Tetrahydronaphthalene derivatives as estrogen receptor degraders

Abstract

Described herein are compounds of Formula I, and their pharmaceutically acceptable salts, solvates, or stereoisomers, and their uses (eg, as estrogen receptor degraders).

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 388,300, filed July 12, 2022, U.S. Provisional Application No. 63 / 408,744, filed September 21, 2022, U.S. Provisional Application No. 63 / 427,277, filed November 22, 2022, and U.S. Provisional Application No. 63 / 460,734, filed April 20, 2023, the contents of each of which are incorporated herein by reference in their entirety. [Background technology]

[0002] background Estrogen receptors (ERs) belong to the steroid / nuclear receptor superfamily, which are involved in regulating eukaryotic gene expression, cell proliferation, and differentiation in target tissues. ERs exist in two forms: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), encoded by the ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors activated by the hormone estrogen (17β-estradiol). In the absence of hormone, ERs are primarily located in the cytosol of cells. Upon binding of the hormone estrogen to ER, ERs translocate from the cytosol to the nucleus, form dimers, and then bind to specific genomic sequences called estrogen response elements (EREs). The DNA / ER complex interacts with coregulators to regulate the transcription of target genes. ERα is primarily expressed in reproductive tissues such as the uterus, ovaries, breast, bone, and white adipose tissue. It is well known that deregulation of ER signaling, particularly through ERα, leads to uncontrolled cell proliferation, ultimately leading to cancer. ER+ breast cancer accounts for approximately 75% of all diagnosed breast cancers, as well as some ovarian and endometrial cancers.

[0003] Current therapies for ER+ breast cancer include drugs that inhibit ER activity through direct binding to the receptor's ligand-binding domain (e.g., tamoxifen), drugs that block estrogen synthesis (e.g., aromatase inhibitors such as anastrozole and letrozole), or drugs that induce ER degradation. Selective estrogen receptor degraders (SERDs) are small molecules that target ERα for proteasome-dependent degradation. Fulvestrant is the only SERD approved for the treatment of postmenopausal women with advanced ER+ breast cancer treated with standard endocrine therapy. Because it has poor solubility and is not orally bioavailable, fulvestrant is clinically administered by monthly intramuscular injection. To address the shortcomings of fulvestrant, orally bioavailable SERDs have been developed. However, despite being potent and effective at inducing ER protein degradation in ER+ breast cancer cells, SERDs typically only achieve partial degradation of ER protein.

[0004] It is thought that ERα degradation can occur when both ERα and a ubiquitin ligase (e.g., cereblon E3 ligase (CRBN)) are bound, bringing them into close proximity for ubiquitination and subsequent degradation by the proteasome. A new approach is to exploit naturally occurring cellular ubiquitin-mediated degradation to develop an entirely new class of therapeutic agents for the treatment of ER+ metastatic breast cancer, involving near-complete degradation of ER proteins. Summary of the Invention

[0005] overview In certain aspects, the present disclosure provides a compound of formula I: TLC(I), and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, During the ceremony, C is of formula I'-1: TIFF2025526290000001.tif25128, T is of formula I-2: TIFF2025526290000002.tif28128, L is of formula I'-3: TIFF2025526290000003.tif11128, Each of the variables of formulas I, I'-1, I-2, and I'-3 is as described, embodied, and exemplified herein. Compounds and pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided.

[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 provides a method of degrading estrogen receptors in a subject, comprising administering to the subject a compound disclosed herein.

[0008] In certain aspects, the present disclosure provides for the use of a compound disclosed herein in the manufacture of a medicament for degrading estrogen receptors in a subject.

[0009] In certain aspects, the present disclosure provides a compound disclosed herein for use in degrading estrogen receptors in a subject.

[0010] In certain aspects, the present disclosure provides methods of 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).

[0011] 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).

[0012] In certain aspects, the disclosure provides 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.

[0013] In certain aspects, the disclosure provides for the use of a compound disclosed herein in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof.

[0014] In certain aspects, the disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof. In certain aspects, the disclosure provides compounds disclosed herein for use in treating a disease or disorder in a subject in need thereof. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description The present disclosure relates to compounds and methods for degrading estrogen receptors, comprising contacting the estrogen receptor with a therapeutically effective amount of an estrogen receptor degrading agent disclosed herein. The present disclosure also relates to methods for treating an estrogen receptor-mediated disease or condition in a subject in need thereof by administering a therapeutically effective amount of an estrogen receptor degrading agent disclosed herein. The present disclosure further relates to methods for treating an estrogen receptor-mediated disease or condition in a subject in need thereof by administering a pharmaceutical composition comprising a therapeutically effective amount of an estrogen receptor degrading agent disclosed herein.

[0016] Compounds of the present application In one aspect, the present disclosure provides a compound of formula I: TLC(I), and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, During the ceremony, C is of formula I'-1: TIFF2025526290000004.tif25128, wherein: R1 However, hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)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 R 2 But *-Cy2 - where * indicates attachment to L; -Cy 2 -But C 3~12 carbocyclylene or 3- to 12-membered heterocyclylene, wherein the carbocyclylene or heterocyclylene is one or more R u or R 1 and R 2 together with the intervening carbon atom to form a ring A attached to L, and ring A is an optionally substituted C 3~12 a carbocyclic ring or a 5- to 16-membered heterocyclic ring, Y" is N or CR 3 and R 3 However, hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)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 or R 2 and R 3 together with the intervening carbon atom form a ring A attached to L, and ring A is an optionally substituted 5- to 16-membered heterocycle; However, R 1 and R 2 and R 2 and R 3 do not both form a ring A attached to L; Y' is N or CR Y’ and R Y’ However, hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, 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 - - - represents an optional covalent bond between Y and U; i) if the bond between Y and U is absent, r is 0 or 1, Y is N or CRY and R Y However, hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, 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 U is hydrogen or one or more R u C optionally substituted with 1~6 is alkyl, ii) the bond between Y and U, if present, is r is 1, Y is C, U is -CH2-, -C(=O)-, -(C=O)-N(R U )-*, or -N=C(R U )-*, R U is H or one or more R u C optionally substituted with 1~6 alkyl, where * indicates attachment to ring B; R 4 However, hydrogen, deuterium, C 1~6 Haloalkyl, or C 1~6 is alkyl, Each R D are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, 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 d is an integer from 0 to 4, q is an integer of 0 to 2, T is of formula I-2: TIFF2025526290000005.tif32128, wherein: X T1 , X T2 , X T3 , and X T4 each independently represents N or CR T and R T Each occurrence of independently represents hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)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 present in one or more R u may be substituted with Each R E are independently halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2ORb , -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 m is an integer selected from 0 to 5; L is of formula I'-3: TIFF2025526290000006.tif10128, wherein: * indicates attachment to T, ** indicates attachment to C, Each L ’ But independently, C 1~6 Alkylene, C 1~6 Heteroalkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 3~12 Carbocyclylene, 3- to 12-membered heterocyclylene, C 6~10 Arylene, 5- to 10-membered heteroarylene, -C(=O)-, -C(=O)N(R L )-, -C(=O)O-, -N(R L )-, -O-, -S-, or -S(=O)2-, and alkylene, heteroalkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is selected from the group consisting of one or more R u may be substituted with R L Each occurrence of is 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, 5-10 membered heteroaryl, -S(=O)2Ra , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with l is an integer selected from 0 to 10; Each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)Ra , -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 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, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 forming a carbocyclyl or a 3- to 12-membered heterocyclyl; Each R a But independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; Each R b are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; Each R c and R d are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; 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 , R c , and R d Each occurrence of may independently be 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 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl; Compounds and pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided.

[0017] In certain aspects, the present disclosure provides a compound of formula (I): TLC(I), and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, During the ceremony, C is of formula I-1: TIFF2025526290000007.tif22128, wherein: R 1 However, hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2Ra , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is present in one or more R u may be substituted with R 2 But *-Cy 2 - where * indicates attachment to L; -Cy 2 -But C 3~12 carbocyclylene or 3- to 12-membered heterocyclylene, wherein the carbocyclylene or heterocyclylene is one or more R u or R 1 and R 2 together with the intervening carbon atom to form a ring A attached to L, and ring A is an optionally substituted C 3~12a carbocyclic ring or a 5- to 16-membered heterocyclic ring, Y" is N or CR 3 and R 3 However, hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)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 R u or R 2 and R 3 together with the intervening carbon atom form a ring A attached to L, and ring A is an optionally substituted 5- to 16-membered heterocycle; However, R 1 and R 2 and R 2 and R 3 do not both form a ring A attached to L; Y' is N or CR Y’ and R Y’ However, hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, 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 - - - represents an optional covalent bond between Y and U; If the bond between Y and U is absent, r is 0 or 1, Y is N or CR Y and R Y However, hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C3~12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, 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 U is hydrogen or one or more R u C optionally substituted with 1~6 is alkyl, The bond between Y and U, if present, r is 1, Y is C, U is -CH2-, -C(=O)-, -(C=O)-N(R U )-*, or -N=C(R U )-*, R U is H or one or more R u C optionally substituted with 1~6 alkyl, where * indicates attachment to ring B; R 4 However, hydrogen, deuterium, C 1~6 Haloalkyl, or C 1~6 is alkyl, q is an integer of 0 to 2, T is of formula I-2: TIFF2025526290000008.tif32128, wherein: X T1 , X T2 , X T3 , and X T4 each independently represents N or CR T and R T Each occurrence of independently represents hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b, -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is present in one or more R u may be substituted with Each R E are independently halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a, -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)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 m is an integer selected from 0 to 5; L is of formula I-3: TIFF2025526290000009.tif10128, wherein: * indicates attachment to T, ** indicates attachment to C, W does not exist, or W is C 1~3 Alkylene, -O-, -NR W - or -(C=O)-, and the alkylene is one or more R u and optionally substituted by Cy 1 but does not exist, or Cy 1 , 6-membered heteroarylene, C6 arylene, C 3~12 carbocyclylene, or 3- to 12-membered heterocyclylene, wherein the arylene, heteroarylene, carbocyclylene, or heterocyclylene is selected from the group consisting of one or more R u and optionally substituted by Z' does not exist, or Each Z' is independently C 1~3 Alkylene, -O-, -NR W -, -(C=O)-, C 3~12 carbocyclylene, or 3- to 12-membered heterocyclylene, wherein the alkylene, carbocyclylene, or heterocyclylene is selected from the group consisting of one or more R u and optionally substituted by R W is hydrogen or one or more R u C optionally substituted with 1~6 is alkyl, p is an integer selected from 0 to 8, Each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR 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 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 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, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 forming a carbocyclyl or a 3- to 12-membered heterocyclyl; Each R a But 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, C1~6 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; 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 , R c , and R d Each occurrence of may independently be 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 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl; Compounds and pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided.

[0018] In certain aspects, the present disclosure provides a compound of formula I: TLC(I), and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, During the ceremony, C is of formula I-1: TIFF2025526290000010.tif22128, wherein: - - - represents an optional covalent bond between Y and U; R 1 However, hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is present in one or more R umay be substituted with R 2 But *-Cy 2 - where * indicates attachment to L; -Cy 2 - is a 3- to 12-membered heterocyclylene, and the heterocyclylene is u or R 1 and R 2 together with the intervening carbon atom to form a ring A attached to L, and ring A is i C optionally substituted with 3~10 a carbocyclic ring or a 5- to 16-membered heterocyclic ring, Y" is N or CR 3 and R 3 However, hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a, -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is present in one or more R u or R 2 and R 3 together with the intervening carbon atom to form a ring A attached to L, and ring A is i is a 5- to 16-membered heterocycle optionally substituted with However, R 1 and R 2 and R 2 and R 3 do not both form a ring A attached to L; Each R i are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR cS(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is present in one or more R u may be substituted with Y' is N or CR Y’ and R Y’ However, hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with Y is N or CR when there is no bond between Y and U. Y or Y, if the bond between Y and U is present, is C; R Y However, hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6Alkylamino, 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 r is 0 or 1, If U is a hydrogen atom or C, and if there is no bond between Y and U, 1~6 alkyl, or When U is a bond between Y and U, it is not -CH2-, -C(=O)-, -(C=O)-N(R U )-*, or -N=C(R U )-*, R U But H or C 1~6 alkyl, where * indicates attachment to ring B; R 4 However, hydrogen, deuterium, C 1~6 Haloalkyl, or C 1~6 is alkyl, q is an integer of 0 to 2, T is of formula I-2: TIFF2025526290000011.tif32128, wherein: X T1 , X T2 , X T3 , and X T4 each independently represents N or CR T and R T Each occurrence of independently represents 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 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c Rd , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is present in one or more R u may be substituted with Each R E are independently halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~14 Aryl, 5-14 membered heteroaryl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NRc S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is present in one or more R u may be substituted with m is an integer selected from 0 to 5; L is of formula I-3: TIFF2025526290000012.tif10128, wherein: W does not exist, or W is -CH2-, -O-, -NR W - or -(C=O)-, R W is hydrogen or C 1~6 is alkyl, * indicates attachment to T, ** indicates attachment to C, Cy 1 , 6-membered heteroarylene, C6 arylene, C 3~12carbocyclylene, or 3- to 12-membered heterocyclylene, wherein the arylene, heteroarylene, carbocyclylene, or heterocyclylene is selected from the group consisting of one or more R u and optionally substituted by Z' does not exist, or Z' is -(C(=O)) p -(O) p’ -(C 1~6 alkylene) u -(3-6 membered heterocyclylene) v -(C(=O)) p -(C 1~6 alkylene) u -(3-6 membered heterocyclylene) v -(C(=O)) p and the alkylene or heterocyclylene is selected from one or more R u and optionally substituted by each occurrence of p, p', and u is independently 0 or 1; each v is an integer independently selected from 0 to 3; Each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -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 oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 optionally substituted with one or more substituents selected from carbocyclyl and 3- to 6-membered heterocyclyl; The Two R's u together with one or more intervening atoms, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 forming a carbocyclyl or a 3- to 10-membered heterocyclyl; Each R a But independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; Each R b are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; Each R c and R d are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl; R c and R d together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl; R a , R b , R c , and R d each independently represents one or more R z may be substituted with Each R z are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl; Compounds and pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided.

[0019] In certain embodiments, when a bond between Y and U exists, U is —CH— or —C(═O)—, and r is 1, R 1 and R 2 , or R 2 and R 3 together with the intervening carbon atom to form a ring A attached to L.

[0020] In certain embodiments, when a bond between Y and U exists, U is —CH 2 — or —C(═O)—, and r is 1, ring A is TIFF2025526290000013.tif18155, where ** indicates attachment to L.

[0021] In certain embodiments, when a bond between Y and U exists, U is —CH 2 — or —C(═O)—, and r is 1, ring A is TIFF2025526290000014.tif18128, where ** indicates attachment to L.

[0022] In certain embodiments, the compound is TIFF2025526290000015.tif98141 or any of its pharmaceutically acceptable salts or stereoisomers.

[0023] In certain embodiments, the compound is TIFF2025526290000016.tif102147 or a pharmaceutically acceptable salt thereof.

[0024] In certain embodiments, 1) When a bond between Y and U exists, U is —CH— or —C(═O)—, and r is 1, then: i) R 1 and R 2 , or R 2 and R 3 together with the intervening carbon atom(s) form ring A attached to L, and / or ii) ring A is TIFF2025526290000017.tif18129, where ** indicates attachment to L, and / or 2) The compound is TIFF2025526290000018.tif98153 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0025] In certain embodiments, 1) When a bond between Y and U exists, U is —CH— or —C(═O)—, and r is 1, then: i) R 1 and R 2 , or R2 and R 3 together with the intervening carbon atom(s) form ring A attached to L, and / or ii) ring A is TIFF2025526290000019.tif18160, where ** indicates attachment to L, and / or 2) The compound is TIFF2025526290000020.tif98153 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0026] In certain embodiments, 1) When a bond between Y and U exists, U is —CH— or —C(═O)—, and r is 1, then: i) R 1 and R 2 , or R 2 and R 3 together with the intervening carbon atom(s) form ring A attached to L, and / or ii) ring A is TIFF2025526290000021.tif18128, where ** indicates attachment to L, and / or 2) The compound is TIFF2025526290000022.tif98153 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0027] In certain embodiments, 1) When a bond between Y and U exists, U is —CH— or —C(═O)—, and r is 1, then: i) R 1 and R 2 , or R 2 and R 3 together with the intervening carbon atom(s) form ring A attached to L, and / or ii) ring A is TIFF2025526290000023.tif18160, where ** indicates attachment to L, and / or 2) The compound is TIFF2025526290000024.tif98153 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0028] In certain embodiments, 1) When a bond between Y and U exists, U is —CH— or —C(═O)—, and r is 1, then: i) R 1 and R 2 , or R 2 and R 3 together with the intervening carbon atom(s) form ring A attached to L, and / or ii) ring A is TIFF2025526290000025.tif18129, where ** indicates attachment to L, and / or 2) The compound is TIFF2025526290000026.tif98153 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0029] In certain embodiments, 1) When a bond between Y and U exists, U is —CH— or —C(═O)—, and r is 1, then: i) R 1 and R 2 , or R 2 and R 3 together with the intervening carbon atom(s) form ring A attached to L, and / or ii) ring A is TIFF2025526290000027.tif18160, where ** indicates attachment to L, and / or 2) The compound is TIFF2025526290000028.tif98153 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0030] In certain embodiments, 1) When a bond between Y and U exists, U is —CH— or —C(═O)—, and r is 1, then: i) R 1 and R 2, or R 2 and R 3 together with the intervening carbon atom(s) form ring A attached to L, and / or ii) ring A is TIFF2025526290000029.tif18128, where ** indicates attachment to L, and / or 2) The compound is TIFF2025526290000030.tif102158 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0031] In certain embodiments, 1) When a bond between Y and U exists, U is —CH— or —C(═O)—, and r is 1, then: i) R 1 and R 2 , or R 2 and R 3 together with the intervening carbon atom(s) form ring A attached to L, and / or ii) ring A is TIFF2025526290000031.tif18160, where ** indicates attachment to L, and / or 2) The compound is TIFF2025526290000032.tif102158 or a pharmaceutically acceptable salt or stereoisomer thereof.

[0032] In certain embodiments, C is of formula I-1-i: TIFF2025526290000033.tif20128.

[0033] In certain embodiments, C is of formula I-1-ii: TIFF2025526290000034.tif20128.

[0034] In certain embodiments, C is of formula I'-1-i: The file is TIFF2025526290000035.tif23128.

[0035] In certain embodiments, C is of formula I'-1-ii: TIFF2025526290000036.tif23128.

[0036] In certain embodiments, U is -CH2- or -C(=O)-. In certain embodiments, U is -CH2- or -C(=O)- when a bond between Y and U exists. In certain embodiments, U is -(C=O)-N(R U )-* or -N=C(R U )-*.

[0037] In certain embodiments, R 1 is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1~6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), 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), 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.

[0038] In certain embodiments, R 1 are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0039] In certain embodiments, R 1 are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6carbocyclyl, 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.

[0040] In certain embodiments, R 1 are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0041] In certain embodiments, R 1 are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0042] In certain embodiments, R 1 is hydrogen, halogen, or C 1~6 It is an alkoxy.

[0043] In certain embodiments, R 2 *-Cy 2 - where * indicates attachment to L.

[0044] In certain embodiments, -Cy 2 -C 3~12Carbocyclylene (e.g., cyclopropylene (C3), cyclopropenylene (C3), cyclobutylene (C4), cyclobutenylene (C4), cyclopentylene (C5), cyclopentenylene (C5), cyclohexylene (C6), cyclohexenylene (C6), cyclohexadienylene (C6), cycloheptyl (C7), cycloheptenylene (C7), cycloheptadienylene (C7), cycloheptatrienylene (C7), cyclooctylene (C8), cyclooctenylene (C8), bicyclo[2.2.1]heptanylene (C7), bicyclo[2.2.2]octanylene (C8), cyclononylene (C9), cyclononenylene (C9), cyclodecylene (C 10 ), cyclodecenylene (C 10 ), octahydro-1H-indenylene (C9), decahydronaphthalenylene (C 10 ), or spiro[4.5]decanylene (C 10 )), or 3- to 12-membered heterocyclylene (e.g., a heterocyclylene containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the carbocyclylene or heterocyclylene is selected from one or more R u may be substituted with.

