IKZF2 decomposition agent and use thereof

Abstract

Described herein are compounds of formula I', and their pharma- ceutically acceptable salts, solvates, or stereoisomers, and their uses (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 / 446,105, filed February 16, 2023, and U.S. Provisional Patent Application No. 63 / 323,792, filed March 25, 2022, the contents of each of which are incorporated herein by reference in their entirety. [Background technology]

[0002] background The IKAROS family zinc finger 2 (IKZF2) (also known as Helios) described herein is one of five members of the Ikaros family of transcription factors found in mammals. IKZF2 contains four zinc finger domains near the N-terminus involved in DNA binding and two zinc finger domains at the 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 a key 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 report grade 3 or higher adverse events. Therefore, there is a strong need for compounds that target Tregs within tumors without causing systemic activation of T effector cells. IKZF2-specific degraders may provide potentially better tolerated and less toxic therapeutic agents for the treatment of cancer by focusing an enhanced immune response to areas within or near the tumor.

[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 IKZF2 loss resulted in increased myeloid differentiation. These data suggest that IKZF2 is differentially required in myeloid leukemia cells compared to normal cells. Thus, depletion 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 The present disclosure provides a compound of formula (I'): TIFF2025512805000001.tif30128 is provided, and each of the variables in Formula I' is explained, 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, the method comprising administering a compound disclosed herein to the subject 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 methods of treating a disease or disorder, comprising administering to a subject in need thereof a compound disclosed herein.

[0011] 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.

[0012] In certain aspects, the present disclosure provides a compound disclosed herein for use in treating a 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 a therapeutically effective amount of an IKZF2 degrading agent. The present invention also relates to a method for treating an IKZF2 protein-mediated disease or condition in a patient by administering a therapeutically effective amount of an IKZF2 degrading agent to the patient in need thereof. The present invention further relates to a method for treating an IKZF2-mediated disease or condition in a patient, comprising administering to the patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of an IKZF2 degrading agent.

[0016] Compounds of the Disclosure In certain aspects, the present disclosure provides a compound of formula (I'): TIFF2025512805000002.tif30128 and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: X is -C(R 3 )2-, -NR 4 -, -O-, -S-, -S(=O)-, or -S(=O)2-; Y is -C(R 3 )2-, -NR 4 -, -O-, -S-, -S(=O)-, or -S(=O)2-; Each Z independently represents -C(R 3 )2-, -NR 4 -, -O-, -S-, -S(=O)-, or -S(=O)2-; p is 0, 1, or 2; Each R 3 are independently deuterium, 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 3-6 Carbocyclyl, 3- to 6-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, aryl, heteroaryl, carbocyclyl, or heterocyclyl is present in one or more of R u may be substituted with Two Germinal R 3 together to form oxo, or Two Germinal R 3 together with the carbon atoms to which they are attached, 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 4 are independently hydrogen or one or more R u C optionally substituted with 1-6 is alkyl, Ring A is C 3-12a carbocyclic ring or a 3- to 12-membered heterocyclic ring, R 1 is hydrogen or -MLQR 2 and M is absent, -(C=O)-, -S(=O)-, or -S(=O)-; L is absent or [W] r and r is an integer from 1 to 3, Each W is independently -C(R L )2-, C 3-4 carbocyclylene or 3- to 4-membered heterocyclylene, wherein the carbocyclylene or heterocyclylene is one or more R u may be substituted with Each R L are independently hydrogen, deuterium, 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, or 3- to 12-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u or Two Germinal R L together with the carbon atoms to which they are attached, 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 Q is absent or -NR Q -, -O-, -C(=O)-, -S(=O)-, or -S(=O)2-; R Q is hydrogen or one or more R u C optionally substituted with 1-6 is alkyl, R2 is C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, and the aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R 2a may be substituted with Each R 2a 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, -(C 1-6 alkyl)-(C 6-10 aryl), -(C 1-6 alkyl)-(5-10 membered heteroaryl), -(C 1-6 alkyl)-(C 3-12 carbocyclyl), -(C 1-6 alkyl)-(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, aryl, heteroaryl, carbocyclyl, or heterocyclyl is present in one or more of R u or The Two R's 2a together with the atoms to which they are attached, C 3-8 form a carbocyclyl or a 3- to 8-membered heterocyclyl, and the carbocyclyl or heterocyclyl is one or more R u may be substituted with R A , R C , and R E Each occurrence of is independently an 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 , -NRb 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 q is an integer from 0 to 2, s is an integer from 0 to 12, valence permitting; e is an integer selected from 0 to 5, U is -CH2- or -C(=O)-; R 5 are hydrogen, deuterium, and C 1-6 Haloalkyl, or C 1-6 is alkyl, t 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, -(C 1-6 alkylene)-(C 6-10 aryl), -(C 1-6alkylene)-(5-10 membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 carbocyclyl), -(C 1-6 Alkylene)-(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, alkylene, 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 6-10 Aryl, 5-10 membered heteroaryl, C3-12 optionally substituted with one or more substituents selected from carbocyclyl and 3- to 12-membered heterocyclyl; The Two R's u together with one or more intervening atoms, form 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; R c and R d 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; or R c and R d together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocyclyl, wherein the heterocyclyl is selected from one or more R z may be substituted with R a , R b , R c , and R d Each occurrence of independently represents one or more R z may be substituted with Each R zare 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 a carbocyclyl or a 3- to 6-membered heterocyclyl.

[0017] In certain embodiments, the compound is a compound of formula (I'-1-i), (I'-1-ii), (I'-1-iii), (I'-1-iv), (I'-1-v), (I'-1-vi), (I'-1-vii), (I'-1-viii), (I'-1-ix), (I'-1-x), (I'-1-xi), (I'-1-xii), or (I'-1-xiii): TIFF2025512805000003.tif208142 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0018] In certain embodiments, the compound is a compound of formula (I'-2-i), (I'-2-ii), (I'-2-iii), (I'-2-iv), (I'-2-v), (I'-2-vi), (I'-2-vii), (I'-2-viii), (I'-2-ix), (I'-2-x), (I'-2-xi), (I'-2-xii), or (I'-2-xiii): TIFF2025512805000004.tif200145 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0019] In certain embodiments, when p is 0, X and Y are both -C(R 3 )2 and / or p is 1, then X, Y, and Z are all -C(R 3 )2.

[0020] In certain embodiments, ring A is 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 )), or 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S).

[0021] In certain embodiments, TIFF2025512805000005.tif22128 is TIFF2025512805000006.tif17128, where m and n are independently integers of 0 to 2.

[0022] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0023] In certain embodiments, each of m and n is 1.

[0024] In certain embodiments, R 1 is hydrogen or -MLQR 2 is.

[0025] In certain embodiments, M is absent, —(C═O)—, —S(═O)—, or —S(═O) 2 —.

[0026] In certain embodiments, L is absent or [W] r is.

[0027] In certain embodiments, each W is independently —C(R L )2-, C 3-4 carbocyclylene (e.g., cyclopropylene (C), cyclopropenylene (C), cyclobutylene (C), or cyclobutenylene (C)), or 3- to 4-membered heterocyclylene (e.g., a heterocyclylene containing one 3- to 4-membered ring and one heteroatom selected from N, O, and S), wherein the carbocyclylene or heterocyclylene is selected from one or more R u may be substituted with.

[0028] In certain embodiments, each R L are independently hydrogen, deuterium, 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), 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 butylamino, 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 1-5 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 1-5 heteroatoms selected from N, O, and S), and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from one or more R u may be substituted with.

[0029] In certain embodiments, each R L are independently hydrogen, deuterium, 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, C aryl, or 5- to 6-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.

[0030] In certain embodiments, each R L are independently hydrogen, deuterium, 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 L are independently hydrogen, deuterium, 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 L are independently hydrogen, deuterium, or C 1-6 It is alkyl.

[0033] In certain embodiments, L is —CH 2 —.

[0034] In certain embodiments, two geminal R L together with the carbon atoms to which they are attached, C3-6 carbocyclyl (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 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 or two 3- to 6-membered rings 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.

[0035] In certain embodiments, r is an integer from 1 to 3. In certain embodiments, r is 1. In certain embodiments, r is 1. In certain embodiments, r is 2. In certain embodiments, r is 3.

[0036] In certain embodiments, Q is absent or -NR Q -, -O-, -C(=O)-, -S(=O)-, or -S(=O)2-.

[0037] In certain embodiments, R Q is hydrogen or one or more R u C optionally substituted with 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)).

[0038] In certain embodiments, R 2 is 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 1-5 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 1-5 heteroatoms selected from N, O, and S), wherein the aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from one or more R 2a may be substituted with.

[0039] In certain embodiments, each R 2a 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 1-6Alkoxy (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 butylamino, 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 1-5 heteroatoms selected from N, O, and S), C 6-10 aryl (e.g., phenyl or naphthyl), 5- to 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), -(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- 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 cS(=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 the alkyl, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0040] In certain embodiments, each R 2a are independently oxo, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkylamino, 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), -(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)2NR c R d , -NR c S(=O)2R a , -NRb C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkylene, 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.

[0041] In certain embodiments, two R 2a together with the atoms to which they are attached, C 3-8 forming a 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)), or a 3- to 8-membered heterocyclyl (e.g., a heterocyclyl containing one or two 3- to 8-membered rings 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.

[0042] In certain embodiments, R A , R C , and R E each occurrence independently represents oxo, halogen (e.g., —F, —Cl, —Br, or —I), —CN, —NO, —OH, —NH, 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), 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 butylamino, 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 1-5 heteroatoms selected from N, O, and S), C 6-10 aryl (e.g., phenyl or naphthyl), 5- to 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), -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)2Ra , -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.

[0043] In certain embodiments, R A , R C , and R E Each occurrence of is independently an 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, C aryl, or 5- to 6-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.

[0044] In certain embodiments, R A , R C , and R E Each occurrence of is independently an 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, 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.

[0045] In certain embodiments, R A , R C , and R E Each occurrence of is independently an 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.

[0046] 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.

[0047] In certain embodiments, s is an integer from 0 to 12, where valence permits. In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, where valence permits, s is 5. In certain embodiments, where valence permits, s is 6. In certain embodiments, where valence permits, s is 7. In certain embodiments, where valence permits, s is 8. In certain embodiments, where valence permits, s is 9. In certain embodiments, where valence permits, s is 10. In certain embodiments, where valence permits, s is 11. In certain embodiments, where valence permits, s is 12.

[0048] In certain embodiments, e is an integer selected from 0 to 5. In certain embodiments, e is 0. In certain embodiments, e is 1. In certain embodiments, e is 2. In certain embodiments, e is 3. In certain embodiments, e is 4. In certain embodiments, e is 5.

[0049] In certain embodiments, X is —C(R 3 )2-, -NR 4 -, -O-, -S-, -S(=O)-, or -S(=O)2-.

[0050] In certain embodiments, Y is —C(R 3 )2-, -NR 4 -, -O-, -S-, -S(=O)-, or -S(=O)2-.

[0051] In certain embodiments, each Z is independently —C(R 3 )2-, -NR 4 -, -O-, -S-, -S(=O)-, or -S(=O)2-.

[0052] In certain embodiments, X is —O— and Y is —C(R 3 )2-. In certain embodiments, X is -C(R 3 )2- and Y is -O-. In certain embodiments, X is -NR 4 - and Y is -C(R 3 )2-.

[0053] In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2.

[0054] In certain embodiments, each R 3 are independently deuterium, hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -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 butylamino, 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 1-5 heteroatoms selected from N, O, and S), C 6-10 aryl (e.g., phenyl or naphthyl), 5- to 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), -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)NRc 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 the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from one or more R u may be substituted with.

[0055] In certain embodiments, each R 3 are independently hydrogen, deuterium, 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, C aryl, or 5- to 6-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.

[0056] In certain embodiments, each R 3 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6Alkynyl, 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.

[0057] In certain embodiments, each R 3 are independently hydrogen, deuterium, 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.

[0058] In certain embodiments, each R 3 are independently hydrogen, deuterium, or C 1-6 It is alkyl.

[0059] In certain embodiments, two geminal R 3 together to form oxo.

[0060] In certain embodiments, two geminal R 3 together with the carbon atoms to which they are attached, C 3-6 carbocyclyl (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 3-12forming 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 or two 3- to 6-membered rings 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.

[0061] In certain embodiments, each R 4 are independently hydrogen or one or more R u C optionally substituted with 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)).

[0062] In certain embodiments, U is —CH 2 — or —C(═O)—.

[0063] In certain embodiments, R 5 are hydrogen, deuterium, and C 1-6 haloalkyl (e.g., C substituted with 1 to 8 halogen atoms selected from -F, -Cl, -Br, or -I) 1-6 alkyl), or 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)).

[0064] In certain embodiments, t is an integer from 0 to 2. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2.

[0065] In certain embodiments, the compound is a compound of formula (I'): TIFF2025512805000007.tif30128 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 1 is hydrogen or -LR 2 and L is -C(R L )2- and Each R L are independently hydrogen, deuterium, 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 R 2 is C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, and the aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R 2a may be substituted with Each R 2a are independently oxo, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkylamino, 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), -(C 1-6 alkylene)-(5-10 membered heteroaryl), -(C 1-6 alkylene)-(C 3-12 carbocyclyl), -(C 1-6alkylene)-(3-12 membered heterocyclyl), -S(=O)R a , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR b C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkylene, 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 R A , R C , and R E Each occurrence of is independently an 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 X is -O- or -NR 4 - and Each R 4 are independently hydrogen or C 1-6 is alkyl, Y is —CH— or —O—; p is 0 or 1.

[0066] In certain aspects, the present disclosure provides a compound of formula (I): TIFF2025512805000008.tif30128 and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: R 1 is hydrogen or -MLQR 2 and M is absent, -(C=O)-, -S(=O)-, or -S(=O)-; L is absent or [-C(R L )2-] r and Each R L 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 3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, 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 L together with the carbon atoms to which they are attached, C 3-12 forming a carbocyclyl or a 3- to 12-membered heterocyclyl; r is an integer from 1 to 3, Q is absent or -NR Q -, -O-, -C(=O)-, -S(=O)-, or -S(=O)2-; R Q is hydrogen, C 1-6 alkyl, wherein the alkyl is one or more R u may be substituted with R 2 is C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, and the aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R 2a may be substituted with Each R 2a are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Alkylamino, 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 alkyl)-(C 6-10 aryl), -(C 1-6 alkyl)-(5-10 membered heteroaryl), -(C 1-6 alkyl)-(C 3-12 carbocyclyl), -(C 1-6 alkyl)-(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 dand alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is present in one or more of R u or The Two R's 2a together to form oxo, R A and R C Each occurrence of is independently an 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 c R d , -C(=O)R a , -C(=O)ORb , 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 q is an integer from 0 to 2, s is an integer from 0 to 12, valence permitting; m and n are independently an integer of 0 to 2, X is -C(R 3 )2-, -NR 4 -, -O-, -S-, -S(=O)-, or -S(=O)2-; Y is -C(R 3 )2-, -NR 4 -, -O-, -S-, -S(=O)-, or -S(=O)2-; Each Z independently represents -C(R 3 )2-, -NR 4 -, -O-, -S-, -S(=O)-, or -S(=O)2-; p is 0 or 1; Each R 3 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 3-6 Carbocyclyl, 3- to 6-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 cS(=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 Two Germinal R 3 together to form oxo, or The Two R's 3 together with the carbon atoms to which they are attached, C 3-12 forming a carbocyclyl or a 3- to 12-membered heterocyclyl; Each R 4 are independently hydrogen or C 1-6 alkyl, wherein the alkyl is one or more R u may be substituted with U is -CH2- or -C(=O)-; R 5 are hydrogen, deuterium, and C 1-6 Haloalkyl, or C 1-6 is alkyl, t 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, C1-6 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, -(C 1-6 alkyl)-(C 6-10 aryl), -(C 1-6 alkyl)-(5-10 membered heteroaryl), -(C 1-6 alkyl)-(C 3-12 carbocyclyl), -(C 1-6 alkyl)-(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 dwherein 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 3-12 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 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 3-12 Carbocyclyl, 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; R a , R b , Rc , and R d Each occurrence of 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 It is a carbocyclyl or a 3- to 6-membered heterocyclyl.

[0067] In certain embodiments, X is —C(R 3 )2-.

[0068] In certain embodiments, X is —NR 4 -It is.

[0069] In certain embodiments, X is —O—.

[0070] In certain embodiments, X is -S-.

[0071] In certain embodiments, X is —S(═O)—.

[0072] In certain embodiments, X is —S(═O) 2 —.

[0073] In certain embodiments, Y is —C(R 3 )2-.

[0074] In certain embodiments, Y is —NR 4 -It is.

[0075] In certain embodiments, Y is —O—.

[0076] In certain embodiments, Y is -S-.

[0077] In certain embodiments, Y is -S(=O)-.

[0078] In certain embodiments, Y is -S(=O)2-.

[0079] In certain embodiments, X is —O— and Y is —C(R 3 )2-. In some embodiments, X is -O- and Y is -CH2-. In certain embodiments, X is -C(R 3 )2- and Y is -O-. In certain embodiments, X is -NR 4 - and Y is -C(R 3 )2-. In certain embodiments, X is -C(R 3 )2- and Y is -NR 4 -It is.

[0080] In some embodiments, X is —O— and Y is —C(R 3 )2- and p is 0.

[0081] In certain embodiments, Z is —C(R 3 )2-, -NR 4 In certain embodiments, Z is —C(R 3 )2 or -O-.

[0082] In certain embodiments, when p is 0, X and Y are both -C(R 3 )2, or when p is 1, X, Y, and Z all are -C(R 3 )2.

[0083] In certain embodiments, p is 0. In certain embodiments, p is 1.

[0084] In certain embodiments, the compound is a compound of formula (I-1-i) to (I-1-xiii): TIFF2025512805000009.tif201144 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0085] In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 -MLQR 2 is.

[0086] In certain embodiments, M is absent. In certain embodiments, M is —(C═O)—, —S(═O)—, or —S(═O)—.

[0087] In certain embodiments, L is —C(R L )2-. In certain embodiments, L is absent.

[0088] In certain embodiments, each R L 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.

[0089] In certain embodiments, each R L are independently hydrogen or C 1-6 It is alkyl.

[0090] In certain embodiments, L is —CH 2 —.

[0091] In certain embodiments, two R L together with the carbon atoms to which they are attached, C 3-12 It forms a carbocyclyl or a 3- to 12-membered heterocyclyl.

[0092] In certain embodiments, Q is absent. In certain embodiments, Q is -NRQ In certain embodiments, Q is -NR Q In certain embodiments, Q is -O-. In certain embodiments, Q is -C(=O)-. In certain embodiments, Q is -S(=O)-. In certain embodiments, Q is -S(=O)-.

[0093] In certain embodiments, R Q is hydrogen or C 1-6 In certain embodiments, R Q is C 1-6 In certain embodiments, R Q is hydrogen.

[0094] In certain embodiments, R 2 is C 6-10 Aryl, 5-10 membered heteroaryl, C 5-10 It is a carbocyclyl or a 5- to 10-membered heterocyclyl.

[0095] In certain embodiments, R 2 is phenyl.

[0096] In certain embodiments, R 2 is a 5- to 10-membered heteroaryl.

[0097] In certain embodiments, R 2 is C 5-10 It is a carbocyclyl.

[0098] In certain embodiments, R 2 is a 5- to 10-membered heterocyclyl.

[0099] In certain embodiments, each R 2a are independently oxo, 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 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.

[0100] In certain embodiments, each R 2a are independently oxo, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 Carbocyclyl, 3-12 membered heterocyclyl, -S(=O)2R a , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR b 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.

[0101] In certain embodiments, two R 2a together to form oxo.

[0102] In certain embodiments, each R 3 are independently H or C 1-6 In certain embodiments, each R 3 is H. In certain embodiments, two geminal R 3 together to form oxo.

[0103] In certain embodiments, each R 4 are independently hydrogen, C 1-6Alkyl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, and the alkyl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u In certain embodiments, each R 4 are independently H or C 1-6 alkyl, which is one or more R u may be substituted with.

[0104] In certain embodiments, R A and R C Each occurrence of is independently an 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.

[0105] In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6. In certain embodiments, s is 7. In certain embodiments, s is 8. In certain embodiments, s is 9. In certain embodiments, s is 10. In certain embodiments, s is 11. In certain embodiments, s is 12.

[0106] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.

[0107] In certain embodiments, m and n are independently 0 or 1. In certain embodiments, each of m and n is 0. In certain embodiments, each of m and n is 1. In certain embodiments, m is 0 and n is 1. In certain embodiments, m is 1 and n is 0.

[0108] In certain embodiments, U is -CH2-. In certain embodiments, U is -C(=O)-.

[0109] In certain embodiments, R 5 are hydrogen, deuterium, and C 1-6 Haloalkyl, or C 1-6 In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is deuterium. In certain embodiments, R 5 is C 1-6 In certain embodiments, R 5 is C 1-6 It is alkyl.

[0110] In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2.

[0111] In certain embodiments, the compound is a compound of formula (II): TIFF2025512805000010.tif28128 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R 1 is hydrogen or -LR 2 and L is -CH-; R 2 is C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, and the aryl, heteroaryl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R 2amay be substituted with Each R 2a are independently oxo, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-12 Carbocyclyl, 3-12 membered heterocyclyl, -S(=O)2R a , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR b 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 X is —O—; Y is -CH2-, p is 0.

[0112] 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 1-5 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 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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 (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 1-5 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 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] In certain embodiments, each R c and each Rd 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 1-5 heteroatoms selected from N, O, and S), C 6-10aryl (e.g., phenyl or naphthyl), or 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 alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0121] In certain embodiments, each R c and each 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.

[0122] 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 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclyl is selected from one or more R z may be substituted with.

[0123] In certain embodiments, R a , R b , R c , and R d independently, one or more R z may be substituted with.

[0124] In certain embodiments, each 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 a carbocyclyl or a 3- to 6-membered heterocyclyl.

[0125] In certain embodiments, each R u 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 1-6 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 butylamino, 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 2-6alkenyl (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 1-5 heteroatoms selected from N, O, and S), C 6-10 aryl (e.g., phenyl or naphthyl), 5- to 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), -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)Ra , -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 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 and 3- to 6-membered heterocyclyl.

