Tetrahydronaphthalene derivatives as estrogen receptor degradation agents

Abstract

Described herein are compounds of Formula I and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, and their uses (e.g., as estrogen receptor degrading agents).

Description

[0001] Related applications

[0002] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 388,300, filed on July 12, 2022; U.S. Provisional Application No. 63 / 408,744, filed on September 21, 2022; U.S. Provisional Application No. 63 / 427,277, filed on November 22, 2022; and U.S. Provisional Application No. 63 / 460,734, filed on April 20, 2023, the contents of each of which are incorporated herein by reference in their entirety. Background Art

[0003] Estrogen receptors (ERs) belong to the steroid / nuclear receptor superfamily and are involved in the regulation of eukaryotic gene expression, cell proliferation, and differentiation in target tissues. There are two forms of ER: estrogen receptor α (ERα) and estrogen receptor β (ERβ), encoded by the ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors activated by estrogen (17β-estradiol). In the absence of hormones, ERs are primarily located in the cytosol of cells. When the hormone estrogen binds to ERs, ERs migrate from the cytosol to the cell's nucleus, forming dimers that then bind to specific genomic sequences called estrogen response elements (EREs). The DNA / ER complex interacts with co-regulatory factors 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 dysregulation of ER signaling, particularly through ERα, leads to uncontrolled cell proliferation and ultimately cancer. ER+ breast cancers account for approximately 75% of all breast cancers diagnosed, as well as some ovarian and endometrial cancers.

[0004] Current therapies for ER+ breast cancer include agents that inhibit ER activity by directly binding to the ligand binding domain of the receptor (e.g., tamoxifen); agents that block the synthesis of estrogen (e.g., aromatase inhibitors, such as anastrozole and letrozole); or agents that induce ER degradation. Selective estrogen receptor degraders (SERDs) are small molecules that target ERα for proteasome-dependent degradation. Fulvestrant is the only SERD that has been approved for the treatment of postmenopausal women with advanced ER+ breast cancer with standard endocrine therapy. Because fulvestrant has poor solubility and is not orally bioavailable, it is clinically administered by monthly intramuscular injection. To address the shortcomings of fulvestrant, orally bioavailable SERDs are being developed. However, although SERDs are generally powerful and effective in inducing ER protein degradation in ER+ breast cancer cells, they are only able to achieve partial degradation of ER proteins.

[0005] It is believed that ERα degradation occurs when ERα and a ubiquitin ligase, such as cereblon E3 ligase (CRBN), bind and come into close proximity for ubiquitination and subsequent degradation by the proteasome. A novel approach is to exploit naturally occurring cellular ubiquitin-mediated degradation to develop a new class of therapeutics for the treatment of ER+ metastatic breast cancer, in which ER proteins are almost completely degraded. Summary of the Invention

[0006] In certain aspects, the present disclosure provides compounds of Formula I:

[0007] TLC(I),

[0008] and pharmaceutically acceptable salts, solvates or stereoisomers thereof,

[0009] in:

[0010] C has the formula I'-1

[0011]

[0012] T has the formula I-2:

[0013] and

[0014] L has the formula I'-3:

[0015]

[0016] Each variable in Formulas I, I'-1, I-2, and I'-3 is described, embodied, and exemplified herein.

[0017] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0018] In certain aspects, the present disclosure provides methods of degrading an estrogen receptor in a subject, the method comprising administering to the subject a compound disclosed herein.

[0019] In certain aspects, the present disclosure provides use of a compound disclosed herein in the manufacture of a medicament for degrading an estrogen receptor in a subject.

[0020] In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading an estrogen receptor in a subject.

[0021] In certain aspects, the present disclosure provides methods of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject a compound disclosed herein (eg, in a therapeutically effective amount).

[0022] In certain aspects, the present disclosure provides methods of treating a disease or condition in a subject in need thereof, comprising administering to the subject a compound disclosed herein (eg, in a therapeutically effective amount).