[0045] In certain embodiments, -Cy 2 -C 5~12 a fused carbocyclene or a 5- to 12-membered fused heterocyclylene, wherein the carbocyclene or heterocyclylene is one or more R u may be substituted with.

[0046] In certain embodiments, *-Cy 2 - is a 5- to 12-membered fused heterocyclylene containing one or two nitrogen atoms, and the heterocyclylene is one or more R u may be substituted with.

[0047] In certain embodiments, *-Cy 2 - is as follows: TIFF2025526290000037.tif14128

[0048] In certain embodiments, R 1 and R 2 together with the intervening carbon atom form a ring A attached to L, and ring A is an optionally substituted 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 )), or 5-16 membered heterocyclyl (e.g., heterocyclyl containing one or two 5-8 membered rings and 1-5 heteroatoms selected from N, O, and S).

[0049] In certain embodiments, Y″ is N or CR 3 is.

[0050] In certain embodiments, R 3 is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1~6Alkoxy (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.

[0051] In certain embodiments, R 3 are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0052] In certain embodiments, R 3 are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6carbocyclyl, 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.

[0053] In certain embodiments, R 3 are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0054] In certain embodiments, R 3 are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0055] In certain embodiments, R 3 is hydrogen, halogen, or C 1~6 It is an alkoxy.

[0056] In certain embodiments, R 2 and R 3 together with the intervening carbon atom form a ring A attached to L, and ring A is an optionally substituted 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 5-16 membered heterocyclyl (e.g., heterocyclyl containing one or two 3-8 membered rings and 1-5 heteroatoms selected from N, O, and S).

[0057] In certain embodiments, R 1 and R 2 and R 2 and R 3 do not both form a ring A attached to L.

[0058] In certain embodiments, Y' is N or CR. Y’ is.

[0059] In certain embodiments, R Y’ is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1~6Alkoxy (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 amino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C 2~6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2~6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from one or more R u may be substituted with.

[0060] In certain embodiments, R Y’ are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, 3- to 6-membered heterocyclyl, 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 Ru may be substituted with.

[0061] In certain embodiments, R Y’ are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0062] In certain embodiments, R Y’ are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0063] In certain embodiments, R Y’ is hydrogen, halogen, or C 1~6 It is an alkoxy.

[0064] In certain embodiments, i) if the bond between Y and U is absent, r is 0 or 1 and Y is N or CR Y and U is hydrogen or one or more R u C optionally substituted with 1~6 It is alkyl.

[0065] In certain embodiments, Y is N. In certain embodiments, Y is CR Y is.

[0066] In certain embodiments, RY is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1~6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1~6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino amino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C 2~6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2~6Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from one or more R u may be substituted with.

[0067] In certain embodiments, R Y are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6carbocyclyl, 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.

[0068] In certain embodiments, R Y are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0069] In certain embodiments, R Y are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0070] In certain embodiments, R Y is hydrogen, halogen, or C 1~6 It is an alkoxy.

[0071] In certain embodiments, ii) if a bond between Y and U is present, r is 1, Y is C, and U is —CH—, —C(═O)—, —(C═O)—N(R U )-*, or -N=C(R U )-*.

[0072] In certain embodiments, R U is H 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)), where * indicates attachment to ring B.

[0073] In certain embodiments, R 4 are hydrogen, deuterium, and C 1~6 Haloalkyl (e.g., C containing 1 to 6 halogen atoms selected from F, Cl, Br, and 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)).

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

[0075] In certain embodiments, each R D are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 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 Ru may be substituted with.

[0076] In certain embodiments, each R D are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 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.

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

[0078] In certain embodiments, d is an integer from 0 to 4. In certain embodiments, d is 0. In certain embodiments, d is 1. In certain embodiments, d is 2. In certain embodiments, d is 3. In certain embodiments, d is 4.

[0079] 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.

[0080] In certain embodiments, ring A is an optionally substituted 7-16 membered fused heterocycle.

[0081] In certain embodiments, ring A is TIFF2025526290000038.tif25128, wherein: ** indicates attachment to L; Ring A I and Ring A II independently, C 4~8 A carbocyclic ring or a 4- to 8-membered heterocyclic ring, III and Ring A IV at least one of the groups is a 4- to 8-membered heterocycle; A 1 and A 2 are independently C, CR Ax , or N, R Ax are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with Each R i are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2Ra , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with s is an integer selected from 0 to 8, valence permitting; Each R i are independently ring A I or ring A II It may be present on either

[0082] In certain embodiments, ring A is TIFF2025526290000039.tif64142, During the ceremony, ** indicates attachment to L; R 5 is hydrogen or one or more R u C optionally substituted with 1~6 is alkyl, Each R iare independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR 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 s is an integer selected from 0 to 8, as far as valence allows.

[0083] In certain embodiments, ring A is TIFF2025526290000040.tif64142, wherein: ** indicates attachment to L; R 5 is hydrogen or one or more R u C optionally substituted with 1~6 is alkyl, Each R i are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR cR d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with s is an integer selected from 0 to 8, as far as valence allows.

[0084] In certain embodiments, ring A is TIFF2025526290000041.tif68142, During the ceremony, ** indicates attachment to L; R 5 is hydrogen or one or more R u C optionally substituted with 1~6 is alkyl, Each R 6 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3-12 membered heterocyclyl, -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with Each R i 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 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with s is an integer selected from 0 to 8, as far as valence allows.

[0085] In certain embodiments, ring A I and Ring A II independently, C 4~8carbocyclic ring (e.g., cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), or cyclooctenyl (C8)), or a 4-8 membered heterocyclic ring (e.g., a heterocyclyl containing one or two 4-8 membered rings and one to four heteroatoms selected from N, O, and S), and ring A III and Ring A IV At least one of the groups is a 4- to 8-membered heterocycle.

[0086] In certain embodiments, A 1 and A 2 are independently C, CR Ax , or N.

[0087] In certain embodiments, R Ax is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1~6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C 1~6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino amino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C 2~6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2~6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6~10 aryl (e.g., phenyl or naphthyl), 5-10 membered heteroaryl (e.g., heteroaryl containing one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from one or more R u may be substituted with.

[0088] In certain embodiments, R Ax are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, 3- to 6-membered heterocyclyl, 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 Ru may be substituted with.

[0089] In certain embodiments, R Ax are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0090] In certain embodiments, R Ax are hydrogen, halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0091] In certain embodiments, R 6 is hydrogen, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 2~6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2~6Alkynyl (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), -S(=O)R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0092] In certain embodiments, R 6 is hydrogen, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0093] In certain embodiments, R 6 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Carbocyclyl or 3- to 6-membered heterocyclyl, -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is selected from one or more R u may be substituted with.

[0094] In certain embodiments, R 6 is hydrogen, C 1~6 Alkyl, C 3~6 Carbocyclyl, 3-6 membered heterocyclyl, -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b, or -C(=O)NR c R d and the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0095] In certain embodiments, ring A is selected from the group consisting of one or more R u may be substituted with.

[0096] In certain embodiments, R u is R Ax In certain embodiments, R u is R 5 In certain embodiments, R u is R i is.

[0097] In certain embodiments, ring A is an optionally substituted 7-16 membered spiroheterocycle.

[0098] In certain embodiments, ring A is TIFF2025526290000042.tif20128, wherein: ** indicates attachment to L; Ring A 2 is C 3~8 a carbocyclic ring or a 3- to 8-membered heterocyclic ring, Each X is independently -C(R X1 )2-, -NR X2 -, -O-, -S-, -S(=O)-, or -S(=O)2-; Each Z is independently -C(R Z1 )2-, -NR Z2 -, -O-, -S-, -S(=O)-, or -S(=O)2-; R X1 and R Z1 Each occurrence of is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6Alkynyl, 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, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with Two Germinal R X1 or two geminal R Z1 together to form oxo, or The Two R's X1 or two R's Z1 together with the intervening carbon atom, C 3~12Form a carbocyclyl or a 3- to 12-membered heterocyclyl, and the carbocyclyl or heterocyclyl is one or more R u may be substituted with R X2 and R Z2 Each occurrence of is independently hydrogen, or one or more R u C optionally substituted with 1~6 is alkyl, m' and n' are independently integers selected from 0 to 3, and m' and n' cannot both be 0; Each R i are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a, -OC(=O)OR b , -OC(=O)NR 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 s is an integer selected from 0 to 8, as far as valence allows.

[0099] In certain embodiments, ring A is TIFF2025526290000043.tif21128, wherein: ** indicates attachment to L; Ring A IV is C 3~8 a carbocyclic ring or a 3- to 8-membered heterocyclic ring, Each X is independently -C(R X1 )2-, -NR X2 -, -O-, -S-, -S(=O)-, or -S(=O)2-; Each Z is independently -C(R Z1 )2-, -NR Z2 -, -O-, -S-, -S(=O)-, or -S(=O)2-; R X1 and R Z1 Each occurrence of is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR cR d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with Two Germinal R X1 or two geminal R Z1 together to form oxo, or The Two R's X1 or two R's Z1 together with the intervening carbon atom, C 3~12 Form a carbocyclyl or a 3- to 12-membered heterocyclyl, and the carbocyclyl or heterocyclyl is one or more R u may be substituted with R X2 and R Z2 Each occurrence of is independently hydrogen, or one or more R u C optionally substituted with 1~6 is alkyl, m' and n' are independently integers selected from 0 to 3, and m' and n' are not both 0; s is an integer selected from 0 to 8, valence permitting; Each R i are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR 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 selected from the group consisting of one or more R u may be substituted with However, if neither m' nor n' is 0, then ring A 1 is a 4- to 9-membered heterocyclic ring.

[0100] In certain embodiments, ring A is 1) TIFF2025526290000044.tif29128, wherein o is 0 or 1; or 2) TIFF2025526290000045.tif25128, where ** indicates attachment to L.

[0101] In certain embodiments, ring A IV is C 3~8 carbocyclic ring (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), or bicyclo[2.2.2]octanyl (C8)), or a 3- to 8-membered heterocyclic ring (e.g., a heterocyclyl containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S).

[0102] In certain embodiments, each X is independently —C(R X1 )2-, -NR X2 In certain embodiments, each X is independently -C(R X1 )2-, -NR X2 - and -O-.

[0103] In certain embodiments, each Z is independently —C(R Z1 )2-, -NR Z2 In certain embodiments, each Z is independently -C(R Z1 )2-, -NR Z2 - or -O-.

[0104] In certain embodiments, R X1 and R Z1 each occurrence independently represents hydrogen, 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 1~6 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), 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.

[0105] In certain embodiments, R X1 and R Z1 Each occurrence of is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0106] In certain embodiments, R X1 and R Z1 Each occurrence of is 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 3~6carbocyclyl, 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.

[0107] In certain embodiments, R X1 and R Z1 Each occurrence of is 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.

[0108] In certain embodiments, R X1 and R Z1 Each occurrence of is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0109] In certain embodiments, two geminal R X1 or two geminal R Z1 together form oxo.

[0110] In certain embodiments, two R X1 or two R's Z1 together with the intervening carbon atom, C 3~12Form a carbocyclyl or a 3- to 12-membered heterocyclyl, and the carbocyclyl or heterocyclyl is one or more R u may be substituted with.

[0111] In certain embodiments, two geminal R X1 or two geminal R Z1 together with the carbon atoms to which they are attached, C 3~12 Form a carbocyclyl or a 3- to 12-membered heterocyclyl, and the carbocyclyl or heterocyclyl is one or more R u may be substituted with.

[0112] In certain embodiments, R X2 and R Z2 Each occurrence of is 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)).

[0113] In certain embodiments, m' is an integer selected from 0 to 3. In certain embodiments, m' is 0. In certain embodiments, m' is 1. In certain embodiments, m' is 2. In certain embodiments, m' is 3.

[0114] In certain embodiments, n' is an integer selected from 0 to 3. In certain embodiments, n' is 0. In certain embodiments, n' is 1. In certain embodiments, n' is 2. In certain embodiments, n' is 3.

[0115] In certain embodiments, m' and n' are not both zero.

[0116] In certain embodiments, ring A is selected from the group consisting of one or more R u may be substituted with.

[0117] In certain embodiments, R u is R X1 In certain embodiments, R u is R X2 In certain embodiments, R u is R Z1 In certain embodiments, R u is R Z2 In certain embodiments, R u is R i is.

[0118] In certain embodiments, ring A is an optionally substituted 5- to 6-membered heterocycle.

[0119] In certain embodiments, ring A is TIFF2025526290000046.tif25138, wherein: ** indicates attachment to L; R 5 is hydrogen or one or more R u C optionally substituted with 1~6 is alkyl, Each R i are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c S(=O)2R a , -NR c S(=O)R a , -NR c S(=O)2OR b , -NRc S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with s is an integer selected from 0 to 8, as far as valence allows.

[0120] In certain embodiments, ring A is selected from the group consisting of one or more R u may be substituted with.

[0121] In certain embodiments, R u is R 5 In certain embodiments, R u is R i is.

[0122] In certain embodiments, R 5 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)).

[0123] In certain embodiments, each R i are independently oxo, hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1~6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1~6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), 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)R a, -NR c S(=O)2OR b , -NR c S(=O)NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0124] In certain embodiments, each R i are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0125] In certain embodiments, each R iare 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, 5- to 6-membered heteroaryl, and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R u may be substituted with.

[0126] In certain embodiments, each R i are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0127] In certain embodiments, each R i are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more R u may be substituted with.

[0128] 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.

[0129] In certain embodiments, X T1 , X T2 , X T3 , and X T4 Each of the T is.

[0130] In certain embodiments, X T1 , X T2 , X T3 , and X T4 Each of X is CH. In certain embodiments, T1 and X T4 Each of X is CH T2 and X T3 one of which is CH and X T2 and X T3 and the other of X is CF. T1 and X T4 one of which is CF or C(OCH3), and X T1 and X T4 the other is CH, and each X T2 and X T3 is CH. In certain embodiments, X T1 is C(OCH3) and X T3 is CF and X T2 and X T4 Each of X is CH. In certain embodiments, T2 is CF and X T4 is C(OCH3) and X T1 and X T3 Each of X is CH. In certain embodiments, T1 is C(OCH3) and X T2 is CF and X T3 and X T4Each of the is CH.

[0131] In certain embodiments, X T1 , X T2 , X T3 , and X T4 One of them is N.

[0132] In certain embodiments, X T1 and X T4 One of the two is N and the other is X T1 and X T4 the other is CH, and X T2 and X T3 Each of X is CH. In certain embodiments, T2 and X T3 One of the two is N and the other is X T2 and X T3 the other is CH, and X T1 and X T4 Each of the is CH.

[0133] In certain embodiments, X T1 , X T2 , X T3 , and X T4 Two of them are N.

[0134] In certain embodiments, X T1 and X T4 Each of X is CH T2 and X T3 Each of is N.

[0135] In certain embodiments, T is The file is TIFF2025526290000047.tif30128.

[0136] In certain embodiments, each R T 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, C6~10 Aryl, 5-10 membered heteroaryl, C 3~12 carbocyclyl, 3- to 12-membered heterocyclyl, and one or more R u may be substituted with.

[0137] In certain embodiments, each R T are independently hydrogen, C 1~6 Alkoxy or halogen.

[0138] In certain embodiments, each R E are independently halogens, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, 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.

[0139] In certain embodiments, R E is a halogen.

[0140] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5.

[0141] In certain embodiments, L is of formula I'-3: TIFF2025526290000048.tif11128, wherein: * indicates attachment to T, ** indicates attachment to C, Each L ’ independently, C 1~6 Alkylene, C 1~6 Heteroalkylene, C 2~6 Alkenylene, C 2~6 Alkynylene, C 3~12 Carbocyclylene, 3- to 12-membered heterocyclylene, C 6~10 Arylene, 5- to 10-membered heteroarylene, -C(=O)-, -C(=O)N(R L )-, -C(=O)O-, -N(R L )-, -O-, -S-, or -S(=O)2-, and alkylene, heteroalkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is selected from the group consisting of one or more R u may be substituted with R L Each occurrence of is 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, 5-10 membered heteroaryl, -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with l is an integer selected from 0 to 10.

[0142] In certain embodiments, each L ’ independently, C 1~6 Alkylene (e.g., methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH 2-), n-butylene (-CH2CH2CH2CH2-), n-pentylene (-CH2CH2CH2CH2CH2-), and n-hexylene (-CH2CH2CH2CH2CH2CH2-)), C 1~6 Heteroalkylene (e.g., C containing 1 to 5 heteroatoms selected from N, O, and S) 1~6 heteroalkylene), C 2~6 Alkenylene (e.g., ethenylene (C2), 1-propenylene (C3), 2-propenylene (C3), 1-butenylene (C4), 2-butenylene (C4), butadienylene (C4), pentenylene (C5), pentadienylene (C5), or hexenylene (C6)), C 2~6 Alkynylene (e.g., ethynylene (C2), 1-propynylene (C3), 2-propynylene (C3), 1-butynylene (C4), 2-butynylene (C4), pentynylene (C5), or hexynylene (C6)), C 3~12 Carbocyclylene (e.g., cyclopropylene (C3), cyclopropenylene (C3), cyclobutylene (C4), cyclobutenylene (C4), cyclopentylene (C5), cyclopentenylene (C5), cyclohexylene (C6), cyclohexenylene (C6), cyclohexadienylene (C6), cycloheptylene (C7), cycloheptenylene (C7), cycloheptadienylene (C7), cycloheptatrienylene (C7), cyclooctylene (C8), cyclooctenylene (C8), bicyclo[2.2.1]heptanylene (C7), bicyclo[2.2.2]octanylene (C8), cyclononylene (C9), cyclononenylene (C9), cyclodecylene (C 10 ), cyclodecenylene (C 10 ), octahydro-1H-indenylene (C9), decahydronaphthalenylene (C 10 ), or spiro[4.5]decanylene (C 10 )), 3- to 12-membered heterocyclylene (e.g., heterocyclylene containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6~10Arylene (e.g., phenylene or naphthylene), 5- to 10-membered heteroarylene (e.g., heteroarylene containing one or two 5- or 6-membered rings and 1 to 5 heteroatoms selected from N, O, and S), —C(═O)—, —C(═O)N(R L )-, -C(=O)O-, -N(R L )-, -O-, -S-, or -S(=O)2-, and alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is selected from the group consisting of one or more R u may be substituted with.

[0143] In certain embodiments, each L ’ independently, C 1~6 Alkylene, C 3~12 Carbocyclylene, 3- to 12-membered heterocyclylene, -C(=O)-, -C(=O)N(R L )-, -C(=O)O-, -N(R L )-, or -O-, and the alkylene, carbocyclylene, or heterocyclylene is selected from one or more R u may be substituted with.

[0144] In certain embodiments, R L Each occurrence of is 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 3~12Carbocyclyl (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), -S(=O)R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0145] In certain embodiments, R L Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6Carbocyclyl, or 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0146] In certain embodiments, R L Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Carbocyclyl or 3- to 6-membered heterocyclyl, -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R d and the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is selected from one or more R u may be substituted with.

[0147] In certain embodiments, R L Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 3~6 Carbocyclyl or 3- to 6-membered heterocyclyl, -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R dand the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R u may be substituted with.

[0148] In certain embodiments, l is 0. In certain embodiments, l is 1. In certain embodiments, l is 2. In certain embodiments, l is 3. In certain embodiments, l is 4. In certain embodiments, l is 5. In certain embodiments, l is 6. In certain embodiments, l is 7. In certain embodiments, l is 8. In certain embodiments, l is 9. In certain embodiments, l is 10.

[0149] In certain embodiments, L is of formula I-3: TIFF2025526290000049.tif10128, wherein: * indicates attachment to T, ** indicates attachment to C, W either does not exist or W is C 1~3 Alkylene, -O-, -NR W - or -(C=O)-, and the alkylene is one or more R u and optionally substituted by Cy 1 does not exist or Cy 1 represents 6-membered heteroarylene, C6 arylene, C 3~12 carbocyclylene, or 3- to 12-membered heterocyclylene, and the arylene, heteroarylene, carbocyclylene, or heterocyclylene is selected from the group consisting of one or more R u and optionally substituted by Z' is either absent or Each Z' is independently C 1~3 Alkylene, -O-, -NR W -, -(C=O)-, C 3~12 carbocyclylene, or 3- to 12-membered heterocyclylene, wherein the alkylene, carbocyclylene, or heterocyclylene is selected from the group consisting of one or more R uand optionally substituted by R W is hydrogen or one or more R u C optionally substituted with 1~6 is alkyl, p is an integer selected from 0 to 8.