[0126] 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 6-10aryl, 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 1-6 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 and 3- to 6-membered heterocyclyl.

[0127] 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 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 and 3- to 6-membered heterocyclyl.

[0128] 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 3-6carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, 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 and 3- to 6-membered heterocyclyl.

[0129] 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 the 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 and 3- to 6-membered heterocyclyl.

[0130] In certain embodiments, two R u together with the carbon atoms to which they are attached, C 3-6 Forms 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).

[0131] In certain embodiments, two geminal R u together with the carbon atoms to which they are attached, C 3-6 Forms 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).

[0132] Embodiments of the variables in any of the formulas described herein, e.g., Formulas I and I', are described below, where applicable. Any of the variables can be any moiety described in the embodiments below. Additionally, combinations of any moiety described for any of the variables with any moiety described for any of the remaining variables are also contemplated, where appropriate.

[0133] While not wishing to be limited by this description, it is understood that although various options for variables are described herein, the present disclosure is intended to encompass operable embodiments having combinations of options. The present disclosure may be interpreted as excluding inoperable embodiments caused by certain combinations of options. For example, although various options for variables X, Y, and Z are described herein, the present disclosure may be interpreted as excluding inoperable compound structures caused by certain combinations of options (e.g., when two adjacent members of X, Y, and Z are both nitrogen, or both oxygen, or when one of two adjacent members of X, Y, and Z is nitrogen while the other is oxygen).

[0134] 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.

[0135] In certain embodiments, the compound is selected from the compounds in Table 1 and their pharmaceutically acceptable salts.

[0136] In certain embodiments, the compound is selected from the compounds in Table 1.

[0137] (Table 1) TIFF2025512805000011.tif194146TIFF2025512805000012.tif198147TIFF2025512805000013.tif197148TIFF2025512805000014.tif194146TIFF2025512805000015.tif196147TIFF2025512805000016.tif194145TIFF2025512805000017.tif207146TIFF2025512805000018.tif204147TIFF2025512805000019.tif189146TIFF2025512805000020.tif204145TIFF2025512805000021.tif187146TIFF2025512805000022.tif203146TIFF2025512805000023.tif183146TIFF2025512805000024.tif187145TIFF2025512805000025.tif208145TIFF2025512805000026.tif210146TIFF2025512805000027.tif193146TIFF2025512805000028.tif211147TIFF2025512805000029.tif200147TIFF2025512805000030.tif210146TIFF2025512805000031.tif211146TIFF2025512805000032.tif180146TIFF2025512805000033.tif189146TIFF2025512805000034.tif208145TIFF2025512805000035.tif190146TIFF2025512805000036.tif194146TIFF2025512805000037.tif195146TIFF2025512805000038.tif201147TIFF2025512805000039.tif198147TIFF2025512805000040.tif194146TIFF2025512805000041.tif193145TIFF2025512805000042.tif195147TIFF2025512805000043.tif194145TIFF2025512805000044.tif197146TIFF2025512805000045.tif188147TIFF2025512805000046.tif204147TIFF202551280500 0047.tif199147TIFF2025512805000048.tif199147TIFF2025512805000049.tif197146TIFF2025512805000050.tif190145TIFF2025512 805000051.tif198146TIFF2025512805000052.tif191146TIFF2025512805000053.tif196147TIFF2025512805000054.tif194146TIFF20 25512805000055.tif196147TIFF2025512805000056.tif194146TIFF2025512805000057.tif198147TIFF2025512805000058.tif197147.

[0138] (Table 2) TIFF2025512805000059.tif198146TIFF2025512805000060.tif188146TIFF2025512805000061.tif204147TIFF2025512805000062.tif205147 TIFF2025512805000063.tif207147TIFF2025512805000064.tif202147TIFF2025512805000065.tif190145TIFF2025512805000066.tif188146

[0139] 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 estrogen receptor activity, more favorable pharmacokinetic properties (e.g., C max , T maxand / or AUC) and / or other cellular targets (e.g., hepatocyte transporters such as OATP1B1), and / or may exhibit reduced interactions 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 may be measured according to methods generally available in the art, such as those exemplified herein.

[0140] Due to the presence of double bonds, compounds of the present disclosure may be in the cis or trans, or Z or E configuration. Although one configuration may be depicted in the structure of a compound or formula of the present disclosure, it is understood that the present disclosure encompasses the other configuration as well. For example, compounds or formulas of the present disclosure may be depicted in the cis or trans, or Z or E configuration.

[0141] 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.

[0142] 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 herein. Other features, objects, and advantages of the present disclosure will be apparent from the description 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.

[0143] Forms of the compounds disclosed herein pharmaceutically acceptable salts In some embodiments, the compounds disclosed herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0144] In some embodiments, the compounds described herein possess acidic or basic groups and thus react with any of a number of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some 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 so formed.

[0145] 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, benzoates ... ester, 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 , hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-fluoroethanesulfonate 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.

[0146] 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.

[0147] In some 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.

[0148] 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 some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

[0149] 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.

[0150] 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.

[0151] In some 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.

[0152] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed. 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.

[0153] 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."

[0154] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, opposite (E), and same (Z) isomers, as well as their corresponding mixtures. All geometric forms of the compounds disclosed herein are contemplated and within the scope of the present invention.

[0155] In some embodiments, the compounds disclosed herein contain 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.

[0156] In additional 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 some 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 recovering the optically pure enantiomer. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomer is then recovered along with the resolving agent.

[0157] tautomers In some embodiments, the compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulae described herein.

[0158] Tautomers are compounds that are interconvertible by the migration of a hydrogen atom, involving 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.

[0159] Pharmaceutical Composition In certain embodiments, the compounds described herein are administered as pure chemicals. In some embodiments, the compounds described herein are administered as pure chemicals, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 2011).st The compound is 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 selected route of administration and standard pharmaceutical practice as described in The Journal of Pharmaceutical Sciences, Vol. 1, No. 1, pp. 111-115, 1997, Ed. Mack Pub. Co., Easton, PA (2005)).

[0160] 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.

[0161] In certain embodiments, the compounds provided herein are substantially pure in that they contain less than about 5%, less than about 1%, or less than about 0.1% of other small organic molecules, e.g., unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic method.

[0162] 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. Generally, 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 mass, weight, or blood volume.

[0163] In some 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 some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, intranasal administration, topical administration, or ocular administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some 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 some embodiments, the pharmaceutical composition is formulated as a tablet.

[0164] isotopic species In some aspects, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds disclosed herein.

[0165] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1 or Table 2.

[0167] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1.

[0169] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 2, or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 2.

[0171] It will be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by carrying out the procedures disclosed in the schemes and / or examples described herein.

[0172] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0173] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0174] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds listed in Table 1 or Table 2.

[0176] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1.

[0178] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 2, or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 2.

[0180] A deuterium-labeled compound is understood to contain deuterium atoms having an abundance of deuterium substantially greater than the natural abundance of deuterium, which is 0.015%.

[0181] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term "deuterium enrichment factor" refers to the ratio between the deuterium abundance and the natural abundance of deuterium.

[0182] It will be appreciated that deuterium-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, substituting a deuterium-labeled compound for a non-deuterium-labeled compound.

[0183] Compounds of the present disclosure containing the aforementioned deuterium atoms, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. 2Substitution with H) may confer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosing requirements.

[0184] Compound preparation and characterization The compounds of the present disclosure can be prepared in a number of ways well 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).

[0185] General synthetic scheme TIFF2025512805000067.tif149145

[0186] Those skilled in the art will recognize if a stereocenter exists in the compounds 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 may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

[0187] 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).

[0188] 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. Additional suitable references and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein or provide 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, T.W.G., “Organic Chemistry” 7th Edition (2000), John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C."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 (more than 55 volumes), and "Chemistry of Functional Groups" John Wiley & Sons (73 volumes). Specific and similar reactants may be identified through an index of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available at most public and university libraries and online. Chemicals that are known in catalogs but not commercially available may be prepared by custom chemical synthesis companies, and many of the 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 P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0189] 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 given 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 120 EC-C18 2.7 μm 4.6 × 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. or 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 5% B at 3.5 min.

[0190] Exemplary Biological Assays The biological activity of the compounds of the present disclosure may be evaluated using methods and assays known in the art.

[0191] Exemplary Cereblon Binding Assay Binding to cereblon (CRBN) is determined using the Cereblon Binding Kit (Cisbio, no. 64BDCRBNPEG) according to the manufacturer's instructions. Briefly, serially diluted compounds are incubated with GST-tagged wild-type human CRBN protein, XL665-labeled thalidomide, and Europium Cryptate-labeled GST antibody. Time-resolved fluorescence resonance energy transfer (TR-FRET) measurements are acquired, for example, using MARS data analysis software (BMG Labtech). Readings are normalized to the control (0.5%) and the IC 50 is calculated by nonlinear regression (four-parameter sigmoid fitted with variable slope) analysis using, for example, GraphPad Prism 8 software.

[0192] Exemplary immunoblots Cells are maintained in appropriate culture medium containing 10% FBS at 37° C. and an atmosphere of 5% CO 2 .

[0193] The cells are lysed, resolved by SDS-PAGE, and transferred to a PVDF membrane (Millipore). The membrane is blocked, for example, using Odyssey TBS Blocker Buffer (LI-COR). Secondary antibodies, for example, IRDye 680RD and 800CW dye-labeled, are used. The washed membrane is scanned, for example, using an Odyssey CLx imager (LI-COR). The intensity of Western blot signaling is quantified using Odyssey software. Primary antibodies used include Helios (D8W4X) XP® Rabbit mAb (Cell Signaling Technology, no. 42427) and GAPDH mouse monoclonal antibody (Santa Cruz Biotechnology, sc-47724).

[0194] Exemplary IKZF2 HiBiT Assay IKZF2 protein degradation is determined by IKZF2 HiBiT assay using Jurkat-IKZF2-HiBiT (Promega) cell line. Briefly, cells are seeded in culture medium. Compounds are serially diluted in culture medium, and a specific volume of diluted compound is added to the appropriate wells of the plate. After compound addition, cells are incubated. At the end of treatment, Nano-Glo HiBiT Lytic Detection Reagent (Promega) is added to each well, and the plate is then incubated at room temperature for a specific period. Luminescence signals are measured using a CALRIOstar plate reader (BMG Labtech). Readings are normalized to DMSO-treated cells, and IC 50 is calculated by nonlinear regression (variable slope, least squares, and four-parameter sigmoid fitted without constraints) analysis using GraphPad Prism 8 software.

[0195] How to use In certain aspects, the present disclosure provides a method of degrading IKZF2 protein in a subject, the method comprising administering to the subject a compound disclosed herein.

[0196] 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.

[0197] In certain aspects, the present disclosure provides a compound disclosed herein for use in degrading IKZF2 protein in a subject.

[0198] 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).

[0199] 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).

[0200] In certain aspects, the present 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.

[0201] In certain aspects, the present 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.

[0202] 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.

[0203] 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.

[0204] In certain embodiments, the disease or disorder is an IKZF2-mediated disease or disorder.

[0205] In certain embodiments, the disease or disorder is cancer.

[0206] In certain embodiments, cancers include, but are not limited to, one or more of the cancers in Table A.

[0207] (Table A) TIFF2025512805000068.tif189146TIFF2025512805000069.tif198146TIFF2025512805000070.tif117146

[0208] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a hematological cancer. Exemplary hematological cancers include, but are not limited to, those listed in Table B. In certain embodiments, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.

[0209] (Table B) TIFF2025512805000071.tif130146

[0210] In certain embodiments, the disease or disorder is T-cell leukemia or T-cell lymphoma, Hodgkin's lymphoma or 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, or gastrointestinal stromal tumor (GIST).

[0211] In certain embodiments, the subject is a mammal.

[0212] In certain embodiments, the subject is a human.

[0213] definition As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated below.

[0214] 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 thEd., inside cover, and specific functional groups are generally defined as described therein. 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. rd Edition, Cambridge University Press, Cambridge, 1987.

[0215] 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).

[0216] The present invention further includes the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0217] 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 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0218] 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. By way of example, "an analog" means one analog or more than one analog.

[0219] As used herein, "alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group having from 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 1-9 In 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 ("C1-7 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 can 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 can be an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-10 Common alkyl abbreviations include Me(-CH), Et(-CHCH), i-Pr(-CH(CH)), n-Pr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0220] As used herein, "alkylene" refers to an alkyl group from which two hydrogens have been removed to provide a divalent radical. When a range or number of carbons for a particular "alkylene" group is provided, 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 may be unsubstituted or substituted with one or more substituents described herein. Exemplary unsubstituted divalent alkylene groups include methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), and propylene (-CHCHCH-). 2- ), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted divalent alkylene groups, for example, 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)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0221] As used herein, "alkenyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., one, two, three, or four carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., one, two, three, or four carbon-carbon triple bonds) ("C 2-20 In certain embodiments, an alkenyl group does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In certain embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9In 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. Additional 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 2-10 In certain embodiments, the alkenyl group is a substituted C 2-10 It is alkenyl.

[0222] As used herein, "alkenylene" refers to an alkenyl group in which two hydrogens have been removed to provide a divalent radical. 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 carbon divalent 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.

[0223] As used herein, "alkynyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., one, two, three, or four carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., one, two, three, or four carbon-carbon double bonds) ("C 2-20 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 2-8 In certain embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7In 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 (such as in 2-butynyl) or terminal (such as in 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 can be independently substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). 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.

[0224] As used herein, "alkynylene" refers to an alkynyl group in which two hydrogens have been removed to provide a divalent radical. 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 linear carbon divalent 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.

[0225] 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 the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the 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 heteroalkyl group is a saturated group having 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 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 one carbon atom and one heteroatom ("heteroC alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having two to six carbon atoms and one or two 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.

[0226] As used herein, the term "heteroalkenyl" refers to an alkenyl group, as defined herein, that 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 a 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, 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 ("heteroC 2-6 In certain embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and one or two heteroatoms ("heteroC 2-5 In certain embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 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 one or two 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.

[0227] As used herein, the term heteroalkynyl refers to an alkynyl group, as defined herein, that 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 within a parent carbon atom 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, 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 one or two 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 2-3In certain embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or two heteroatoms ("heteroC 2-6 Unless 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.

[0228] Analogous to "alkylene," "alkenylene," and "alkynylene" defined above, as used herein, "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" refer to the divalent radical of a heteroalkyl, heteroalkenyl, and heteroalkynyl group, respectively. When a range or number of carbons is provided for a particular "heteroalkylene," "heteroalkenylene," 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.

[0229] "Aryl" refers to an aromatic ring system ("C 6-14 "C6 aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the ring ("C6 aryl"). 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"). 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14aryl", e.g., anthracyl).

[0230] Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, 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 may be independently 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.

[0231] As used herein, "arylene" refers to an aryl group in which two hydrogens have been removed to provide a divalent radical. 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.

[0232] "Heteroaryl" refers to the radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1 to 8 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings.

[0233] "Heteroaryl" also includes ring systems in which a heteroaryl group, as defined above, is fused with one or more aryl groups, 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 instances, 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 heteroatoms (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).

[0234] In certain embodiments, heteroaryl 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 independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In certain embodiments, heteroaryl 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 independently selected from nitrogen, oxygen, and sulfur ("5- to 9-membered heteroaryl"). In certain embodiments, heteroaryl 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 independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In certain embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, 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 independently selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group may independently be 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.

[0235] 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.

[0236] As used herein, "heteroarylene" refers to a heteroaryl group in which two hydrogens have been removed to provide a divalent radical. When a range or number of ring members for a particular "heteroarylene" group is provided, it is understood that the range or number refers to the number of ring members in the heteroaryl group. "Heteroarylene" groups can be substituted or unsubstituted with one or more substituents described herein.

[0237] "Carbocyclyl" refers to a group of aryl groups having 3 to 12 ring carbon atoms in a non-aromatic ring system ("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, a 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.

[0238] 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 5-8In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 5 or 6 ring carbon atoms ("C 5-6 Carbocyclyl). 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.

[0239] As the preceding 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 may independently be 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.

[0240] "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.

[0241] "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.

[0242] "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.

[0243] As used herein, "carbocyclylene" refers to a carbocyclyl group in which two hydrogens have been removed to provide a divalent radical. The divalent radicals 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.

[0244] "Heterocyclyl" refers to the radical of 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.

[0245] 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.

[0246] 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 a heterocyclyl group, as defined above, is fused to one or more carbocyclyl groups, and the point of attachment is on either the carbocyclyl ring 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 one or more of the carbocyclyl groups. Unless otherwise specified, each instance of heterocyclyl can independently be substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). 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.

[0247] "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 number of ring members 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.

[0248] "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.

[0249] "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.

[0250] As used herein, "heterocyclylene" refers to a heterocyclyl group in which two hydrogens have been removed to provide a divalent radical. The divalent radicals can be on different atoms or the same atom of the heterocyclylene group. When a range or number of ring members for a particular "heterocyclylene" group is provided, it is understood that the range or number refers to the number of ring members in the heterocyclylene group. A "heterocyclylene" group can be substituted or unsubstituted with one or more substituents described herein.

[0251] As used herein, "alkoxy" refers to an -OR group, 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 An exemplary C 1-6 Alkyl is described above.

[0252] 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 An exemplary C 1-6 Alkyl is described above.

[0253] "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.

[0254] "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.

[0255] 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 subsequent 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.

[0256] 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)).

[0257] 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)).

[0258] 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)).

[0259] 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.

[0260] 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.

[0261] 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.

[0262] "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. Salts further 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.

[0263] "Solvate" refers to a form of a compound associated with a solvent or water (also referred to as a "hydrate"), usually by solvolysis. 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, a solvate is capable of isolation, 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.

[0264] "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.

[0265] 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.

[0266] "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).

[0267] 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.

[0268] "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.

[0269] It should also be understood that compounds that have the same molecular formula but 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 only in the arrangement of their atoms in space are termed "stereoisomers."

[0270] 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."

[0271] "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 π 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 desired compound.

[0272] The terms "enantiomerically pure" or "pure enantiomer" indicate that a compound contains greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 98.5%, greater than 99%, greater than 99.2%, greater than 99.5%, greater than 99.6%, greater than 99.7%, greater than 99.8%, or greater than 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.

[0273] 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.

[0274] As used herein, and unless otherwise indicated, the term "enantiomerically pure (S)-compound" refers to at least about 95% by weight of the (S)-compound and at most about 5% by weight of the (R)-compound, at least about 99% by weight of the (S)-compound and at most about 1% by weight of the (R)-compound, or at least about 99.9% by weight of the (S)-compound and at most about 0.1% by weight of the (R)-compound. In certain embodiments, the weights are based on the total weight of the compound.

[0275] In the compositions provided herein, the enantiomerically pure compound, or its pharmaceutically acceptable salt, solvate, hydrate, or prodrug, may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing 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 containing 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 may be formulated with few or no excipients or carriers.

[0276] 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.

[0277] 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 statistical experimental error, and thus, in some instances, the numerical value or numerical range varies by 1% to 15% of the stated numerical value or numerical range. In certain embodiments, the numerical value or numerical range varies by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% of the stated numerical value or numerical range.

[0278] The term "comprising" (and related terms, e.g., "comprise" or "comprises," or "having" or "including") is not intended to exclude that in certain other embodiments, any embodiment of the material, composition, method, or process described herein, "consists of" or "consists essentially of" the recited features.

[0279] 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 (which may include elements other than B), in another embodiment to B only (which may include elements other than A), in yet another embodiment to both A and B (which may include other elements), etc.

[0280] 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.

[0281] 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" may refer in one embodiment to at least one A, which may include more than one, and no B (and may include elements other than B); in another embodiment to at least one B, which may include more than one, and no A (and may include elements other than A); in yet another embodiment to at least one A, which may include more than one, and at least one B, which may include more than one (and may include other elements).

[0282] 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.

[0283] 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.

[0284] 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]

[0285] 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.

[0286] I. Synthetic Routes and Procedures 3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione (C-1) TIFF2025512805000072.tif141142

[0287] Process 1~2: To a solution of pyridin-4-ylmethanol (WP08-1, 100 g, 916 mmol, 1.0 equiv.) in DMF (400 mL) was added BnBr (172 g, 1.0 mol, 1.1 equiv.). The mixture was heated to 100° C. and stirred for 3 h. TLC showed that no starting material remained and a new spot had formed. The residue was dissolved in EtOH (1500 mL), and then 45 g of sodium borohydride (1.19 mol, 1.3 equiv.) was added in small portions at 0° C. The mixture was kept stirring at 0° C. for 1 h and then at reflux for 2 h. The solvent was evaporated under reduced pressure, then water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (DCM:MeOH=100:0 to 30:1) to give 107 g of product WP08-3 (viscous oil, 2 steps, 80% yield).

[0288] LC / MS(ESI)m / z:204.14; 1 H NMR(400MHz, CDCl3):7.25-7.41(m,5H),5.59-5.66(m,1H),4.01(s,2H),3.60(s, 2H), 2.95-3.02 (m, 2H), 2.61 (t, J=5.8Hz, 2H), 2.36 (s, br, 1H), 2.10-2.21 (m, 2H).

[0289] Step 3: To a solution of 5-bromo-3H-isobenzofuran-1-one (1) (100 g, 1 equiv.) in trifluoromethanesulfonic acid (1000 g, 10 equiv.) was added NIS (125 g, 1.2 equiv.) in small portions at 0 °C. The mixture was allowed to warm to room temperature and stirred overnight. TLC showed that no starting material remained and two new spots had formed. The reaction mixture was poured into ice water, causing the precipitation of a yellow solid. The mixture was filtered, and the filter cake was washed with ice-cold water. The filter cake was dried to give a mixture of product 2 (upper spot on TLC) and product 2b (lower spot on TLC, which was not further reacted in the next step) as a yellow solid (100 g, 62% yield).

[0290] LC / MS(ESI)m / z:337.84; 1 H NMR (400MHz, CDCl3): 7.83 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 5.10 (s, 2H).