[0023] In certain aspects, the present disclosure provides 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.

[0024] In certain aspects, the present disclosure provides use of a compound disclosed herein in the manufacture of a medicament for treating a disease or condition in a subject in need thereof.

[0025] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.

[0026] In certain aspects, the present disclosure provides a compound disclosed herein for use in treating a disease or disorder in a subject in need thereof. DETAILED DESCRIPTION

[0027] The present disclosure relates to compounds and methods for degrading estrogen receptors, the method comprising contacting an estrogen receptor with a therapeutically effective amount of an estrogen receptor degrader disclosed herein. The present disclosure also relates to methods for treating estrogen receptor-mediated diseases or conditions in subjects in need thereof by administering a therapeutically effective amount of an estrogen receptor degrader disclosed herein. The present disclosure further relates to methods for treating estrogen receptor-mediated diseases or conditions in subjects in need thereof, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of an estrogen receptor degrader disclosed herein.

[0028] Compounds of the present application

[0029] In one aspect, the present disclosure provides compounds of Formula I:

[0030] TLC(I),

[0031] and pharmaceutically acceptable salts, solvates or stereoisomers thereof,

[0032] in:

[0033] C has the formula I'-1

[0034]

[0035] in:

[0036] R 1 For hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution;

[0037] R 2 *-Cy 2 -, where * indicates attachment to L;

[0038] -Cy 2 - for C 3-12 Carbocyclylene or 3 to 12 membered heterocyclylene, wherein the carbocyclylene or heterocyclylene is separated by one or more R u optionally substituted; or

[0039] R 1 and R 2 Together with the intervening carbon atom, it forms Ring A to which L is attached, wherein Ring A is an optionally substituted C 3-12 carbocyclic ring or 5- to 16-membered heterocyclic ring;

[0040] Y" is N or CR 3 ;

[0041] R 3 For 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- to 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)2NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-OS(=O)2R a 、-OS(=O)2OR b 、-OS(=O)2NR c R d 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R dwherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u optionally substituted; or

[0042] R 2 and R 3 together with the intervening carbon atoms, form Ring A to which L is attached, wherein Ring A is an optionally substituted 5- to 16-membered heterocyclic ring;

[0043] The condition is R 1 and R 2 and R 2 and R 3 Not all form ring A attached to L;

[0044] Y' is N or CR Y’ ;

[0045] R Y’ For 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- to 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 replaced by one or more R u Optional substitution;

[0046] represents an optional covalent bond between Y and U;

[0047] i) When the bond between Y and U does not exist:

[0048] r is 0 or 1;

[0049] Y is N or CR Y ;

[0050] R Y For 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- to 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 replaced by one or more R uOptional substitution;

[0051] U is hydrogen or is replaced by one or more R u Optionally substituted C 1-6 alkyl;

[0052] ii) When a bond between Y and U exists:

[0053] r is 1;

[0054] Y is C;

[0055] U is -CH2-, -C(=O)-, -(C=O)-N(R U )-*or-N=C(R U )-*;

[0056] R U H or one or more R u Substituted C 1-6 alkyl, and * indicates attachment to ring B;

[0057] R 4 For hydrogen, deuterium, C 1-6 Haloalkyl or C 1-6 alkyl; and

[0058] 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- to 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 replaced by one or more R u Optional substitution;

[0059] d is an integer from 0 to 4; and

[0060] q is an integer from 0 to 2,

[0061] T has the formula I-2:

[0062]

[0063] in:

[0064] X T1 、X T2 、X T3 and X T4 Each of is independently N or CRT ;

[0065] R T Each occurrence 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution;

[0066] Each R Eare independently 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution;

[0067] m is an integer selected from 0 to 5;

[0068] L has the formula I'-3:

[0069]

[0070] in:

[0071] * indicates attachment to T, and ** indicates attachment to C;

[0072] Each L ’ Independently C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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-, wherein the alkylene, heteroalkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene or heteroarylene is replaced by one or more R u Optional substitution;