[0150] In certain embodiments, W is absent.

[0151] In certain embodiments, W is C 1~3 Alkylene (e.g., methylene (-CH2-), ethylene (-CH2CH2-), or n-propylene (-CH2CH2CH 2- )), -O-, -NR W - or -(C=O)-, and the alkylene is one or more R u may be substituted by

[0152] In certain embodiments, Cy 1 does not exist.

[0153] In certain embodiments, Cy 1 is C6 arylene (i.e., phenylene), 6-membered heteroarylene (e.g., heteroarylene containing one 6-membered ring and 1 to 4 heteroatoms selected from N, O, and S), C 3~12 Carbocyclylene (e.g., cyclopropyl (C3), cyclopropenylene (C3), cyclobutylene (C4), cyclobutenylene (C4), cyclopentylene (C5), cyclopentenylene (C5), cyclohexylene (C6), cyclohexenylene (C6), cyclohexadienylene (C6), cycloheptylene (C7), cycloheptenylene (C7), cycloheptadienylene (C7), cycloheptatrienylene (C7), cyclooctylene (C8), cyclooctenylene (C8), bicyclo[2.2.1]heptanylene (C7), bicyclo[2.2.2]octanylene (C8), cyclononylene (C9), cyclononenylene (C9), cyclodecylene (C 10 ), cyclodecenylene (C 10), octahydro-1H-indenylene (C9), decahydronaphthalenylene (C 10 ), or spiro[4.5]decanylene (C 10 )), or 3- to 12-membered heterocyclylene (e.g., a heterocyclylene containing one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the arylene, heteroarylene, carbocyclylene, or heterocyclylene is selected from one or more R u may be substituted by

[0154] In certain embodiments, Cy 1 are morpholinylene, piperidinylene, piperazinylene, 7-azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene, 2-azaspiro[3.5]nonanylene, 2,7-diazaspiro[3.5]nonanylene, 1-oxa-8-azaspiro[4.5]decenylene, 2-oxa-8-azaspiro[4.5]decenylene, 5-oxa-2-azaspiro[3. 4]octanylene, 6-oxa-2-azaspiro[3.4]octanylene, 3,9-diazaspiro[5.5]undecanylene, 5-oxa-2-azaspiro[3.5]nonanylene, 1-oxa-9-azaspiro[5.5]undecanylene, 1-oxa-4,9-diazaspiro[5.5]undecanylene, 2,6-diazaspiro[3.3]heptanylene, 2-azaspiro[3.3] ]heptanylene, 1,5-dioxa-9-azaspiro[5.5]undecanylene, 1,4-dioxa-9-azaspiro[5.5]undecanylene, 5,9-dioxa-2-azaspiro[3.5]nonanylene, 5,8-dioxa-2-azaspiro[3.5]nonanylene, 6-oxa-2-azaspiro[3.5]nonanylene, 1-oxa-7-azaspiro[3.5]nonanylene, 5 -oxa-2-azaspiro[3.6]decenylene, 5-oxa-2-azaspiro[3.6]decenylene, 5,9-dioxa-2-azaspiro[3.6]decenylene, 5,8-dioxa-2-azaspiro[3.6]decenylene, and 6,9-dioxa-2-azaspiro[3.6]decenylene, wherein the heterocyclylene is selected from one or more R u may be substituted by

[0155] In certain embodiments, Cy 1 teeth, TIFF2025526290000050.tif115154; A heterocyclylene may be one or more R u may be substituted by

[0156] In certain embodiments, Z' is absent.

[0157] In certain embodiments, each Z' is independently C 1~3 Alkylene (e.g., methylene (-CH2-), ethylene (-CH2CH2-), or n-propylene (-CH2CH2CH 2- )), -O-, -NR W -, -(C=O)-, 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 )), or 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 alkylene, carbocyclylene, or heterocyclylene is selected from one or more R u may be substituted by

[0158] In certain embodiments, R W 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)).

[0159] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6. In certain embodiments, p is 7. In certain embodiments, p is 8.

[0160] In certain embodiments, -[Z'] p - is -C(=O)-, C 1~6 Alkylene, *-O-(C 1~6 alkylene)-, *-(C 1~6 alkylene)-(C(=O))-O-, *-(C 1~6 alkylene)-O-, *-C(=O)-(C 1~6 alkylene)-, *-(C 1~6 alkylene)-C(=O)-, 3- to 12-membered heterocyclylene, *-C(=O)-(3- to 12-membered heterocyclylene)-, *-(3- to 12-membered heterocyclylene)-C(=O)-, *-(3- to 12-membered heterocyclylene)-(C 1~6 alkylene)-, *-(C 1~6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C 1~6 alkylene)-(3- to 12-membered heterocyclylene)-(C 1~6 alkylene)-, *-(C 1~6 alkylene)-(3 to 12-membered heterocyclylene)-(C(=O))-, *-(C(=O))-(3 to 12-membered heterocyclylene)-(C 1~6 alkylene)-, *-(3- to 12-membered heterocyclylene)-(C 1~6alkylene)-(C(=O))-, *-(C(=O))-(C 1~6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C 1~6 alkylene)-(C(=O))-(3 to 12-membered heterocyclylene)-, or *-(3 to 12-membered heterocyclylene)-(C(=O))-(C 1~6 alkylene)-, and the alkylene or heterocyclylene is one or more R u where * indicates attachment to C.

[0161] In certain embodiments, -[Z'] p - is -C(=O)-, C 1~6 Alkylene, *-(C 1~6 alkylene)-(C(=O))-O-, *-C(=O)-(C 1~6 alkylene)-, *-(C 1~6 alkylene)-C(=O)-, 3- to 12-membered heterocyclylene, *-(3- to 12-membered heterocyclylene)-(C 1~6 alkylene)-, *-(C(=O))-(3-12 membered heterocyclylene)-(C 1~6 alkylene)-, *-(C(=O))-(C 1~6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C 1~6 alkylene)-(C(═O))-(3- to 12-membered heterocyclylene)-, wherein the alkylene or heterocyclylene is selected from the group consisting of one or more R u where * indicates attachment to C.

[0162] In certain embodiments, L' is W. In certain embodiments, L' is Cy 1 In certain embodiments, L' is Z'.

[0163] In certain embodiments, l is p. In certain embodiments, l is p+1. In certain embodiments, l is p+2.

[0164] In certain embodiments, C is of formula I-1-i: TIFF2025526290000051.tif20128, wherein: R 1 and R 2 together with the intervening carbon atoms form a ring A attached to L, or R 2 and R 3 together with the intervening carbon atom form a ring A attached to L, Ring A is an optionally substituted 7- to 16-membered fused heterocycle or an optionally substituted 7- to 16-membered spiro heterocycle, T is of formula I-2: TIFF2025526290000052.tif27128, wherein: X T1 , X T2 , X T3 , and X T4 Each of the T and i)X T1 is C(OCH3) and X T3 is CF and X T2 and X T4 each of which is CH, or ii) X T1 is C(OCH3) and X T2 is CF and X T3 and X T4 each of which is CH; L is of formula I-3: TIFF2025526290000053.tif10128, wherein: W does not exist, Cy 1 is C 3~12 carbocyclylene or 3- to 12-membered heterocyclylene, wherein the carbocyclylene or heterocyclylene is one or more R u and optionally substituted by Each Z' is independently hydrogen or one or more R u C may be substituted by 1~3 is alkylene, p is an integer selected from 0 to 6.

[0165] In certain embodiments, ring A is TIFF2025526290000054.tif29128, wherein ** indicates attachment to L, and s is an integer selected from 0 to 8, valence permitting; Ring A 2 is C 3~8 It is a carbocyclic ring or a 3- to 8-membered heterocyclic ring.

[0166] 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 3~12 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.

[0167] 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.

[0168] In certain embodiments, each R a independently, 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.

[0169] 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.

[0170] In certain embodiments, each R b are independently hydrogen, C 1~6Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 2~6 Alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C 2~6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3~12 Carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), or spiro[4.5]decanyl (C 10 )), 3- to 12-membered heterocyclyl (e.g., heterocyclyl containing one or two 3- to 8-membered rings and 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 uis optionally replaced by

[0171] 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.

[0172] 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.

[0173] 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.

[0174] In certain embodiments, each R c and each R d 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 2~6Alkynyl (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), 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.

[0175] 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.

[0176] 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 u may be substituted with.

[0177] In certain embodiments, R a , R b , R c , and R d may independently be one or more R z may be substituted with.

[0178] In certain embodiments, R z are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 It is a carbocyclyl or a 3- to 6-membered heterocyclyl.

[0179] 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 1~6alkylamino (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), 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 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.

[0180] In certain embodiments, each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Carbocyclyl, 3- to 12-membered heterocyclyl, C 6~10 aryl, or 5-10 membered heteroaryl, and alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6It may be substituted with one or more substituents selected from carbocyclyl and 3- to 6-membered heterocyclyl.

[0181] 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.

[0182] In certain embodiments, each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6It may be substituted with one or more substituents selected from carbocyclyl and 3- to 6-membered heterocyclyl.

[0183] In certain embodiments, each R u are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 3~6 carbocyclyl, or 3- to 6-membered heterocyclyl, and alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is oxo, halogen, -CN, -NO2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylamino, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 It may be substituted with one or more substituents selected from carbocyclyl and 3- to 6-membered heterocyclyl.

[0184] 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).

[0185] In certain embodiments, two geminal R u together with the carbon atoms to which they are attached, C 3~6Forms 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).

[0186] 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.

[0187] 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 specific combinations of options. For example, although various options for variables X and Z are described herein, the present disclosure may be interpreted as excluding inoperable compound structures caused by specific combinations of options (e.g., when two Xs or two Zs are both nitrogens or both oxygens, or when one of two Xs or one of two Zs is nitrogen while the other is oxygen).

[0188] 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 , C2~4 , 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.

[0189] In certain embodiments, the compound is selected from the compounds of Table X below, or a pharmaceutically acceptable salt thereof.

[0190] In certain embodiments, the compound is selected from the compounds of Table X below.

[0191] [Table X] TIFF2025526290000056.tif216140TIFF2025526290000057.tif213148TIFF2025526290000058.tif214149TIFF2025526290 000059.tif218149TIFF2025526290000060.tif213148TIFF2025526290000061.tif217148TIFF2025526290000062.tif22614 8TIFF2025526290000063.tif218148TIFF2025526290000064.tif219142TIFF2025526290000065.tif218148TIFF2025526290 000066.tif213148TIFF2025526290000067.tif223148TIFF2025526290000068.tif221144TIFF2025526290000069.tif62148

[0192] In certain embodiments, the compound is selected from the compounds in Tables 1-3 or a pharmaceutically acceptable salt thereof.

[0193] In certain embodiments, the compound is selected from the compounds in Tables 1-3.

[0194] In certain embodiments, the compound is selected from the compounds of Table 1 and Table 2 or a pharmaceutically acceptable salt thereof.

[0195] In certain embodiments, the compound is selected from the compounds of Table 1 and Table 2.

[0196] In certain embodiments, the compound is selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof.

[0197] In certain embodiments, the compound is selected from the compounds in Table 1.

[0198] In certain embodiments, the compound is selected from the compounds in Table 2 or a pharmaceutically acceptable salt thereof.

[0199] In certain embodiments, the compound is selected from the compounds in Table 2.

[0200] In certain embodiments, the compound is selected from the compounds in Table 3 or a pharmaceutically acceptable salt thereof.

[0201] In certain embodiments, the compound is selected from the compounds in Table 3.

[0202] [Table 1] TIFF2025526290000071.tif220118TIFF2025526290000072.tif220135TIFF2025526290000073.tif223136TIFF2025526290000074.tif223126TIFF2025526290000075.tif223128TIFF2025526290000076.tif226138TIFF2025526290000077.tif224137TIFF2025526290000078.tif224137TIFF2025526290000079.tif22198TIFF2025526290000080.tif224119TIFF2025526290000081.tif221114TIFF2025526290000082.tif221139TIFF2025526290000083.tif220126TIFF2025526290000084.tif221135TIFF2025526290000085.tif22299TIFF2025526290000086.tif225144TIFF2025526290000087.tif221103TIFF2025526290000088.tif222128TIFF2025526290000089.tif224114TIFF2025526290000090.tif223136TIFF2025526290000091.tif224123TIFF2025526290000092.tif223112TIFF2025526290000093.tif220123TIFF2025526290000094.tif222113TIFF2025526290000095.tif224132TIFF2025526290000096.tif224133TIFF2025526290000097.tif221135TIFF2025526290000098.tif226133TIFF2025526290000099.tif223127TIFF2025526290000100.tif223122TIFF2025526290000101.tif222140TIFF2025526290000102.tif221126TIFF2025526290000103.tif224127TIFF2025526290000104.tif222127TIFF2025526290000105.tif224137TIFF2025526290000106.tif224137TIFF2025526290000107.tif223121TIFF2025526290000108.tif224125TIFF2025526290000109.tif221135TIFF2025526290000110.tif223132TIFF2025526290000111.tif221130TIFF2025526290000112.tif222134TIFF2025526290000113.tif224133TIFF2025526290000114.tif223138TIFF2025526290000115.tif224133TIFF2025526290000116.tif228139TIFF2025526290000117.tif223139TIFF2025526290000118.tif222136TIFF2025526290000119.tif223129TIFF2025526290000120.tif223137TIFF2025526290000121.tif222136TIFF2025526290000122.tif222136TIFF2025526290000123.tif222127TIFF2025526290000124.tif225137TIFF2025526290000125.tif224137TIFF2025526290000126.tif224132TIFF2025526290000127.tif224137TIFF2025526290000128.tif225137TIFF2025526290000129.tif223141TIFF2025526290000130.tif224142TIFF2025526290000131.tif224128TIFF2025526290000132.tif225128TIFF2025526290000133.tif223137TIFF2025526290000134.tif222126TIFF2025526290000135.tif222126TIFF2025526290000136.tif222131TIFF2025526290000137.tif224137TIFF2025526290000138.tif222136TIFF2025526290000139.tif223127TIFF2025526290000140.tif222127TIFF2025526290000141.tif223136TIFF2025526290000142.tif224137TIFF2025526290000143.tif225133TIFF2025526290000144.tif223137TIFF2025526290000145.tif224141TIFF2025526290000146.tif224137TIFF2025526290000147.tif223104TIFF2025526290000148.tif224141TIFF2025526290000149.tif224100TIFF2025526290000150.tif222140.

[0203]

Table 2

[0204]

Table 3

[0205] The compounds of the present disclosure may have advantageous characteristics compared to known compounds, such as known estrogen receptor 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 max and / 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 can be measured according to methods generally available in the art, such as those exemplified herein.

[0206] Due to the presence of double bonds, compounds of the present disclosure may be in the cis or trans, or Z or E configuration. It is understood that while one configuration may be depicted in the structure of a compound or formula of the present disclosure, the present disclosure encompasses other configurations. For example, compounds or formulas of the present disclosure may be depicted in the cis or trans, or Z or E configuration.

[0207] In certain embodiments, 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 certain embodiments, 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 certain embodiments, a compound of the present disclosure (e.g., a compound of any of the formulas disclosed herein or any individual compound) is a hydrate.

[0208] pharmaceutically acceptable salts In certain embodiments, the compounds disclosed herein are present as their pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0209] In certain embodiments, the compounds described herein possess acidic or basic groups and thus react with any of a number of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In certain embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting the purified compound, in its free form, with a suitable acid or base and isolating the salt so formed.

[0210] Examples of pharmaceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, benzoyl ... Etate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, odor Hydrogen chloride, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenanthate Examples of suitable amines include phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undecanoate, and xylenesulfonate.

[0211] 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.

[0212] In certain embodiments, compounds described herein containing free acid groups are reacted with a suitable base, such as a hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1~4 alkyl)4.

[0213] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In certain embodiments, aqueous or oil-soluble or dispersible products are obtained by such quaternization.

[0214] solvate "Solvate" refers to a form of a compound associated with a solvent or water (also referred to as a "hydrate"), usually by a solvolysis reaction. This physical association involves hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the present disclosure may be prepared, for example, in crystalline form, and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In certain instances, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0215] Those skilled in the art of organic chemistry will understand 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 disclosure.

[0216] It will also be understood 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 are within the scope of this disclosure.

[0217] In certain embodiments, the compounds described herein exist as solvates. The present disclosure provides methods of treating diseases by administering such solvates. The present disclosure further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0218] Solvates contain either stoichiometric or non-stoichiometric amounts of solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein can exist in unsolvated and solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0219] Isomers (stereoisomers, geometric isomers, tautomers, etc.) 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."

[0220] 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."

[0221] As used herein, a pure enantiomer is substantially free of the other enantiomer or stereoisomer of the compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" indicate that a compound contains greater than 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.5%, 99.6%, 99.7%, 99.8%, or 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.

[0222] 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.

[0223] 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.

[0224] In the compositions provided herein, the enantiomerically pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure (R)-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such a composition may contain, for example, at least about 95% by weight of the (R)-compound and up to about 5% by weight of the (S)-compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure (S)-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions may comprise, for example, at least about 95% by weight of the (S)-compound and up to about 5% by weight of the (R)-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with few or no excipients or carriers.

[0225] 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.

[0226] In certain embodiments, the compounds described herein exist as geometric isomers. In certain embodiments, the compounds described herein have one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as all corresponding mixtures thereof. All geometric forms of the compounds disclosed herein are contemplated and are within the scope of the present disclosure.

[0227] In certain embodiments, the compounds disclosed herein have one or more chiral centers, and each center exists in the R or S configuration. The compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms, and their corresponding mixtures. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the present disclosure.

[0228] In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and collecting the optically pure enantiomers. In certain embodiments, dissociable complexes are preferred. In certain embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by exploiting these differences. In certain embodiments, diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In certain embodiments, the optically pure enantiomers are then collected with a resolving agent.

[0229] tautomers In certain embodiments, the compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulae described herein.

[0230] 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. 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 may be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest. All tautomeric forms of the compounds disclosed herein are contemplated and within the scope of this disclosure. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0231] 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)).

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] Compound preparation and characterization The compounds of the present disclosure can be prepared in several ways known to those skilled in the art of organic synthesis. As an example, the compounds of the present disclosure can be synthesized using the methods described below, along with synthetic methods known in the art of synthetic organic chemistry, or variations thereof, as will be understood by those skilled in the art. The compounds of the present disclosure (i.e., compounds of the present application (e.g., any compound of the formulas disclosed herein or any individual compound)) can be synthesized by following the steps outlined in the following general synthetic schemes, as well as the examples, schemes, procedures, and / or syntheses described herein (e.g., in the Examples).

[0237] General synthesis method The compounds of the present disclosure can generally be prepared by first preparing a pool of intermediates including a pool of cereblon ligands, a pool of linkers, and a pool of inhibitors, as detailed in the Examples section, followed by subsequent reactions to attach the linkers to the inhibitors and cereblon ligands via metal-catalyzed coupling reactions and reductive amination. Larger pools of compounds can be prepared by selecting different combinations of cereblon ligands, linkers, and inhibitors from each pool. A general synthetic route for preparing inhibitor-linker conjugates via metal-catalyzed coupling reactions, which are then further coupled to cereblon ligands via reductive amination, is summarized below. TIFF2025526290000300.tif139147TIFF2025526290000301.tif122148

[0238] 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 formulae disclosed herein or in any individual compound). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis), including not only racemates but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material can be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds," E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

[0239] 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).

[0240] Suitable references and papers detailing the synthesis of reactants useful in preparing the compounds described herein or providing references to articles describing the preparation include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions", 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L.G. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Further suitable references and papers detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to articles describing the preparation include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons, ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN: 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J.“Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley&Sons, ISBN:0-471-60180-2, Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1, Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9, Solomons, TWG “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0, Stowell, JC, “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2, "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X (8 volumes), "Organic Reactions (1942-2000)" John Wiley & Sons (over 55 volumes), and "Chemistry of Functional Groups" John Wiley & Sons (73 volumes).