[0291] Step 4: To a mixture of compound 2 (100 g, 1 equiv.), sodium hydroxide (57.5 g, 5 equiv.) in water (1000 mL, 1.5 M), and N,N-dimethylacetamide (600 mL) was added cuprous oxide (8.5 g, 0.2 equiv.). The reaction mixture was heated to 80 °C and stirred for 12 h. TLC showed that compound 2 (the top spot on the TLC) was completely consumed. The reaction mixture was poured into water (1000 mL), treated with solid K2CO3 until pH reached 8-9, and extracted with EA. The aqueous layer was neutralized using 1 N hydrochloric acid solution, extracted with ethyl acetate, washed with brine, then dried over sodium sulfate and evaporated. The crude product was purified by silica gel column chromatography to give compound WP08-4 as a yellow solid (42 g, 39% yield).

[0292] LC / MS(ESI)m / z:228.94; 1 H NMR (400MHz, DMSO-d6) δ 10.90 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.35 (s, 2H).

[0293] Step 5: To a solution of WP08-4 (20 g, 1.0 equiv.) in 200 mL of THF, compound WP08-3 (23.1 g, 1.3 equiv.) and PPh3 (34.4 g, 1.55 equiv.) were added. The reaction mixture was cooled to 0 °C, and DIAD (27.1 mL, 1.55 equiv.) was added dropwise. The resulting mixture was then stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography using 0-100% EtOAc / hexanes. The desired product, WP08-5, was obtained as a yellow foam (17.7 g, 49% yield).

[0294] LC / MS(ESI) m / z: 414.0.

[0295] Step 6: To a solution of WP08-5 (14.8 g, 35.7 mmol, 1.0 equiv.) in toluene (150 mL) was added n-Bu3SnH (41.6 g, 142.9 mmol, 4.0 equiv.) and AIBN (0.6 g, 3.57 mmol, 0.1 equiv.). The mixture was heated to reflux and stirred overnight. TLC (PE:EA = 1:1) showed that no starting material remained and a new spot had formed. The reaction mixture was poured into saturated aqueous KF solution (100 mL) and stirred overnight. The reaction mixture was then extracted with ethyl acetate, washed with brine, and then dried over sodium sulfate. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give compound WP08-6 as a white solid (7.1 g, 60% yield).

[0296] LC / MS(ESI) m / z: 336.15.

[0297] Steps 7~8: To a solution of WP08-6 (10 g, 29.8 mmol, 1.0 equiv.) in DCE (100 mL) was added α-chloroethyl chloroformate (ACE-Cl, 1.0 equiv.) at 0 °C, and the mixture was then refluxed for 1 h. The intermediate ACE-piperidine was formed and was directly de-ACEylated to WP08-7, typically by evaporating the reaction mixture in vacuo and then heating the residue in MeOH. The residue was dissolved in THF (100 mL), and then 4.5 g of triethylamine (44.7 mmol, 1.5 equiv.) and BocO (38.7 mmol, 1.3 equiv.) were added. The mixture was left stirring at room temperature for 3 h. The solvent was evaporated under reduced pressure, then water was added, and the mixture was extracted with EA. The combined organic phases were dried over NaSO and evaporated. The residue was purified by flash chromatography to give 6.0 g of product WP08-8 (two steps, 60% yield).

[0298] LC / MS(ESI) m / z: 346.16.

[0299] Step 9: To a solution of compound WP08-8 (15 g, 1 eq.) in tetrahydrofuran (100 mL) and water (100 mL), sodium hydroxide (8.7 g, 5 eq.) was added. The mixture was stirred at 20° C. for 16 hours. TLC (ethyl acetate:hexane=1:1) showed the reaction was complete. The mixture was adjusted to pH=5-6 with aqueous hydrochloric acid (1 M) and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The crude material was used crude in the next step without further purification.

[0300] LC / MS(ESI) m / z: 364.17.

[0301] Step 10: To a solution of compound WP08-9 (15 g, crude, 1 eq.) in dichloromethane (300 mL) was added manganese dioxide (20 eq.). The mixture was stirred at 20° C. for about 1 hour. TLC showed that the reaction was complete. The mixture was diluted with dichloromethane and filtered through a pad of Celite. The filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM:MeOH=10:1). The desired compound WP08-10 was obtained as a yellow solid (8 g, 2 steps, 60%).

[0302] LC / MS(ESI) m / z: 362.15.

[0303] Step 11: To a mixture of compound WP08-10 (3 g, 1.0 equiv.) in methanol (20 mL) and dichloromethane (20 mL), 3-aminopiperidine-2,6-dione (4.0 g, 3 equiv., TFA salt), AcONa (3.08 g, 6.0 equiv.), and AcOH (5.1 mL, 10.0 equiv.) were added. The mixture was stirred at 25° C. for 2 hours, and then sodium cyanoborohydride (1.57 g, 3.0 equiv.) was added, and the mixture was stirred for an additional 30 minutes. LCMS showed the reaction was complete. The reaction mixture was then quenched with water and concentrated under reduced pressure to give a residue that was redissolved in acetonitrile and water (1:1, 30 mL). The solution was mixed well at the beginning. After standing overnight at 0-5°C, the mixture was filtered, and the filter cake was washed with acetonitrile and water (1:1) and dried in vacuo to give the crude product WP08-11 as a solid (900 mg, 60% yield).

[0304] LC / MS(ESI) m / z: 474.22.

[0305] Step 12: To a solution of compound WP08-11 (900 mg, 1.0 equiv.) in DMF (15 mL), HATU (795 mg, 1.1 equiv.) and DIPEA (0.72 mL, 3.0 equiv.) were added, and the reaction was stirred at room temperature for 30 min. UPLC-MS showed a new major peak indicating the desired product had formed. Following quenching with water, the mixture was extracted with ethyl acetate, washed with brine, and then dried over sodium sulfate. The target compound, WP08-12, was obtained as a brown solid (675 mg, 75% yield).

[0306] LC / MS(ESI) m / z: 456.21. 1 H NMR(400MHz,chloroform-d)δ 8.00(s,1H),7.50(d,J=7.7Hz,1H),7.28(s,1H),5.23(dd,J=13.3,5.1Hz,1H),4.55(d,J=1.4Hz,2H),4.46(d,J=16.0Hz,1H),4.32(d,J=16.0Hz) ,1H),4.15(s,2H),3.01-2.77(m,4H),2.38(dd,J=13.1,5.0Hz,1H),2.2 9-2.17(m,1H),1.92(t,J=12.5Hz,2H),1.83-1.72(m,2H),1.52(s,9H).

[0307] Step 13: Compound WP08-12 was treated with TFA in DCM at room temperature to deprotect the N-Boc group to give cereblon ligand C-1.

[0308] LC / MS(ESI) m / z: 355.1.

[0309] 3-(7'-oxo-2',3',7',9'-tetrahydro-8'H-spiro[piperidine-4,4'-pyrano[2,3-e]isoindol]-8'-yl)piperidine-2,6-dione (C-2): TIFF2025512805000073.tif143144

[0310] Process 1~2: To a solution of 2-(pyridin-4-yl)ethan-1-ol (WP09-1, 10 g, 91.6 mmol, 1.0 equiv.) in DMF (40 mL) was added BnBr (15.3 g, 108 mmol, 1.1 equiv.). The mixture was heated to 100° C. and stirred for 3 h. TLC showed that no starting material remained and a new spot had formed. The residue was dissolved in EtOH (150 mL), and then 4.0 g of sodium borohydride (119.1 mmol, 1.3 equiv.) was added in small portions at 0° C. The mixture was continued to stir at 0° C. for 1 h and then at reflux for 2 h. The solvent was evaporated under reduced pressure, then water was added, and the mixture was extracted with EA. The combined organic phases were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (DCM:MeOH=100:0 to 30:1) to give 10 g of product WP09-3 (viscous oil, 2 steps, 56% yield).

[0311] LC-MS: 218 [M+H] + .

[0312] Step 3: To a solution of compound WP09-3 (10 g, 1 eq.) in DCM (200.0 mL) was added DMAP (0.1 eq.) and TEA (2 eq.) at 0° C. Then EsCl (1.5 eq.) was added slowly, and the mixture was stirred at room temperature for 1 h. The reaction was partitioned between EtOAc and water. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography to give compound WP09-4 as a yellow solid (10 g, 70% yield).

[0313] LC-MS: 310 [M+H] + .

[0314] Step 4: To a solution of 5-bromo-3H-isobenzofuran-1-one (1) (10 g, 1 equiv.) in trifluoromethanesulfonic acid (100 g, 10 V) was added NIS (12.5 g, 1.2 equiv.) in small portions at 0 °C. The mixture was allowed to warm to room temperature and stirred overnight. TLC showed that no starting material remained and two new spots had formed. The reaction mixture was poured into ice water, causing the precipitation of a yellow solid. The mixture was filtered, and the filter cake was washed with ice-cold water. The filter cake was dried to give a mixture of product 2 (upper spot on TLC) and product 2b (lower spot on TLC, which was not further reacted in the next step) as a yellow solid (10 g, 62% yield).

[0315] Step 5: To a mixture of compound 2 (10 g, 1 equiv.), sodium hydroxide (5.75 g, 5 equiv.), and N,N-dimethylacetamide (60 mL) in water (100 mL, 1.5 M) was added cuprous oxide (0.85 g, 0.2 equiv.). The reaction mixture was heated to 80 °C and stirred for 12 h. TLC showed that compound 2 (the top spot on the TLC) was completely consumed. The reaction mixture was poured into water (100 mL), treated with solid K2CO3 until pH reached 8-9, and extracted with EA. The aqueous layer was neutralized using 1 N hydrochloric acid solution, extracted with ethyl acetate, washed with brine, then dried over sodium sulfate and evaporated. The crude product was purified by silica gel column chromatography to give compound WP08-4 as a yellow solid (4.2 g, 39% yield).

[0316] LC-MS: 229 / 231 [M+H] + .

[0317] Step 6: To a solution of compound WP08-4 (10 g, 1.0 equiv.) in 100 mL of DMF, compound WP09-4 (16.2 g, 1.2 equiv.) and K2CO3 (1.6 equiv.) were added. The reaction mixture was heated to 70 °C and stirred overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography using 0-100% EtOAc / hexanes. The desired product, WP09-5, was obtained as a yellow foam (11 g, 60% yield).

[0318] LC-MS: 428 / 430 [M+H] + .

[0319] Step 7: To a solution of WP09-5 (5 g, 1.0 equiv.) in toluene (50 mL) was added n-Bu3SnH (13.6 g, 4.0 equiv.) and AIBN (0.4 g, 0.1 equiv.). The mixture was heated to reflux and stirred overnight. TLC (PE:EA = 1:1) showed that no starting material remained and a new spot had formed. The reaction mixture was poured into saturated aqueous KF solution (100 mL) and stirred overnight. The reaction mixture was then extracted with ethyl acetate, washed with brine, and then dried over sodium sulfate. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give compound WP09-6 as a white solid (2 g, 50% yield).

[0320] LC-MS: 350 [M+H] + .

[0321] Steps 8~9: To a solution of WP09-6 (3.0 g, 1.0 equiv.) in DCE (100 mL) was added α-chloroethyl chloroformate (ACE-Cl, 1.2 equiv.) at 0 °C, and the mixture was then refluxed for 15 h. The intermediate ACE-piperidine was formed and was directly deACEylated to WP09-7, typically by evaporating the reaction mixture in vacuo and then heating the residue in MeOH. The residue was dissolved in THF (100 mL), and then trimethylamine (3.0 equiv.) and BocO (1.3 equiv.) were added. The mixture was left stirring at room temperature for 3 h. The solvent was evaporated under reduced pressure, then water was added, and the mixture was extracted with EA. The combined organic phases were dried over NaSO and evaporated. The residue was purified by flash chromatography to give WP09-8 (1.5 g, 2 steps, 50% yield).

[0322] LC-MS: 360 [M+H] + . 1 H NMR(600MHz,chloroform-d)δ 7.47(d,J=7.6Hz,1H),7.08(d,J=7.6Hz,1H),5.24(s,2H),4.16(t,J=6.7Hz,2H),3.8 8(m,2H),3.51(m,2H),2.52(t,J=6.8Hz,2H),2.13(m,2H),1.61(m,2H),1.46(s,9H).

[0323] Step 10: To a solution of compound WP09-8 (2 g, 1 eq.) in tetrahydrofuran (10 mL) and water (10 mL), sodium hydroxide (1.2 g, 5 eq.) was added. The mixture was stirred at 20° C. for 16 hours. TLC (ethyl acetate:hexane=1:1) showed the reaction was complete. The mixture was adjusted to pH=5-6 with aqueous hydrochloric acid (1 M) and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The crude material was used crude in the next step without further purification.

[0324] Step 11: To a solution of compound WP09-9 (2 g, crude, 1 eq.) in dichloromethane (30 mL), manganese dioxide (20 eq.) was added. The mixture was stirred at 20° C. for about 1 hour. TLC showed that the reaction was complete. The mixture was diluted with dichloromethane and filtered through a pad of Celite. The filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM:MeOH=10:1). The desired compound WP09-10 was obtained as a yellow solid. (1.2 g, 2 steps, 60%)

[0325] LC-MS: 376 [M+H] + .

[0326] Step 12: To a mixture of compound WP09-10 (532 mg, 1.0 equiv.) in methanol (5 mL) and dichloromethane (5 mL), 3-aminopiperidine-2,6-dione (698 mg, 3 equiv., HCl salt), AcONa (698 mg, 6.0 equiv.), and AcOH (0.85 mL, 10.0 equiv.) were added. The mixture was stirred at 25 °C for 1 h, and then sodium cyanoborohydride (268 mg, 3.0 equiv.) was added, and the mixture was stirred for an additional 30 min. LCMS showed the reaction was complete. The reaction mixture was then quenched with water and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (20%-50% ACN, neutral). The desired product WP09-11 (415 mg, 60% yield) was obtained as a solid after lyophilization.

[0327] Step 13: To a solution of compound WP09-11 (415 mg, 1.0 equiv.) in DMF (5 mL), HATU (421 mg, 1.3 equiv.) and DIPEA (0.47 mL, 3.0 equiv.) were added, and the reaction was stirred at room temperature for 30 min. UPLC-MS showed a new major peak indicating the desired compound had formed. Following quenching with water, the mixture was extracted with ethyl acetate, washed with brine, and then dried over sodium sulfate. The desired compound WP09-12 was obtained as a brown solid (300 mg, 75% yield).

[0328] LC-MS: 470 [M+H] + .

[0329] Step 14: Compound WP09-12 was treated with TFA in DCM at room temperature to deprotect the N-Boc group to give cereblon ligand C-2.

[0330] LC / MS(ESI) m / z: 369.2.

[0331] (S)-3-(6'-oxo-1',2',6',8'-tetrahydro-7'H-spiro[piperidine-4,3'-pyrrolo[3,4-g]indol]-7'-yl)piperidine-2,6-dione (C-3), and (S)-3-(1'-methyl-6'-oxo-1',2',6',8'-tetrahydro-7'H-spiro[piperidine-4,3'-pyrrolo[3,4-g]indol]-7'-yl)piperidine-2,6-dione (C-5) TIFF2025512805000074.tif123142

[0332] Step 1: To a solution of 5-bromo-3H-isobenzofuran-1-one (1) (10 g, 1 equiv.) in trifluoromethanesulfonic acid (100 g, 10 V) was added NIS (12.5 g, 1.2 equiv.) in small portions at 0 °C. The mixture was allowed to warm to room temperature and stirred overnight. TLC showed that no starting material remained and two new spots had formed. The reaction mixture was poured into ice water, causing the precipitation of a yellow solid. The mixture was filtered, and the filter cake was washed with ice-cold water. The filter cake was dried to give a mixture of product 2 (upper spot on TLC) and product 2b (lower spot on TLC, which was not further reacted in the next step) as a yellow solid (10 g, 62% yield).

[0333] Step 2: Compound 3 was prepared according to a reported procedure (Bioorg. Med. Chem. Lett. 2016, 26, 228-234). To a flask containing compound 2 (500 mg, 1.0 equiv.), compound 3 (377 mg, 1.2 equiv.), Pd(dba) (136 mg, 0.1 equiv.), Xantphos (257 mg, 0.3 equiv.), and CsCO (1447 mg, 3.0 equiv.), toluene (15 mL) was added. The reaction was evacuated and backfilled with N three times. The reaction was stirred at 80 °C for 6 h, then allowed to cool to room temperature and filtered. The filtrate was evaporated, and the residue was purified by silica gel chromatography (0–25% ethyl acetate in hexanes) to give product 4 as a pale yellow powder, 316 mg (yield = 51%).

[0334] LC-MS:323.14[M+H]+. 1H NMR (400MHz, chloroform-d)δ 7.61(d,J=8.0Hz,1H),7.17(d,J=7.9Hz,1H),5.64-5.53(m,1H),5.36(s,2H) ),3.93-3.79(m,4H),3.53(t,J=5.7Hz,2H),2.17-2.05(m,2H),1.46(s,9H).

[0335] Steps 3 and 4: To a solution of compound 4 (300 mg, 1.0 equiv.) and AIBN (35 mg, 0.3 equiv.) in toluene (10 mL) was added BuSnH (954 μL, 5.0 equiv.). The reaction was stirred in a sealed tube at 110 °C for 24 h. It was then cooled to room temperature and quenched with saturated aqueous KF (20 mL), and the mixture was allowed to stir overnight. The resulting mixture was extracted with ethyl acetate (3 times). The combined organic layers were washed with brine (3 times), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude mixture. The mixture was purified by silica gel chromatography (0–30% ethyl acetate in hexanes) to give the crude product 5 (90 mg) as a pale yellow oil.

[0336] LC-MS: 343.37 [M+H] + .

[0337] To a solution of compound 5 (90 mg) in MeOH (5 mL) was added Pd / C (90 mg). The reaction was evacuated, backfilled with H2, and stirred under an H2 atmosphere at room temperature for 6 h. It was then filtered through Celite, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (0 to 50% ethyl acetate in hexanes) to give compound 6 as a white solid (50 mg, 20% yield for steps 3 and 4).

[0338] LC-MS: 345.22 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.37 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 5.20 (s, 2H), 4.19-4.04 (m, 2H), 3.67 (s, 2H), 3.00-2.77 (m, 2H), 1.91-1.68 (m, 4H), 1.48 (s, 9H). 13 C NMR(101MHz, CDCl3)δ 171.42,154.87,143.02,142.81,128.22,126.10,123.66,117.49,79.98,67.97,56.18,44.96,40.85,35.64,28.54.

[0339] Step 5: To a solution of 6 (48 mg, 1.0 equiv) in THF / MeOH / HO (2 mL / 2 mL / 1 mL) was added NaOH (111 mg, 20 equiv). The reaction was stirred at room temperature overnight and then concentrated to remove most of the THF / MeOH. The residue was diluted with 1 mL of water, subsequently neutralized with 2 N aqueous HCl to pH 4-6, and then extracted with EA (5 mL, 6 times). The combined organic layers were washed with brine, filtered, dried over NaSO, and concentrated under reduced pressure to give 50 mg of crude product 7 as a pale yellow oil, which was used directly in the next step.

[0340] LC-MS: 363.28 [M+H] + .

[0341] Step 6: To a solution of 7 (40 mg, 1.0 equiv) in DCM (5 mL) was added NaHCO (28 mg, 3.0 equiv), followed by portionwise addition of DMP (47 mg, 1.0 equiv). After 10 min, the reaction mixture was diluted with DCM, washed with brine, dried over NaSO, filtered, and concentrated to give crude product 8 as a yellow oil (40 mg), which was used directly in the next step. LC-MS: 361.27 [M+H] + .

[0342] Step 7: To a solution of 9 (73 mg, 4.0 equiv.) and NaOAc (28 mg, 4 equiv.) in MeOH (4 mL), 8 (40 mg, 1.0 equiv.) and AcOH (317 μL, 50 equiv.) were added. After 15 min, NaBHCN (34.5 mg, 5.0 equiv.) was added, and the resulting mixture was stirred at 40 °C for 3 h. The reaction mixture was concentrated to remove some of the MeOH and then purified by preparative HPLC to give Boc-protected C-3, which was further treated with TFA and concentrated to remove the TFA. The final compound C-3 was obtained as a white solid (10 mg).

[0343] LC-MS: 423.16 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 7.28-7.17(m,2H),5.14(dd,J=13.3,5.2Hz,1H),4.39-4.23(m,2H),3.67(s,2H),3.51-3.39(m,2H ),3.25-3.12(m,2H),2.98-2.84(m,1H),2.84-2.72(m,1H),2.56-2.39(m,1H),2.23-1.96(m,5H).

[0344] Step 8: To a solution of 9 (18 mg, 4.0 equiv.) and NaOAc (6.9 mg, 4 equiv.) in MeOH (3 mL) was added 8 (40 mg, 1.0 equiv.) and AcOH (0.5 mL). After 15 min, NaBHCN (34.5 mg, 20 equiv.) was added portionwise, and the resulting mixture was stirred at 40 °C overnight. The reaction mixture was concentrated to remove some of the MeOH and then purified by preparative HPLC to give Boc-protected C-5, which was further treated with TFA and concentrated to remove the TFA. The final compound C-5 was obtained as a gray solid, 4.7 mg.

[0345] LC-MS: 469.26 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 7.21(s,2H),5.14(dd,J=13.3,5.2Hz,1H),4.72-4.55(m,2H),3.51-3.39(m,4H),3.24-3.13(m,2H),2.9 9(s,3H),2.96-2.83(m,1H),2.83-2.74(m,1H),2.60-2.46(m,1H),2.22-2.03(m,3H),2.03-1.94(m,2H).

[0346] 3-(6-oxo-6,8-dihydrospiro[furo[3,4-e]isoindole-3,4'-piperidine]-7(1H)-yl)piperidine-2,6-dione (C7) TIFF2025512805000075.tif128146

[0347] Step 1: To a solution of 5-bromo-3H-isobenzofuran-1-one (C-7.1) (10 g, 1 equiv.) in trifluoromethanesulfonic acid (80 mL, 20 equiv.) was added NIS (12.5 g, 1.2 equiv.) in small portions at 0 °C. The mixture was allowed to warm to room temperature and stirred overnight. TLC showed that no starting material remained and two new spots had formed. The reaction mixture was poured into ice water, causing the precipitation of a yellow solid. The mixture was filtered, and the filter cake was washed with ice-cold water. The filter cake was dissolved in DCM and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give a yellow solid. The crude product was purified by silica gel flash chromatography. The less polar product (top spot on TLC) C-7.2 was obtained as a brown solid (8 g, 50% yield).

