6 member heterocyclyl, C ６ Aryl, 5-6 member heteroaryl, or -NR ｃ S(=O)R ａ The alkyl, alkoxy, alkylamino, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It is also fine if it is replaced with; The compound according to claim 1, wherein n is 0, 1, or 2.

20. The compound according to claim 1, wherein n is 0, 1, or 2.

21. Each R Ｂ However, independently, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ３～６ Carbocyclyl or 3-6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocykyl, or heterocyclyl is one or more R ｕ The compound according to claim 1, which may be substituted with

22. The compound according to claim 1, wherein p is 0 or 1.

23. U is -C(R ４ ) ２－ And each R ４ However, independently, hydrogen or C １～６ The compound according to claim 1, wherein it is alkyl.

24. The compound according to claim 1, wherein d is 0.

25. R ３ The compound according to claim 1, wherein the compound is hydrogen.

26. The compound according to claim 1, wherein q is 1.

27. ​​The compound is the following formula II-2: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, Two R's １ However, together with the nitrogen atom to which they are bonded, one or more R １ｂ They form 3- to 12-membered heterocyclines which may be substituted with Each R １ｂ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, -SR ｂ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S(=O)R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -OS (=O) ２ R ａ , -OS (=O) ２ OR ｂ , -OS (=O) ２ NR ｃ R ｄ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may be replaced with, or, Two Vicinal R １ｂ However, together with the intervening atom, C ６ An aryl or 5-6 membered heteroaryl is formed, and the aryl or heteroaryl is one or more R ｕ It may also be replaced with Each R ２ However, it is hydrogen, m is 1, Ring A is a 9 or 10-membered bicyclic condensed heteroaryl or one 5 or 6-membered heteroaryl and one C ５～６ It is a 9- or 10-membered bicyclic condensed ring system containing a carbocyclyl, Each R Ａ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, -SR ｂ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S(=O)R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -OS (=O) ２ R ａ , -OS (=O) ２ OR ｂ , -OS (=O) ２ NR ｃ R ｄ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with n is an integer between 0 and 2, Each R Ｂ However, independently, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, -SR ｂ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S(=O)R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -OS (=O) ２ R ａ , -OS (=O) ２ OR ｂ , -OS (=O) ２ NR ｃ R ｄ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with p is an integer between 0 and 3, U is -CH ２ - and Each R Ｄ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ３～６ Carbocyclyl or 3-6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocykyl, or heterocyclyl is one or more R ｕ It may also be replaced with d is an integer selected from 0 to 4. R ３ However, hydrogen, deuterium, C １～６ Haloalkyl, or C １～６ It is alkyl, q is 1. The compound according to claim 1.

28. The compound according to claim 1, wherein the compound is selected from the compounds in Table 1 below and their pharmaceutically acceptable salts; (Table 1) 。

29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 and one or more pharmaceutically acceptable excipients.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, for treating or preventing a disease or disorder in a subject where such treatment is necessary, wherein the disease or disorder is an IKZF2-mediated disease or disorder.

31. Use of a compound according to any one of claims 1 to 28 in the manufacture of a drug for treating or preventing a disease or disorder in a subject that needs it, wherein the disease or disorder is an IKZF2-mediated disease or disorder.

32. The pharmaceutical composition according to claim 30, wherein the disease or disorder is T-cell leukemia, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, or gastrointestinal stromal tumor (GIST).

33. The use according to claim 31, wherein the disease or disorder is T-cell leukemia, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, or gastrointestinal stromal tumor (GIST).

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