[0241] Specific and similar reactants are optionally identified through an index of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries and online. Known but not commercially available chemicals in catalogs are optionally prepared by custom chemical synthesis companies, and many standard chemical supply companies (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0242] 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 the internal standard. Liquid chromatography-mass spectrometry (LC / MS) was collected using a SHIMADZU LCMS-2020EV or an Agilent 1260-6125B LCMS. Purity and low-resolution mass spectral data were measured using an Agilent 1260-6125B LCMS system (equipped with a Diode Array Detector and an Agilent G6125BA Mass Spectrometer) or a Waters Acquity UPLC system (equipped with a Diode Array Detector and a Waters 3100 Mass Detector). Purity was characterized by UV wavelengths of 214 nm, 220 nm, and 254 nm, and by ESI. Column: Poroshell 120EC-C18 2.7 μm 4.6 x 100 mm, flow rate 0.8 mL / min, solvent A (100 / 0.1 water / formic acid), solvent B (100 acetonitrile), gradient: 5% B until 0.3 min, 5 to 95% B from 0.3 to 2 min, 95% B until 4.8 min, 95 to 5% B from 4.8 to 5.4 min, then 5% B until 6.5 min. Alternatively, column: Acquity UPLC BEH C18 1.7 μm 2.1 × 50 mm, flow rate 0.5 mL / min, solvent A (0.1% formic acid in water), solvent B (acetonitrile), gradient: hold 5% B for 0.2 min, 5 to 95% B from 0.2 to 2.0 min, hold 95% B until 3.1 min, then hold 5% B for 3.5 min.

[0243] Biological assays The biological activity of the compounds of the present application may be evaluated using methods and assays known in the art.

[0244] The CRBN-DDB1 binding ability of the present disclosure is determined using HTRF assay technology (Perkin Elmer). Compounds are serially diluted and transferred to a multi-well plate. His-tagged (e.g., CRBN+DDB-DLS7+CXU4) is added, followed by the addition of 60 nM fluorescent probe (e.g., Cy5-labeled thalidomide) and MAb anti-6HIS Tb cryptate gold in assay buffer, and the reaction is carried out. After incubation at room temperature for 1 hour, the HTRF signal is read, for example, on an Envision reader (Perkin Elmer).

[0245] The ER degradation activity of compounds can be evaluated in MCF-7 and T47D cells. MCF-7 and T47D cells are seeded and then treated with compounds at specific concentrations (e.g., 0.02-300 nM). DMSO can be used as a vehicle control. Cells are fixed, blocked with Intercept (PBS) Blocking Buffer (e.g., Li-COR, Odyssey Blocking Buffer), and stained with ER (e.g., 1:500, Cell signaling) primary antibody overnight in a cold room (e.g., 4°C). Secondary antibodies (e.g., IRDye800CW goat anti-rabbit IgG) and CellTag700 staining solution are added in Intercept (PBS) Blocking Buffer. Finally, the cell plate is placed in an incubator to dry. Images and signals are captured on an Odyssey® DLx Imaging System.

[0246] In vitro assays can be performed using the MCF-7 and T47D Cell Titer Glo (CTG) assay. MCF-7 and T47D cells (derived from HDB) are cultured in multi-well white plates containing phenol red-free RPMI 1640 + 10% CS-FBS + 1% P / S medium (e.g., 1,000 cells / well). On day 0, cells are treated with specific concentrations (e.g., 0.5-10,000 nM) of compounds (DMSO and staurosporine as controls). On days 0 and 6, Cell Titer Glo reagent is added, followed by a 30-minute incubation for data generation, followed by reading on an EnVision.

[0247] For intracellular Western blot analysis, cells are seeded into multi-well plates (e.g., 40,000 or 10,000 cells / well). A specific concentration of diluted compound is added (final 0.5% DMSO), and the cells are incubated for a specific period (e.g., 16 hours). Formaldehyde (e.g., PBS:FA=9:1) is added, followed by washing with PBS. The cells are blocked with Licor blocking buffer (Li-Cor). The relative ER percentage in treated cells is obtained by comparing the value in treated wells with the values in untreated wells and DMSO-treated wells, which are set as 100%.

[0248] For Western blot analysis, compound-treated cells were lysed in radioimmunoprecipitation assay protein lysis and extraction buffer (e.g., 25 mmol / L Tris.HCl, pH 7.6, 150 mmol / L NaCl, 1% Nonidet P-40, 1% sodium deoxycholate, and 0.1% sodium dodecyl sulfate) containing a proteinase inhibitor cocktail. Equal amounts of total protein were electrophoresed through a 10% SDS-polyacrylamide gel after determining protein concentration by BCA assay. Separated protein bands were transferred onto PVDF membranes and blotted against different antibodies. The blots were scanned, and band intensities were quantified (e.g., by using GelQuant.NET software provided by biochemlabsolutions.com). The relative mean intensities of the target proteins are shown after normalization to the intensity of the glyceraldehyde-3-phosphate dehydrogenase band.

[0249] For cell proliferation assays, cells are seeded overnight in multi-well plates at a specific concentration (e.g., 1500 / well). Then, the cells are treated with compounds. After compound treatment, 10% WST-8 reagent is added to the culture medium for a specific period (e.g., 4 days) and incubated under specific conditions (e.g., 2.5 hours in a CO2 incubator at 37°C). The absorbance is measured for each sample using a microplate reader at a specific wavelength (e.g., 450 nm). The relative absorbance is calculated relative to the vehicle control from three individual replicates.

[0250] For in vivo pharmacodynamic and efficacy studies, breast cancer cell line xenografts are developed as follows: mice are given 17β-estradiol in their drinking water for a specific period of time. A specific number of cells (e.g., 5 million) in 50% Matrigel are injected subcutaneously into SCID mice to induce tumor formation. Tumors are then grown to a specific size (e.g., 100-400 mm). 3), mice are treated with vehicle control (e.g., 5% DMSO, 10% solvate, 85% water) or compound and sacrificed at various time points. Tumor tissues are collected for analysis. Tumor size and animal weights are measured 2-3 times a week. Tumor volume (mm 3 ) = (length × width2) / 2. Tumor growth inhibition was calculated using TGI (%) = (Vc - Vt) / (Vc - Vo) × 100, where Vc, Vt are the median values of the control and treated groups at the end of the study, and Vo is at the beginning.

[0251] How to use In certain aspects, the present disclosure provides a method of degrading estrogen receptors in a subject, comprising administering to the subject a compound disclosed herein.

[0252] In certain aspects, the present disclosure provides for the use of a compound disclosed herein in the manufacture of a medicament for degrading estrogen receptors in a subject.

[0253] In certain aspects, the present disclosure provides a compound disclosed herein for use in degrading estrogen receptors in a subject.

[0254] In certain aspects, the present disclosure provides methods of 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).

[0255] 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).

[0256] In certain aspects, the disclosure provides 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.

[0257] In certain aspects, the disclosure provides for the use of a compound disclosed herein in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof.

[0258] In certain aspects, the disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.

[0259] In certain aspects, the disclosure provides compounds disclosed herein for use in treating a disease or disorder in a subject in need thereof.

[0260] In certain embodiments, the disease or disorder is an estrogen receptor-mediated disease or disorder.

[0261] In certain embodiments, the disease or disorder is cancer.

[0262] In certain embodiments, the disease or disorder is breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or esophageal cancer.

[0263] In certain embodiments, cancers include, but are not limited to, one or more of the cancers in Table A.

[0264] [Table A] TIFF2025526290000303.tif226149TIFF2025526290000304.tif138149

[0265] 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.

[0266] [Table B]

[0267] In certain embodiments, the subject is a mammal.

[0268] In certain embodiments, the subject is a human.

[0269] definition As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings indicated below.

[0270] chemical definition Definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Organic compounds are generally identified according to the principles of organic chemistry, and specific functional groups are generally defined as described therein, Ed. (inside cover). Further, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley&Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd Edition, Cambridge University Press, Cambridge, 1987.

[0271] 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).

[0272] The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0273] 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.

[0274] 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 disclosure. In describing the present disclosure, 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.

[0275] As used herein, "alkyl" refers to an alkyl group having 1 to 20 carbon atoms ("C 1~20 In certain embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1~12 In certain embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In certain embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 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 ("C 1~7In 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). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10 Common alkyl abbreviations include Me(-CH), Et(-CHCH), i-Pr(-CH(CH)), n-Pr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0276] 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 is provided for a particular "alkylene" group, it is understood that the range or number refers to the range or number of carbons in a linear divalent chain of carbons. An "alkylene" group may be unsubstituted or substituted with one or more substituents described herein. Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCHCH-), and the like. For example, exemplary substituted divalent alkylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0277] As used herein, "alkenyl" refers to an alkyl group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20 In certain embodiments, alkenyl groups have 2 to 10 carbon atoms ("C 2~10 In certain embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In certain embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8In 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 is independently optionally 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.

[0278] 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 divalent carbon chain. An "alkenylene" group may be substituted or unsubstituted with one or more substituents described herein. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH-, -CH-CH=CH-). For example, exemplary substituted divalent alkenylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0279] As used herein, "alkynyl" refers to an alkyl group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and, optionally, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2~20 In certain embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 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 2~7 In certain embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2~6 In certain embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In certain embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4 In certain embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In certain embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted ("substituted alkynyl") with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0280] 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.

[0281] As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, where one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, heteroalkyl groups have 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("C 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 ("C 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 ("C 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 ("C 1~7 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("C 1~6 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("C 1~5 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and / or 2 heteroatoms ("C 1~4 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("C 1~3 In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("C 1~2In certain embodiments, the heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("C heteroalkyl"). In certain embodiments, the heteroalkyl group is a saturated group having two to six carbon atoms and one or two heteroatoms ("C heteroalkyl"). 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 C 1~10 In certain embodiments, the heteroalkyl group is a substituted C 1~10 It is heteroalkyl.

[0282] As used herein, the term "heteroalkenyl" refers to an alkenyl group, as defined herein, that further contains one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), where one or more heteroatoms are inserted between adjacent carbon atoms in 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 ("C 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 ("C 2~9 In certain embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("C 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 ("C 2~7In certain embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("C 2~6 In certain embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("C 2~5 In certain embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("C 2~4 In certain embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom ("C 2~3 In certain embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("C 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 C 2~10 In certain embodiments, the heteroalkenyl group is a substituted C 2~10 It is heteroalkenyl.

[0283] As used herein, the term "heteroalkynyl" refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein 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 heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("C 2~10In certain embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("C 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 (“C 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 ("C 2~7 In certain embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("C 2~6 In certain embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("C 2~5 In certain embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("C 2~4 In certain embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom ("C 2~3 In certain embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("C 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 C 2~10 In certain embodiments, the heteroalkynyl group is a substituted C 2~10 It is heteroalkynyl.

[0284] 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," "heteroalkynylene," or "heteroalkynylene" group, it is understood that the range or number refers to the range or number of carbons in a linear divalent chain. "Heteroalkylene," "heteroalkenylene," and "heteroalkynylene" groups can be substituted or unsubstituted with one or more substituents described herein.

[0285] "Aryl" means 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 0 heteroatoms provided in the aryl group ("C6 aryl," e.g., phenyl). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl," e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C6 aryl," e.g., phenyl). 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"aryl" (e.g., anthracyl). Typical aryl groups include, but are not limited to, groups derived from acentrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, obolene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group may independently be substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0286] "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 pi electrons shared by the cyclic array) having ring carbon atoms and 1 to 8 ring heteroatoms provided to the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings.

[0287] "Heteroaryl" also includes ring systems in which the heteroaryl group is fused to one or more aryl groups, as defined above, and the point of attachment is on either the heteroaryl group or the one or more aryl groups; in such cases, the number of ring members refers to the total number of ring members in the fused (aryl / heteroaryl) ring system. If substitution is indicated in such cases, unless otherwise specified, the substitution can occur on either the heteroaryl group or the one or more aryl groups. In bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring containing the heteroatom (e.g., 2-indolyl) or on the ring without the heteroatom (e.g., 5-indolyl).

[0288] 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, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In certain embodiments, a 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group may be independently 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.

[0289] 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.

[0290] "Carbocyclyl" means a non-aromatic ring system containing 3 to 12 ring carbon atoms ("C 3~12"Carbocyclyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3~10 In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms ("C 5~12 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms ("C 5~8 In certain embodiments, the carbocyclyl group has 5 or 6 ring carbon atoms ("C 5~6 carbocyclyl). Exemplary C 3~6 Carbocyclyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3~8 As for carbocyclyl, the aforementioned C 3~6 Examples 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 (C10 ), spiro[4.5]decanyl (C 10 ) and the like, but are not limited to these.

[0291] In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 12 ring carbon atoms ("C 3~12 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 8 ring carbon atoms ("C 3~8 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 6 ring carbon atoms ("C 3~6 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 5 to 12 ring carbon atoms ("C 5~12 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms ("C 5~8 In certain embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 5 or 6 ring carbon atoms ("C 5~6 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 3~6Examples 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.

[0292] 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.

[0293] "Fused carbocyclyl" or "fused carbocycle" refers to a ring system in which a carbocyclyl group, as defined above, is fused, i.e., shares one common bond with, one or more carbocyclyl groups, as defined above, 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 carbocyclyl fused ring system. If substitution is indicated, unless otherwise specified, the substitution can occur on either of the fused rings.

[0294] "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 either of the carbocyclyl rings 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 either of the carbocyclyl rings in which the spiro structure is embedded.

[0295] "Bridged carbocyclyl" or "bridged carbocycle" refers to a ring system in which a carbocyclyl group, as defined above, forms a bridged structure, i.e., shares two or more common atoms (and therefore two or more bonds) with one or more carbocyclyl groups, as defined above, 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 bridged ring. If substitution is indicated, unless otherwise specified, the substitution can occur on either of the carbocyclyl rings in which the bridged structure is embedded.

[0296] "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.

[0297] 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 one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0298] In certain embodiments, heterocyclyl groups contain fused, bridged, or spiro ring systems and can be either monocyclic ("monocyclic heterocyclyl") or polycyclic ("polycyclic heterocyclyl"), which can be saturated or partially unsaturated. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl group is fused to one or more carbocyclyl groups, as defined above, and the point of attachment is on either the carbocyclyl or the heterocyclyl ring; in such cases, the number of ring members indicates the total number of ring members in the entire ring system. If substitution is indicated in such instances, unless otherwise specified, the substitution can occur on either the heterocyclyl group or the one or more carbocyclyl groups. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 12-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 12-membered heterocyclyl.

[0299] "Fused heterocyclyl" or "fused heterocycle" refers to a ring system in which a heterocyclyl group, as defined above, is fused, i.e., shares a common bond with, one or more heterocyclyl or carbocyclyl groups, as defined above, and the point of attachment is on either of the fused rings. In such instances, the number of carbons 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.

[0300] "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.

[0301] "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 two or more common atoms (and therefore two or more bonds) with one or more heterocyclyl or carbocyclyl groups, as defined above, and the point of attachment is on either of the heterocyclyl or carbocyclyl rings 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 can occur on either of the bridged rings.

[0302] "Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group are replaced by a nitrogen, oxygen, sulfur, boron, phosphorus, or silicon heteroatom, where valence allows. Hetero can apply to any of the above hydrocarbyl groups having 1 to 5, especially 1 to 3, heteroatoms.

[0303] As used herein, "alkoxy" refers to the group -OR, where R is alkyl as defined herein. 1~6 Alkoxy refers to an —OR group, where each R is a C as defined herein. 1~6 An exemplary C 1~6Alkyl is described above.

[0304] 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.

[0305] "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.

[0306] "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.

[0307] As used herein, "protecting group" is art-recognized and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction. Common functional groups that need to be protected include, but are not limited to, hydroxyl, amino, thiol, and carboxylic acid. Accordingly, the protecting groups are referred to as hydroxyl-protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid-protecting groups, respectively.

[0308] 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)).

[0309] 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)).

[0310] 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)).

[0311] 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.

[0312] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present disclosure is not intended to be limited in any way by the above exemplary list of substituents.

[0313] 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.

[0314] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure 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-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, and camphorsulfonic acid. or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinates with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Further salts include, by way of example only, salts of non-toxic organic or inorganic acids such as sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the compound contains a basic functional group, hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc.

[0315] "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.

[0316] 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 affect such treatment or prevention. The "effective amount" may vary depending on the compound, the disease and its severity, and 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.

[0317] "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).

[0318] 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.

[0319] "Treating" or "treatment" or "therapeutic treatment" of any disease or disorder, in certain embodiments, refers 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 certain embodiments, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In certain embodiments, "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 further embodiments, "treating" or "treatment" relates to slowing the progression of the disease.

[0320] 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; 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. In certain embodiments, the numerical value or numerical range varies by 1%, 2%, 3%, 4%, or 5% of the stated numerical value or numerical range. In certain embodiments, the numerical value or numerical range varies by 1%, 2%, or 3% of the stated numerical value or numerical range.

[0321] The term "comprising" (and related terms, e.g., "comprise" or "comprises," or "having" or "including") is not intended to exclude that in other particular embodiments, any embodiment of the material, composition, method, or process described herein, "consists of" or "consists essentially of" the recited features.

[0322] 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 certain embodiments, to A only (optionally including elements other than B); in certain embodiments, to B only (optionally including elements other than A); in certain embodiments, to both A and B (optionally including other elements); etc.

[0323] 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.

[0324] 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 certain embodiments, to at least one A, optionally including more than one, and no B (and optionally including elements other than B); at least one B, optionally including more than one, and no A (and optionally including elements other than A); in certain embodiments, at least one A, optionally including more than one, and at least one B, optionally including more than one (and optionally including other elements);

[0325] 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.

[0326] 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.

[0327] 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 appended claims, and equivalents thereto, are claimed. [Example]

[0328] 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.

[0329] It should be understood that values presented in the examples are approximate and subject to instrument and / or experimental variation.

[0330] The following abbreviations have been used in the description and examples: ACN acetonitrile; AIBN azobisisobutyronitrile; BINAP ([1,1'-binaphthalene]-2,2'-diyl)bis(diphenylphosphane); BPO dibenzoyl peroxide; DCE 1,2-dichloroethane; DCM dichloromethane; DEAD diethyl azodicarboxylate; DIPEA N,N-diisopropylethylamine; DMF N,N-dimethylformamide; DMA N,N-dimethylacetamide; DMSO dimethyl sulfoxide; EA ethyl acetate; FA formic acid; HMTA 1,3,5,7-tetraazaadamantane; hr hour; hrs hour; IPA isopropyl alcohol; IPE diisopropyl ether; K2CO3 potassium carbonate; m-CPBA 3-chlorobenzenecarboperoxy acid; LC / MS liquid chromatography-mass spectrometry; MeOH methanol; MS mass spectrometry; mL milliliter; NaBH3CN Sodium cyanoborohydride; NBS N-bromosuccinimide; NCS N-chlorosuccinimide; NMP N-methylpyrrolidinone; NMR Nuclear magnetic resonance; PE Petroleum ether; ppm / parts per million; T3P Propanephosphonic anhydride; TEA Triethylamine; THF Tetrahydrofuran

[0331] I. Synthesis and Characterization of Intermediates and "A" Compounds Chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company) and used without further purification.

[0332] To obtain the compounds described in the following examples and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

[0333] The LC-MS method is outlined below. Method A: Waters SunFire C18 50*4.6mm 5um 2.000ml / min 2.6min Column temperature: 40℃ Gradient: 5% B held for 0.2 min, increased to 95% B within 1.40 min, held at 95% B for 0.9 min, then returned to 5% B within 0.01 min Pump A: 0.1% formic acid (FA) and 10% acetonitrile (ACN) in HO Pump B: 0.1% FA and 10% HO in ACN. Method B: Waters SunFire C18 50*4.6mm 5um 2.000ml / min 2.6min Column temperature: 40℃ Gradient: 5% B held for 0.2 min, increased to 95% B within 1.40 min, held at 95% B for 0.9 min, then returned to 5% B within 0.01 min Pump A: 0.03% trifluoroacetic acid (TFA) in HO Pump B: 0.03% TFA in ACN Method C: Column: Sunfire C18 150*4.6mm 5um 1.00ml / min Column temperature: 40℃ Gradient: 10% B held for 1.8 min, increased to 95% B within 10.2 min, Hold for 3.0 minutes, then return to 10% B within 0.01 minutes Pump A: 0.03% TFA in HO Pump B: 0.03% TFA in ACN Method D: Column: Luna C18 30 x 2.0 mm 3 μm 1,200 ml / min 1.5 min Column temperature: 50°C 5% B increased to 95% B within 0.7 min, held at 95% B for 0.4 min, returned to 5% B within 0.01 min Pump A: 0.03% TFA in HO Pump B: 0.03% TFA in ACN Method E: SunFire C18 50*4.6mm 5um 2.6min 2.0ml / min Temperature: 40℃ Gradient: 10% B increased to 30% B in 0.40 min, increased to 95% B within 1.60 min, held at 95% B for 0.90 min, returned to 10% B within 0.01 min, A70B30 Method F: SunFire C18 50*4.6mm 5um 2.6min 2.0ml / min Temperature: 40℃ Gradient: 10% B increasing to 30% B in 0.40 min, increasing to 95% B within 1.60 min, holding at 95% B for 0.90 min, returning to 10% B within 0.01 min, A50B50.