[0348] Step 2: A vial was charged with compound C-7.2 (8 g, 1 equiv.), Pd(dppf)Cl (0.2 equiv.), KCO (3 equiv.), and dioxane-HO (100 mL / 20 mL). The mixture was purged with nitrogen, and potassium vinyltrifluoroborate (2.0 equiv.) was added. The reaction was heated to 65 °C for 16 h. TLC indicated the reaction was complete. The mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine and dried over sodium sulfate. The crude product was purified by silica gel column chromatography using 0–50% EtOAc / hexane to give compound C-7.3 as a yellow foam (3.2 g, 57% yield).

[0349] LC-MS: 239 / 241 [M+H] + ; 1 H NMR (600 MHz, chloroform-d) δ 7.70 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 6.92 (dd, J = 18.0, 11.6 Hz, 1H), 5.62 (d, J = 11.6 Hz, 1H), 5.42 (d, J = 18.0 Hz, 1H), 5.33 (s, 2H).

[0350] Step 3: A solution of compound C-7.3 (5 g) in CH2Cl2 (100 mL) was cooled to -78 °C, and then O3 was bubbled into the solution. The passage of O3 was continued for another 30 min until the color became pale blue, and then air was bubbled into the solution for 10 min to remove excess O3. After Me2S (2 mL) was added dropwise, the solution was kept stirring and allowed to warm to room temperature. The mixture was diluted with water and extracted with DCM. The organic layer was washed with brine and dried over MgSO4. The residue was quickly purified by chromatography to give compound C-7.4 (4 g).

[0351] Step 4: To a solution of compound C-7.4 (4 g, 1.0 equiv.) in MeOH (40 mL, 10 V) was added NaBH (1.9 g, 3 equiv.) in small portions at 0 °C. TLC showed that compound 4 was completely consumed, and LCMS showed the presence of the desired product. The reaction mixture was quenched by adding HO at 20 °C and then concentrated under reduced pressure to remove MeOH. The mixture was then extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 1 to ethyl acetate) to give compound C-7.5 (3 g, 75% yield).

[0352] Step 5: A round-bottom flask equipped with a stir bar was charged with a mixture of compound C-7.5 (4 g, 1.0 equiv.), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.7 g, 1.5 equiv.), potassium carbonate (6.9 g, 3.0 equiv.), and Pd(dppf)Cl (2.4 g, 0.2 equiv.). The flask was evacuated and backfilled with nitrogen (×3). A mixture of dioxane-HO (100 mL / 20 mL) was added, and stirring was continued at 90 °C for 10 h. The cooled reaction mixture was diluted with EtOAc and filtered through Celite™ to remove insoluble material. The filtrate was washed with water, saturated aqueous sodium chloride, then dried over magnesium sulfate, filtered, and the filtrate was concentrated. The crude material was purified by flash silica chromatography, elution gradient MeOH in DCM. Pure fractions were combined and concentrated to give compound C-7.6 (5 g, 89%).

[0353] Step 6: To a mixture of compound C-7.6 (6 g, 1 eq.) in MeCN (60 mL) was added NBS (3.7, 1.2 eq.) in one portion. The mixture was stirred at 20° C. for 16 h. The mixture was concentrated in vacuo, and the crude material was purified by flash silica chromatography, elution gradient MeOH in DCM, to give compound C-7.7 as a white solid (6.6 g, 90% yield).

[0354] 1 H NMR(600MHz,chloroform-d)δ 7.87(d,J=7.9Hz,1H),7.66(d,J=7.9Hz,1H),5.25(s,2H),5.16(d,J=13.0Hz,1H),5.05(d,J=13.0Hz,1H ),4.25(m,2H),4.08-3.81(m,2H),3.33(m,1H),2.68-2.56(m,1H),1.65(d,J=13.9Hz,1H),1.50(s,9H).

[0355] Step 7: To a solution of compound C-7.7 (500 mg, 1.0 equiv.) in toluene (10 mL) and MeOH (1 mL), n-Bu3SnH (5.0 equiv.) and AIBN (0.1 equiv.) were added. The mixture was heated to reflux and stirred overnight. After cooling, additional n-Bu3SnH (5.0 equiv.) was added to the above mixture, and stirring was continued at 100 °C for another 12 h. TLC showed that no starting material remained, so the reaction mixture was poured into saturated aqueous KF solution (100 mL) and stirred for 1 h. The reaction mixture was then filtered, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The crude product was purified by silica gel column chromatography (PE:EA=4:1) to give compound C-7.8 as a white solid (60% yield). LC-MS: 346 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ 7.78(d,J=7.8Hz,1H),7.57(d,J=7.8Hz,1H),5.39(s,2H),5.09(s,2H),3.98(brs,2H), 3.07(brs,2H),1.88(td,J=13.1,4.9Hz,2H),1.64(dd,J=13.8,2.4Hz,2H),1.43(s,9H).

[0356] Step 8: To a solution of compound C-7.8 (1.25 g, 1 equiv.) in tetrahydrofuran (10 mL) and water (10 mL), sodium hydroxide (720 mg, 5 equiv.) was added. The mixture was stirred at 20 °C for 16 h. TLC (ethyl acetate:hexane = 1:1) showed the reaction was complete. The mixture was adjusted to pH = 5-6 with aqueous hydrochloric acid (1 M) and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The crude material 9 was used crude in the next step without further purification.

[0357] Step 9: To a solution of compound C-7.9 (1 g, crude, 1 eq.) in dichloromethane (50 mL) was added manganese dioxide (20 eq.). The mixture was stirred at 20 °C for about 1 h. TLC showed that the reaction was complete. The mixture was diluted with dichloromethane and MeOH and then filtered through a pad of Celite. The filtrate was concentrated in vacuo, and the crude product C-7.10 (0.6 g, crude) was used directly in the next step.

[0358] Step 10: To a mixture of compound C-7.10 (300 mg, crude, 1.0 equiv.) in methanol (5 mL) and dichloromethane (5 mL), 3-aminopiperidine-2,6-dione (162 mg, 1.5 equiv., HCl salt), AcONa (204 mg, 3.0 equiv.), and AcOH (150 μL, 3.0 equiv.) were added. The mixture was stirred at 20 °C for 1 h, then sodium cyanoborohydride (104 mg, 2.0 equiv.) was added, and the mixture was stirred for an additional 30 min. LCMS indicated the reaction was complete. The reaction mixture was then concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (20%-50% ACN, neutral). The desired product C-7.11 was obtained as a white solid (120 mg) after lyophilization.

[0359] Step 11: To a solution of compound C-7.11 (180 mg, 1.0 equiv.) in DMF (3 mL) was added HATU (216 mg, 1.5 equiv.) and DIPEA (0.2 mL, 3.0 equiv.) at 0 °C, and the reaction was stirred at room temperature for 30 min. UPLC-MS showed a new major peak indicating the desired product was formed. After quenching with water, the mixture was extracted with ethyl acetate, washed with brine, and then dried over sodium sulfate. The target compound C-7.12 was obtained as a brown solid (100 mg, 60% yield).

[0360] LC-MS: 456 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 11.01(s,1H),7.66(d,J=7.7Hz,1H),7.47(d,J=7.7Hz,1H),5.16-5.11(m,1H),5.08(m,2H),4.44(d,J=17.4Hz,1H),4.29(d,J=17.4Hz,1 H),3.98(m,2H),3.04(m,3H),2.60(d,J=17.0Hz,1H),2.42-2.31(m,1H),2.04-1.93(m,1H),1.92-1.80(m,2H),1.64(m,2H),1.43(s,9H).

[0361] Step 12: Compound C-7.12 was treated with TFA in DCM at room temperature to deprotect the N-Boc group to give cereblon ligand C-7. LC / MS(ESI) m / z: 355.1.

[0362] Synthetic procedures for preparing IKZF2 degraders 3-362 TIFF2025512805000076.tif27144

[0363] To a solution of A (0.02 mmol) in MeOH (4 mL) was added NaOAc (0.06 mmol), followed by B (0.06 mmol). After stirring at room temperature for 30 min, 5 equivalents of NaBHCN (0.10 mmol) were added. After 12 h, an additional 5 equivalents of NaBHCN (0.1 mmol) were added. The resulting reaction mixture was continued to stir for an additional 12 h. The solvent was then removed under reduced pressure, and the resulting residue was purified by preparative HPLC to give the title compound 3-362.

[0364] II. Compound Characterization Compound characterization data are shown in Table E2.

[0365] (Table E1) Characterization data TIFF2025512805000077.tif199147TIFF2025512805000078.tif195147TIFF20255128050 00079.tif224146TIFF2025512805000080.tif218141TIFF2025512805000081.tif218145 TIFF2025512805000082.tif217144TIFF2025512805000083.tif203147TIFF20255128050 00084.tif223147TIFF2025512805000085.tif216146TIFF2025512805000086.tif218145 TIFF2025512805000087.tif215142TIFF2025512805000088.tif208146TIFF20255128050 00089.tif195145TIFF2025512805000090.tif224146TIFF2025512805000091.tif218145 TIFF2025512805000092.tif216143TIFF2025512805000093.tif216143TIFF20255128050 00094.tif218145TIFF2025512805000095.tif217140TIFF2025512805000096.tif234145

[0366] Compounds B-1 to B-58 Intermediate B1: tert-butyl 4-(chloromethyl)-3,6-dihydro-2H-pyridine-1-carboxylate TIFF2025512805000097.tif12128

[0367] Step A: tert-Butyl 3-hydroxy-4-methylenepiperidine-1-carboxylate A suspension of SeO (61.8 g, 558 mmol, 0.55 equiv) in DCM (3000 mL) was cooled to −10 °C, followed by dropwise addition of 2-hydroperoxy-2-methyl-propane (274 g, 291 mL, 2.10 equiv, 70% purity) in HO, and the resulting mixture was stirred at −10 °C for 30 min. The reaction mixture was further cooled to −30 °C, followed by dropwise addition of a solution of compound 5-1 (200 g, 1.01 mol, 1 equiv) in DCM (1000 mL), and the resulting mixture was stirred at −30 °C for an additional 1 h. The reaction mixture was warmed to 20 °C and stirred for an additional 18 h. After this, the mixture was cooled to 0 °C, and ice chips and water (1.0 L) were added. The resulting mixture was stirred at 0 °C for 30 min. The organic phase was separated, and the aqueous phase was extracted with DCM (500 mL). To the combined organic phases, 10% w / v NaHSO solution (1000 mL) was added portionwise at 0 °C, while maintaining the temperature below 10 °C. The mixture was stirred for an additional 5 min after the addition. The organic phase was separated, and the aqueous phase was extracted with DCM (500 mL). The combined organic phases were washed with brine (1000 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). tert-Butyl 3-hydroxy-4-methylenepiperidine-1-carboxylate (370 g) was obtained as a white solid, with a typical yield of 34.2%. 1 H NMR(400MHz,DMSO-d6)δ=5.22(br d,J=3.9Hz,1H),4.98(s,1H),4.79(s,1H),3.93-3.76(m,2H),3.71(td,J=4.3,12.6Hz,1H),2.9 2-2.77(m,1H),2.76-2.53(m,1H),2.30(td,J=3.5,13.4Hz,1H),2.10-1.95(m,1H),1.40(s,9H).

[0368] Step B: tert-butyl 4-(chloromethyl)-3,6-dihydro-2H-pyridine-1-carboxylate To a solution of tert-butyl 3-hydroxy-4-methylenepiperidine-1-carboxylate (100 g, 469 mmol, 1.00 equiv.) in toluene (2000 mL) was added 2,6-dimethylpyridine (55.2 g, 60.0 mL, 516 mmol, 1.10 equiv.) at 15 °C. After the mixture was cooled to 0 °C, SOCl (66.9 g, 40.8 mL, 563 mmol, 1.20 equiv.) was added dropwise to the mixture under a N atmosphere while maintaining the temperature below 10 °C. The mixture was stirred at 110 °C for 3 h and then cooled to 20 °C. Brine (2 × 600 mL) was added, and the resulting mixture was stirred at 20 °C for 30 min. The organic phase was separated, and saturated NaHCO solution (600 mL) was added in small portions at 15 °C. The organic phase was separated, washed with brine (1000 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give tert-butyl 4-(chloromethyl)-3,6-dihydro-2H-pyridine-1-carboxylate (200 g) as a red oil, with a typical yield of 49.0%. 1 H NMR (400MHz, CDCl3-d) δ=5.72(br s,1H),3.98(s,2H),3.88(br s,2H),3.49(br t,J=5.6Hz,2H),2.17(br s,2H),1.43(s,9H).

[0369] Intermediate B2: (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione TIFF2025512805000098.tif24128

[0370] Step A: Methyl 4-bromo-2-formyl-3-hydroxybenzoate To a solution of methyl 4-bromo-3-hydroxybenzoate (200 g, 865 mmol, 1.00 equiv.) in TFA (2.0 L) was added HMTA (485 g, 3.46 mol, 4.00 equiv.) at 20 °C, and the resulting mixture was stirred at 125 °C for 12 h. The mixture was cooled to 20 °C and quenched with 2 N HCl solution (5 V), and a yellow precipitate was observed. After stirring the mixture for 10 min, additional HO (5 V) was added, and the reaction mixture was stirred for an additional 1 h. The mixture was filtered, and the filter cake was dissolved in DCM (2.0 L), filtered through Celite, dried over anhydrous NaSO, and concentrated in vacuo. Methyl 4-bromo-2-formyl-3-hydroxybenzoate (144 g) was obtained as a gray solid, with a typical yield of 64.2%. 1 HNMR (400MHz, DMSO-d6) δ = 12.06 (br s, 1H), 10.38 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 3.87 (s, 3H).

[0371] Step B: (S)-tert-butyl 5-amino-4-(5-bromo-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate To a suspension of methyl 4-bromo-2-formyl-3-hydroxybenzoate (17.3 g, 72.4 mmol, 1.05 equiv., HCl salt) in MeOH (300 mL), DIPEA (9.37 g, 72.4 mmol, 12.6 mL, 1.05 equiv.), compound 2 (17.8 g, 69.0 mmol, 1.00 equiv.), and AcOH (6.22 g, 103 mmol, 5.92 mL, 1.50 equiv.) were added at 20° C. and stirred for 1.5 h. After stirring, NaBHCN (8.67 g, 138 mmol, 2.00 equiv.) was added in portions at 20° C., and the resulting mixture was stirred at 20° C. for 3 h. The mixture was quenched with HO (200 mL) at 20° C. and concentrated under reduced pressure. The solvent residue was then extracted with EtOAc (3 × 150 mL), and the combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 100% ethyl acetate). (S)-tert-butyl 5-amino-4-(5-bromo-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (23.0 g) was obtained as a yellow solid, with a typical yield of 78.4%. 1 H NMR(400MHz,DMSO-d6)δ=10.44(s,1H),7.67-7.55(m,2H),7.20(s,1H),7.11(d,J=7.9Hz,1H),4.76-4.67( m,1H),4.58(d,J=17.9Hz,1H),4.39(d,J=17.9Hz,1H),2.23-2.07(m,3H),2.03-1.91(m,1H),1.32(s,9H).

[0372] Step C: (S)-tert-butyl 4-(((2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-1-oxoisoindolin-4-yl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate To a solution of tert-butyl 4-(chloromethyl)-3,6-dihydro-2H-pyridine-1-carboxylate (150 g, 363 mmol, 1.00 equiv.) in MeCN (2000 mL) was added KCO (150.49 g, 1.09 mmol, 3.00 equiv.), NaI (5.44 g, 0.36 mmol, 0.10 equiv.), and (S)-tert-butyl 5-amino-4-(5-bromo-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (136 g, 472 mmol, 1.30 equiv., 80% purity) at 20 °C. The reaction mixture was stirred at 60 °C for 12 h and then cooled back to 20 °C. The resulting mixture was filtered, and the filter cake was washed with DCM (2 × 500 mL). The filtrate was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). (S)-tert-butyl 4-(((2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-1-oxoisoindolin-4-yl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate (337 g) was obtained as a red solid, with a typical yield of 72.4%. 1 H NMR(400MHz,CDCl3-d)δ=7.67(d,J=8.0Hz,1H),7.44(d,J=8.0Hz,1H),6.33(br s,1H),5.86(br s,1H),5.48(br s,1H),4.90(dd,J=6.3,8.6Hz,1H),4.66-4.59(m,1H),4.53(s,1H),4.50(br s,2H),3.98(br s,2H),3.60(br t,J=5.5Hz,2H),2.43-2.10(m,7H),1.49(s,9H),1.41(s,9H).

[0373] Step D: tert-Butyl 7-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-6-oxo-spiro[2,8-dihydrofuro[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate To a solution of tert-butyl (S)-4-(((2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-1-oxoisoindolin-4-yl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate (125 g, 205 mmol, 1.00 equiv) in toluene (1500 mL) was added AIBN (5.06 g, 0.03 mmol, 0.15 equiv) and BuSnH (270 mL, 1.02 mmol, 4.98 equiv) at 20° C. The reaction mixture was stirred at 110° C. for 12 h and then cooled to 20° C. Saturated KF solution (1000 mL) was added and the resulting mixture was stirred at 20° C. for an additional 2 h. The mixture was filtered, and the filter cake was washed with EtOAc (2×500 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3 × 500 mL). The combined organic phases were washed with brine (500 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). tert-Butyl 7-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-6-oxo-spiro[2,8-dihydrofuro[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (160 g) was obtained as a white solid, with a typical yield of 56.6%. 1 H NMR(400MHz,CDCl3-d)δ=7.40(d,J=7.6Hz,1H),7.20(d,J=7.6Hz,1H),6.41(br s,1H),5.61(br s,1H),4.92-4.85(m,1H),4.55-4.49(m,2H),4.12(q,J=7.1Hz,3H),2.88(br t,J=12.0Hz,2H),2.40-2.09(m,5H),1.94-1.82(m,2H),1.77-1.68(m,2H),1.50-1.47(m,9H),1.42-1.40(m,9H).

[0374] Step E: (3S)-3-(6-oxospiro[2,8-dihydrofuro[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione benzenesulfonate A solution of benzenesulfonic anhydride (19.6 g, 124 mmol, 2.00 equiv.) in MeCN (400 mL) was heated to 100 °C, and then a solution of tert-butyl 7-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-6-oxo-spiro[2,8-dihydrofuro[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (47.0 g, 62.1 mmol, 1.00 equiv., 70% purity) in MeCN (100 mL) was added dropwise to the mixture. The mixture was stirred at 100 °C for 12 hours and then cooled to 20 °C. The mixture was filtered, and the filter cake was dried under reduced pressure. The title compound (37.0 g) was obtained as a white solid, with a typical yield of 92.8%. 1 H NMR(400MHz,D2O-d2)δ=7.75(br d,J=7.4Hz,2H),7.55-7.36(m,5H),5.11(br dd,J=5.2,13.4Hz,1H),4.64(s,2H),4.53-4.35(m,2H),3.49(br d,J=13.2Hz,2H),3.20-3.06(m,2H),2.99-2.78(m,2H),2.48(dq,J=5.3,13.1Hz,1H),2.25-2.08(m,3H),2.05-1.93(m,5H).

[0375] Step F: (3S)-3-(6-oxospiro[2,8-dihydrofuro[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione hydrochloride A solution of (3S)-3-(6-oxospiro[2,8-dihydrofuro[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione benzenesulfonate (37 g) in HCl / dioxane (4 M, 370 mL) was stirred at 20°C for 12 hours, after which the mixture was filtered and the cake was washed with MeCN (2 x 200 mL). The filter cake was dried under reduced pressure. The title compound (24.0 g) was obtained as a red solid, with a typical yield of 80.7%. 1H NMR(400MHz,D2O-d2)δ=7.48-7.36(m,2H),5.12(dd,J=5.3,13.3Hz,1H),4.69-4.61(m,2H),4.53-4.37(m,2H),3.51(br dd,J=3.4,13.3Hz,2H),3.22-3.06(m,2H),2.98-2.80(m,2H),2.56-2.43(m,1H),2.29-2.08(m,3H),2.05-1.90(m,2H).

[0376] Intermediate B3: (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl-2,2-d2)piperidine-2,6-dione TIFF2025512805000099.tif22128

[0377] Step A: 1-(tert-butyl) 4-methyl 3,6-dihydropyridine-1,4(2H)-dicarboxylate To a solution of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (10.0 g, 30.2 mmol, 1.0 equiv) in MeOH (150.0 mL) were added DIPEA (39.0 g, 52.6 mL, 302 mmol, 10.0 equiv) and Pd(dppf)Cl (2.21 g, 3.02 mmol, 0.1 equiv). The resulting mixture was stirred at 70 °C under CO (1 atm) for 1 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with HO (30.0 mL) and extracted with EA (60 mL × 3). The organic layer was washed with brine (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate in petroleum ether, 0% to 19%) to give 1-(tert-butyl) 4-methyl 3,6-dihydropyridine-1,4(2H)-dicarboxylate (5.80 g, 79% yield) as a yellow oil. LC-MS (ESI): C 12 H 19 Calculated mass of NO4: 241.29; measured m / z: 186.7 [M-55]+ . 1 H NMR(400MHz,DMSO-d6)δ 6.86(s,1H),4.00(d,J=2.4Hz,2H),3.68(s,3H),3.42(t,J=5.6Hz,2H),2.28-2.25(m,2H),1.41(s,9H).

[0378] Step B: tert-butyl 4-(hydroxymethyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of 1-(tert-butyl) 4-methyl 3,6-dihydropyridine-1,4(2H)-dicarboxylate (2.10 g, 8.70 mmol, 1.0 equiv.) in anhydrous THF (50.0 mL) was added LiAlD4 (402 mg, 9.57 mmol, 1.1 equiv.) in small portions at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Na2SO4 . 10HO (5 g) was slowly added to the above solution, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate in petroleum ether, 0% to 70%) to give tert-butyl 4-(hydroxymethyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate (700 mg, 37% yield) as a yellow oil. LC-MS (ESI): C 11 H 17 Calculated mass for D2NO3, 215.29; observed m / z, no MS signal. 1 H NMR (400MHz, DMSO-d6) δ 5.56 (s, 1H), 4.71 (s, 1H), 3.80 (s, 2H), 3.39 (t, J = 5.6Hz, 2H), 2.02-1.92 (m, 2H), 1.39 (s, 9H).