[0073] R L Each occurrence is independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 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 wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u optionally substituted; and

[0074] l is an integer selected from 0 to 10;

[0075] in:

[0076] 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 6-10Aryl, 5- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl and 3- to 6-membered heterocyclyl; or

[0077] Two R's u Together with one or more intervening atoms, it forms C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 a carbocyclyl group or a 3- to 12-membered heterocyclyl group;

[0078] Each R a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl;

[0079] Each R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; and

[0080] Each R c and R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; or

[0081] R c and R d together with the nitrogen atom to which they are attached, form a 3- to 12-membered heterocyclic group,

[0082] where R a 、R b 、R c and R d Each occurrence is followed by one or more R z are independently and optionally substituted; and

[0083] 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 a carbocyclic group or a 3- to 6-membered heterocyclic group.

[0084] In certain aspects, the present disclosure provides compounds of Formula I:

[0085] TLC(I),

[0086] and pharmaceutically acceptable salts, solvates or stereoisomers thereof,

[0087] in:

[0088] C has the formula I-1

[0089]

[0090] in:

[0091] R 1 For 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- to 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)2NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-OS(=O)2R a 、-OS(=O)2OR b 、-OS(=O)2NR c R d 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R dwherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution;

[0092] R 2 *-Cy 2 -, where * indicates attachment to L;

[0093] -Cy 2 - for C 3-12 Carbocyclylene or 3 to 12 membered heterocyclylene, wherein the carbocyclylene or heterocyclylene is separated by one or more R u optionally substituted; or

[0094] R 1 and R 2 Together with the intervening carbon atom, it forms Ring A to which L is attached, wherein Ring A is an optionally substituted C 3-12 carbocyclic ring or 5- to 16-membered heterocyclic ring;

[0095] Y" is N or CR 3 ;

[0096] R 3 For 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- to 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)2NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)ORb 、-OS(=O)2R a 、-OS(=O)2OR b 、-OS(=O)2NR c R d 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u optionally substituted; or

[0097] R 2 and R 3 together with the intervening carbon atoms, form Ring A to which L is attached, wherein Ring A is an optionally substituted 5- to 16-membered heterocyclic ring;

[0098] The condition is R 1 and R 2 and R 2 and R 3 Not all form ring A attached to L;

[0099] Y' is N or CR Y’ ;

[0100] R Y’ For 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- to 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 replaced by one or more R u Optional substitution;

[0101] represents an optional covalent bond between Y and U;

[0102] When the bond between Y and U does not exist:

[0103] r is 0 or 1;

[0104] Y is N or CR Y ;

[0105] R Y For 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- to 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 replaced by one or more R u Optional substitution;

[0106] U is hydrogen or is replaced by one or more R u Optionally substituted C 1-6 alkyl;

[0107] When the bond between Y and U exists:

[0108] r is 1;

[0109] Y is C;

[0110] U is -CH2-, -C(=O)-, -(C=O)-N(R U )-*or-N=C(R U )-*;

[0111] R U H or one or more R u Substituted C 1-6 alkyl, and * indicates attachment to ring B;

[0112] R 4 For hydrogen, deuterium, C 1-6 Haloalkyl or C 1-6 alkyl; and

[0113] q is an integer from 0 to 2,

[0114] T has the formula I-2:

[0115]

[0116] in:

[0117] X T1 、X T2 、X T3 and X T4 Each of is independently N or CR T ;

[0118] R TEach occurrence 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution;

[0119] Each R E are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution;

[0120] m is an integer selected from 0 to 5,

[0121] L has the formula I-3:

[0122]

[0123] in:

[0124] * indicates attachment to T and ** indicates attachment to C;

[0125] W does not exist; or

[0126] W is C 1-3 Alkylene, -O-, -NR W - or -(C=O)-, wherein the alkylene group is replaced by one or more R u Optional substitution;

[0127] Cy 1 does not exist; or

[0128] 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 separated by one or more R u Optional substitution;