[0334] Unless otherwise noted, reaction mixtures were magnetically stirred under a nitrogen atmosphere at room temperature (rt). When solutions were "dried," they were typically dried over a desiccant such as NaSO or MgSO. When mixtures, solutions, and extracts were "concentrated," they were typically concentrated on a rotary evaporator under reduced pressure.

[0335] Compound purification was performed as needed using a variety of conventional methods, including, but not limited to, normal-phase or reverse-phase HPLC, or preparative chromatography under acidic, neutral, or basic conditions using either flash columns or preparative TLC plates.

[0336] Flash chromatography was performed on a Biotage Isolera One using columns with 200-300 mesh silica gel particles. Analytical and preparative thin-layer chromatography was performed using silica gel 60 GF254 plates. Normal-phase silica gel chromatography (FCC) was also performed on silica gel (SiO2) using prepacked cartridges.

[0337] Preparative reversed-phase high performance liquid chromatography (RP HPLC) was performed either: Method 1. Preparative HPLC using a Waters-Sunfire C18 21.2 x 250 mm x 10 um and a mobile phase of 10-20% ACN in water (0.1% HCOOH) over 15 minutes, followed by a 5 minute hold at 100% ACN at a flow rate of 20 mL / min; or

[0338] Method 2. Preparative supercritical fluid high performance liquid chromatography (SFC) was performed on a Waters 150 Prep-SFC system. The ABPR was set at 100 bar to maintain CO2 at SF conditions, and flow rates ranged from 70 g / min to 140 g / min, depending on the compound characteristics. The column temperature was ambient.

[0339] Unless otherwise specified, nuclear magnetic resonance (NMR) spectra were recorded using a Brucker AVANCE NEO 400 MHz at approximately 20-30°C. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet; ddd, double of doublet; dt, double of triplet; bs, broad signal. Chemical shifts are reported in parts per million (ppm, δ) downfield from tetramethylsilane. It will be understood that for compounds containing exchangeable protons, the protons may or may not be visible on the NMR spectrum, depending on the choice of solvent used to run the NMR spectrum and the concentration of the compound in solution.

[0340] Mass spectra (MS) were obtained on a SHIMADZU LC-MS-2020MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated masses correspond to exact masses.

[0341] Chemical names were generated using ChemDraw Ultra 12.0, ChemDraw Ultra 14.0 (CambridgeSoft Corp., Cambridge, MA), or ACD / Name Version 10.01 (Advanced Chemistry).

[0342] Compounds designated as R* or S* are enantiopure compounds where the absolute configuration has not been determined.

[0343] Intermediate 1: 1-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine TIFF2025526290000306.tif110148

[0344] Step 1: 6-(benzyloxy)-3,4-dihydronaphthalen-1(2H)-one To a solution of 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (25 g, 154.14 mmol, 1 equiv.) and KCO (46.2 g, 308.28 mmol, 2 equiv.) in CHCN (350 mL) was added BnBr (3.1 g, 184.96 mmol, 1.2 equiv.) and stirred at 50 °C for 2 h. LCMS showed the reaction was complete. The reaction was concentrated in vacuo to give the product 6-(benzyloxy)-3,4-dihydronaphthalen-1(2H)-one (30.3 g, 78%). LC-MS purity 100% (UV at 254 nm), 253 [M+H]. + .

[0345] Step 2: 6-(benzyloxy)-1-(4-bromo-2-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-ol To a solution of 4-bromo-1-iodo-2-methoxybenzene (14.9 g, 47.6 mmol, 1.2 equiv) in THF (100 mL) cooled to −80° C., n-BuLi (2.5 M, 19.1 mL, 47.6 mmol, 1.2 equiv) was added and stirred under N for 1 h. Then, 6-(benzyloxy)-3,4-dihydronaphthalen-1(2H)-one (10 g, 39.6 mmol, 1.2 equiv) in THF (30 mL) was added and stirred at −80° C. for 3 h. Upon completion of the reaction, the mixture was quenched with HO (200 mL) and extracted with EA (400 mL) to give the crude product. The residue was purified by column chromatography on silica gel (PE:EA=10:1) to give the product 6-(benzyloxy)-1-(4-bromo-2-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-ol (7.3 g, 42%) as an oil.

[0346] LC-MS purity: 100% (UV at 254 nm), 439, 451 [M+H] + .

[0347] Step 3: 7-(benzyloxy)-4-(4-bromo-2-methoxyphenyl)-1,2-dihydronaphthalene To a mixture of 6-(benzyloxy)-1-(4-bromo-2-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-ol (7 g, 15.98 mmol, 1 equiv.) in MeOH (70 mL), TsOH (60 mg, 0.32 mmol, 0.02 equiv.) was added and stirred at 50° C. for 0.5 h. LCMS showed the reaction was complete. The mixture was concentrated to give 7-(benzyloxy)-4-(4-bromo-2-methoxyphenyl)-1,2-dihydronaphthalene (5.8 g, 86%) as a white solid. LC-MS purity: 99.26% (UV at 254 nm), 421, 423 [M+H] + .

[0348] Step 4: 1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine Ruphos (134.0 mg, 0.286 mmol, 0.2 equiv.), Ruphos Pd G3 (240.0 mg, 0.286 mmol, 0.2 equiv.), and t-BuONa (550.0 mg, 5.72 mmol, 4.0 equiv.) were added to a degassed solution of 7-(benzyloxy)-4-(4-bromo-2-methoxyphenyl)-1,2-dihydronaphthalene (600.0 mg, 1.428 mmol, 1.0 equiv.) and 4-(dimethoxymethyl)piperidine (340.2 mg, 2.14 mmol, 1.5 equiv.) in 1,4-dioxane (30 mL). The reaction mixture was stirred at 100° C. for 2 hours. LC-MS indicated the reaction was complete. The reaction mixture was cooled to room temperature, filtered, and the precipitate was washed with THF (30 mL × 2). The filtrate was evaporated, and the residue was purified by SiO column chromatography (EtOAc:PE = 1:5) to give 1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine (530 mg, 74.3%) as a yellow oil. LC-MS purity: 98.3% (UV at 254 nm), 500.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.43-7.32(m,5H),7.03(d,J=8.0Hz,1H),6.80(d,J=2.4Hz,1H),6.69-6.62(m,2 H),6.55-6.53(m,2H),5.86(t,J=4.4Hz,1H),5.03(s,2H),4.10(d,J=7.6Hz,1H) ,3.75-3.72(m,2H),3.68(s,3H),3.39(s,6H),2.87-2.83(m,2H),2.75-2.68(m, 2H), 2.42-2.36 (m, 2H), 1.89-1.86 (m, 2H), 1.80-1.75 (m, 1H), 1.53-1.43 (m, 2H).

[0349] Step 5: 11-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine To a mixture of 1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine (1.85 g, 3.7 mmol, 1 equiv.) in DMF (20 mL) was slowly added dropwise PyBr (1.18 g, 3.7 mmol, 1 equiv.) in DMF (10 mL) over 30 min at 0 °C, then stirred at 0 °C for 1 h. LC-MS showed the reaction was complete. 10 mL of saturated NH Cl solution was added followed by 110 mL of water and extracted with EtOAc (120 mL × 3). The combined organic layers were washed with water (120 mL × 2), brine (120 mL), dried over Na SO , filtered, and the filtrate was evaporated. The residue was purified by Chem-flash to give 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine (1.51 g, 70.1%) as a yellow solid.

[0350] LC-MS purity: 88.4% (UV at 254 nm), 580.2 [M+H] + .

[0351] Step 6: 1-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine Pd(dppf)Cl (227 mg, 0.311 mmol, 0.1 equiv.) and NaCO (660 mg, 6.22 mmol, 2.0 equiv.) were added to a degassed solution of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine (1.79 g, 3.11 mmol, 1.0 equiv.) and phenylboronic acid (532 mg, 4.35 mmol, 1.4 equiv.) in 1,4-dioxane / HO (40 mL / 4 mL). The reaction mixture was stirred at 90 °C for 16 h. LC-MS indicated the reaction was complete. The reaction mixture was cooled to room temperature, filtered, the precipitate was washed with THF (40 mL × 2), the filtrate was evaporated, and the residue was purified by Chemflash to give 1-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine (1.48 g, 82.8%) as a yellow oil.

[0352] LC-MS purity: 99.4% (UV at 254 nm), 576.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.43-7.32(m,5H),7.10-6.99(m,5H),6.83(d,J=2.4Hz,1H),6.74(d,J=8.0Hz, 1H),6.68-6.61(m,2H),6.40-6.37(m,2H),5.05(s,2H),4.08(d,J=7.6Hz,1H),3 .68-3.64(m,2H),3.51(s,3H),3.37(s,6H),2.98-2.92(m,2H),2.80-2.76(m,2 H),2.68-2.62(m,2H),1.87-1.84(m,2H),1.77-1.73(m,1H),1.51-1.44(m,2H).

[0353] Step 7: 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol A mixture of 1-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine (1.48 g, 2.57 mmol, 1.0 equiv) and Pd / C (700 mg) in MeOH (150 mL) was degassed under reduced pressure and purged with H atmosphere, and the reaction mixture was heated to 40 °C for 16 h. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature, filtered, the precipitate was washed with EtOAc (20 mL × 2), the filtrate was evaporated, and the residue was purified by Chemflash to give 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (1.12 g, 89.4%) as a yellow solid.

[0354] LC-MS purity: 99.4% (UV at 254 nm), 488.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.10-7.03(m,3H),6.79-6.76(m,3H),6.65(s,1H),6.51-6.48(m,2H),6.34(d,J =8.0Hz,1H),6.10(s,1H),4.77(d,J=4.8Hz,1H),4.07(d,J=7.2Hz,1H),3.60-3.5 7(m,2H),3.36(s,6H),3.29-3.25(m,1H),3.00-2.97(m,5H),2.59(t,J=11.2Hz, 2H), 2.32-2.21(m, 1H), 1.83-1.80(m, 2H), 1.73-1.68(m, 3H), 1.49-1.43(m, 2H).

[0355] Step 8: (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol and (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (1.12 g, 2.3 mmol) was separated by SFC to give (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (550 mg) and (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (550 mg).

[0356] Step 9: 1-(4-((1S,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methoxyphenyl)piperidine-4-carbaldehyde and 1-(4-((1R,2R)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methoxyphenyl)piperidine-4-carbaldehyde A mixture of (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (100 mg) or (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (100 mg) and formic acid (5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give 1-(4-((1S,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methoxyphenyl)piperidine-4-carbaldehyde and 1-(4-((1R,2R)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methoxyphenyl)piperidine-4-carbaldehyde (105 mg, crude) as a dark red oil, which was used directly without further purification.

[0357] LC-MS purity: 99.5% (UV at 254 nm), 442.2 [M+H] + .

[0358] Intermediate 2: 5-(4-(3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decan-8-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol TIFF2025526290000307.tif53148 Process 2-1: 8-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decane To a solution of 7-(benzyloxy)-4-(4-bromo-2-methoxyphenyl)-1,2-dihydronaphthalene (1.1 g, 2.61 mmol, 1 equiv.), 3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decane (562.1 mg, 2.61 mmol, 1 equiv.), t-BuONa (752.7 mg, 7.83 mmol, 3.0 equiv.), and Ruphos (121.6 mg, 0.26 mmol, 0.1 equiv.) in 1,4-dioxane (20 mL) was added Ruphos Pd G3 (218.2 mg, 0.26 mmol, 0.1 equiv.) under a N2 atmosphere. The mixture was heated to 100 °C for 2 h. LC-MS indicated the reaction was complete. The reaction mixture was cooled to room temperature, filtered, and the precipitate was washed with THF (30 mL × 2). The filtrate was evaporated, and the residue was purified by SiO column chromatography (EtOAc:PE = 1:5) to give 8-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decane (1.2 g, 82.7%) as a yellow oil.

[0359] LC-MS purity: 100% (UV at 254 nm), LC-MS: 556.2 [M+H] + .

[0360] Step 2-2: 8-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decane To a mixture of 8-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decane (1.2 g, 2.16 mmol, 1 equiv.) in DMF (20 mL) was slowly added dropwise PyBr (686.3 mg, 2.16 mmol, 1 equiv.) in DMF (10 mL) over 30 min at 0 °C, then stirred at 0 °C for 1 h. LC-MS showed the reaction was complete. 10 mL of saturated NH Cl solution was added followed by 110 mL of water and extracted with EtOAc (120 mL × 3). The combined organic layers were washed with water (120 mL × 2), brine (120 mL), dried over Na SO , filtered, and the filtrate was evaporated. The residue was purified by Chem-flash to give 8-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decane (900 mg, 65.7%) as a yellow solid.

[0361] LC-MS purity: 100% (UV at 254 nm), LC-MS: 634.1, 636.3 [M+H] + .

[0362] Step 2-3: 8-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decane To a solution of compound 1 (900 mg, 1.42 mmol, 1 equiv.) in dioxane (20 mL), compound 2 (207.98 mg, 1.70 mmol, 1.2 equiv.), HO (2 mL), KCO (386.73 mg, 2.84 mmol, 2 equiv.), and Pd(dppf)Cl (51.9 mg, 0.07 mmol, 0.05 equiv.) were added under a N atmosphere. The mixture was heated to 100 °C for 2 h. The solution was red and cloudy. LC-MS showed that the starting material was completely consumed and the desired compound was detected. The mixture was concentrated to give a residue. The residue was purified by Chemflash to give 8-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decane (815 mg, yellow, oil, 90.96% yield). LC-MS purity: 100% (UV at 254 nm), LC-MS: 632.1 [M+H] + .

[0363] Step 2-4: 5-(4-(3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decan-8-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol To a solution of 8-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decane (815 mg, 1.29 mmol, 1 equiv.) in MeOH (15 mL) was added Pd / C (82 mg, 0.38 mmol, 0.3 equiv.) under an atmosphere of H (15 Psi). The mixture was heated to 40° C. for 16 h. The solution was black and cloudy. LC-MS showed that the starting material was completely consumed and the desired compound was detected. The mixture was filtered and concentrated to give a residue. The residue was purified by Chemflash to give 5-(4-(3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decan-8-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (640 mg, yellow, oil, 91.25% yield).

[0364] LC-MS purity: 100% (UV at 254 nm), LC-MS: 544.2 [M+H] +

[0365] Intermediate 3: 5-(4-(2-(dimethoxymethyl)-7-azaspiro[3.5]nonan-7-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol TIFF2025526290000308.tif67149 Process 3-1: 7-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane Ruphos (332.0 mg, 0.712 mmol, 0.2 equiv.), Ruphos Pd G3 (596.0 mg, 0.712 mmol, 0.2 equiv.), and t-BuONa (1.37 g, 14.2 mmol, 4.0 equiv.) were added to a degassed solution of 7-(benzyloxy)-4-(4-bromo-2-methoxyphenyl)-1,2-dihydronaphthalene (1.5 g, 3.56 mmol, 1.0 equiv.) and 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane (710.0 mg, 3.56 mmol, 1.0 equiv.) in 1,4-dioxane (20 mL). The reaction mixture was heated to 100 °C and stirred for 16 h. LC-MS indicated the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water, washed with EA, and the organic phase was dried over NaSO and concentrated in vacuo. The residue was purified by SiO column chromatography (EtOAc:PE=1:5) to give 7-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane (856 mg, 45%) as a yellow oil.

[0366] LC-MS purity: 100% (UV at 254 nm), MS: 540.3 [M+H] + .

[0367] Step 3-2: 7-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane To a mixture of 7-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane (856 mg, 1.59 mmol, 1 equiv.) in DMF (20 mL) was slowly added dropwise PyBr (507.8 mg, 1.59 mmol, 1 equiv.) in DMF (10 mL) over 30 min at 0 °C, then stirred at 0 °C for 1 h. LC-MS showed the reaction was complete. 10 mL of saturated NH Cl solution was added followed by water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na SO , filtered, and the filtrate was evaporated. The residue was purified by Chem-flash to give 7-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane (750 mg, 76%) as a yellow solid.

[0368] LC-MS purity: 100% (UV at 254 nm), MS: 618.2 [M+H] + .

[0369] Step 3-3: 7-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane Pd(dppf)Cl (88.4 mg, 0.121 mmol, 0.1 equiv.) and NaCO (384.7 mg, 3.63 mmol, 3.0 equiv.) were added to a degassed solution of 7-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane (750 mg, 1.21 mmol, 1.0 equiv.) and phenylboronic acid (177 mg, 1.452 mmol, 1.2 equiv.) in 1,4-dioxane / HO (30 mL / 3 mL). The reaction mixture was stirred at 90 °C for 16 h. LC-MS indicated the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water, washed with EtOAc, and the organic phase was dried over NaSO and concentrated in vacuo. The residue was purified by SiO column chromatography (EtOAc:PE=1:5) to give 7-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane (605 mg, 81%) as a yellow oil.

[0370] LC-MS purity: 100% (UV at 254 nm), MS: 616.4 [M+H] + .

[0371] Step 3-4: 5-(4-(2-(dimethoxymethyl)-7-azaspiro[3.5]nonan-7-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol A mixture of 7-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane (605 mg, 0.98 mmol, 1.0 equiv) and Pd / C (182 mg) in MeOH (20 mL) was degassed under reduced pressure and purged with an H atmosphere, and the reaction mixture was heated to 40° C. for 16 h. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature, filtered, the precipitate washed with MeOH, the filtrate evaporated, and the residue purified by Chemflash to give 5-(4-(2-(dimethoxymethyl)-7-azaspiro[3.5]nonan-7-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (387.7 mg, 74.8%) as a yellow solid.

[0372] LC-MS purity: 100% (UV at 254 nm), LC-MS: 528.4 [M+H] + .

[0373] 1 H NMR(400MHz,DMSO-d6)δ 9.04(s,1H),7.06(d,J=6.8Hz,3H),6.76-6.70(m,2H),6.55(dd,J=8.1,5.3Hz,2H),6.44(dd,J=8 .3,2.4Hz,1H),6.35(d,J=8.4Hz,1H),6.29(dd,J=8.3,1.1Hz,1H),6.10(s,1H),4.64(d,J=5.1Hz ,1H),4.28(d,J=7.0Hz,1H),3.20(s,8H),2.97(d,J=4.2Hz,2H),2.93(s,3H),2.89(dd,J=11.2,6 .0Hz,3H),2.22-2.11(m,1H),1.78(dd,J=11.0,10.1Hz,2H),1.56(ddd,J=19.8,9.2,2.8Hz,8H).

[0374] Intermediate 4: 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (two isomers) TIFF2025526290000309.tif63149Step 1: 1-(4-bromo-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine To a mixture of 1-bromo-4,5-difluoro-2-methoxybenzene (8.5 g, 38.1 mmol, 1 equiv.) and 4-(dimethoxymethyl)piperidine (6.1 g, 38.1 mmol, 1 equiv.) in NMP (50 mL) was added CsCO (37.3 g, 114 mmol, 3 equiv.). The mixture was purged with nitrogen and stirred at 145 °C overnight. The mixture was cooled to room temperature and then poured into HO (500 mL). The mixture was then extracted with EtOAc (150 mL). The organic phase was dried over NaSO and concentrated. The residue was purified by column chromatography on silica gel eluting with 0–20% EtOAc / hexane to give 1-(4-bromo-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine as a yellow oil (2.5 g, 18% yield).