[0379] Step C: tert-butyl 4-(bromomethyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of tert-butyl 4-(hydroxymethyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate (1.90 g, 8.83 mmol, 1.0 equiv.) and triphenylphosphine (3.47 g, 13.2 mmol, 1.5 equiv.) in DCM (50.00 mL) was added CBr4 (4.39 g, 13.2 mmol, 1.5 equiv.) in small portions under N2. The reaction mixture was stirred at 0 °C for 5 h. After evaporation, the residue was purified by flash column chromatography (ethyl acetate in petroleum ether, 0% to 19%) to give tert-butyl 4-(bromomethyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate (1.60 g, 65% yield) as a yellow oil. LC-MS (ESI) C 11 H 16 Calculated mass of D2BrNO2: 278.19; observed m / z: 224.0 [M-55] + .

[0380] Step D: tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate A mixture of tert-butyl 4-(bromomethyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate (2.00 g, 7.19 mmol, 1.0 equiv), 5-bromo-4-hydroxyisobenzofuran-1(3H)-one (1.65 g, 7.19 mmol, 1.0 equiv), and K2CO3 (1.99 g, 14.4 mmol, 2.0 equiv) in DMF (30.0 mL) was stirred for 2 h at 50° C. After cooling to room temperature, the mixture was dissolved in EA (100 mL), washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate in petroleum ether, 0% to 40%) to give tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate (2.30 g, 75% yield) as a yellow oil. LC-MS (ESI): C 19 H 20Calculated mass for D2BrNO5: 426.30; observed m / z: 450.1 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)δ 7.89(d,J=8.0Hz,1H),7.51(d,J=8.0Hz,1H),5.95(s,1H),5.72(s,2H),3.93(s,2H),3.53(t,J=5.6Hz,2H),2.28(d,J=1.8Hz,2H),1.47(s,9H).

[0381] Step E: 6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate-2,2-d2tert-butyl To a solution of tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl-d2)-3,6-dihydropyridine-1(2H)-carboxylate (2.20 g, 5.16 mmol, 1.0 equiv) and AIBN (254 mg, 1.55 mmol, 0.3 equiv) in toluene (30.0 mL) was added tributyltin hydride (9.01 g, 8.38 mL, 31.0 mmol, 6.0 equiv). The reaction mixture was stirred in a sealed tube at 120° C. for 16 h. After cooling to room temperature, the mixture was quenched with aqueous KF solution (30 mL), and the mixture was stirred for 2 h. After filtration, the filtrate was extracted with EA (50 mL × 3). The organic phase was washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate in petroleum ether, 0% to 33%) to give 2,2-tert-butyl 6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (1.50 g, 83% yield) as a white solid. LC-MS (ESI): C 19 H 21 Calculated mass of D2NO5: 347.41; observed m / z: 292.2 [M-55] + . 1H NMR(400MHz,DMSO-d6)δ 7.52(d,J=7.6Hz,1H),7.38(d,J=7.6Hz,1H),5.36(s,2H),3.95(d,J=12.2Hz ,2H),2.91-2.87(s,2H),1.85-1.77(m,2H),1.71-1.67(m,2H),1.42(s,9H).

[0382] Step F: 1'-(tert-butoxycarbonyl)-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid-2,2-d2 acid To a solution of 2,2-tert-butyl 6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (600 mg, 1.73 mmol, 1.0 equiv.) in THF (12.0 mL), MeOH (12.0 mL), and HO (4.00 mL) was added NaOH (138 mg, 3.45 mmol, 2.0 equiv.). The reaction mixture was stirred at 40 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EA (40 mL), adjusted to pH 4–5 with aqueous HCl (3 N), and extracted with EA (50 mL × 4). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1'-(tert-butoxycarbonyl)-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic-2,2-d2 acid (600 mg, 95% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H 23 Calculated mass of D2NO6: 365.42; measured m / z: 364.3 [MH] - .

[0383] Step G: 8-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate-2,2-d2tert-butyl To a solution of 1'-(tert-butoxycarbonyl)-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic-2,2-d2 acid (1.50 g, 4.10 mmol, 1.0 equiv.) in DCM (20.0 mL) was added activated manganese dioxide (7.14 g, 82.1 mmol, 20.0 equiv.) at 25 °C. The reaction mixture was stirred at 25 °C for 4 h. After filtration through a short silica gel column, the filtrate was collected and concentrated under reduced pressure to give 8-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate-2,2-d2 tert-butyl ester (760 mg, 52%) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS(ESI):C 19 H 21 Calculated mass of D2NO6: 363.41; observed m / z: 364.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.09(s,1H),7.55(d,J=7.6Hz,1H),7.33(d,J=7.6Hz,1H),6.65(s,1H),3.95(d, J=12.2Hz,2H),2.89(s,2H),1.83-1.78(m,2H),1.70-1.67(m,2H),1.43(s,9H).

[0384] Step H: (S)-2,2-d2tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate To a solution of 8-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate-2,2-d2 tert-butyl (350 mg, 963 μmol, 1.0 equiv.) and (S)-4,5-diamino-5-oxopentanoate tert-butyl hydrochloride (460 mg, 1.93 mmol, 2.0 equiv.) in DMF (10.0 mL) was added acetic acid (578 mg, 554 μL, 9.63 mmol, 10.0 equiv.). The reaction mixture was stirred at 40° C. for 2 hours, and then sodium triacetoxyborohydride (4.08 g, 19.3 mmol, 20.0 equiv.) was added. The mixture was stirred at 40° C. for 16 hours. After cooling to room temperature, the mixture was dissolved in EA (40 mL), washed with brine (30 mL × 3), 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 90%) to give (S)-2,2-d2tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (300 mg, 58%) as a white solid. LC-MS (ESI): C 28 H 37 Calculated mass for D2N3O7: 531.65; observed m / z: 532.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.60(s,1H),7.45(d,J=7.6Hz,1H),7.30(d,J=7.6Hz,1H),7.23(s,1H),4.77-4.73(m,1H),4.56(d,J=17.2Hz,1H),4.45(d,J=17.2Hz,1H), 4.00(d,J=12.8Hz,2H),2.96(s,2H),2.23-2.20(m,3H),2.09-2.02(m ,1H),1.97-1.84(m,2H),1.82-1.74(m,2H),1.49(s,9H),1.38(s,9H).

[0385] Step I: (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl-2,2-d2)piperidine-2,6-dione benzenesulfonate To a solution of (S)-2,2-dtert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (350 mg, 660 μmol, 1.0 equiv) in MeCN (10.0 mL) was added benzenesulfonic anhydride (313 mg, 1.98 mmol, 3.0 equiv) and the reaction mixture was stirred at 90°C for 7 h. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was slurried with acetonitrile (10 mL) to give (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl-2,2-d2)piperidine-2,6-dione benzenesulfonate (300 mg, 88% yield) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS (ESI): C 25 H 25 Calculated mass of D2N3O7S, 515.58; observed m / z, 358.3 [M+H] + .

[0386] Intermediate B4: (S)-tert-butyl 5-amino-4-(5-fluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)-5-oxopentanoate TIFF2025512805000100.tif31128

[0387] Step A: 4-Bromo-2-fluoro-5-hydroxybenzoic acid To a solution of compound 2-fluoro-5-hydroxybenzoic acid (10.0 g, 1.0 equivalent) in MeCN (100 mL) was added TsOH (10.1 g, 1.0 equivalent) at room temperature. The mixture was stirred for 10 minutes, and then NBS (11.4 g, 1.1 equivalent) in MeCN (50 mL) was added dropwise over a period of 20 minutes. The reaction mixture was stirred overnight at room temperature and concentrated to give the title compound (15.0 g) as a crude product, which was used in the next step without further purification.

[0388] Step B: Methyl 4-bromo-2-fluoro-5-hydroxybenzoate To a solution of 4-bromo-2-fluoro-5-hydroxybenzoic acid (crude, 15.0 g, 1.0 equiv.) in MeOH (100 mL) was added 2,2-dimethoxypropane (18.3 g, 3.0 equiv.) at room temperature. The reaction mixture was stirred at 60° C. overnight. After cooling to room temperature and concentrating, the residue was purified by flash column chromatography (PE / EA) to give the title compound (600 mg).

[0389] Step C: 4-bromo-6-fluoro-2-formyl-3-hydroxybenzoate methyl To a solution of methyl 4-bromo-2-fluoro-5-hydroxybenzoate (249 mg, 1 mmol, 1 equiv.) in TFA (5 mL) was added HMTA (560 mg, 4 mmol, 4 equiv.) at 20° C. The mixture was stirred at 125° C. for 12 hours. TLC (petroleum ether / ethyl acetate = 5 / 1) showed complete consumption of the starting material and the presence of the desired product. The mixture was quenched with 2 N HCl (5 V), and a yellow solid formed. The mixture was stirred for 10 minutes, then additional water (5 V) was added and stirred for 1 hour. The mixture was filtered. The filter cake was dissolved in DCM, filtered over Celite, dried, and then most of the solvent was removed in vacuo. The title compound (110 mg, 0.4 mmol, 40% yield) was obtained as a gray solid.

[0390] 1H NMR (400 MHz, chloroform-d) δ 12.28 (s, 1H), 10.08 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 4.01 (s, 3H). LC-MS (m / z): [M−H] + =274.99.

[0391] Step D: (S)-tert-butyl 5-amino-4-(5-bromo-7-fluoro-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (S)-tert-Butyl 4,5-diamino-5-oxopentanoate (212 mg, 1.05 mmol, 1.05 equiv., HCl) was added to MeOH (5 mL) at 20 °C. Then, DIEA (1.05 mmol, 1.05 equiv.), methyl 4-bromo-6-fluoro-2-formyl-3-hydroxybenzoate (277 mg, 1 mmol, 1 equiv.), and AcOH (1.5 mmol, 1.5 equiv.) were added to the mixture at the same temperature. After 1.5 h, NaBHCN (2 mmol, 2 equiv.) was added portionwise, and the mixture was stirred at 20 °C for 3 h. After the reaction was complete, the reaction mixture was quenched by adding HO at 20 °C and then concentrated under reduced pressure to remove MeOH. The mixture was then extracted with EtOAc. The combined organic layers were washed with brine (200 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to ethyl acetate). The title compound (293 mg, 0.68 mmol, 65% yield) was obtained as a yellow solid.

[0392] Step E: (S)-4-(((2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate benzyl (S)-tert-Butyl 5-amino-4-(5-bromo-7-fluoro-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (202 mg, 0.47 mmol, 1 equiv.), benzyl 4-(chloromethyl)-3,6-dihydropyridine-1(2H)-carboxylate (280 mg, 0.49 mmol, 1.05 equiv.), and K2CO3 (194 mg, 1.41 mmol, 3 equiv.) were added in DMF (5 mL) at 20 °C. The mixture was then stirred at 60 °C for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give a residue, to which water (20 mL) was added. The product was extracted with DCM (20 mL × 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel to give the title compound as a yellow solid (194 mg, 60% yield).

[0393] Step F: (S)-benzyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-fluoro-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (S)-benzyl 4-(((2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-6-fluoro-1-oxoisoindolin-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (330 mg, 0.5 mmol, 1 equiv.), BuSnH (614 mg, 2 mmol), and AIBN (8.2 mg, 0.05 mmol, 0.1 equiv.) were added in toluene (5 mL) at 20° C., and the mixture was then stirred at 110° C. for 12 hours. After the reaction was complete, the mixture was quenched by adding saturated potassium fluoride solution and stirred for 1 hour. The product was extracted with EA. The organic layer was dried over NaSO and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel to give the title compound as a yellow solid (84 mg, 29% yield).

[0394] 1H NMR(400MHz,CDCl3)δ 7.38-7.31(m,5H),6.84(d,J=8.4Hz,1H),6.40(s,1H),5.35(s,1H),5.16(s,2H),4.85(dd,J=8.9,6.1Hz,1H),4.52(s,2H),4.48(d,J= 17.2Hz,1H),4.36(d,J=17.2Hz,1H),4.20(brs,2H),4.12(q,J=7.1Hz,1H),2.94(m,2H),2.37-2.16(m,6H),1.76(m,2H),1.42(s,9H).

[0395] Step G: (S)-tert-butyl 5-amino-4-(5-fluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)-5-oxopentanoate To a 100 mL flask equipped with a magnetic stir bar was added benzyl (S)-7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-fluoro-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (200 mg), MeOH (10 mL), and then 10% Pd / C (20 mg). The flask was then flushed with hydrogen, a balloon containing hydrogen was attached, and the reaction mixture was stirred for 2 h. Upon complete consumption of the starting material by TLC monitoring (DCM:MeOH = 10:1), the reaction mixture was filtered through Celite and washed with additional MeOH. The solvent was removed, and the residue, the title compound (120 mg), as a white solid was used directly in the next step.

[0396] Intermediate B5: (S)-3-(5-chloro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione TIFF2025512805000101.tif19128

[0397] Step A: (S)-tert-butyl 7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate To a mixture of (S)-3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (100 mg, 0.28 mmol, 1.0 equiv.) and TEA (85 mg, 0.84 mmol, 3 equiv.) in dry DCM (10 mL) was slowly added di-tert-butyl dicarbonate (123 mg, 0.56 mmol, 2.0 equiv.). The mixture was stirred at room temperature under a N atmosphere for 5 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (15 mL × 3). The 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 (ethyl acetate in petroleum ether, 0% to 50%) to give tert-butyl (S)-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (120 mg, 94% yield) as a pale yellow solid. LC-MS (ESI): mass calculated for C24H29N3O6: 455; m / z found, 456.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.97(s,1H),7.42(d,J=7.6Hz,1H),7.27(d,J=7.6Hz,1H),5.11-5.06(m,1 H),4.65-4.50(m,2H),4.39(d,J=17.2Hz,1H),4.22(d,J=17.2Hz,1H),3.94 (d,J=11.2Hz,2H),3.07-2.76(m,3H),2.62-2.56(m,1H),2.42-2.33(m,1H) ,2.05-1.91(m,1H),1.88-1.76(m,2H),1.70(d,J=10.6Hz,2H),1.43(s,9H).

[0398] Step B: (S)-tert-butyl 5-chloro-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate To a solution of (S)-tert-butyl 7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (60 mg, 132 μmol, 1.0 equiv.) in dry ACN (5.0 mL), NCS (18 mg, 132 μmol, 1.0 equiv.) was added, and the mixture was stirred at room temperature under a N atmosphere for 6 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (15 mL × 3). The 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 (ethyl acetate in petroleum ether, 0% to 50%) to afford tert-butyl (S)-4-chloro-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (60.0 mg, 93% yield) as a pale yellow solid. LC-MS (ESI): C 24 H 28 Calculated mass of ClN3O6: 489; observed m / z: 490.2 [M+H] + 。 1 H NMR(400MHz,DMSO-d6)δ 11.10(s,1H),7.62(s,1H),5.20-5.15(m,1H),4.80-4.67(m,1H),4.47(d,J=17.4Hz,1H),4.30(d,J=17.4Hz,1H),4.15-4.05(m,2H) ),3.10-2.91(m,3H),2.65-2.611(m,1H),2.53-2.45(m,1H),2.11-2.06(m,1H),2.03-1.94(m,2H),1.86-1.75(m,2H),1.56(s,9H).

[0399] Step C: (S)-3-(5-chloro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione To a solution of tert-butyl (S)-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (50 mg, 110 μmol, 1.0 equiv.) in EA (5.0 mL), HCl-dioxane (4N) (0.25 mL, 1.00 mmol, 10.0 equiv.) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give (S)-3-(4-chloro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione hydrochloride (40.0 mg, 93% yield) as a pale yellow solid. LC-MS(ESI):C 19 H 20 Calculated mass of ClN3O4: 389; observed m / z: 390.2 [M+H] + .

[0400] Intermediate B6: (S)-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-5-carbonitrile TIFF2025512805000102.tif19128

[0401] Step A: (S)-tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-cyano-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate To a solution of tert-butyl (S)-7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (200 mg, 329 μmol, 1.0 equiv.) in DMF (10.0 mL) was added cuprous cyanide (88.3 mg, 986 μmol, 3.0 equiv.) at 25°C. The reaction mixture was stirred at 140°C for 5 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 mL) and extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL x 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 give (S)-tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-cyano-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4′-piperidine]-1′-carboxylate (160 mg, 88% yield) as a yellow solid. LC-MS (ESI): Mass calculated: C 29 H 38 NO7554.27; m / z observed, 555.3 [M+H] + .

[0402] Step B: (S)-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-5-carbonitrile To a solution of (S)-tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-cyano-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4′-piperidine]-1′-carboxylate (160 mg, 288 μmol, 1.0 equiv.) in MeCN (5.0 mL) was added benzenesulfonic anhydride (151.4 mg, 288 μmol, 3.0 equiv.) at 0° C. The reaction mixture was stirred at 80° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give crude (S)-7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-5-carbonitrile (20.0 mg, 18% yield) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS (ESI): Mass calculated: C 20 H 20 NO4 380.15; m / z observed, 381.2 [M+H] + .

[0403] Intermediate B7: (S)-3-(5-methyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione TIFF2025512805000103.tif22128

[0404] Step A: (S)-tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate To a solution of tert-butyl (S)-7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (200 mg, 378 μmol, 1.0 equiv) in MeCN (5.0 mL) was added NBS (67.2 mg, 378 μmol, 1.0 equiv) at 25°C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 3). The organic layer was washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EA=2 / 1) to give (S)-tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4′-piperidine]-1′-carboxylate (180 mg, 78% yield) as a white solid. LC-MS (ESI): Mass calculated: C 28 H 38 BrNO7607.2; m / z observed, 608.2 [M+H] + .

[0405] Step B: (S)-tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-methyl-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate To a solution of tert-butyl (S)-7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-bromo-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (200 mg, 329 μmol, 1.0 equiv.), potassium carbonate (136 mg, 986 μmol, 3.0 equiv.), and Pd(dppf)Cl (48.1 mg, 65.7 μmol, 0.2 equiv.) in 1,4-dioxane (5.0 mL) and water (0.5 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (82.5 mg, 657 μmol, 2.0 equiv.) at 25 °C. The reaction mixture was stirred at 80° C. under N for 2 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The organic layer was washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=1 / 1) to give tert-butyl (S)-7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-methyl-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4′-piperidine]-1′-carboxylate (141 mg, 79% yield) as a yellow solid. LC-MS (ESI): Mass calculated: C 29 H 41 NO7543.3; m / z observed, 544.3 [M+H] + .

[0406] Step C: (S)-3-(5-methyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione To a solution of (S)-tert-butyl 7-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-5-methyl-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4′-piperidine]-1′-carboxylate (141 mg, 259 μmol, 1.0 equiv.) in MeCN (5.0 mL) was added benzenesulfonic acid (123 mg, 778 μmol, 3.0 equiv.) at 25° C. The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give (S)-3-(5-methyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione benzenesulfonic acid (360 mg, 79% yield, 30% purity) as a yellow oil. The crude product was used directly in the next step without further purification. LC-MS (ESI): Mass calculated: C 20 H 23 N3O4 369.2; m / z observed, 370.2 [M+H] + .

[0407] Intermediate B8: 3-(3'-methyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione TIFF2025512805000104.tif24128

[0408] Step A: tert-Butyl 4-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate To a solution of trimethyl(oxo)sulfonium iodide (8.25 g, 37.5 mmol, 4.0 equiv.) in DMSO (10.0 mL) was added NaH (60% suspension in oil) (1.5 g, 37.5 mmol, 4.0 equiv.) at 0 °C, and the mixture was stirred at room temperature under N for 1 h. Then, tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (2.00 g, 9.38 mmol, 1.0 equiv.) was added to the above mixture, and the resulting mixture was stirred at room temperature under N for 16 h. The reaction mixture was quenched with ice water (50 mL) and extracted with EA (100 mL × 3). The organic layer was washed with brine (100 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, 20% to 50%) to give tert-butyl 4-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (400 mg, 19% yield) as a pale yellow solid. LC-MS (ESI): C 12 H 21 Calculated mass of NO3: 227.30; measured m / z: 172.1 [M-55] + . 1 H NMR(400MHz,DMSO-d6)δ 3.48-3.40(m,3H),3.14(s,1H),2.75(d,J=4.6Hz,1H),2.55(dd,J=12.0, 8.6Hz, 1H), 1.73 (s, 1H), 1.52 (s, 2H), 1.41 (s, 9H), 0.75 (d, J=6.8Hz, 3H).

[0409] Step B: tert-butyl 4-(hydroxymethyl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate To a solution of tert-butyl 4-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1.00 g, 4.40 mmol, 1.0 equiv) in toluene (10.0 mL) was added aluminum isopropoxide (2.70 g, 2.60 mL, 13.2 mmol, 3.0 equiv). The mixture was stirred at 110 °C for 16 h under N. After cooling to room temperature, the reaction mixture was adjusted to pH 4-5 with aqueous HCl (3 N) and extracted with EA (50 mL × 3). The 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 (ethyl acetate in petroleum ether, 20%-50%) to give tert-butyl 4-(hydroxymethyl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate (850 mg, 85% yield) as a pale yellow oil. LC-MS: No MS signal under routine conditions. LC-MS (ESI): C 12 H 21 Calculated mass for NO3, 227.30; observed m / z, no MS signal.

[0410] Step C: tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate To a solution of 5-bromo-4-hydroxyisobenzofuran-1(3H)-one (420 mg, 1.83 mmol, 1.0 equiv) in THF (20.0 mL) was added triphenylphosphine (721 mg, 2.75 mmol, 1.5 equiv) and tert-butyl 4-(hydroxymethyl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate (417 mg, 1.83 mmol, 1.0 equiv). The mixture was stirred under N at 0°C for 20 min, and then DIAD (556 mg, 535 μL, 2.75 mmol, 1.5 equiv) was added dropwise to the above mixture. The resulting mixture was stirred at room temperature overnight. After evaporation, the crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 20%) to give tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate (180 mg, 22% yield) as a yellow oil. LC-MS (ESI): C 20 H 24 Calculated mass of BrNO5: 438.32; observed m / z: 342.0 [M-55] + .