[0129] Z' does not exist; or

[0130] 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 separated by one or more R u Optional substitution;

[0131] R W is hydrogen or is replaced by one or more R u Optionally substituted C 1-6 alkyl; and

[0132] p is an integer selected from 0 to 8,

[0133] in:

[0134] 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- to 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)2Ra 、-NR c S(=O)R a 、-NR c S(=O)2OR b 、-NR c S(=O)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl and 3- to 6-membered heterocyclyl; or

[0135] Two R's u Together with one or more intervening atoms, it forms C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 a carbocyclyl group or a 3- to 12-membered heterocyclyl group;

[0136] Each R a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl;

[0137] Each Rb are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; and

[0138] Each R c and R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; or

[0139] R c and R d together with the nitrogen atom to which they are attached, form a 3- to 12-membered heterocyclic group,

[0140] where R a 、R b 、R c and R d Each occurrence is followed by one or more R z are independently and optionally substituted; and

[0141] 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 a carbocyclic group or a 3- to 6-membered heterocyclic group.

[0142] In certain aspects, the present disclosure provides compounds of Formula I:

[0143] TLC(I),

[0144] and pharmaceutically acceptable salts, solvates or stereoisomers thereof,

[0145] in:

[0146] C has the formula I-1

[0147]

[0148] in:

[0149] represents an optional covalent bond between Y and U;

[0150] R 1 For 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution;

[0151] R 2 *-Cy 2 -, where * indicates attachment to L;

[0152] -Cy 2 - is a 3- to 12-membered heterocyclylene group, wherein the heterocyclylene group is separated by one or more R u optionally substituted; or

[0153] R 1 and R 2 Together with the intervening carbon atom, it forms Ring A to which L is attached, wherein Ring A is surrounded by one or more R i Optionally substituted C 3-10 carbocyclic ring or 5- to 16-membered heterocyclic ring;

[0154] Y" is N or CR 3 ;

[0155] R 3 For 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u optionally substituted; or

[0156] R 2 and R 3 Together with the intervening carbon atom, it forms Ring A to which L is attached, wherein Ring A is surrounded by one or more R i an optionally substituted 5- to 16-membered heterocyclic ring;

[0157] The condition is R 1 and R 2 and R 2 and R 3 Not all form ring A attached to L;

[0158] 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution;

[0159] Y' is N or CR Y’ ;

[0160] R Y’ For 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, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution;

[0161] When the bond between Y and U is absent, Y is N or CR Y ; or when a bond between Y and U exists, Y is C;

[0162] R Y For 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, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution;

[0163] r is 0 or 1;

[0164] When the bond between Y and U is absent, U is hydrogen or C 1-6 Alkyl; or

[0165] When a bond between Y and U exists, U is -CH2-, -C(=O)-, -(C=O)-N(R U )-*or-N=C(R U)-*;

[0166] R U H or C 1-6 alkyl, and * indicates attachment to ring B;

[0167] R 4 For hydrogen, deuterium, C 1-6 Haloalkyl or C 1-6 alkyl; and

[0168] q is an integer from 0 to 2;

[0169] T has the formula I-2:

[0170]

[0171] in:

[0172] X T1 、X T2 、X T3 and X T4 Each of is independently N or CR T ;

[0173] R T Each occurrence 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 6-14 Aryl, 5- to 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)2NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NRb 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution;

[0174] Each R E are independently 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution;

[0175] m is an integer selected from 0 to 5,

[0176] L has the formula I-3:

[0177]

[0178] in:

[0179] W does not exist; or

[0180] W is -CH2-, -O-, or -NR W -or -(C=O)-;

[0181] R W is hydrogen or C 1-6 alkyl;

[0182] * indicates attachment to T and ** indicates attachment to C;

[0183] 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 separated by one or more R u Optional substitution;