[0375] LC-MS purity: 100% (UV at 254 nm), 362.1 / 364.1 [M+H] + .

[0376] Step 2: 6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-ol To a mixture of 1-(4-bromo-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine (5.0 g, 13.8 mmol, 1 equiv.) in dry THF (25 mL) under argon, n-BuLi (2.50 M, 6.6 mL, 1.2 equiv.) was added dropwise. The mixture was stirred at −75° C. for 1.5 hours, and 6-(benzyloxy)-3,4-dihydronaphthalen-1(2H)-one (4.2 g, 16.6 mmol, 1.1 equiv.) in dry THF (10 mL) was added dropwise. The mixture was stirred at −75° C. for 3 hours. The mixture was quenched by the addition of saturated aqueous NH4Cl. The mixture was poured into HO (40 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 0-30% EtOAc / hexane to give 6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-ol (2.0 g, 26.8% yield) as a white solid.

[0377] LC-MS purity: 100% (UV at 254 nm), 536.1 [M+H] + .

[0378] Step 3: 1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine To a mixture of 6-(benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-ol (2.5 g, 4.7 mmol, 1 equiv.) in MeOH (8 mL) was added TsOH (171 mg, 0.9 mmol, 0.2 equiv.). The mixture was stirred at 70 °C for 3 h and concentrated. The residue was purified by column chromatography on silica gel eluting with 0-30% EtOAc / hexane to give 1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine (1.6 g, 65.7% yield) as a yellow solid.

[0379] LC-MS purity: 100% (UV at 254 nm), 518.3 [M+H] + .

[0380] Step 4: 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine To a mixture of 1-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine (1.6 g, 3.1 mmol, 1 equiv.) and DIEA (0.8 g, 6.2 mmol, 2 equiv.) in DMA (10 mL) was added pyridinium tribromide (1.2 g, 3.7 mmol, 1.2 equiv.) at 0° C. The mixture was stirred at room temperature for 3 h. The mixture was poured into HO (50 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (40 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 0-20% EtOAc / hexane to give 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine (1.6 g, 86.6% yield) as a yellow solid.

[0381] LC-MS purity: 100% (UV at 254 nm), 598.2 [M+H] + .

[0382] Step 5: 1-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine To a mixture of 1-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine (1.8 g, 3.0 mmol, 1 equiv.) in dioxane (16 mL) and HO (2 mL) was added phenylboronic acid (522 mg, 4.5 mmol, 1.5 equiv.), KCO (636 mg, 3 mmol, 2 equiv.), followed by Pd(dppf)Cl (137 mg, 0.15 mmol, 0.05 equiv.). The mixture was stirred under argon at 100 °C for 16 h. The mixture was cooled to room temperature, poured into HO (50 mL), and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (40 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 0-20% EtOAc / hexane to give 1-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine (1.3 g, 72.2% yield) as a yellow solid.

[0383] LC-MS purity: 100% (UV at 254 nm), 594.3 [M+H] + .

[0384] Step 6: 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol To a mixture of 1-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine (440 mg, 0.7 mmol, 1 equiv.) in MeOH (10 mL) was added Pd / C (100 mg, 10% on carbon, wet with approximately 55% water). The mixture was stirred under H at room temperature overnight. The catalyst was removed by filtration, and the filtrate was concentrated to give 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (200 mg, 53.3% yield) as a white solid.

[0385] LC-MS purity: 68.0% (UV at 254 nm), 506.5 [M+H] + . Step 7: (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol and (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol

[0386] 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (200 mg, 0.4 mmol) was separated by SFC to give (5S,6S)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (90 mg) and (5R,6R)-5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (90 mg), both of whose structures were tentatively assigned.

[0387] Intermediate 5: 7-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-7-azaspiro[3.5]nonane-2-carbaldehyde TIFF2025526290000310.tif34149 Process 5-1: 7-(4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane To a mixture of 4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (100 mg, 0.15 mmol, 1.0 equiv), 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane (30 mg, 0.15 mmol, 1.0 equiv), t-BuONa (44 mg, 0.46 mmol, 3.0 equiv), and Ruphos (7 mg, 0.02 mmol, 0.1 equiv) in 1,4-dioxane (5 mL) was added Ruphos PdG3 (13 mg, 0.02 mmol, 0.1 equiv), followed by stirring at 100 °C for 16 h. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water, washed with EtOAc, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by SiO2 column chromatography (EtOAc:PE = 1:20) to give 7-(4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane (26 mg, 31%) as a yellow oil.

[0388] LC-MS purity: 62.1% (UV at 254 nm), LC-MS: 554.3 [M+H] + .

[0389] Step 5-2: 7-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-7-azaspiro[3.5]nonane-2-carbaldehyde A mixture of 7-(4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane (26 mg, 0.04 mmol, 1 equiv) in HCOOH (3 mL) was stirred at 25° C. for 16 h. The mixture was concentrated to give the crude product 7-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-7-azaspiro[3.5]nonane-2-carbaldehyde (13 mg, 69%) as a colorless liquid.

[0390] LC-MS purity: 100% (UV at 254 nm), LC-MS: 452.2 [M+H] + .

[0391] Intermediate 6: (R)-N-((S)-2,6-dioxopiperidin-3-yl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide hydrochloride TIFF2025526290000311.tif69149 Step 1: (R)-1-((9H-fluoren-9-yl)methyl) 4-tert-butyl 2-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate To a mixture of methyl 5-bromo-6-oxo-1,6-dihydropyridine-2-carboxylate (2.5 g, 10.7 mmol, 1 equiv.) in THF (50 mL) was added (R)-1-((9H-fluoren-9-yl)methyl)4-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (5.7 g, 12.9 mmol, 1.2 equiv.) and PPh3 (8.4 g, 32.1 mmol, 3 equiv.), and the mixture was stirred at 60° C. To the mixture was added dropwise DIAD (6.5 g, 32.1 mmol, 3 equiv.), and the mixture was stirred at room temperature for 12 h. The mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with 0-30% EtOAc / hexanes to give (R)-1-((9H-fluoren-9-yl)methyl)4-tert-butyl 2-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate (5.0 g, 70% yield) as a yellow solid.

[0392] Step 2: (R)-tert-butyl 3-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1-carboxylate To a mixture of (R)-1-((9H-fluoren-9-yl)methyl)4-tert-butyl 2-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate (5 g, 7.6 mmol, 1 equiv.) in DMF (50 mL) was added piperidine (1.1 g, 15.2 mmol, 2 equiv.). The mixture was stirred at room temperature for 1 h, diluted with ethyl acetate (100 mL), and washed with water (50 mL). The organic phase was washed with brine, dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo. The crude material was purified by column chromatography on silica gel eluting with 0-5% DCM in methanol to give (R)-tert-butyl 3-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1-carboxylate (2.4 g, 75% yield). LC-MS purity: 100% (UV at 254 nm), ms: 430.2 [M+1] + .

[0393] Step 3: (R)-3-tert-butyl 8-methyl 1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate To a mixture of (R)-tert-butyl 3-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1-carboxylate (2.4 g, 5.6 mmol, 1 equiv.), XantPhos (486 mg, 0.84 mmol, 0.15 equiv.), and CsCO (5.4 g, 16.8 mmol, 3 equiv.) in dioxane (50 mL), Pd(dba) (511 mg, 0.56 mmol, 0.1 equiv.) was added under a stream of Ar, and the mixture was stirred at 100 °C for 16 h. The mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL). The organic phase was washed with brine, dried over NaSO, and filtered. The filtrate was evaporated in vacuo, and the residue was purified by column chromatography on silica gel eluting with 0-50% EtOAc / hexane to give (R)-3-tert-butyl 8-methyl 1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate (1.3 g, 68% yield) as a white solid. LC-MS purity: 100% (UV at 254 nm), 350.4 [M+H] + .

[0394] Step 4: (R)-3-(tert-butoxycarbonyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxylic acid To a mixture of (R)-3-tert-butyl 8-methyl 1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate (1.3 g, 3.7 mmol, 1 equiv.) in THF (10 mL) and water (10 mL), sodium hydroxide (590 mg, 14.8 mmol, 4 equiv.) was added and the mixture was stirred at room temperature for 2 h. The mixture was adjusted to pH 5-6 with aqueous HCl (1 M) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was evaporated to give (R)-3-(tert-butoxycarbonyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxylic acid (1.3 g, crude) as a white solid. LC-MS purity: 100% (UV at 254 nm), 336.3 [M+H] + .

[0395] Step 5: (R)-8-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylate tert-butyl To a mixture of (R)-3-(tert-butoxycarbonyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxylic acid (1.3 g, 3.8 mmol, 1 equiv.) in DMF (10 mL) was added HATU (1.7 g, 4.6 mmol, 1.2 equiv.) and DIPEA (980 mg, 7.6 mmol, 2 equiv.), and the mixture was stirred at room temperature for 1 h. The mixture was directly purified by reverse-phase column chromatography (0–90% acetonitrile / 0.05% formic acid) to afford (R)-tert-butyl 8-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylate (1.3 g, 76% yield) as a white solid. LC-MS purity: 100% (UV at 254 nm), 446.2 [M+H] + .

[0396] Step 6: (R)—N-((S)-2,6-dioxopiperidin-3-yl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide hydrochloride A mixture of (R)-tert-butyl 8-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylate (1.3 g, 2.9 mmol, 1 equivalent) in HCl / dioxane (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give (R)-N-((S)-2,6-dioxopiperidin-3-yl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide hydrochloride (1.0 g, 91% yield) as a white solid.

[0397] LC-MS purity: 100% (UV at 254 nm), ms: 346.2 [M+1] + .

[0398] 1 H NMR(400MHz,DMSO):δ 10.84(s,1H),9.63-9.33(m,2H),8.56(d,J=8.4Hz,1H),7.62(d,J=8.2Hz,1H),7.44(d,J=8.4Hz,1H),4.77-4.70(m,1H),4.51-4.49(m,2) H),4.20-4.05(m,2H),3.66-3.55(m,1H),3.47-3.39(m,2H),3.22-2.98(m,2H),2.89-2.67(m,2H),2.26-2.11(m,1H),2.02-1.90(m,1H).

[0399] Intermediate 7: (S)-N-((S)-2,6-dioxopiperidin-3-yl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide hydrochloride TIFF2025526290000312.tif69148 Step 1: (S)-1-((9H-fluoren-9-yl)methyl)4-tert-butyl 2-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate To a mixture of methyl 5-bromo-6-oxo-1,6-dihydropyridine-2-carboxylate (2.5 g, 10.7 mmol, 1 equiv.) in THF (50 mL) was added (R)-1-((9H-fluoren-9-yl)methyl)4-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (5.7 g, 12.9 mmol, 1.2 equiv.) and PPh3 (8.4 g, 32.1 mmol, 3 equiv.), and the mixture was stirred at 60° C. To the mixture was added dropwise DIAD (6.5 g, 32.1 mmol, 3 equiv.), and the mixture was stirred at room temperature for 12 h. The mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with 0-30% EtOAc / hexanes to give (R)-1-((9H-fluoren-9-yl)methyl)4-tert-butyl 2-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate (3.0 g, 50% yield) as a yellow solid.

[0400] Step 2: (S)-tert-butyl 3-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1-carboxylate To a mixture of (R)-1-((9H-fluoren-9-yl)methyl)4-tert-butyl 2-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate (3 g, 5.6 mmol, 1 equiv.) in DMF (50 mL) was added piperidine (1.1 g, 15.2 mmol, 3 equiv.). The mixture was stirred at room temperature for 1 h, diluted with ethyl acetate (100 mL), and washed with water (50 mL). The organic phase was washed with brine, dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with 0-5% DCM in methanol to give (R)-tert-butyl 3-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1-carboxylate (2.4 g, 95% yield). LC-MS purity: 100% (UV at 254 nm), ms: 430.2 [M+H] + .

[0401] Step 3: (S)-3-tert-butyl 8-methyl 1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate To a mixture of (R)-tert-butyl 3-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1-carboxylate (2.4 g, 5.6 mmol, 1 equiv.), XantPhos (486 mg, 0.84 mmol, 0.15 equiv.), and CsCO (5.4 g, 16.8 mmol, 3 equiv.) in dioxane (50 mL), Pd(dba) (511 mg, 0.56 mmol, 0.1 equiv.) was added under a stream of Ar, and the mixture was stirred at 100 °C for 16 h. The mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL). The organic phase was washed with brine, dried over NaSO, and filtered. The filtrate was evaporated in vacuo, and the residue was purified by column chromatography on silica gel eluting with 0-50% EtOAc / hexane to give (R)-3-tert-butyl 8-methyl 1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate (1.3 g, 68% yield) as a white solid. LC-MS purity: 100% (UV at 254 nm), ms: 350.4 [M+H] + .

[0402] Step 4: (S)-3-(tert-butoxycarbonyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxylic acid To a mixture of (R)-3-tert-butyl 8-methyl 1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate (1.3 g, 3.7 mmol, 1 equiv.) in THF (10 mL) and water (10 mL), sodium hydroxide (590 mg, 14.8 mmol, 4 equiv.) was added and the mixture was stirred at room temperature for 2 h. The mixture was adjusted to pH 5-6 with aqueous HCl (1 M) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was evaporated to give (R)-3-(tert-butoxycarbonyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxylic acid (1.3 g, crude) as a white solid. LC-MS purity: 100% (UV at 254 nm), 336.3 [M+H] + .

[0403] Step 5: (S)-tert-butyl 8-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylate To a mixture of (S)-3-(tert-butoxycarbonyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxylic acid (880 mg, 2.6 mmol, 1 equiv.) in DMF (10 mL) was added T3P (3.2 mL, 5.2 mmol, 2 equiv.) and DIPEA (0.64 mL, 5.2 mmol, 2 equiv.). The mixture was stirred at room temperature for 1 h, quenched with water (10 mL), and directly purified by reverse-phase column chromatography (0–90% acetonitrile / 0.05% formic acid) to afford (S)-tert-butyl 8-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylate (620 mg, 76% yield) as a white solid. LC-MS purity: 100% (UV at 254 nm), ms: 446.2 [M+H]. + .

[0404] Step 6: (S)—N-((S)-2,6-dioxopiperidin-3-yl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide hydrochloride A mixture of (R)-tert-butyl 8-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylate (620 mg, 1.4 mmol, 1 equiv.) in HCl / dioxane (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give (R)-N-((S)-2,6-dioxopiperidin-3-yl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide hydrochloride (520 mg, crude) as a white solid.

[0405] LC-MS purity: 100% (UV at 254 nm), 346.2 [M+H] + .

[0406] 1 H NMR(400MHz,DMSO):δ 10.84(s,1H),9.63-9.33(m,2H),8.56(d,J=8.4Hz,1H),7.62(d,J=8.2Hz,1H),7.44(d,J=8.4Hz,1H),4.77-4.70(m,1H),4.51-4.49(m,2) H),4.20-4.05(m,2H),3.66-3.55(m,1H),3.47-3.39(m,2H),3.22-2.98(m,2H),2.89-2.67(m,2H),2.26-2.11(m,1H),2.02-1.90(m,1H).

[0407] Intermediate 8: 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride TIFF2025526290000313.tif33149 Step 1: tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate To a mixture of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (1.5 g, 5.4 mmol, 1.0 equiv.) in DMA (8 mL) was added 3-bromopiperidine-2,6-dione (1.0 g, 5.428 mmol, 1.0 equiv.) and NaHCO (456 mg, 5.4 mmol, 1.0 equiv.). The mixture was stirred at 80 °C overnight and cooled to room temperature. The mixture was concentrated, and the residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc / hexane to afford tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate as a pale blue solid (1.6 g, 76.0% yield). LC-MS purity: 100% (UV at 254 nm), 388.0 [M+H]. + .

[0408] Step 2: 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride A mixture of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (1.6 g, 4.1 mmol, 1.0 equiv.) in HCl / dioxane (10 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (1.5 g, crude). LC-MS purity: 100% (UV at 254 nm), 288.0 [M+H] + . 1H NMR(400MHz,DMSO)δ 10.83(s,1H),9.11-8.76(m,2H),6.98(d,J=8.4Hz,2H),6.72(d,J=8.4Hz,2H),4.33(dd,J=11.6,4.8H z,1H),3.35-3.25(m,2H),3.00-2.84(m,2H),2.79-2.56(m,3H),2.15-2.01(m,1H),1.92-1.73(m,5H).

[0409] Intermediate 9: (R or S)-3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride TIFF2025526290000314.tif26148 Step 1: (R / S)-tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (1.9 g, 5 mmol) was purified via SFC to give (R / S)-tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (P1: 450 mg, P2: 480 mg), LC-MS purity: 100% (UV at 254 nm), 388.0 [M+H] + obtained.

[0410] Step 2: (R / S)-3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride A mixture of (R / S)-tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (100 mg, 0.25 mmol, 1.0 equiv.) in HCl / dioxane (2 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give (R / S)-3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (90 mg, 100% crude yield). LC-MS purity: 100% (UV at 254 nm), 288.0 [M+H] + . 1 H NMR(400MHz,DMSO)δ 10.83(s,1H),9.11-8.76(m,2H),6.98(d,J=8.4Hz,2H),6.72(d,J=8.4Hz,2H),4.33(dd,J=11.6,4.8H z,1H),3.35-3.25(m,2H),3.00-2.84(m,2H),2.79-2.56(m,3H),2.15-2.01(m,1H),1.92-1.73(m,5H).

[0411] Intermediate 10: 3-((S)-8-oxo-1,2,3,4,4a,5,8,10-octahydro-9H-pyrazino[1',2':4,5][1,4]oxazino[2,3-f]isoindol-9-yl)piperidine-2,6-dione hydrochloride TIFF2025526290000315.tif68149Step 1: 5-Fluoro-6-nitroisobenzofuran-1(3H)-one To a solution of 5-fluoroisobenzofuran-1(3H)-one (10 g, 65.8 mmol, 1.0 equiv.) in H2SO4 (50 mL) was added KNO3 (9.97 g, 98.7 mmol, 1.5 equiv.) in small portions. The reaction mixture was stirred at room temperature for 3 h and slowly poured into ice-water. The organic phase was washed with brine, dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo, and the residue was purified by column chromatography on silica gel eluting with 0-50% EtOAc / hexane to give 5-fluoro-6-nitroisobenzofuran-1(3H)-one (10.4 g, 80% yield) as a white solid.

[0412] Step 2: (S)-3-(hydroxymethyl)-4-(6-nitro-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate tert-butyl To a solution of 5-fluoro-6-nitroisobenzofuran-1(3H)-one (1 g, 5.0 mmol, 1 equiv.) and (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.7 g, 7.5 mmol, 1.5 equiv.) in acetonitrile (10 mL) was added DIPEA (2.2 mL, 12.5 mmol, 2.5 equiv.), and the mixture was stirred at 60° C. for 6 h. The mixture was concentrated, and the residue was purified by column chromatography on silica gel eluting with 0–5% MeOH / DCM to give tert-butyl (S)-3-(hydroxymethyl)-4-(6-nitro-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate (1.3 g, 66% yield) as a yellow foam.

[0413] Step 3: (S)-tert-butyl 4-(6-amino-1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-(hydroxymethyl)piperazine-1-carboxylate To a solution of (S)-tert-butyl 3-(hydroxymethyl)-4-(6-nitro-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate (1.0 g, 2.8 mmol, 1 equiv.) in MeOH (15 mL) was added Pd / C (300 mg, 10% on carbon, approximately 55% water wet). The mixture was degassed, purged with H2 three times, and stirred at room temperature for 4 h. The catalyst was removed by filtration, and the filtrate was evaporated to give (S)-tert-butyl 4-(6-amino-1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-(hydroxymethyl)piperazine-1-carboxylate as a pale yellow foam (860 mg, 93% yield).