[0411] Step D: tert-butyl 3'-methyl-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate (180 mg, 411 μmol, 1.0 equiv) and AIBN (13.5 mg, 82.1 μmol, 0.2 equiv) in toluene (20.0 mL) was added tributyltin hydride (478 mg, 444 μL, 1.64 mmol, 4.0 equiv). The reaction was stirred at 110° C. for 16 h under N. After cooling to room temperature, the mixture was quenched with saturated aqueous KF solution (30 mL) and stirred for 1 h. The reaction mixture was extracted with EA (30 mL × 3). The organic phases were combined, washed with brine (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The mixture was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 30%) to give tert-butyl 3'-methyl-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (120 mg, 81% yield) as a white solid. LC-MS (ESI): C 20 H 25 Calculated mass of NO5: 359.42; measured m / z: 304.0 [M-55] + . 1 H NMR(400MHz,DMSO-d6)δ 7.47(d,J=7.6Hz,1H),7.40(d,J=7.6Hz,1H),5.36(d,J=2.4Hz,2H),4.79(d,J=9.8Hz,1H),4.48(d,J=9.8Hz,1H),3. 99-3.77(m,2H),3.04-2.66(m,2H),2.01(d,J=10.8Hz,3H),1.97-1.87(m,2H),1.77(d,J=13.2Hz,1H),1.43(s,9H).

[0412] Step E: tert-butyl 3'-methyl-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 3'-methyl-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (110 mg, 306 μmol, 1.0 equiv.) in THF (9.00 mL), MeOH (9.00 mL), and HO (3.00 mL) was added NaOH (24 mg, 612 μmol, 2.0 equiv.). The reaction mixture was stirred at 40 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EA (20 mL), adjusted to pH 4–5 with aqueous HCl (3 N), and extracted with EA (40 mL × 4). The organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 3'-methyl-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (110 mg, 90% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 20 H 27 Calculated mass of NO6: 377.44; measured m / z: 376.4 [MH] - .

[0413] Step F: 1'-(tert-butoxycarbonyl)-7-formyl-3'-methyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid A mixture of 1'-(tert-butoxycarbonyl)-7-(hydroxymethyl)-3'-methyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (110 mg, 291 μmol, 1.0 equiv.) and activated manganese dioxide (507 mg, 5.83 mmol, 20.0 equiv.) in DCM (20.0 mL) was stirred at room temperature for 16 h. After filtration through a short column, the filtrate was collected and concentrated under reduced pressure to give 1'-(tert-butoxycarbonyl)-7-formyl-3'-methyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (100 mg, 91% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 20 H 25Calculated mass of NO6: 375.42; observed m / z: 376.1 [M+H] + .

[0414] Step G: tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3'-methyl-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate To a solution of 1'-(tert-butoxycarbonyl)-7-formyl-3'-methyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (110 mg, 293 μmol, 1.0 equiv) and 3-aminopiperidine-2,6-dione hydrochloride (96.5 mg, 586 μmol, 2.0 equiv) in DMF (10.0 mL) was added acetic acid (0.52 g, 0.50 mL, 8.7 mmol, 30.0 equiv), and the reaction mixture was stirred at 40° C. for 2 h. Sodium triacetoxyborohydride (186 mg, 879 μmol, 3.0 equiv) was then added to the above mixture, and the mixture was stirred at 40° C. for 16 h. After cooling to room temperature, the mixture was dissolved in EA (40 mL), washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3′-methyl-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4′-piperidine]-1′-carboxylate (80.0 mg, 58% yield) as a gray solid. LC-MS (ESI): C 25 H 31 Calculated mass of N3O6: 469.54; observed m / z: 470.2 [M+H] + .

[0415] Step H: 3-(3'-methyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione To a solution of tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3'-methyl-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (70.0 mg, 149 μmol, 1.0 equiv.) in DCM (3 mL) was added HCl-dioxane (4N) (8.0 mL, 32 mmol, 10.4 equiv.) dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give 3-(3'-methyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione hydrochloride (30.0 mg, 54% yield) as a gray solid. The crude product was used directly in the next step without further purification. LC-MS (ESI): C 20 H 23 Calculated mass of N3O4: 369.42; observed m / z: 370.1 [M+H] + .

[0416] Intermediate B9: 3-(3'-hydroxy-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione TIFF2025512805000105.tif22128

[0417] Step A: 1'-(tert-butoxycarbonyl)-3'-hydroxy-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid To a mixture of tert-butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (400 mg, 1.11 mmol, 1.0 equiv) in THF (9.00 mL), MeOH (9.00 mL), and HO (3.00 mL), NaOH (89 mg, 2.21 mmol, 2.0 equiv) was added, and the reaction mixture was stirred at 40 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EA (20 mL), adjusted to pH 4–5 with aqueous HCl (3 N), and extracted with EA (40 mL × 4). The organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1'-(tert-butoxycarbonyl)-3'-hydroxy-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (400 mg, 95% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H 25 Calculated mass of NO7: 379.41; measured m / z: 378.3 [MH] - .

[0418] Step B: 1'-(tert-butoxycarbonyl)-7-formyl-3'-hydroxy-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid A mixture of 1'-(tert-butoxycarbonyl)-3'-hydroxy-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (420 mg, 1.11 mmol, 1.0 equiv.) and activated manganese dioxide (1.92 g, 22.1 mmol, 20.0 equiv.) in DCM (40.0 mL) was stirred at room temperature for 16 hours. After filtration through a short column, the filtrate was collected and concentrated under reduced pressure to give 1'-(tert-butoxycarbonyl)-7-formyl-3'-hydroxy-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (260 mg, 62% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H 21Calculated mass of F2NO6: 377.39; observed m / z: 378.1 [M+H] + .

[0419] Step C: tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3'-hydroxy-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate To a solution of 1'-(tert-butoxycarbonyl)-7-formyl-3'-hydroxy-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (260 mg, 689 μmol, 1.0 equiv) and 3-aminopiperidine-2,6-dione hydrochloride (227 mg, 1.38 mmol, 2.0 equiv) in DMF (10.0 mL) was added acetic acid (1.0 mL), and the reaction mixture was stirred at 40° C. for 2 hours. Sodium triacetoxyborohydride (438 mg, 2.07 mmol, 3.0 equiv) was added to the above mixture, and the resulting mixture was stirred at 40° C. for 16 hours. After cooling to room temperature, the mixture was dissolved in EA (40 mL), washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH in DCM, 10%) to give tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3'-hydroxy-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (260 mg, 80% yield) as a gray solid. LC-MS (ESI): C 24 H 29 Calculated mass of N3O7: 471.51; observed m / z: 472.2 [M+H] + .

[0420] Step D: 3-(3'-hydroxy-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione To a solution of tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3'-hydroxy-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (260 mg, 551 μmol, 1.0 equiv.) in DCM (5.0 mL), TFA (1.7 mL, 22.1 mmol, 40.0 equiv.) was added, and the reaction mixture was stirred at room temperature for 6 hours. The mixture was carefully concentrated under reduced pressure to give 3-(3'-hydroxy-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione trifluoroacetate (100 mg, 48% yield) as a yellow oil. The crude product was used directly in the next step without further purification. LC-MS (ESI): C 19 H 21 Calculated mass of N3O5: 371.39; observed m / z: 372.2 [M+H] + .

[0421] Intermediate B10. 3-(3',3'-difluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione TIFF2025512805000106.tif19128

[0422] Step A: tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of 5-bromo-4-hydroxyisobenzofuran-1(3H)-one (5.0 g, 21.80 mmol, 1.0 equiv) in THF (150 mL) was added tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (5.59 g, 26.2 mmol, 1.2 equiv) and triphenylphosphine (8.59 g, 32.7 mmol, 7.31 mL, 1.5 equiv). The mixture was stirred at 0° C. under N for 20 minutes. DIAD (6.62 g, 32.7 mmol, 6.37 mL, 1.5 equiv) was then added dropwise to the above mixture, and the mixture was stirred at room temperature overnight. After evaporation, the crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 20%) to give tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (9.0 g, 97% yield) as a yellow solid. LC-MS (ESI): C 19 H 22 Calculated mass for BrNO5: 424.29; observed m / z: 369.9 [M+H-56] + . 1 H NMR(400MHz,DMSO-d6)δ 7.83(d,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),5.89(s,1H),5.66(s,2H),4.66 (s,2H),3.88(s,2H),3.48(dd,J=14.6,9.0Hz,2H),2.22(s,2H),1.41(s,9H).

[0423] Step B: tert-butyl 6-oxo-2',3',6,8-tetrahydro-1'H,2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-pyridine]-1'-carboxylate To a solution of tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (5.00 g, 7.90 mmol, 1.0 equiv) in DMF (30.0 mL) was added sodium formate (591 mg, 8.69 mmol, 1.1 equiv), palladium diacetate (177 mg, 790 μmol, 0.1 equiv), sodium acetate (1.62 g, 19.7 mmol, 2.5 equiv), and TEA (1.44 g, 8.69 mmol, 1.33 mL, 1.1 equiv). The mixture was stirred at 70 °C under N for 16 h. After cooling to room temperature, the mixture was filtered and the cake was washed with EA (100 mL). The filtrate was washed with brine (60 mL × 3), 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 30%) to give tert-butyl 6-oxo-2',3',6,8-tetrahydro-1'H,2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-pyridine]-1'-carboxylate (1.70 g, 62.7% yield) as a colorless oil. LC-MS (ESI): C 19 H 21 Calculated mass of NO5: 343.38; observed m / z: 344.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.41(d,J=7.6Hz,1H),7.34(d,J=7.6Hz,1H),7.03-6.98(m,1H),5.38(s,2H),4.88-4.82(m,1H),4.60(d,J=9.2Hz,1 H),4.39(d,J=9.2Hz,1H),3.81-3.75(m,1H),3.47-3.41(m,1H),2.02-1.98(m,1H),1.84-1.78(m,1H),1.47(s,9H).

[0424] Step C: tert-butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 6-oxo-2',3',6,8-tetrahydro-1'H,2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-pyridine]-1'-carboxylate (4.70 g, 13.7 mmol, 1.0 equiv.) in THF (60.0 mL) was added BH3-THF (1N) (34.2 mL, 34.2 mmol, 2.5 equiv.) under N2 at -78 °C. The reaction was allowed to slowly warm to 0 °C and stirred at 0 °C for 5 h. Water (5 mL) was added to the above mixture, followed by sodium perborate (5.60 g, 68.4 mmol, 5.0 equiv.). The resulting mixture was stirred overnight. The mixture was diluted with DCM (100 mL), washed with brine (50 mL × 2), 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 40%) to give tert-butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (2.70 g, 54% yield) as a white powder. LC-MS (ESI): C 19 H 23 Calculated mass of NO6: 361.39; observed m / z: 306.1 [M+H-56] + . 1 H NMR(400MHz,DMSO-d6)δ 7.51(d,J=7.6Hz,1H),7.37(d,J=7.6Hz,1H),5.35(d,J=2.6Hz,2H),5.31(d,J=4.6Hz,1H),4.83(d,J=9.0Hz,1H),4. 53(d,J=9.0Hz,1H),4.01(s,1H),3.87(s,1H),3.76-3.73(m,1H),2.83-2.56(m,2H),1.88-1.74(m,2H),1.43(s,9H).

[0425] Step D: tert-butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (1.80 g, 4.98 mmol, 1.0 equiv.) in DCM (30.0 mL) was added Dess-Martin periodinane (5.28 g, 12.5 mmol, 2.5 equiv.). The mixture was stirred at room temperature for 4 h. The reaction was diluted with DCM (60 mL) and washed with aqueous sodium thiosulfate (30 mL × 2) and brine (40 mL × 2). The organic layer was 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 40%) to give tert-butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (1.3 g, 72.6% yield) as a colorless oil. LC-MS (ESI): C 19 H 21 Calculated mass of NO6: 359.38; observed m / z: 360.1 [M+H] + .

[0426] Step E: tert-butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (1.20 g, 3.34 mmol, 1.0 equiv), triethylammonium fluoride (3.23 g, 3.27 mL, 20.0 mmol, 6.0 equiv), and N,N-diethyl-S,S-difluoro-sulfiriminium tetrafluoroborate (3.44 g, 15.0 mmol, 4.5 equiv) in DCM (50.0 mL) was added TEA (845 mg, 1.16 mL, 8.35 mmol, 2.5 equiv) at 25 °C, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with DCM (30 mL x 3). The separated organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate in petroleum ether, 0% to 30%) to give tert-butyl 3',3'-difluoro-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (260 mg, 20% yield) as a yellow oil. LC-MS (ESI): C 19 H 21 Calculated mass of F2NO5: 381.38; observed m / z: 382.1 [M+H] + .

[0427] Step F: 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid To a solution of tert-butyl 3',3'-difluoro-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (280 mg, 734 μmol, 1.0 equiv.) in THF (9.00 mL), MeOH (9.00 mL), and HO (3.00 mL) was added NaOH (44 mg, 1.10 mmol, 1.5 equiv.). The mixture was stirred at 40 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EA (20 mL), adjusted to pH 4–5 with aqueous HCl (3 N), and extracted with EA (40 mL × 4). The organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (290 mg, 99% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H 23 Calculated mass of F2NO6: 399.39; measured m / z: 398.3 [MH] - .

[0428] Step G: 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-formyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid A solution of 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (260 mg, 651 μmol, 1.0 equiv.) and activated manganese dioxide (1.13 g, 13.0 mmol, 20.0 equiv.) in DCM (20.0 mL) was stirred at room temperature for 16 hours. After filtration through a short column, the filtrate was collected and concentrated under reduced pressure to give 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-formyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (250 mg, 96.6% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H21 Calculated mass of F2NO6: 397.37; observed m / z: 398.1 [M+H] + .

[0429] Step H: tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3',3'-difluoro-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate To a solution of 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-formyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (260 mg, 654 μmol, 1.0 equiv) and 3-aminopiperidine-2,6-dione hydrochloride (215 mg, 1.31 mmol, 2.0 equiv) in DMF (10.0 mL) was added acetic acid (0.52 g, 0.50 mL, 8.7 mmol, 13.0 equiv) and the reaction was stirred for 2 hours at 40° C. Sodium triacetoxyborohydride (416 mg, 1.96 mmol, 3.0 equiv) was added to the above mixture and the resulting mixture was stirred at 40° C. for 16 hours. After cooling to room temperature, the mixture was dissolved in EA (60 mL), 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 (ethyl acetate in petroleum ether, 0% to 90%) to afford tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3',3'-difluoro-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (220 mg, 68.4% yield) as a gray solid. LC-MS (ESI): C 24 H 27 Calculated mass of F2N3O6: 491.49; observed m / z: 492.2 [M+H] + .

[0430] Step I: Obtaining 3-(3',3'-difluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione To a solution of tert-butyl 7-(2,6-dioxopiperidin-3-yl)-3',3'-difluoro-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (200 mg, 407 μmol, 1.0 equiv) in DCM (5.00 mL) was added trifluoroacetic acid (2.99 g, 2.00 mL, 26.3 mmol, 64.5 equiv) and the reaction was stirred at 25°C for 1 hour. The mixture was concentrated and dried to give 3-(3',3'-difluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione trifluoroacetate (150 mg, 94% yield) as a gray solid. LC-MS (ESI): C 19 H 19 Calculated mass of F2N3O4: 391.37; observed m / z: 392.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.99(d,J=4.4Hz,1H),9.67(s,1H),7.48-7.37(m,2H),5.16-4.96(m,2H),4 .74-4.63(m,1H),4.44(t,J=17.0Hz,1H),4.27(t,J=16.6Hz,1H),3.93-3.71( m,2H),3.03(t,J=12.0Hz,1H),2.97-2.83(m,1H),2.60(d,J=17.2Hz,1H),2. 46-2.40(m,2H),2.26-2.23(m,1H),2.08(d,J=5.0Hz,1H),2.00-1.98(m,1H).

[0431] Intermediate B11: (3S)-3-(3',3'-difluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione TIFF2025512805000107.tif21128

[0432] Step A: tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of 5-bromo-4-hydroxyisobenzofuran-1(3H)-one (10.0 g, 43.60 mmol, 1.0 equiv) in THF (300 mL) was added tert-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (11.18 g, 52.4 mmol, 1.2 equiv) and triphenylphosphine (17.18 g, 65.4 mmol, 14.62 mL, 1.5 equiv). The mixture was stirred at 0° C. under N for 20 min. DIAD (13.24 g, 65.4 mmol, 12.74 mL, 1.5 equiv) was then added dropwise to the above mixture, and the mixture was stirred at room temperature overnight. After evaporation, the crude product was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 20%) to give tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (18.0 g, 97% yield) as a yellow solid. LC-MS (ESI): C 19 H 22 Calculated mass for BrNO5: 424.29; observed m / z: 369.9 [M+H-56] + . 1 H NMR(400MHz,DMSO-d6)δ 7.83(d,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),5.89(s,1H),5.66(s,2H),4.66 (s,2H),3.88(s,2H),3.48(dd,J=14.6,9.0Hz,2H),2.22(s,2H),1.41(s,9H).

[0433] Step B: tert-butyl 6-oxo-2',3',6,8-tetrahydro-1'H,2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-pyridine]-1'-carboxylate To a solution of tert-butyl 4-(((5-bromo-1-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (15.00 g, 23.70 mmol, 1.0 equiv) in DMF (90.0 mL) was added sodium formate (1.77 g, 26.07 mmol, 1.1 equiv), palladium diacetate (531 mg, 2.37 mmol, 0.1 equiv), sodium acetate (4.86 g, 59.1 mmol, 2.5 equiv), and TEA (4.32 g, 26.07 mmol, 3.99 mL, 1.1 equiv). The mixture was stirred at 70 °C under N for 16 h. After cooling to room temperature, the mixture was filtered and the cake was washed with EA (300 mL). The filtrate was washed with brine (60 mL × 3), 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 30%) to give tert-butyl 6-oxo-2',3',6,8-tetrahydro-1'H,2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-pyridine]-1'-carboxylate (5.10 g, 62.7% yield) as a colorless oil. LC-MS (ESI): C 19 H 21 Calculated mass of NO5: 343.38; observed m / z: 344.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.41(d,J=7.6Hz,1H),7.34(d,J=7.6Hz,1H),7.03-6.98(m,1H),5.38(s,2H),4.88-4.82(m,1H),4.60(d,J=9.2Hz,1 H),4.39(d,J=9.2Hz,1H),3.81-3.75(m,1H),3.47-3.41(m,1H),2.02-1.98(m,1H),1.84-1.78(m,1H),1.47(s,9H).

[0434] Step C: tert-butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 6-oxo-2',3',6,8-tetrahydro-1'H,2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-pyridine]-1'-carboxylate (5.10 g, 14.87 mmol, 1.0 equiv.) in THF (60.0 mL) was added BH3-THF (1N) (37.1 mL, 37.1 mmol, 2.5 equiv.) under N2 at -78 °C. The reaction was allowed to warm slowly to 0 °C and stirred at 0 °C for 5 h. Water (10 mL) was added to the above mixture, followed by sodium perborate (6.07 g, 74.2 mmol, 5.0 equiv.). The resulting mixture was stirred overnight. The mixture was diluted with DCM (100 mL), washed with brine (50 mL × 2), 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 40%) to afford tert-butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (2.93 g, 54% yield) as a white powder. LC-MS (ESI): C 19 H 23 Calculated mass of NO6: 361.39; observed m / z: 306.1 [M+H-56] + . 1 H NMR(400MHz,DMSO-d6)δ 7.51(d,J=7.6Hz,1H),7.37(d,J=7.6Hz,1H),5.35(d,J=2.6Hz,2H),5.31(d,J=4.6Hz,1H),4.83(d,J=9.0Hz,1H),4. 53(d,J=9.0Hz,1H),4.01(s,1H),3.87(s,1H),3.76-3.73(m,1H),2.83-2.56(m,2H),1.88-1.74(m,2H),1.43(s,9H).

[0435] Step D: tert-butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 3'-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (2.90 g, 8.10 mmol, 1.0 equiv.) in DCM (60.0 mL) was added Dess-Martin periodinane (8.60 g, 20.35 mmol, 2.5 equiv.). The mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with aqueous sodium thiosulfate (60 mL) and extracted with DCM (90 mL × 3). The organic layer was washed with saturated aqueous NaHCO3 (60 mL × 2), brine (40 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (2.12 g, 72.6% yield) as a colorless oil. The crude product was used directly in the next step without further purification. LC-MS (ESI): C 19 H 21 Calculated mass of NO6: 359.38; observed m / z: 360.1 [M+H] + .

[0436] Step E: tert-butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 3',6-dioxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (2.0 g, 5.57 mmol, 1.0 equiv), triethylammonium fluoride (5.38 g, 5.44 mL, 33.4 mmol, 6.0 equiv), and N,N-diethyl-S,S-difluoro-sulfiriminium tetrafluoroborate (XtalFluor-E) (5.73 g, 25.0 mmol, 4.5 equiv) in DCM (100.0 mL) was added TEA (1.41 g, 1.94 mL, 13.9 mmol, 2.5 equiv) at 0 °C, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (60 mL) and extracted with DCM (100 mL x 3). The separated organic phase was washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate in petroleum ether, 0% to 30%) to give tert-butyl 3',3'-difluoro-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (1.0 g, 47% yield) as a yellow oil. LC-MS (ESI): C 19 H 21 Calculated mass of F2NO5: 381.38; observed m / z: 382.1 [M+H] + .

[0437] Step F: 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid To a solution of tert-butyl 3',3'-difluoro-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (280 mg, 734 μmol, 1.0 equiv.) in THF (9.00 mL), MeOH (9.00 mL), and HO (3.00 mL) was added NaOH (44 mg, 1.10 mmol, 1.5 equiv.). The mixture was stirred at 40 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EA (20 mL), adjusted to pH 4–5 with aqueous HCl (3 N), and extracted with EA (40 mL × 4). The organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (290 mg, 99% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H 23 Calculated mass of F2NO6: 399.39; measured m / z: 398.3 [MH] - .