[0184] Z' does not exist; or

[0185] Z' is -(C(=O)) p -(O) p’ -(C 1-6 alkylene) u -(3- to 6-membered heterocyclylene) v -(C(=O)) p -(C 1-6 alkylene) u -(3- to 6-membered heterocyclylene) v -(C(=O)) pwherein the alkylene or heterocyclylene is replaced by one or more R u Optional substitution;

[0186] p, p' and u are independently 0 or 1 at each occurrence; and

[0187] Each v is an integer independently selected from 0 to 3,

[0188] in:

[0189] 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- to 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)2NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-OS(=O)2R a 、-OS(=O)2OR b 、-OS(=O)2NR c R d 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NRc R d wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 carbocyclyl and 3- to 6-membered heterocyclyl; or

[0190] Two R's u Together with one or more intervening atoms, it forms C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 a carbocyclyl group or a 3- to 10-membered heterocyclyl group;

[0191] Each R a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl;

[0192] Each R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; and

[0193] Each R c and R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; or

[0194] R c and R d together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocyclic group,

[0195] where R a 、R b 、R c and R d Each of them is represented by one or more R z are independently and optionally substituted; and

[0196] Each Rz are independently oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 a carbocyclic group or a 3- to 6-membered heterocyclic group.

[0197] In certain embodiments, when a bond between Y and U exists, U is -CH2- or -C(=O)-, and r is 1, then R 1 and R 2 or R 2 and R 3 Together with the intervening carbon atom, they form ring A to which L is attached.

[0198] In certain embodiments, when a bond between Y and U is present, U is -CH2- or -C(=O)-, and r is 1, then Ring A is not

[0199]

[0200] Where ** indicates attachment to L.

[0201] In certain embodiments, when a bond between Y and U is present, U is -CH2- or -C(=O)-, and r is 1, then Ring A is not

[0202]

[0203] Where ** indicates attachment to L.

[0204] In certain embodiments, the compound is not

[0205]

[0206] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0207] In certain embodiments, the compound is not

[0208]

[0209] or a pharmaceutically acceptable salt thereof.

[0210] In certain embodiments,

[0211] 1) When a bond between Y and U exists, U is -CH2- 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, it forms Ring A to which L is attached; and / or ii) Ring A is not

[0212]

[0213] Where ** indicates attachment to L, and / or

[0214] 2) The compound is not

[0215]

[0216] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0217] In certain embodiments,

[0218] 1) When a bond between Y and U exists, U is -CH2- 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, it forms Ring A to which L is attached; and / or ii) Ring A is not

[0219]

[0220] Where ** indicates attachment to L, and / or

[0221] 2) The compound is not

[0222]

[0223] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0224] In certain embodiments,

[0225] 1) When a bond between Y and U exists, U is -CH2- 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, it forms Ring A to which L is attached; and / or ii) Ring A is not

[0226]

[0227] Where ** indicates attachment to L, and / or

[0228] 2) The compound is not

[0229]

[0230] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0231] In certain embodiments,

[0232] 1) When a bond between Y and U exists, U is -CH2- 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, it forms Ring A to which L is attached; and / or ii) Ring A is not

[0233]

[0234] Where ** indicates attachment to L, and / or

[0235] 2) The compound is not

[0236]

[0237] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0238] In certain embodiments,

[0239] 1) When a bond between Y and U exists, U is -CH2- 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, it forms Ring A to which L is attached; and / or ii) Ring A is not

[0240]

[0241] Where ** indicates attachment to L, and / or

[0242] 2) The compound is not

[0243]

[0244] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0245] In certain embodiments,

[0246] 1) When a bond between Y and U exists, U is -CH2- 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, it forms Ring A to which L is attached; and / or ii) Ring A is not

[0247]

[0248] Where ** indicates attachment to L, and / or

[0249] 2) The compound is not

[0250]

[0251] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0252] In certain embodiments,

[0253] 1) When a bond between Y and U exists, U is -CH2- 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, it forms Ring A to which L is attached; and / or ii) Ring A is not

[0254]