[0414] Step 4: (S)-tert-butyl 4-(6-bromo-1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-(hydroxymethyl)piperazine-1-carboxylate To a solution of tert-butyl (S)-4-(6-amino-1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (468 mg, 1.3 mmol, 1 equiv.) in acetonitrile (25 mL) cooled in an ice bath, t-BuONO (0.2 mL, 1.7 mmol, 1.3 equiv.) was added, and the mixture was stirred for 30 min. A solution of CuBr (300 mg, 1.3 mmol, 1 equiv.) in acetonitrile (6 mL) was then added dropwise, and the mixture was stirred at room temperature for 3 h. The mixture was then diluted with EA (120 mL) and water (120 mL). The organic phase was washed with brine, dried over NaSO, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with 0-5% MeOH / DCM to give (S)-tert-butyl 4-(6-bromo-1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-(hydroxymethyl)piperazine-1-carboxylate as a brown oil (415 mg, 75% yield).

[0415] Step 5: (S)-tert-butyl 8-oxo-1,2,4a,5,8,10-hexahydroisobenzofuro[5,6-b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate A mixture of (S)-tert-butyl 4-(6-bromo-1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (140 mg, 0.3 mmol, 1 equiv.), Pd(OAc) (36.8 mg, 0.15 mmol, 0.5 equiv.), JohnPhos (118 mg, 0.36 mmol, 1.2 equiv.), and CsCO (214 mg, 0.7 mmol, 2 equiv.) in toluene was degassed and purged with N three times, then the mixture was stirred at 90 °C for 3 h. The mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated. The residue was triturated with MeOH and the solid was collected by filtration to give (S)-tert-butyl 8-oxo-1,2,4a,5,8,10-hexahydroisobenzofuro[5,6-b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate as a yellow solid (90 mg, 80% yield).

[0416] Step 6: (S)-3-(tert-butoxycarbonyl)-9-(hydroxymethyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid To a solution of tert-butyl (S)-8-oxo-1,2,4a,5,8,10-hexahydroisobenzofuro[5,6-b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (87 mg, 0.25 mmol, 1 equiv.) in THF (3 mL) was added a solution of NaOH (60 mg, 1.3 mmol, 6 equiv.) in HO (1 mL), and the mixture was stirred at 40 °C for 6 h. The mixture was then concentrated, and the residue was diluted with water (4 mL) and acidified to pH 3-4 with 2 N HCl. The mixture was extracted with DCM (10 mL), and the organic phase was washed with brine, dried over NaSO, and filtered. The filtrate was evaporated in vacuo to give (S)-3-(tert-butoxycarbonyl)-9-(hydroxymethyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid as a white powder (76 mg, 83% yield).

[0417] Step 7: (S)-3-(tert-butoxycarbonyl)-9-formyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid To a solution of (S)-3-(tert-butoxycarbonyl)-9-(hydroxymethyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid (54 mg, 0.15 mmol, 1 equiv.) in DCM (10 mL) cooled at 0 °C, DMP (93.7 mg, 0.23 mmol, 1.5 equiv.) was added in small portions, and the mixture was stirred at 0 °C for 30 min. The mixture was then diluted with DCM and washed with brine. The organic phase was dried over Na SO and filtered. The filtrate was evaporated in vacuo to give (S)-3-(tert-butoxycarbonyl)-9-formyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid as a yellow solid (50 mg, crude).

[0418] Step 7: (4aS)-3-(tert-butoxycarbonyl)-9-(((2,6-dioxopiperidin-3-yl)amino)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid To a mixture of (S)-3-(tert-butoxycarbonyl)-9-formyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid (70 mg, 0.2 mmol, 1 equiv.), 3-aminopiperidine-2,6-dione (47.6 mg, 0.3 mmol, 1.5 equiv.), and NaOAc (23.7 mg, 0.3 mmol, 1.5 equiv.) dissolved in MeOH (6 mL) was added NaBHCN (36 mg, 0.6 mmol, 3 equiv.), and the mixture was stirred at room temperature for 1 h. The reaction was then quenched with water, and the mixture was purified by reverse-phase column chromatography (0–50% acetonitrile / 0.05% formic acid) to give (4aS)-3-(tert-butoxycarbonyl)-9-(((2,6-dioxopiperidin-3-yl)amino)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid as a white powder (35 mg, 38% yield) after lyophilization.

[0419] Step 8: (4aS)-9-(2,6-dioxopiperidin-3-yl)-8-oxo-1,2,4a,5,9,10-hexahydro-8H-pyrazino[1',2':4,5][1,4]oxazino[2,3-f]isoindole-3(4H)-carboxylate tert-butyl To a solution of (4aS)-3-(tert-butoxycarbonyl)-9-(((2,6-dioxopiperidin-3-yl)amino)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid (47 mg, 0.1 mmol, 1 equiv) in DMF (2.5 mL) was added HATU (54 mg, 0.15 mmol, 1.5 equiv) followed by DIPEA (40 mg, 0.3 mmol, 3 equiv) and the mixture was stirred at room temperature for 1 h. The reaction was then quenched with water, and the mixture was purified by reverse-phase column chromatography (0–50% acetonitrile / 0.05% formic acid) to afford tert-butyl (4aS)-9-(2,6-dioxopiperidin-3-yl)-8-oxo-1,2,4a,5,9,10-hexahydro-8H-pyrazino[1′,2′:4,5][1,4]oxazino[2,3-f]isoindole-3(4H)-carboxylate as a white powder (30 mg, 66% yield).

[0420] Step 9: 3-((S)-8-oxo-1,2,3,4,4a,5,8,10-octahydro-9H-pyrazino[1',2':4,5][1,4]oxazino[2,3-f]isoindol-9-yl)piperidine-2,6-dione hydrochloride trifluoroacetate A mixture of tert-butyl (4aS)-9-(2,6-dioxopiperidin-3-yl)-8-oxo-1,2,4a,5,9,10-hexahydro-8H-pyrazino[1',2':4,5][1,4]oxazino[2,3-f]isoindole-3(4H)-carboxylate (30 mg, 1.0 equivalent) and HCl / dioxane (2 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give 3-((S)-8-oxo-1,2,3,4,4a,5,8,10-octahydro-9H-pyrazino[1',2':4,5][1,4]oxazino[2,3-f]isoindol-9-yl)piperidine-2,6-dione trifluoroacetate as a white solid (26 mg, crude). LC-MS: [M+H] + =356.90. 1H NMR(400MHz, methanol-d4)δ 7.15(s,1H),7.11(d,J=5.7Hz,1H),5.13-5.02(m,1H),4.41-4.27(m,3H),4.20(d,J=13.6Hz,1H),4.12-4.01(m,1H),3.62-3. 43(m,3H),3.30-3.10(m,2H),3.03-2.94(m,1H),2.94-2.82(m,1H),2.82-2.71(m,1H),2.52-2.38(m,1H),2.20-2.09(m,1H). 13 C NMR(101MHz,MeOD)δ 174.68,172.52,172.49,171.63,171.59,146.42,146.37,139.22,139.20,138.12,138.08,123.85,123.78,111.88, 108.70,108.65,66.94,53.72,53.57,50.79,50.75,48.90,48.68,44.36,44.17,44.10,43.63,43.61,32.35,24.08.

[0421] Intermediate 11: N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)picolinamide hydrochloride TIFF2025526290000316.tif93148Step 1: tert-Butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate To a mixture of methyl 5-bromopicolinate (15 g, 69.4 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (12.9 g, 69.4 mmol, 1 equiv.), and CsCO (45 g, 139 mmol, 2 equiv.) in dioxane (150 mL) was added Ruphos-G3-Pd (2.2 g, 3.5 mmol, 0.05 equiv.) under an Ar stream. The mixture was stirred at 100 °C for 16 h and cooled to room temperature. The residue was purified by column chromatography on silica gel eluting with 0–50% EtOAc / hexane to give tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (22 g, crude).

[0422] Step 2: 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid To a mixture of tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (22 g, 68.5 mmol, 1 equiv.) in MeOH (40 mL) / THF (100 mL) / HO (40 mL) was added LiOH (5.5 g, 137 mmol, 2 equiv.), and the mixture was stirred at room temperature for 16 h. The mixture was concentrated, and the residue was adjusted to pH 6 with 1 N HCl. The precipitate was collected by filtration and dried in vacuo to give 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid (16.3 g, 76.4% yield).

[0423] Step 3: tert-Butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate To a mixture of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid (1 g, 3.2 mmol, 1 equiv.), 3-aminopiperidine-2,6-dione (537 mg, 3.2 mmol, 1 equiv.) in DMA (5 mL) was added TEA (0.8 mL, 6.4 mmol, 2 equiv.) and T3P (3 mL, 4.8 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 2 h, poured into water (50 mL), and extracted with EtOAc (20 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc / hexanes to give tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate (1.0 g, 78%) as a white solid.

[0424] Step 4: N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)picolinamide hydrochloride A mixture of tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate (1 g, 2.5 mmol, 1.0 equiv.) in HCl / dioxane (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)picolinamide hydrochloride as a white solid (950 mg, crude).

[0425] Intermediate 12: N-(2,6-dioxopiperidin-3-yl)-6-methoxy-5-(piperazin-1-yl)picolinamide hydrochloride TIFF2025526290000317.tif55149Step 1: tert-Butyl 4-(2-methoxy-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate To a mixture of methyl 5-bromo-6-methoxypicolinate (900 mg, 3.7 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (818 mg, 4.4 mmol, 1.2 equiv.), and CsCO (1.4 g, 4.4 mmol, 1.2 equiv.) in dioxane (15 mL), Ruphos-G3-Pd (153 mg, 0.18 mmol, 0.05 equiv.) was added under Ar flow. The mixture was stirred at 100 °C for 16 h and cooled to room temperature. The residue was purified by column chromatography on silica gel eluting with 0–50% EtOAc / hexane to give tert-butyl 4-(2-methoxy-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (770 mg, 50%).

[0426] Step 2: 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methoxypicolinic acid To a mixture of tert-butyl 4-(2-methoxy-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (70 mg, 0.2 mmol, 1 equiv.) in MeOH (1 mL) / THF (1 mL) / HO (1 mL) was added LiOH (14 mg, 0.6 mmol, 3 equiv.), and the mixture was stirred at room temperature for 16 h. The mixture was concentrated, and the residue was adjusted to pH=6 with 1 N HCl. The precipitate was collected by filtration and dried in vacuo to give 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methoxypicolinic acid (65 mg, crude).

[0427] Step 3: tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-methoxypyridin-3-yl)piperazine-1-carboxylate To a mixture of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methoxypicolinic acid (80 mg, 0.24 mmol, 1 equiv.), 3-aminopiperidine-2,6-dione (46 mg, 0.28 mmol, 1.2 equiv.) in DMA (3 mL) was added TEA (48 mg, 0.48 mmol, 2 equiv.) and T3P (152 mg, 0.48 mmol, 2 equiv.). The reaction mixture was stirred at room temperature for 2 h, poured into water (30 mL), and extracted with EtOAc (10 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc / hexanes to give tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-methoxypyridin-3-yl)piperazine-1-carboxylate (101 mg, 97%) as a white solid.

[0428] Step 4: N-(2,6-dioxopiperidin-3-yl)-6-methoxy-5-(piperazin-1-yl)picolinamide hydrochloride A mixture of tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-methoxypyridin-3-yl)piperazine-1-carboxylate (450 mg, 1 mmol, 1.0 equiv.) in HCl / dioxane (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give N-(2,6-dioxopiperidin-3-yl)-6-methoxy-5-(piperazin-1-yl)picolinamide hydrochloride as a white solid (950 mg, crude).

[0429] Intermediate 13: N-(2,6-dioxopiperidin-3-yl)-4-methoxy-5-(piperazin-1-yl)picolinamide hydrochloride. TIFF2025526290000318.tif51148Step 1: tert-Butyl 4-(4-methoxy-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate To a mixture of methyl 5-bromo-4-methoxypicolinate (1 g, 4.0 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (818 mg, 4.4 mmol, 1.2 equiv.), and CsCO (1.4 g, 4.4 mmol, 1.2 equiv.) in dioxane (15 mL), Ruphos-G3-Pd (153 mg, 0.18 mmol, 0.05 equiv.) was added under Ar flow. The mixture was stirred at 100 °C for 16 h and cooled to room temperature. The residue was purified by column chromatography on silica gel eluting with 0–50% EtOAc / hexane to give tert-butyl 4-(4-methoxy-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (370 mg, 23% yield).

[0430] Step 2: 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-methoxypicolinic acid To a mixture of tert-butyl 4-(2-methoxy-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (70 mg, 0.2 mmol, 1 equiv.) in MeOH (1 mL) / THF (1 mL) / HO (1 mL) was added LiOH (14 mg, 0.6 mmol, 3 equiv.), and the mixture was stirred at room temperature for 16 h. The mixture was concentrated, and the residue was adjusted to pH=6 with 1 N HCl. The precipitate was collected by filtration and dried in vacuo to give 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-methoxypicolinic acid (65 mg, crude).

[0431] Step 3: tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)-4-methoxypyridin-3-yl)piperazine-1-carboxylate To a mixture of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-methoxypicolinic acid (160 mg, 0.48 mmol, 1 equiv.), 3-aminopiperidine-2,6-dione (92 mg, 0.56 mmol, 1.2 equiv.) in DMA (3 mL) was added TEA (97 mg, 0.97 mmol, 2 equiv.) and T3P (152 mg, 0.48 mmol, 1 equiv.). The reaction mixture was stirred at room temperature for 2 h, poured into water (30 mL), and extracted with EtOAc (10 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc / hexanes to give tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)-4-methoxypyridin-3-yl)piperazine-1-carboxylate (97 mg, 95%) as a white solid.

[0432] Step 4: N-(2,6-dioxopiperidin-3-yl)-4-methoxy-5-(piperazin-1-yl)picolinamide hydrochloride A mixture of tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)-4-methoxypyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.22 mmol, 1.0 equiv) in HCl / dioxane (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give N-(2,6-dioxopiperidin-3-yl)-4-methoxy-5-(piperazin-1-yl)picolinamide hydrochloride as a white solid (90 mg, crude).

[0433] Intermediate 14. 3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione trifluoroacetate TIFF2025526290000319.tif111149Step 1: tert-Butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate A mixture of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate 1 (25 g, 117.4 mmol) and aluminum isopropoxide (35.9 g, 176 mmol) in anhydrous toluene (300 mL) was heated under reflux for 36 h. The reaction was allowed to cool and then poured into aqueous hydrogen chloride (1 M). The aqueous phase was extracted into EA, and the organic extract was dried (NaSO) and concentrated under reduced pressure. Chromatography of the residue afforded the title compound 2 as a colorless oil (12 g, 48%).

[0434] Step 2: 4-bromo-2-formyl-3-hydroxybenzoate methyl To a solution of methyl 4-bromo-3-hydroxybenzoate 3 (18 g, 77.9 mmol) in TFA (150 mL) was added HMTA (41.5 g, 296 mmol). The solution was stirred at 90 °C overnight. 2N HCl was added, and a yellow solid formed. The mixture was stirred for 10 min, then an additional 1 L of water was added and stirred for 1 h. 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 resulting mixture was triturated with MeOH and filtered to give methyl 4-bromo-2-formyl-3-hydroxybenzoate 4 as a yellow solid (12 g, 59%).

[0435] Step 3: tert-butyl 4-((6-bromo-2-formyl-3-(methoxycarbonyl)phenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of compound 2 (6 g, 23.2 mmol, 1.0 equiv.) in dry THF (50 mL) was added compound 4 (5.9 g, 27.8 mmol, 1.2 equiv.) and PPh3 (7.9 g, 30.1 mmol, 1.3 equiv.). The reaction mixture was cooled to 0 °C, and DIAD (6.6 g, 32.4 mmol, 1.4 equiv.) was added dropwise. The resulting mixture was then stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography using 0–20% EtOAc / hexane. The desired product 5 was obtained as a yellow oil (4 g, 38%).

[0436] Step 4: 1'-(tert-butyl) 6-methyl 7-formyl-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1',6-dicarboxylate To a solution of compound 5 (4 g, 8.8 mmol, 1.0 equiv.) in DMA (30 mL) was added NaCOOH (0.72 g, 10.6 mmol, 1.2 equiv.), EtNCl.HO (1.95 g, 10.6 mmol, 1.2 equiv.), Pd(OAc) (0.2 g, 0.88 mmol, 0.1 equiv.), and NaOAc (1.44 g, 17.6 mmol, 2 equiv.). The mixture was purged with nitrogen and heated to 100 °C overnight. 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 0–30% EtOAc / hexane to give compound 6 as a yellow oil (720 mg, 24% yield).

[0437] Step 5: tert-butyl 7-(2,6-dioxopiperidin-3-yl)-6-oxo-2',3',7,8-tetrahydro-1'H,2H,6H-spiro[furo[2,3-e]isoindole-3,4'-pyridine]-1'-carboxylate To a solution of compound 6 (780 mg, 2.09 mmol, 1 equiv.) and compound 6 (344 mg, 2.09 mmol, 1 equiv.) in MeOH (10 mL), TEA (211 mg, 2.09 mmol, 1 equiv.) and AcOH (627 mg, 10.5 mmol, 5 equiv.) were added, followed by NaBHCN (395 mg, 6.27 mmol, 3 equiv.). The mixture was stirred at room temperature for 16 h, diluted with EA, washed with brine, and then dried over sodium sulfate. The solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography using 0–100% EtOAc / hexanes to give compound 8 as a white solid (400 mg, 42%).

[0438] Step 6: 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 solution of compound 8 (400 mg, 0.88 mmol, 1 equiv.) in MeOH, Pd / C (200 mg, 10% on carbon, wet with approximately 55% water) and Pd(OH) (200 mg) were added. The mixture was purged with H and stirred overnight at room temperature under H. The mixture was filtered through Celite, and the filtrate was concentrated. The crude product was purified by silica gel chromatography. The desired compound, 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, was obtained as a white solid (220 mg, 55%). LC / MS (ESI) m / z: 356.2 [M+H] + . 1 H NMR(400MHz,DMSO)δ 10.97(s,1H),7.42(d,J=7.2Hz,1H),7.26(d,J=7.6Hz,1H),5.11-5.06(m ,1H),4.62-4.57(m,2H),4.38(d,J=17.2Hz,1H),4.21(d,J=17.2Hz,1H), 3.95-3.92(m,2H),2.95-2.83(m,3H),2.61-2.56(m,1H),2.47-2.39(m,1 H),1.98-1.96(m,1H),1.83-1.77(m,2H),1.71-1.65(m,2H),1.42(s,9H).

[0439] Step 7: 3-(6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-7-yl)piperidine-2,6-dione trifluoroacetate Compound 9 was treated with TFA in DCM at room temperature to deprotect the N-Boc group to give intermediate I-14. LC / MS (ESI) m / z: 356.15. 1H NMR(400MHz,CDCl3)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),2.29-2.17(m,1H),1.92(t,J=12.5Hz,2H),1.83-1.72(m,2H).

[0440] Intermediate 15: 2-(Dimethoxymethyl)-7-azaspiro[3.5]nonane TIFF2025526290000320.tif60148Step 1: Benzyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate To a stirred solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (24 g, 0.1 mol, 1 equiv.) in EA (50 mL) at room temperature, concentrated HCl (45 mL, 0.5 mol, 5 equiv.) was slowly added, and the reaction mixture was stirred at room temperature for 1 h. Upon completion of the reaction, the mixture was diluted with EA (150 mL) and poured into a Na2CO3 suspension (106 g, 1 mol, 10 equiv. in 500 mL of water), and the mixture was stirred for 20 min. CbzOSu (25 g, 0.1 mmol, 1 equiv.) was added to the mixture, and the mixture was stirred for 1 h. The organic phase was separated, washed with brine, dried, concentrated, and the residue was purified by silica column chromatography eluting with 50% EA in PE to obtain the compound benzyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (27 g, 0.1 mol, 100%) as a pale yellow oil.

[0441] Step 2: Benzyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (68 g, 0.2 mol, 2 equiv.) in dry THF (300 mL) cooled at -70 °C, NaHMDS (100 mL, 0.2 mol, 2 equiv.) was added dropwise, and the mixture was slowly warmed to 0 °C and stirred for 2 h. The mixture was then cooled to -70 °C, and a solution of benzyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (27 g, 0.1 mol, 1 equiv.) in THF (50 mL) was added. The mixture was slowly warmed to room temperature and stirred for 2 h. TLC was performed to detect the reaction progress. When no starting material remained, the mixture was quenched with NH4Cl solution (500 mL) and diluted with EA (200 mL). The organic phase was separated, washed with brine, dried, concentrated, and the residue was purified by silica column chromatography eluting with 30% EA in PE to obtain the compound benzyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate (20 g, 0.067 mol, 67%) as a pale yellow oil.