[0438] Step G: tert-butyl 2,2-difluoro-8-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate A solution of 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (1.6 g, 4.01 mmol, 1.0 equiv.) and activated manganese dioxide (6.97 g, 80.1 mmol, 20.0 equiv.) in DCM (30.0 mL) was stirred at room temperature for 16 hours. After filtration through a short column, the filtrate was collected and concentrated under reduced pressure to give tert-butyl 2,2-difluoro-8-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (1.5 g, 96.6% yield) as a colorless oil. The crude product was used directly in the next step without purification. LC-MS (ESI): C 19 H 21 Calculated mass of F2NO6: 397.37; observed m / z: 398.1 [M+H] + .

[0439] Step H: tert-butyl 7-((S)-1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-3',3'-difluoro-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate To a solution of tert-butyl 3',3'-difluoro-8-hydroxy-6-oxo-6,8-dihydro-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidine]-1'-carboxylate (1.60 g, 4.03 mmol, 1.0 equiv.) and tert-butyl (S)-4,5-diamino-5-oxopentanoate hydrochloride (1.92 g, 8.05 mmol, 2.0 equiv.) in DMF (30.0 mL), acetic acid (2.42 g, 2.32 mL, 40.3 mmol, 10.0 equiv.) was added, and the reaction mixture was stirred for 2 hours at 40° C. Sodium triacetoxyborohydride (2.56 g, 1.79 mL, 12.1 mmol, 3.0 equiv.) was added to the above mixture, and the resulting mixture was stirred at 40° C. for 16 hours. After cooling to room temperature, the mixture was diluted with EA (100 mL), washed with brine (100 mL × 3), 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 90%) to afford tert-butyl 7-((S)-1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-3',3'-difluoro-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (1.80 g, 79% yield) as a white solid. LC-MS (ESI): C 28 H 37 Calculated mass of F2N3O7: 565.61; observed m / z: 566.4 [M+H] + .

[0440] Step I: (3S)-3-(3',3'-difluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione benzenesulfonate To a solution of tert-butyl 7-((S)-1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-3',3'-difluoro-6-oxo-7,8-dihydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-carboxylate (1.80 g, 3.18 mmol, 1.0 equiv) in MeCN (30.0 mL) was added benzenesulfonic anhydride (1.51 g, 9.55 mmol, 3.0 equiv) and the reaction mixture was stirred at 90°C under N for 7 h. After cooling to room temperature, the mixture was concentrated and the residue was slurried with acetonitrile (30 mL) to give (3S)-3-(3',3'-difluoro-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione benzenesulfonate (1.20 g, 68% yield) as a white solid. LC-MS (ESI): C 19 H 19 Calculated mass of F2N3O4: 391.37; observed m / z: 392.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.99(d,J=4.6Hz,1H),9.48(s,2H),7.64-7.59(m,2H),7.46(d,J=7.6Hz,1H),7.39(d ,J=7.7Hz,1H),7.35-7.29(m,3H),5.17-4.99(m,2H),4.74-4.66(m,1H),4.43(t,J=17 .2Hz,1H),4.27(t,J=17.2Hz,1H),3.98-3.72(m,2H),3.40(d,J=13.0Hz,1H),3.06-2. 88(m,2H),2.60-2.58(m,1H),2.46-2.38(m,2H),2.27-2.22(m,1H),2.01-1.98(m,1H).

[0441] Intermediate B12: 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde TIFF2025512805000108.tif16128

[0442] Step A: (Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate ethyl ester A mixture of ethyl 4,4,4-trifluoro-3-oxobutanoate (1.00 g, 5.43 mmol, 1.0 equiv.) and acetic anhydride (1.66 g, 1.54 mL, 16.3 mmol, 3.0 equiv.) in triethyl orthoformate (8.00 mL) was stirred at 130° C. for 4 h. The reaction mixture was concentrated under reduced pressure to give (Z)-ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (1.20 g, 92% yield) as a yellow oil. The crude product was used directly in the next step without further purification. LC-MS: No ion signals were observed under routine conditions. LC-MS (ESI): CH 11 Calculated mass of F3O4, 240.06; observed m / z, 241.1 [M+H] + .

[0443] Step B: ethyl 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate To a solution of (Z)-ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (1.20 g, 5.00 mmol, 1.0 equiv.) in EtOH (30.0 mL), triethylamine (607 mg, 836 μL, 6.00 mmol, 1.2 equiv.) and (4-chlorophenyl)hydrazine hydrochloride (1.07 g, 6.00 mmol, 1.2 equiv.) were added at room temperature. The mixture was heated to 100° C. for 5 h. After evaporation, the residue was diluted with ethyl acetate (50 mL), washed with brine (30 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (PE / EA=50 / 1) to give ethyl 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (723 mg, 45% yield) as a yellow solid. LC-MS (ESI): C 11 Calculated mass of H8D2F2N2O: 318.04; observed m / z: 319.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.32(s,1H),7.69-7.66(m,2H),7.63-7.60(m,2H),4.32(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H).

[0444] Step C: (1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)methanol To a solution of ethyl 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (350 mg, 1.10 mmol, 1.0 equiv.) in THF (10.0 mL) was added lithium aluminum hydride (83.4 mg, 2.20 mmol, 20 equiv.) at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes. The reaction mixture was diluted with NaSO . The mixture was carefully quenched with 10H2O and stirred for 30 minutes. After filtration, the filtrate was diluted with water (10 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, and filtered. The filtrate was concentrated under reduced pressure to give (1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (300 mg, 98% yield) as a yellow oil. The crude product was used directly in the next step without further purification. LC-MS (ESI): C 11 Calculated mass for H8ClF3N2O: 276.03; observed m / z: 277.1 [M+H] + .

[0445] Step D: 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde To a solution of (1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (300 mg, 1.08 mmol, 1.0 equiv) in DMSO (10.0 mL) was added IBX (759 mg, 2.71 mmol, 2.5 equiv) at room temperature. The reaction mixture was stirred at 25 °C for 30 minutes. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with saturated aqueous NaSO (30 mL), saturated aqueous NaHCO (30 mL), and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (PE / EA=20 / 1) to give 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (227 mg, 76% yield) as a yellow solid. LC-MS (ESI): C 11 Calculated mass for H6ClF3N2O: 274.01; observed m / z: 275.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 10.07 (s, 1H), 8.44 (s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H).

[0446] Intermediate B13: 3-(4-chlorophenyl)isoxazole-5-carbaldehyde TIFF2025512805000109.tif19128

[0447] Step A: (Z)-4-Chlorobenzaldehyde oxime 4-Chlorobenzaldehyde (6.00 g, 42.7 mmol, 1.0 equiv.), hydroxylammonium chloride (2.97 g, 42.7 mmol, 1.0 equiv.), and CsCO (2.26 g, 21.3 mmol, 0.5 equiv.) in MeOH (36.0 mL) and HO (18.00 mL) were stirred at 30 °C for 3 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (100 mL × 3). The organic layer was 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, 0–20%) to give (Z)-4-chlorobenzaldehyde oxime (5 g, 75% yield) as a white solid. LC-MS (ESI): mass calculated: C7H6ClNO 155.01; m / z found, 156.0 [M+H] +

[0448] Step B: (E)-4-Chloro-N-hydroxybenzimidoyl chloride To a solution of (Z)-4-chlorobenzaldehyde oxime (1.00 g, 6.43 mmol, 1 equiv.) in DMF (20 mL) was added NCS (171.6 mg, 1.286 mmol, 0.2 equiv.). NCS (686.4 mg, 5.144 mmol, 0.8 equiv.) was then added portionwise, and the resulting mixture was stirred at 30 °C for 24 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (50 mL × 3). The organic layer was washed with brine (50 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, 0–20%) to give (E)-4-chloro-N-hydroxybenzimidoyl chloride (0.8 g, 66% yield) as a white solid. LC-MS(ESI): Mass calculation value: C7H5Cl2NO 188.97; m / z actual value, 190.0[M+H] + .

[0449] Step C: (3-(4-chlorophenyl)isoxazol-5-yl)methanol To a solution of (E)-4-chloro-N-hydroxybenzimidoyl chloride (0.6 g, 3.2 mmol, 1.0 equiv.) and propargyl alcohol (0.19 g, 3.5 mmol, 1.1 equiv.) in t-BuOH (5.0 mL) and HO (5.0 mL), sodium ascorbate (63.0 mg, 0.32 mmol, 0.1 equiv.) and copper(II) sulfate pentahydrate (24 mg, 95.0 μmol, 0.03 e) were added. The reaction mixture was stirred for 30 min. KHCO (961 mg, 9.6 mmol, 3.0 equiv.) was then added to the above mixture, and the resulting mixture was stirred at 30 °C for 1.5 h. The reaction mixture was quenched with water (30 mL) 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 residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0-35%) to give (3-(4-chlorophenyl)isoxazol-5-yl)methanol (0.38 g, 57% yield) as a white solid. LC-MS (ESI): Mass calculated: C 10 H8ClNO2 209.02; m / z observed, 210.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.88(d,J=8.6Hz,1H),7.58(d,J=8.6Hz,1H),6.96(s,1H),5.73(t,J=6.0Hz,1H),4.61(d,J=6.0Hz,2H).

[0450] Step D: 3-(4-chlorophenyl)isoxazole-5-carbaldehyde To a solution of (3-(4-chlorophenyl)isoxazol-5-yl)methanol (120 mg, 572 μmol, 1.0 equiv.) in DCM (5.0 mL) was added Dess-Martin periodinane (267 mg, 630 μmol, 1.1 equiv.). The mixture was stirred at room temperature for 2 h. The reaction was diluted with EA (60 mL), washed with saturated aqueous NaSO (30 mL), saturated aqueous NaHCO (30 mL), and brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EA / PE = 1 / 10) to give 3-(4-chlorophenyl)isoxazole-5-carbaldehyde (100 mg, 84% yield) as a yellow solid. LC-MS (ESI): Mass calculated: C 10 H6ClNO2207.01; m / z measured, no MS signal observed.

[0451] Intermediate B14: 3-(4-chlorophenyl)isothiazole-5-carbaldehyde TIFF2025512805000110.tif17128

[0452] Step A: 3-(4-chlorophenyl)isothiazole A mixture of 3-bromoisothiazole (100 mg, 610 μmol, 1.0 equiv.), (4-chlorophenyl)boronic acid (143 mg, 915 μmol, 1.5 equiv.), tetrakis(triphenylphosphine)palladium(o) (70.5 mg, 61.0 μmol, 0.1 equiv.), and potassium carbonate (169 mg, 1.2 mmol, 2.0 equiv.) in 1,4-dioxane (6.0 mL) and HO (1.0 mL) was stirred at 80 °C for 4 h under N. After cooling to room temperature, the mixture was diluted with DCM (50 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (EA / PE = 1 / 10) to give 3-(4-chlorophenyl)isothiazole (82.0 mg, 68% yield) as a yellow oil. LC-MS (ESI): calculated mass for CHClNS, 195.0; observed m / z, 196.1 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ 9.18(d,J=0.6Hz,1H),8.07(d,J=8.4Hz,2H),7.98(d,J=0.6Hz,1H),7.56(d,J=8.4Hz,2H).

[0453] Step B: 3-(4-chlorophenyl)isothiazole-5-carbaldehyde To a mixture of 3-(4-chlorophenyl)isothiazole (50.0 mg, 256 μmol, 1.0 equiv.) in anhydrous THF (5.0 mL) was added n-butyllithium (2.5 M in n-hexane) (0.16 mL, 384 μmol, 1.5 equiv.) at −78° C. under N2, and the mixture was stirred at this temperature for 30 min. Anhydrous DMF (93.4 mg, 1.3 mmol, 5.0 equiv.) was then added to the above mixture, and the resulting mixture was stirred at −78° C. under N2 for 30 min. The mixture was quenched by the addition of saturated aqueous NH4Cl (20 mL), stirred for 15 min, and extracted with EA (20 mL × 4). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EA / PE=1 / 10) to give 3-(4-chlorophenyl)isothiazole-5-carbaldehyde (28.0 mg, 49% yield) as a yellow solid. LC-MS (ESI): C 10 Calculated mass of H6ClNOS: 223.0; observed m / z: 224.1 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),8.72(s,1H),8.11(d,J=8.8Hz,2H),7.62(d,J=8.8Hz,2H).

[0454] Intermediate B15: 3-chloro-1-(4-chlorophenyl)-1H-pyrazole-4-carbaldehyde TIFF2025512805000111.tif31128POCl3 (5.51 g, 3.35 mL, 36.0 mmol, 7.0 equiv) was added dropwise to DMF (10.0 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 5 minutes. 1-(4-Chlorophenyl)-1,2-dihydro-3H-pyrazol-3-one (1.00 g, 5.14 mmol, 1.0 equiv) was added to the above mixture, and the resulting reaction mixture was heated to 105 °C and stirred for 16 hours. After cooling to room temperature, the mixture was poured onto crushed ice, causing a brown solid to precipitate. The solid was collected by filtration and washed with water (30 mL). The solid cake was dissolved in DCM (150 mL), washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM / MeOH=10 / 1) to give 3-chloro-1-(4-chlorophenyl)-1H-pyrazole-4-carbaldehyde (40.0 mg, 3% yield) as a yellow solid. LC-MS (ESI): Mass calculated: C 10 H8N2O 172.19; no m / z mass signal. 1 H NMR (400MHz, DMSO-d6) δ 9.87 (s, 1H), 9.33 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H).

[0455] Intermediate B16: 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde A mixture of 3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (50.0 mg, 305 μmol, 1.0 equiv.), copper diacetate (111 mg, 609 μmol, 2.0 equiv.), (4-chlorophenyl)boronic acid (71.5 mg, 457 μmol, 1.5 equiv.), 2,2′-bipyridine (95.2 mg, 609 μmol, 2.0 equiv.), and sodium carbonate (161 mg, 1.5 mmol, 5.0 equiv.) in DCE (6.0 mL) was stirred at 70 °C for 5 h under O. After cooling to room temperature, the mixture was filtered, and the filtrate was quenched with water (20 mL) and extracted with DCM (20 mL × 3). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (EA / PE=3 / 1) to give 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (34.0 mg, 41% yield) as a white solid. LC-MS (ESI): C 11 Calculated mass for H6ClF3N2O, 274.0; no m / z signal. 1 H NMR (400MHz, DMSO-d6) δ 9.98 (s, 1H), 9.51 (s, 1H), 7.98 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H).

[0456] Intermediate B17: 1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazole-4-carbaldehyde To a solution of 1H-pyrazole-4-carbaldehyde (1.95 g, 20.3 mmol, 1.0 equiv) and CsCO (13.2 g, 40.5 mmol, 2.0 equiv) in DMF (5.00 mL) was added 4-(bromomethyl)tetrahydro-2H-pyran (5.44 g, 30.4 mmol, 1.5 equiv). The reaction mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the mixture was diluted with EA (100 mL), washed with brine (50 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 / EA=1 / 1) to give 1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazole-4-carbaldehyde (2 g, 50% yield) as a yellow solid. LC-MS (ESI): Mass calculated: C 10 H 14 N2O2 194.11; m / z observed, 195.1 [M+H] + .

[0457] Intermediate B18: 6-(bromomethyl-d2)-2-methyl-2H-indazole TIFF2025512805000114.tif16128

[0458] Step A: (2-methyl-2H-indazol-6-yl)methane-d2-ol To a solution of methyl 2-methyl-2H-indazole-6-carboxylate (400 mg, 2.10 mmol, 1.0 equiv.) in THF (8.00 mL) was added LiAlD (88.3 mg, 2.10 mmol, 1.0 equiv.) in portions at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with EtOAc (30 mL), carefully quenched with sodium sulfate decahydrate, and stirred for 0.5 h. After filtration, the filtrate was concentrated under reduced pressure to give (2-methyl-2H-indazol-6-yl)methan-d-ol (340 mg, 98% yield) as a yellow oil. LC-MS (ESI): mass calculated for CHDNO, 164.20; m / z found, 165.1 [M+H]. + .

[0459] Step B: 6-(bromomethyl-d2)-2-methyl-2H-indazole To a solution of (2-methyl-2H-indazol-6-yl)methan-d2-ol (340 mg, 2.07 mmol, 1.0 equiv) in DCM (5.0 mL) was added triphenylphosphine (815 mg, 3.11 mmol, 1.5 equiv), and the mixture was stirred at 50 °C for 5 min. Then, a solution of CBr4 (1.03 g, 3.11 mmol, 1.5 equiv) in DCM (5.0 mL) was added to the above mixture, and the reaction mixture was stirred at 50 °C for 2 h. After evaporation, the residue was purified by flash column chromatography on silica gel (PE / EA = 2 / 1) to give 6-(bromomethyl-d2)-2-methyl-2H-indazole (100 mg, 21% yield) as a yellow solid. LC-MS (ESI): mass calculated for C9H7D2BrN2, 226.01; m / z found, 227.0 [M+H] + .

[0460] Intermediate B19: 6-(bromomethyl-d2)-1-methyl-1H-indazole TIFF2025512805000115.tif16128

[0461] Step A: Methyl 1-methyl-1H-indazole-6-carboxylate and methyl 2-methyl-2H-indazole-6-carboxylate To a solution of methyl 1H-indazole-6-carboxylate (2.00 g, 11.4 mmol, 1.0 equiv.) and iodomethane (4.83 g, 34.1 mmol, 3.0 equiv.) in DMF (20 mL) was added cesium carbonate (7.40 g, 22.7 mmol, 2.0 equiv.), and the reaction mixture was stirred at room temperature for 2 h. After filtration, the filtrate was diluted with EtOAc (100 mL) and washed with brine (30 mL × 5). The organic layer was 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 give methyl 1-methyl-1H-indazole-6-carboxylate (1.35 g, 62% yield) as a yellow solid and methyl 2-methyl-2H-indazole-6-carboxylate (800 mg, 37% yield) as a yellow oil.

[0462] Methyl 1-methyl-1H-indazole-6-carboxylate: LC-MS(ESI):C 10 H 10 Calculated mass of N2O2: 190.20; observed m / z: 191.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.30(s,3H),8.17(s,1H),7.92-7.84(m,1H),7.70(dd,J=8.4,1.2Hz,1H),4.14(s,3H),3.91(s,3H).

[0463] Methyl 2-methyl-2H-indazole-6-carboxylate: LC-MS(ESI):C 10 H 10 Calculated mass of N2O2: 190.20; observed m / z: 191.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.46(s,1H),8.28(s,1H),7.81(d,J=8.8Hz,1H),7.56(dd,J=8.8,1.2Hz,1H),4.23(s,3H),3.88(s,3H).

[0464] Step B: (1-methyl-1H-indazol-6-yl)methane-d2-ol To a solution of methyl 1-methyl-1H-indazole-6-carboxylate (700 mg, 3.68 mmol, 1.0 equiv.) in THF (20 mL) was added LiAlD (155 mg, 3.68 mmol, 1.0 equiv.) in portions at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h. The reaction was diluted with EtOAc (50 mL), quenched with sodium sulfate decahydrate, and stirred for 0.5 h. After filtration, the filtrate was concentrated under reduced pressure to give (1-methyl-1H-indazol-6-yl)methan-d-ol (600 mg, 99% yield) as a yellow solid. LC-MS (ESI): mass calculated for CHDNO, 164.20; m / z found, 165.1 [M+H]. + .

[0465] Step C: 6-(bromomethyl-d2)-1-methyl-1H-indazole To a solution of (1-methyl-1H-indazol-6-yl)methan-d2-ol (500 mg, 3.05 mmol, 1.0 equiv) in DCM (5.0 mL) was added triphenylphosphine (1.20 g, 4.57 mmol, 1.5 equiv), and the mixture was stirred at 50 °C for 5 min. Then, a solution of CBr4 (1.51 g, 4.57 mmol, 1.5 equiv) in DCM (5.0 mL) was added dropwise to the above mixture, and the resulting reaction mixture was stirred at 50 °C for 2 h. After evaporation, the residue was purified by flash column chromatography on silica gel (PE / EA = 2 / 1) to give 6-(bromomethyl-d2)-1-methyl-1H-indazole (300 mg, 43% yield) as a yellow solid. LC-MS (ESI): mass calculated for C9H7D2BrN2, 226.01; m / z found, 227.0 [M+H] + .

[0466] Intermediate B20: 4-(3-(bromomethyl-d2)phenyl)-1-(methyl-d3)-1H-pyrazole TIFF2025512805000116.tif23128

[0467] Step A: 4-Bromo-1-(methyl-d3)-1H-pyrazole To a solution of 4-bromo-1H-pyrazole (1.00 g, 6.80 mmol, 1.0 equiv) in DMF (5.00 mL) was added CsCO (4.43 g, 13.6 mmol, 2.0 equiv) and iodomethane-d (635 μL, 10.2 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 16 h. After filtration, the mixture was diluted with EA (30 mL), washed with brine (20 mL × 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-bromo-1-(methyl-d)-1H-pyrazole (1.10 g, 98% yield) as a yellow oil. LC-MS (ESI): mass calculated for CHDBrN, 162.99; m / z found, 164.1 [M+H]. + .

[0468] Step B: Methyl 3-(1-(methyl-d3)-1H-pyrazol-4-yl)benzoate To a solution of 4-bromo-1-(methyl-d3)-1H-pyrazole (500 mg, 3.05 mmol, 1.0 equiv), (3-(methoxycarbonyl)phenyl)boronic acid (658 mg, 3.66 mmol, 1.2 equiv), and potassium carbonate (1.26 g, 9.15 mmol, 3.0 equiv) in 1,4-dioxane (10.0 mL) and water (0.10 mL) was added Pd(dppf)Cl2 (249 mg, 305 μmol, 0.1 equiv). The reaction mixture was stirred at 100 °C under N2 for 2 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA / PE=1 / 1) to give methyl 3-(1-(methyl-d3)-1H-pyrazol-4-yl)benzoate (400 mg, 60% yield) as a yellow oil. LC-MS (ESI): C 12 Calculated mass of H9D3N2O2, 219.11; observed m / z, 220.2 [M+H] + .