[0255] Where ** indicates attachment to L, and / or

[0256] 2) The compound is not

[0257]

[0258] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0259] In certain embodiments,

[0260] 1) When a bond between Y and U exists, U is -CH2- 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, it forms Ring A to which L is attached; and / or ii) Ring A is not

[0261]

[0262] Where ** indicates attachment to L, and / or

[0263] 2) The compound is not

[0264]

[0265] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0266] In certain embodiments, C has the formula I-1-i

[0267]

[0268] In certain embodiments, C has the formula I-1-ii

[0269]

[0270] In certain embodiments, C has the formula I'-1-i

[0271]

[0272] In certain embodiments, C has the formula I'-1-ii

[0273]

[0274] In certain embodiments, U is -CH2- or -C(=O)-. In certain embodiments, when a bond between Y and U is present, U is -CH2- or -C(=O)-. In certain embodiments, when a bond between Y and U is present, U is -(C=O)-N(R U )-*or-N=C(R U )-*.

[0275] 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), pentyloxy (C5), or hexyloxy (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 propyl-n-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 3-12 Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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), -SRb 、-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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution.

[0276] In certain embodiments, R 1 For 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 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0277] In certain embodiments, R 1 For hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl, 3 to 6 membered heterocyclyl, C6 aryl or 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0278] In certain embodiments, R 1 For 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, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0279] In certain embodiments, R 1 For 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, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0280] In certain embodiments, R 1 is hydrogen, halogen or C 1-6 Alkoxy.

[0281] In certain embodiments, R 2 *-Cy 2 -, where * indicates attachment to L.

[0282] In certain embodiments, -Cy 2 - for 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]heptylene (C7), bicyclo[2.2.2]octylene (C8), cyclononylene (C9), cyclononenylene (C9), cyclodecylene (C9), 10 ), cyclodecenylene (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthylene (C 10 ) or spiro[4.5]decylene (C 10 )) or a 3 to 12 membered heterocyclylene (e.g., a heterocyclylene comprising one or two 3 to 8 membered rings and 1-5 heteroatoms selected from N, O and S), wherein the carbocyclylene or heterocyclylene is replaced by one or more R u Optional substitution.

[0283] In certain embodiments, *-Cy 2 - for C 5-12 A fused carbocyclylene or a 5- to 12-membered fused heterocyclylene, wherein the carbocyclylene or heterocyclylene is surrounded by one or more R u Optional substitution.

[0284] In certain embodiments, *-Cy 2 - is a 5- to 12-membered fused heterocyclylene group containing 1 or 2 nitrogen atoms, wherein the heterocyclylene group is separated by one or more R u Optional substitution.

[0285] In certain embodiments, *-Cy 2 -for

[0286]

[0287] In certain embodiments, R 1 and R 2 Together with the intervening carbon atom, it forms Ring A to which L is attached, wherein Ring A is an optionally substituted C 3-12Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl (C 10 )) or a 5- to 16-membered heterocyclyl (e.g., a heterocyclyl comprising one or two 5- to 8-membered rings and 1-5 heteroatoms selected from N, O and S).

[0288] In certain embodiments, Y" is N or CR 3 .

[0289] 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 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentyloxy (C5), or hexyloxy (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 propyl-n-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 3-12 Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution.

[0290] In certain embodiments, R 3 For 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 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0291] In certain embodiments, R 3 For hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl, 3 to 6 membered heterocyclyl, C6 aryl or 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0292] In certain embodiments, R 3 For 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, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0293] In certain embodiments, R 3 For 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, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0294] In certain embodiments, R 3 is hydrogen, halogen or C 1-6 Alkoxy.

[0295] In certain embodiments, R 2 and R 3 Together with the intervening carbon atom, it forms Ring A to which L is attached, wherein Ring A is an optionally substituted C 3-12Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl (C 10 )) or a 5- to 16-membered heterocyclyl (e.g., a heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O and S).

[0296] In certain embodiments, R 1 and R 2 and R 2 and R 3 Not all form a ring A attached to L.