[0442] Step 3: Benzyl 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate A solution of benzyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate (24 g, 0.67 mol, 1 equiv.) in FA (50 mL) was stirred at room temperature for 4 hours. TLC was performed to detect the reaction process. Upon completion of the reaction, the mixture was concentrated, and the residue was dissolved in MeOH (120 mL). To the mixture, CH(OMe) (10.6 g, 0.1 mol, 1.5 equiv.) was added, followed by TsOH·HO (1.5 g, 0.07 mol, 0.1 equiv.), and the mixture was stirred at 70 °C for 12 hours. TLC was performed to detect the reaction process. Upon completion of the reaction, the mixture was concentrated, and the residue was purified by silica column chromatography eluting with 20% EA in PE to obtain the compound benzyl 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (14.6 g, 0.44 mol, 67%) as a pale yellow oil.

[0443] Step 4: 2-(Dimethoxymethyl)-7-azaspiro[3.5]nonane To a solution of benzyl 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (14.6 g, 0.44 mol, 1 equiv.) in MeOH (100 mL), Pd / C (4 g, 10% on carbon, wet with approximately 55% water) was added, and the mixture was stirred under H (balloon) at room temperature for 12 hours. TLC was performed to detect the reaction process. Upon completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated to obtain the compound 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane (8.9 g, 0.44 mol, 100%) as a white paste.

[0444] LCMS[M+H]:200.0. 1 H NMR(400MHz,DMSO-d6)δ 4.57(d,J=6.8Hz,1H),3.20(m,6H),2.61(s,2H),2.47-2.43(m,1H),1.74(t,2H),1.54-1.44(m,4H),1.34(t,2H).

[0445] Intermediate 16: 4-(Dimethoxymethyl)piperidine TIFF2025526290000321.tif23149 Step 1 and Step 2: Benzyl 4-formylpiperidine-1-carboxylate To a stirred solution of compound tert-butyl 4-formylpiperidine-1-carboxylate (500 g, 2.2 mol, 1 eq) in EA (500 mL) at room temperature, concentrated HCl (600 mL, 6.6 mol, 3 eq) was slowly added, and the reaction mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, the mixture was diluted with EA (500 mL) and poured into a Na2CO3 suspension (1160 g, 11 mol, 5 eq) in 3000 mL of water, and the mixture was stirred for 20 minutes. CbzOSu (550 g, 2.2 mmol, 1 eq) was added to the mixture, and the mixture was stirred for 1 hour. The organic phase was separated, washed with brine, dried, concentrated, and the residue was purified by silica column chromatography eluting with 50% EA in PE to give compound benzyl 4-formylpiperidine-1-carboxylate (550 g, 2.1 mol, 95%) as a pale yellow oil.

[0446] Step 3: Benzyl 4-(dimethoxymethyl)piperidine-1-carboxylate To a solution of benzyl 4-formylpiperidine-1-carboxylate (150 g, 0.5 mol, 1 equiv.) in MeOH (500 mL), CH(OMe) (212 g, 1 mol, 2 equiv.) was added followed by TsOH·HO (19 g, 0.1 mol, 0.1 equiv.), and the mixture was stirred at 70 °C for 12 h. Upon completion of the reaction, the mixture was concentrated, and the residue was purified by silica column chromatography eluting with 20% EA in PE to give compound benzyl 4-(dimethoxymethyl)piperidine-1-carboxylate (120 g, 0.41 mol, 82%) as a pale yellow oil.

[0447] Step 4: 4-(Dimethoxymethyl)piperidine To a solution of compound 4-(dimethoxymethyl)piperidine-1-carboxylate (120 g, 0.44 mol, 1 equiv.) in MeOH (400 mL) was added Pd / C (20 g, 10% on carbon, wet with approximately 55% water), and the mixture was stirred under H (balloon) at room temperature for 12 h. Upon completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated to give compound 4-(dimethoxymethyl)piperidine (65 g, 0.41 mol, 100%) as a white paste.

[0448] Intermediate 17: 7-(Dimethoxymethyl)-2-azaspiro[3.5]nonane TIFF2025526290000322.tif155146Step 1: Benzyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate To a ...

Claims

1. Compound of formula I: T-L-C(I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, C is the one in equation I'-1: And in the formula, R ｃ , ｂ , ａ , ２ , ｄ , ａ , ａ , ｃ , ｂ , ａ , ｄ , ｂ , ２ , ｂ , ２ , ｃ , ｂ , ２ , ｄ , ｂ , ｂ , ｃ , ａ , ｃ , ａ , ｂ , ｃ , ｃ , ｃ , ａ , ２ , ｄ , ２ , ｃ , ｂ , ｄ , ２ , ２ , ｃ , ２ , ｄ is hydrogen, halogen, -CN, -NO ２ , -OH, -NH ２ , C １～６ alkyl, C １～６ alkoxy, C １～６ alkylamino, C ２～６ alkenyl, C ２～６ alkynyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, C ３～１２ carbocyclic, 3- to 12-membered heterocyclic, -SR ｂ , -S(=O)R[[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with R ２ However, *-Cy ２ - and in the formula, * indicates adhesion to L. -Cy ２ - but C ３～１２ It is a carbocyclylene or a 3- to 12-membered heterocyclylene, and the carbocyclylene or heterocyclylene is one or more R ｕ Is it okay if it is replaced with, or R １ and R ２ However, together with the intervening carbon atom, it forms a ring A attached to L, and ring A may be substituted C ３～１２ It is a carbon ring or a 5-16 membered heterocycle, Y'' is N or CR ３ And, R ３ is hydrogen, halogen, -CN, -NO ２ , -OH, -NH ２ 2, C １～６ alkyl, C １～６ alkoxy, C １～６ alkylamino, C ２～６ alkenyl, C ２～６ alkynyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, C ３～１２ carbocyclic, 3- to 12-membered heterocyclic, -SR ｂ , -S(=O)R ａ , -S(=O) ２ 2R ａ , -S(=O) ２ 2OR ｂ , -S(=O) ２ 2NR ｃ 2R ｄ , -NR ｃ 2S(=O) ２ 2R ａ , -NR ｃ 2S(=O)R ａ , -NR ｃ 2S(=O) ２ 2OR ｂ , -NR ｃ 2S(=O) ２ 2NR ｃ 2R ｄ , -NR ｂ 2C(=O)NR ｃ 2R ｄ , -NR ｂ 2C(=O)R ａ , -NR ｂ 2C(=O)OR ｂ , -OS(=O) ２ 2R ａ , -OS(=O) ２ 2OR ｂ , -OS(=O) ２ 2NR ｃ 2R ｄ 、-OC(=O)R ａ 、-OC(=O)OR ｂ 、-OC(=O)NR ｃ R ｄ 、-C(=O)R ａ 、-C(=O)OR ｂ 、又は-C(=O)NR ｃ R ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ Is it okay if it is replaced with, or R ２ and R ３ However, together with the intervening carbon atom, it forms a ring A attached to L, and ring A is a 5-16 member heterocycle which may be substituted. However, R １ and R ２ And R ２ and R ３ Under the condition that neither of them forms a ring A attached to L, Y' is N or CR Ｙ’ And, R Ｙ’ However, hydrogen, halogens, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl or 3-12 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocykyl, or heterocyclyl is one or more R ｕ It may also be replaced with --- This indicates an optional covalent bond between Y and U, i) If the aforementioned connection between Y and U does not exist, r is 0 or 1, Y is N or CR Ｙ And, R Ｙ However, hydrogen, halogens, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl or 3-12 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocykyl, or heterocyclyl is one or more R ｕ It may also be replaced with U is hydrogen, or one or more R ｕ C may be replaced with １～６ It is alkyl, ii) If the aforementioned connection between Y and U exists, r is 1, Y is C, U is -CH ２ -, -C(=O)-, -(C=O)-N(R Ｕ ) - *, or -N = C(R Ｕ ) - * and R Ｕ However, H, or one or more R ｕ C may be replaced with １～６ It is an alkyl group, and * indicates attachment to ring B. R ４ However, hydrogen, deuterium, C １～６ Haloalkyl, or C １～６ It is alkyl, Each R Ｄ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C 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 It may also be replaced with d is an integer between 0 and 4, q is an integer between 0 and 2, T is the one in equation I-2: And in the formula, X Ｔ１ , X Ｔ２ , X Ｔ３ , and X Ｔ４ Each of these independently determines N or CR Ｔ And, R Ｔ Each occurrence is independently of 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, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with Each R Ｅ However, independently, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, -SR ｂ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S(=O)R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -OS (=O) ２ R ａ , -OS (=O) ２ OR ｂ , -OS (=O) ２ NR ｃ R ｄ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with m is an integer selected from 0 to 5. L is the one in equation I'-3: And in the formula, * indicates adhesion to T, and ** indicates adhesion to C. Each L ’ However, independently, C １～６ Alkylene, C １～６ Heteroalkylene, C ２～６ Alkenylene, C ２～６ Alkinylene, C ３～１２ Carbocyclylene, 3-12 member heterocyclylene, C ６～１０ Arylene, 5-10 member heteroarylene, -C(=O)-, -C(=O)N(R) Ｌ )-, -C(=O)O-, -N(R Ｌ )-, -O-, -S-, or -S(=O) ２ - and the alkylene, heteroalkylene, alkenylene, alkynylene, carbocyrene, heterocyclylene, arylene, or heteroarylene is one or more R ｕ It may also be replaced with R Ｌ Each appearance of hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, C ６～１０ Aryl, 5-10 member heteroaryl, -S (=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with l is an integer selected from 0 to 10. Each R ｕ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, -SR ｂ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S(=O)R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -OS (=O) ２ R ａ , -OS (=O) ２ OR ｂ , -OS (=O) ２ NR ｃ R ｄ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ It may be substituted with one or more substituents selected from carbocyclyls and 3- to 6-membered heterocyclyls, or Two R's ｕ However, together with one or more intervening atoms, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ They form carbocyclils or 3-12 member heterocyclils. Each R ａ However, independently, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, C ６～１０ It is an aryl or a 5- to 10-membered heteroaryl, Each R ｂ However, independently, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, C ６～１０ It is an aryl or a 5- to 10-membered heteroaryl, Each R ｃ and R ｄ However, independently, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, C ６～１０ It is an aryl, or a 5- to 10-membered heteroaryl, or R ｃ and R ｄ However, together with the nitrogen atoms to which they are attached, they form 3- to 12-membered heterocyclines. R ａ , R ｂ , R ｃ , and R ｄ Each occurrence of independently determines one or more R ｚ It may also be replaced with Each R ｚ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Carbocyclyl, or 3- to 6-membered heterocyclyl; Furthermore, 1) If the bond between Y and U exists, and U is -CH2- or -C(=O)-, and r is 1, i) R1 and R2, or R2 and R3, together with the intervening carbon atom, form a ring A attached to L; and, ii) Ring A is a substituted 7- to 16-membered fused heterocycle or a substituted 7- to 16-membered spiroheterocycle; and 2) The compound is or none of the pharmaceutically acceptable salts, solvates, or stereoisomers thereof, The compound, or its pharmaceutically acceptable salts, solvates, or stereoisomers.

2. C is the one in equation I'-1-i: The compound according to claim 1.

3. U is -CH ２ The compound according to claim 1, wherein it is - or -C(=O)-.

4. C is the one in equation I'-1-ii: The compound according to claim 1.

5. Y is CR Ｙ And R Ｙ However, hydrogen, halogen, or C １～６ The compound according to claim 1, wherein it is an alkoxy.

6. R １ and R ２ The compound according to claim 1, wherein, together with an intervening carbon atom, it forms a ring A attached to L, and the ring A is a substituted 5-16 member heterocycle.

7. Y" is CR ３ And R ３ However, hydrogen, halogens, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl 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

8. R ２ and R ３ The compound according to claim 1, wherein, together with an intervening carbon atom, it forms a ring A attached to L, and the ring A is a substituted 5-16 member heterocycle.

9. R １ However, hydrogen, halogens, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl 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

10. Ring A is And in the formula, ** indicates adhesion to L, Ring A Ｉ and ring A ＩＩ However, independently, C ４～８ It is a carbon ring or a 4- to 8-membered heterocycle, and ring A ＩＩＩ and ring A ＩＶ At least one of them is a 4- to 8-membered complex ring, A １ and A ２ However, independently, C, CR Ａｘ , or N, R Ａｘ However, hydrogen, halogens, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, C ６～１０ The aryl or 5-10 membered heteroaryl is one or more alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, or heteroaryl. ｕ It may also be replaced with Each R ｉ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, C ６～１０ Aryl, 5-10 member heteroaryl, -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 s is an integer selected from 0 to 8, as long as the valence allows. Each R ｉ However, independently, Circle A Ｉ or Ring A ＩＩ It may exist on any of the following: The compound according to claim 1.

11. Ring A is And, During the ceremony, ** indicates adhesion to L, R ５ However, hydrogen, or one or more R ｕ C may be replaced with １～６ It is alkyl, Each R ｉ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, -SR ｂ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S(=O)R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -OS (=O) ２ R ａ , -OS (=O) ２ OR ｂ , -OS (=O) ２ NR ｃ R ｄ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with s is an integer selected from 0 to 8, as long as the valence allows. The compound according to claim 1.

12. The compound according to claim 1, wherein ring A is a substituted 7- to 16-membered spiroheterocycle.

13. Ring A is And in the formula, ** indicates adhesion to L, Ring A ＩＶ However, C ３～８ It is a carbon ring or a 3- to 8-membered heterocycle. Each X independently, -C(R Ｘ１ ) ２ -, -NR Ｘ２ -, -O-, -S-, -S(=O)-, or -S(=O) ２ - and Each Z independently, -C(R Ｚ１ ) ２ -, -NR Ｚ２ -, -O-, -S-, -S(=O)-, or -S(=O) ２ - and R Ｘ１ and R Ｚ１ Each occurrence is independently of 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 ３～６ Carbocyclyl, 3-6 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 Is it okay if it is replaced with, or Two Geminal R Ｘ１ Or two Geminal R Ｚ１ Together they form an oxo, R Ｘ２ and R Ｚ２ Each occurrence independently represents hydrogen or one or more R ｕ C may be replaced with １～６ It is alkyl, m' and n' are independent integers selected from 0 to 3, and m' and n' are not both necessarily 0. s is an integer selected from 0 to 8, as long as the valence allows. Each R ｉ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, -SR ｂ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S(=O)R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -OS (=O) ２ R ａ , -OS (=O) ２ OR ｂ , -OS (=O) ２ NR ｃ R ｄ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with However, if neither m' nor n' is 0, then ring A １ However, this is conditional on it being a 4- to 9-membered complex ring. Each R ｉ However, independently, Circle A ＩＩＩ or Ring A ＩＶ It may exist on any of the following: The compound according to claim 1.

14. Ring A is １） And, In the formula, o is either 0 or 1, or ２） And, In the formula, ** indicates adhesion to L. The compound according to claim 1.

15. The compound according to claim 1, wherein ring A is a substituted or otherwise substituted 5-6 membered heterocycle.

16. Ring A is And, During the ceremony, ** indicates adhesion to L, R ５ However, hydrogen, or one or more R ｕ C may be replaced with １～６ It is alkyl, Each R ｉ However, independently, oxo, halogen, -CN, -NO ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkylamino, C ２～６ Alkenil, C ２～６ Alkinyl, C ６～１０ Aryl, 5-10 member heteroaryl, C ３～１２ Carbocyclyl, 3-12 member heterocyclyl, -SR ｂ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ OR ｂ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ S (=O) ２ R ａ , -NR ｃ S(=O)R ａ , -NR ｃ S (=O) ２ OR ｂ , -NR ｃ S (=O) ２ NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -OS (=O) ２ R ａ , -OS (=O) ２ OR ｂ , -OS (=O) ２ NR ｃ R ｄ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , or -C(=O)NR ｃ R ｄ The alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl is one or more R ｕ It may also be replaced with s is an integer selected from 0 to 8, as long as the valence allows. The compound according to claim 1.

17. X Ｔ１ , X Ｔ２ , X Ｔ３ , and X Ｔ４ Each of them is CR Ｔ The compound according to claim 1.

18. (i) X Ｔ１ , X Ｔ２ , X Ｔ３ , and X Ｔ４ Is each of them CH? (ii) Whether X T1 is C(OCH3), X T3 is CF, and X T2 and X T4 are each CH; (iii) X T2 is CF, X T4 is C(OCH3), and X T1 and X T3 are each CH; (iv) one of X T1 and X T4 is CF or C(OCH3), the other of X T1 and X T4 is CH, and each of X T2 and X T3 is CH; or (v) X T1 is C(OCH3), X T2 is CF, and X T3 and X T4 are each CH. The compound according to claim 1.

19. The compound according to claim 1, wherein m is 0.

20. L is the one in formula I-3: And in the formula, * indicates adhesion to T, and ** indicates adhesion to C. W does not exist, or W is C １～３ Alkylene, -O-, -NR Ｗ -, or -(C=O)-, and the alkylene is one or more R ｕ It may also be replaced by, Cy １ However, it does not exist, or Cy １ However, 6-member heteroarylene, C ６ Ariren, C ３～１２ Carbocyclylene or 3- to 12-membered heterocyclylene, wherein the allerene, heteroarylene, carbocyclylene, or heterocyclylene contains one or more R ｕ It may also be replaced by, Z' does not exist, or Each Z' independently, C １～３ Alkylene, -O-, -NR Ｗ -, -(C=O)-,C ３～１２ Carbocyclylene or 3- to 12-membered heterocyclylene, wherein the alkylene, carbocyclylene, or heterocyclylene comprises one or more R ｕ It may also be replaced by, R Ｗ However, hydrogen, or one or more R ｕ C may be replaced with １～６ It is alkyl, p is an integer selected from 0 to 8. The compound according to claim 1.

21. - [Z'] ｐ - but -C (=O)-, C １～６ Alkylene, *-O-(C) １～６ Alkylene) -, *-(C １～６ Alkylene) - (C (=O)) - O -, * - (C １～６ Alkylene)-O-, *-C(=O)-(C １～６ Alkylene) -, *-(C １～６ Alkylene)-C(=O)-, 3-12 member heterocyclylene, *-C(=O)-(3-12 member heterocyclylene)-, *-(3-12 member heterocyclylene)-C(=O)-, *-(3-12 member heterocyclylene)-(C １～６ Alkylene) -, *-(C １～６ Alkylene)-(3-12 member heterocyclylene)-, *-(C) １～６ Alkylene) - (3-12 member heterocyclylene) - (C １～６ Alkylene) -, *-(C １～６ Alkylene) - (3-12 member heterocyclylene) - (C(=O)) -, * - (C(=O)) - (3-12 member heterocyclylene) - (C １～６ Alkylene) -, * - (3-12 member heterocyclylene) - (C １～６ Alkylene) - (C (=O)) -, * - (C (=O)) - (C １～６ Alkylene)-(3-12 member heterocyclylene)-, *-(C) １～６ Alkylene)-(C(=O))-(3-12 member heterocyclylene)-, or *-(3-12 member heterocyclylene)-(C(=O))-(C １～６ Alkylene) - and the alkylene or heterocyclylene is one or more R ｕ The compound according to claim 20, which may be substituted by and where * indicates attachment to C.

22. A compound selected from Tables 1 and 2 and Table X, or a pharmaceutically acceptable salt thereof: (Table X) 。

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 and one or more pharmaceutically acceptable excipients.

24. A pharmaceutical composition comprising the compound described in any one of claims 1 to 22 for treating a disease or disorder in a patient in need, or for degrading estrogen receptor proteins.

25. Use of the compound according to any one of claims 1 to 22 in the manufacture of a drug for treating a disease or disorder in a patient or for degrading estrogen receptor proteins.

26. The disease or disorder is an estrogen receptor-mediated disease or disorder; The pharmaceutical composition according to claim 24, wherein optionally, the disease or disorder is breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or esophageal cancer.

27. ​​The disease or disorder is an estrogen receptor-mediated disease or disorder; The use according to claim 25, optionally wherein the disease or disorder is breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or esophageal cancer.

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