[0469] Step C: (3-(1-(methyl-d3)-1H-pyrazol-4-yl)phenyl)methane-d2-ol To a solution of methyl 3-(1-(methyl-d3)-1H-pyrazol-4-yl)benzoate (400 mg, 1.82 mmol, 1.0 equiv.) in THF (10.0 mL) was added LiAlD4 (153 mg, 3.65 mmol, 2.0 equiv.) in portions at 0 °C. The reaction mixture was stirred at 0 °C for 40 min. The mixture was carefully quenched with sodium sulfate decahydrate (500 mg) and filtered. The filtrate was concentrated under reduced pressure to give (3-(1-(methyl-d3)-1H-pyrazol-4-yl)phenyl)methan-d2-ol (300 mg, 85% yield) as a white solid. LC-MS (ESI): C 11 Calculated mass of H7D5N2O: 193.12; observed m / z: 194.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 7.69 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.34-7.25 (m, 2H), 7.14 (d, J = 7.4Hz, 1H).

[0470] Step D: 4-(3-(bromomethyl-d2)phenyl)-1-(methyl-d3)-1H-pyrazole To a solution of (3-(1-(methyl-d3)-1H-pyrazol-4-yl)phenyl)methan-d2-ol (300 mg, 1.55 mmol, 1.0 equiv) and triphenylphosphine (611 mg, 2.33 mmol, 1.5 equiv) in DCM (5.00 mL) was added CBr4 (772 mg, 2.33 mmol, 1.5 equiv) under N2. The reaction mixture was stirred at 50 °C for 2 h. After evaporation, the residue was purified by flash column chromatography on silica gel (EA / PE=1 / 1) to give 4-(3-(bromomethyl-d2)phenyl)-1-(methyl-d3)-1H-pyrazole (350 mg, 88% yield) as a white solid. LC-MS (ESI): C 11 Calculated mass for H6D5BrN2: 255.04; observed m / z: 256.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.15(s,1H),7.87(s,1H),7.65(s,1H),7.51(d,J=7.6Hz,1H),7.35(t,J=7.6Hz,1H),7.26(d,J=7.6Hz,1H).

[0471] Intermediate B21: 4-(3-(bromomethyl-d2)phenyl)-1-(difluoromethyl)-1H-pyrazole TIFF2025512805000117.tif27128

[0472] Step A: Methyl 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzoate To a solution of 4-bromo-1-(difluoromethyl)-1H-pyrazole (500 mg, 2.54 mmol, 1.0 equiv.), (3-(methoxycarbonyl)phenyl)boronic acid (548 mg, 3.05 mmol, 1.2 equiv.), and cesium carbonate (2.48 g, 7.61 mmol, 3.0 equiv.) in 1,4-dioxane (20.0 mL) and water (5.00 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (186 mg, 254 μmol, 1.0 equiv.). The reaction mixture was stirred at 90°C under nitrogen for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (PE / EA=20 / 1) to give methyl 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzoate (580 mg, 90% yield) as a yellow oil. LC-MS (ESI): C 12 H 10 Calculated mass of F2N2O2: 252.07; observed m / z: 253.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.87(s,1H),8.37(s,1H),8.24(t,J=1.6Hz,1H),8.02-7.97(m,1H),7.89 -7.87(m,1H),7.86(t,J=67.6Hz,1H),7.58(t,J=7.8Hz,1H),3.89(s,3H).

[0473] Step B: (3-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)methane-d2-ol To a solution of methyl 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)benzoate (200 mg, 793 μmol, 1.0 equiv.) in dry THF (10.0 mL) was added LiAlD (66.6 mg, 1.59 mmol, 2.0 equiv.) at 0° C. The reaction mixture was stirred at 0° C. for 20 min. The reaction mixture was diluted with NaSO . The mixture was carefully quenched with 10H2O and stirred for 30 minutes. After filtration, the filtrate was diluted with water and extracted with ethyl acetate (25 mL x 3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (PE / EA = 4 / 1) to give (3-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)methan-d2-ol (158 mg, 88% yield) as a yellow oil. LC-MS (ESI): mass calculated for CHD2F2N2O, 226.09; m / z found, 227.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.72(s,1H),8.29(s,1H),7.93(t,J=67.6Hz,1H),7.69-7.55(m,2H),7.41(d,J=7.6Hz,1H),7.32-7.23(m,1H),5.22(s,1H).

[0474] Step C: 4-(3-(bromomethyl-d2)phenyl)-1-(difluoromethyl)-1H-pyrazole To a solution of (3-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)methan-d2-ol (145 mg, 641 μmol, 1.0 equiv) in DCM (10.0 mL) were added triphenylphosphine (252 mg, 961 μmol, 1.5 equiv) and carbon tetrabromide (319 mg, 961 μmol, 1.5 equiv). The reaction mixture was stirred at 50° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted with DCM (20 mL), washed with saturated aqueous sodium bicarbonate (20 mL), water (20 mL), and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=10 / 1) to give 4-(3-(bromomethyl-d2)phenyl)-1-(difluoromethyl)-1H-pyrazole (172 mg, 93% yield) as a white solid. LC-MS (ESI): C 11 Calculated mass for H7D2BrF2N2: 288.00; observed m / z: 289.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.75(s,1H),8.29(s,1H),7.85(t,J=59.2Hz,1H),7.83(d,J=7.6Hz,1H),7.67-7.63(m,1H),7.43-7.35(m,2H).

[0475] Intermediate B22: 4-(3-(bromomethyl-d2)phenyl)-1-methyl-1H-pyrazole TIFF2025512805000118.tif23128

[0476] Step A: Methyl 3-(1-methyl-1H-pyrazol-4-yl)benzoate To a solution of 4-bromo-1-methyl-1H-pyrazole (6.00 g, 37.3 mmol, 1.0 equiv.), (3-(methoxycarbonyl)phenyl)boronic acid (8.05 g, 44.7 mmol, 1.2 equiv.), and potassium carbonate (15.5 g, 112 mmol, 3.0 equiv.) in 1,4-dioxane (80.0 mL) and water (8.00 mL) was added Pd(dppf)Cl (1.52 g, 1.86 mmol, 0.05 equiv.). The reaction mixture was stirred at 100 °C under N for 3 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v / v) to give methyl 3-(1-methyl-1H-pyrazol-4-yl)benzoate (6.50 g, 80% yield) as a yellow oil. LC-MS (ESI): C 12 H 12 Calculated mass of N2O2, 216.09; observed m / z, 217.1 [M+H] + .

[0477] Step B: (3-(1-methyl-1H-pyrazol-4-yl)phenyl)methane-d2-ol To a solution of methyl 3-(1-methyl-1H-pyrazol-4-yl)benzoate (7.50 g, 34.7 mmol, 1.0 equiv.) in dry THF (50.0 mL), LiAlD4 (2.18 g, 52.0 mmol, 1.5 equiv.) was added portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 40 minutes. Sodium sulfate decahydrate (5 g) was then carefully added to the above mixture, followed by filtration. The filtrate was concentrated under reduced pressure to give (3-(1-methyl-1H-pyrazol-4-yl)phenyl)methan-d2-ol (5.30 g, 80% yield) as a white solid. LC-MS (ESI): C 11 H 10 Calculated mass of D2N2O: 190.11; observed m / z: 191.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 7.70(s,1H),7.55(s,1H),7.41(s,1H),7.34-7.26(m,2H),7.15(d,J=7.4Hz,1H),3.87(s,3H).

[0478] Step C: 4-(3-(bromomethyl-d2)phenyl)-1-methyl-1H-pyrazole To a solution of (3-(1-methyl-1H-pyrazol-4-yl)phenyl)methan-d2-ol (500 mg, 2.63 mmol, 1.0 equiv) in DCM (10.0 mL) was added triphenylphosphine (1.03 g, 3.94 mmol, 1.5 equiv) at room temperature. A solution of perbromomethane (1.31 g, 3.94 mmol, 1.5 equiv) in DCM (3 mL) was then added to the above mixture under N2, and the resulting mixture was stirred at 50 °C under N2 for 2 h. After evaporation, the residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 17% v / v) to give 4-(3-(bromomethyl-d2)phenyl)-1-methyl-1H-pyrazole (490 mg, 74% yield) as a white solid. LC-MS (ESI): C 11 Calculated mass for H9D2BrN2: 252.02; observed m / z: 253.2 [M+H] + .

[0479] Intermediate B23: 3-(1-(methyl-d3)-1H-pyrazol-4-yl)benzaldehyde TIFF2025512805000119.tif23128

[0480] Step A: 4-Bromo-1-(methyl-d3)-1H-pyrazole To a solution of 4-bromo-1H-pyrazole (3.00 g, 20.4 mmol, 1.0 equiv.) in DMF (60.0 mL) was added cesium carbonate (13.3 g, 40.8 mmol, 2.0 equiv.), and the reaction mixture was stirred at room temperature for 1 hour. CD3I (5.92 g, 2.54 mL, 40.8 mmol, 2.0 equiv.) was then added dropwise to the mixture, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EA (200 mL) and filtered. The filtrate was washed with brine (100 mL × 5), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4-bromo-1-(methyl-d3)-1H-pyrazole (2.40 g, 72% yield) as a yellow oil. LC-MS (ESI): calculated mass for C4H2D3BrN2, 162.98; observed m / z, 164.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.85 (s, 1H), 7.44 (s, 1H).

[0481] Step B: 3-(1-(methyl-d3)-1H-pyrazol-4-yl)benzaldehyde To a solution of (3-formylphenyl)boronic acid (2.00 g, 13.3 mmol, 1.0 equiv.), 4-bromo-1-(methyl-d3)-1H-pyrazole (2.84 g, 17.3 mmol, 1.3 equiv.), and cesium carbonate (13.0 g, 40.0 mmol, 3.0 equiv.) in 1,4-dioxane (70.0 mL) and water (20.0 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (976 mg, 1.33 mmol, 0.1 equiv.). The reaction mixture was stirred at 90°C under nitrogen for 1 hour. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (PE / EA=2 / 1) to give 3-(1-(methyl-d3)-1H-pyrazol-4-yl)benzaldehyde (1.85 g, 73% yield) as a yellow oil. LC-MS (ESI): C 11 Calculated mass of H7D3N2O: 189.10; observed m / z: 190.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 10.03(s,1H),8.27(s,1H),8.09(s,1H),7.97(s,1H),7.93-7.88(m,1H),7.73(d,J=7.6Hz,1H),7.59(t,J=7.6Hz,1H).

[0482] Intermediate B24: 4-(4-formyl-1H-pyrazol-1-yl)benzonitrile To a solution of 1H-pyrazole-4-carbaldehyde (5.0 g, 52.0 mmol, 1.0 equiv) in DMF (50 mL) was added NaH (60% suspension in oil) (1.5 g, 62.4 mmol, 1.2 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. 4-Fluorobenzonitrile (6.9 g, 57.2 mmol, 1.1 equiv) was added to the above mixture, and the reaction mixture was stirred at 25 °C for 16 h. The mixture was quenched with HO (100 mL) and extracted with EtOAc (50 mL × 3). The organic layer was washed with brine (100 mL × 4), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EA=2 / 1) to give 4-(4-formyl-1H-pyrazol-1-yl)benzonitrile (3.0 g, 29% yield) as a white solid. LC-MS (ESI): 11 Calculated mass of H7N3O, 197.06; observed m / z, no mass value [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.94(s,1H),9.41(s,1H),8.37(s,1H),8.15(d,J=8.8Hz,2H),8.05(d,J=8.8Hz,2H).

[0483] Intermediate B25: 2-Oxoindoline-5-carbaldehyde TIFF2025512805000121.tif14128

[0484] Step A: 5-Vinylindolin-2-one To a mixture of 5-bromoindolin-2-one (1.0 g, 4.72 mmol, 1.0 equiv.) and potassium ethenyltrifluoroborate (948 mg, 7.07 mmol, 1.5 equiv.) in 1,4-dioxane (20.0 mL) and HO (2.00 mL), Pd(PPh3)4 (545 mg, 472 μmol, 0.1 equiv.) and Na2CO3 (1.50 g, 14.1 mmol, 3.0 equiv.) were added. The reaction mixture was stirred at 100 °C under N2 for 4 h. After cooling to room temperature, the mixture was filtered, and the filtrate was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE / EtOAc=1 / 1) to give 5-vinylindolin-2-one (500 mg, 66% yield) as a brown solid. LC-MS (ESI): C 10 Calculated mass of HNO: 159.07; observed m / z: 160.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.42(s,1H),7.36(s,1H),7.24(d,J=8.0Hz,1H),6.77(d,J=8.0Hz,1H),6.66(dd, J=17.6,10.8Hz,1H),5.66(d,J=17.6Hz,1H),5.09(d,J=10.8Hz,1H),3.47(s,2H).

[0485] Step B: 2-oxoindoline-5-carbaldehyde Ozone was bubbled into a solution of 5-vinylindolin-2-one (200 mg, 1.26 mmol, 1.0 equiv) in DCM (10.0 mL) at -78 °C for 1 h. Upon completion, excess ozone was purged from the reaction mixture with nitrogen. Dimethyl sulfide (5 mL) was then added to the above mixture, and the reaction mixture was stirred for 30 min. After evaporation, the residue was purified by flash column chromatography on silica gel (PE / EA = 1 / 1) to give 2-oxoindoline-5-carbaldehyde (180 mg, 89% yield) as a pale yellow solid. LC-MS (ESI): mass calculated for CHNO, 161.05; m / z found, 162.2 [M+H].+ .

[0486] Intermediate B26: 1-((2-chlorophenyl)sulfonyl)-1H-pyrazole-4-carbaldehyde To a solution of 1H-pyrazole-4-carbaldehyde (500 mg, 5.20 mmol, 1.0 equiv.) and triethylamine (796 μL, 5.72 mmol, 1.1 equiv.) in DCM (5.00 mL) was added 2-chlorobenzenesulfonyl chloride (1.10 g, 5.20 mmol, 1.0 equiv.) in small portions. The reaction mixture was stirred at room temperature for 2 h. After filtration, the mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (EA / PE=1 / 10) to give 1-((2-chlorophenyl)sulfonyl)-1H-pyrazole-4-carbaldehyde (780 mg, 55% yield) as a yellow solid. LC-MS (ESI): C 10 Calculated mass of H7ClNO3S, 269...

Claims

1. Compound of formula (I'): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the formula, X is -C(R ３ ) ２ -, -NR ４ -, -O-, -S-, -S(=O)-, or -S(=O) ２ - and Y is -C(R ３ ) ２ -, -NR ４ -, -O-, -S-, -S(=O)-, or -S(=O) ２ - and Each Z is independently, -C(R ３ ), -NR ２ -, -O-, -S-, -S(=O)-, or -S(=O) ４ - and is ２ -. p is 0, 1, or 2. Each R ３ These are independently deuterium, hydrogen, halogen, -CN, and -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, aryl, heteroaryl, carbocykyl, or heterocyclyl is one or more R ｕ Is it okay if it is replaced with? Two Geminal R ３ They come together to form an oxo, or Two Geminal R ３ Together with the carbon atoms to which they are attached, 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 ４ Independently, hydrogen, or one or more R ｕ C may be replaced with １－６ It is alkyl, Ring A is C ３－１２ It is a carbocyclic ring or a 3- to 12-membered heterocyclic ring. R １ is hydrogen or -M-L-Q-R ２ And, M does not exist, or is -(C=O)-, -S(=O)-, or -S(=O) ２ - and L does not exist, or [W] ｒ And, r is an integer between 1 and 3. Each W is independent of -C(R Ｌ ) ２ -, C ３－４ Carbocyclylene or 3-4 membered heterocyclylene, wherein the carbocyclylene or heterocyclylene contains one or more R ｕ It may also be replaced with Each R Ｌ is independently hydrogen, deuterium, 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, or 3- to 12-membered heterocyclic, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclic, or heterocyclic may be substituted with one or more R ｕ or Two Geminal R Ｌ Together with the carbon atoms to which they are attached, 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 Q is absent or is -NR Ｑ -, -O-, -C(=O)-, -S(=O)-, or -S(=O) ２ - and R Ｑ is hydrogen, or one or more R ｕ C may be replaced with １－６ It is alkyl, R ２ C ６－１０ Aryl, 5-10 member heteroaryl, C ３－１２ Carbocyclyl or 3- to 12-membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl, or heterocyclyl is one or more R ２ａ It may also be replaced with Each R ２ａ These are independently oxo, halogen, -CN, and -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, -(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 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, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocykyl, or heterocyclyl is one or more R ｕ It may be replaced with, or Two R's ２ａ Together with the atoms to which they are bonded, C ３－８ It forms a carbocyclyl or a 3-8 membered heterocyclyl, and the carbocyclyl or heterocyclyl is one or more R ｕ It may also be replaced with R Ａ , R Ｃ , and R Ｅ Each occurrence is independent of oxo, halogen, -CN, and -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 q is an integer between 0 and 2. s is an integer between 0 and 12, as long as the valence allows. e is an integer selected from 0 to 5. U is -CH ２ - or -C (=O)-, R ５ is hydrogen, deuterium, C １－６ Haloalkyl, or C １－６ It is alkyl, t is an integer between 0 and 2. Each R ｕ These are independently oxo, halogen, -CN, and -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, -(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 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, alkylene, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is 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 It may be substituted with one or more substituents selected from carbocyclyls and 3- to 12-membered heterocyclyls, or Two R's ｕ It combines 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 C is independent 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 These are independently hydrogen and 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. R ｃ and R ｄ These are independently hydrogen and 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 These, together with the nitrogen atoms to which they are attached, form a 3- to 12-membered heterocycline, and the heterocycline contains one or more R ｚ It may also be replaced with R ａ , R ｂ , R ｃ , and R ｄ Each occurrence of is independent of one or more R ｚ It may also be replaced with Each R ｚ These are independently oxo, halogen, -CN, and -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 ３－６ It is a carbocyclyl, or a 3- to 6-membered heterocyclyl. A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. X is -O- and Y is -C(R ３ ) ２ - is; X is -C(R3)2- and Y is -O-; or, X is -NR 4- and Y is -C(R 3) 2-; The compound according to claim 1.

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

4. The compound is of the formula (I'-1-ii), (I'-1-iii), (I'-1-iv), (I'-1-v), (I'-1-vi), (I'-1-vii), (I'-1-ix), or (I'-1-xii): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, The compound according to claim 1.

5. The compound according to claim 1, wherein ring A is a 3- to 12-membered heterocycle.

6. is, In the formula, m and n are independent integers between 0 and 2. The compound according to claim 1.

7. The compound is of the formula (I'-2-ii), (I'-2-iii), (I'-2-iv), (I'-2-v), (I'-2-vi), (I'-2-vii), (I'-2-ix), or (I'-2-xii): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, The compound according to claim 1.

8. The compound according to claim 7, wherein each of m and n is 1.

9. R １ The compound according to claim 1, wherein the compound is hydrogen or -L-R2.

10. L is -C(R Ｌ ) ２ - The compound according to claim 1.

11. Each R Ｌ These independently produce hydrogen, deuterium, halogens, -CN, and -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 ３－６ Carbocyclyl or 3-6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is one or more R ｕ The compound according to claim 1, which may be substituted with

12. L is -CH ２ - The compound according to claim 1.

13. R ２ However, C ６－１０ An aryl or a 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is one or more R ２ａ The compound according to claim 1, which may be substituted with

14. R ２ However, one or more R ２ａ The compound according to claim 1, wherein the phenyl is substituted with a phenyl compound.

15. Each R ２ａ These are independently oxo, halogen, -CN, and -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 or 3-12 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocykyl, or heterocyclyl is one or more R ｕ The compound according to claim 1, which may be substituted with

16. Each R ３ These independently produce hydrogen, deuterium, halogens, -CN, and -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 ３－６ Carbocyclyl or 3-6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is one or more R ｕ The compound according to claim 1, which may be substituted with

17. Each R ４ Independently, hydrogen or C １－６ The compound according to claim 1, wherein it is alkyl.

18. The compound according to claim 1, wherein e is 0.

19. U is -CH ２ - The compound according to claim 1.

20. R ５ The compound according to claim 1, wherein the compound is hydrogen.

21. The compound according to claim 1, wherein t is 1.

22. The aforementioned compound is of formula (I'): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the formula, R １ is hydrogen or -L-R ２ And, L is -C(R Ｌ ) ２ - and Each R Ｌ These are independently hydrogen, deuterium, halogen, -CN, and -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 ３－６ Carbocyclyl or 3-6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is one or more R ｕ It may also be replaced with R ２ C ６－１０ Aryl, 5-10 member heteroaryl, C ３－１２ Carbocyclyl or 3- to 12-membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl, or heterocyclyl is one or more R ２ａ It may also be replaced with Each R ２ａ These are independently oxo, halogen, -CN, -OH, and C １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkylamino, 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 heterocyclyl),-S(=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｂ C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkylene, alkoxy, alkylamino, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with R Ａ and R Ｃ Each occurrence is independent of oxo, halogen, -CN, and -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 ３－６ The molecule is a carbocyclyl or a 3-6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is one or more R ｕ It may also be replaced with e is 0, X is -O- or -NR ４ - and Each R ４ These are independently hydrogen or C １－６ It is alkyl, Y is -CH ２ - or -O-, p is either 0 or 1. The compound according to claim 1.

23. The compound according to claim 1, wherein the compound is selected from the compounds in Tables 1 and 2 below and their pharmaceutically acceptable salts; (Table 1) (Table 2) 。

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23 and one or more pharmaceutically acceptable excipients.

25. A pharmaceutical composition for treating or preventing a disease or disorder in a subject where such treatment is necessary, comprising the compound described in any one of claims 1 to 23.

26. Use of a compound according to any one of claims 1 to 23 in the manufacture of a drug for treating or preventing a disease or disorder in a subject where such treatment is necessary.

27. The pharmaceutical composition according to claim 25, wherein the disease or disorder is an IKZF2-mediated disease or disorder.

28. The pharmaceutical composition according to claim 25, wherein the disease or disorder is T-cell leukemia, T-cell lymphoma, Hodgkin lymphoma or 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).

29. The use according to claim 26, wherein the disease or disorder is an IKZF2-mediated disease or disorder.

30. The use according to claim 26, wherein the disease or disorder is T-cell leukemia, T-cell lymphoma, Hodgkin lymphoma or 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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