[0297] In certain embodiments, Y' is N or CR Y’ .

[0298] 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 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentyloxy (C5), or hexyloxy (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 propyl-n-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 3-12 Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-10Aryl (e.g., phenyl or naphthyl), 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), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is replaced by one or more R u Optional substitution.

[0299] In certain embodiments, R Y’ For hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl, 3 to 6 membered heterocyclyl, C6 aryl or 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0300] In certain embodiments, R Y’ For 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, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0301] In certain embodiments, R Y’ For 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, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0302] In certain embodiments, R Y’ is hydrogen, halogen or C 1-6 Alkoxy.

[0303] In certain embodiments, i) when the bond between Y and U is absent, then r is 0 or 1, and Y is N or CR Y , and U is hydrogen or is replaced by one or more R uOptionally substituted C 1-6 alkyl.

[0304] In certain embodiments, Y is N. In certain embodiments, Y is CR Y .

[0305] 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 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentyloxy (C5), or hexyloxy (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 propyl-n-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 3-12Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is replaced by one or more R u Optional substitution.

[0306] In certain embodiments, R Y For hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl, 3 to 6 membered heterocyclyl, C6 aryl or 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0307] In certain embodiments, R Y For 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, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0308] In certain embodiments, R Y For 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, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0309] In certain embodiments, R Y is hydrogen, halogen or C 1-6 Alkoxy.

[0310] In certain embodiments, ii) when a bond between Y and U is present, then r is 1, Y is C, and U is -CH2-, -C(=O)-, -(C=O)-N(R U )-*or-N=C(R U )-*.

[0311] In certain embodiments, R U H or one or more R u Optionally substituted 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)), and * indicates attachment to ring B.

[0312] In certain embodiments, R 4 For hydrogen, deuterium, C 1-6 Haloalkyl (e.g., C containing 1-6 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)).

[0313] 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 1-6Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentyloxy (C5), or hexyloxy (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 propyl-n-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 3-12 Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl(C 10)), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is replaced by one or more R u Optional substitution.

[0314] 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, C6 aryl or 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0315] 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, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0316] 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, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0317] 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.

[0318] 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.

[0319] In certain embodiments, Ring A is an optionally substituted 7- to 16-membered fused heterocyclic ring.

[0320] In certain embodiments, Ring A is

[0321]

[0322] in:

[0323] ** indicates attachment to L;

[0324] Ring A I and Ring A II Independently C 4-8 Carbocyclic or 4- to 8-membered heterocyclic ring; wherein Ring A III and Ring A IV At least one of is a 4- to 8-membered heterocycle;

[0325] A 1 and A 2 Independently C, CR Ax or N;

[0326] R Ax For 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 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution;

[0327] 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, C3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 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)2R a 、-NR c S(=O)R a 、-NR c S(=O)2OR b 、-NR c S(=O)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u optionally substituted; and

[0328] When valence permits, s is an integer selected from 0 to 8,

[0329] Each R i Can exist independently in ring A I or ring II superior.

[0330] In certain embodiments, Ring A is

[0331]

[0332] in:

[0333] ** indicates attachment to L;

[0334] R 5 is hydrogen or is replaced by one or more R u Optionally substituted C 1-6 alkyl;

[0335] 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- to 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)2NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-OS(=O)2R a 、-OS(=O)2OR b 、-OS(=O)2NR c R d 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R dwherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u optionally substituted; and

[0336] s is an integer selected from 0 to 8 when valence permits.

[0337] In certain embodiments, Ring A is

[0338]

[0339] ** indicates attachment to L;

[0340] R 5 is hydrogen or is replaced by one or more R u Optionally substituted C 1-6 alkyl;

[0341] 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- to 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)2NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-OS(=O)2R a 、-OS(=O)2OR b 、-OS(=O)2NR c Rd 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u optionally substituted; and

[0342] s is an integer selected from 0 to 8 when valence permits.

[0343] In certain embodiments, Ring A is

[0344]

[0345] in:

[0346] ** indicates attachment to L;

[0347] R 5 is hydrogen or is replaced by one or more R u Optionally substituted C 1-6 alkyl;

[0348] Each R 6 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclyl, 3- to 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 wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution;

[0349] 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u optionally substituted; and

[0350] s is an integer selected from 0 to 8 when valence permits.

[0351] In certain embodiments, Ring A I and Ring A II Independently C 4-8a carbocyclic 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- to 8-membered heterocyclic ring (e.g., a heterocyclic ring comprising one or two 4- to 8-membered rings and 1-4 heteroatoms selected from N, O, and S); wherein Ring A III and Ring A IV At least one of them is a 4- to 8-membered heterocyclic ring.

[0352] In certain embodiments, A 1 and A 2 Independently C, CR Ax or N.

[0353] 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), pentyloxy (C5), or hexyloxy (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 propyl-n-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), C2-6 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 Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is replaced by one or more R u Optional substitution.

[0354] In certain embodiments, R Ax For hydrogen, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl, 3 to 6 membered heterocyclyl, C6 aryl or 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0355] In certain embodiments, R AxFor 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, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0356] In certain embodiments, R Ax For 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, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0357] In certain embodiments, R 6 For hydrogen, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12 Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C8), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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)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 wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0358] In certain embodiments, R 6 For hydrogen, C 1-6 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 wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0359] In certain embodiments, R 6 For hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group, -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 cR d wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is replaced by one or more R u Optional substitution.

[0360] In certain embodiments, R 6 For hydrogen, C 1-6 Alkyl, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, -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 wherein the alkyl, carbocyclic or heterocyclic group is replaced by one or more R u Optional substitution.

[0361] In certain embodiments, Ring A is replaced by one or more R u Optional substitution.

[0362] In certain embodiments, R u R Ax In certain embodiments, R u R 5 In certain embodiments, R u R i .

[0363] In certain embodiments, Ring A is an optionally substituted 7- to 16-membered spiroheterocycle.

[0364] In certain embodiments, Ring A is:

[0365]

[0366] in:

[0367] ** indicates attachment to L;

[0368] Ring A 2 C 3-8 Carbocyclic or 3- to 8-membered heterocyclic ring;

[0369] Each X is independently -C(R X1 )2-、-NR X2 -, -O-, -S-, -S(=O)- or -S(=O)2-;

[0370] Each Z is independently -C(R Z1 )2-、-NR Z2-, -O-, -S-, -S(=O)- or -S(=O)2-;

[0371] R X1 and R Z1 Each occurrence 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- to 10-membered heteroaryl, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, -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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution;

[0372] Two RX1 or two R Z1 together to form an oxo group; or

[0373] Two R's X1 or two R Z1 Together with the intervening carbon atom, it forms C 3-12 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is separated by one or more R u Optional substitution;

[0374] R X2 and R Z2 Each occurrence is independently hydrogen or replaced by one or more R u Optionally substituted C 1-6 alkyl;

[0375] m' and n' are independently integers selected from 0-3, wherein m' and n' are not both 0;

[0376] 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u optionally substituted; and

[0377] s is an integer selected from 0 to 8 when valence permits.

[0378] In certain embodiments, Ring A is

[0379]

[0380] in:

[0381] ** indicates attachment to L;

[0382] Ring A IV C 3-8 Carbocyclic or 3- to 8-membered heterocyclic ring;

[0383] Each X is independently -C(R X1 )2-、-NR X2 -, -O-, -S-, -S(=O)- or -S(=O)2-;

[0384] Each Z is independently -C(R Z1 )2-、-NR Z2 -, -O-, -S-, -S(=O)- or -S(=O)2-;

[0385] R X1 and R Z1 Each occurrence 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution;

[0386] Two R X1 or two R Z1 together to form an oxo group; or

[0387] Two R's X1 or two R Z1 Together with the intervening carbon atom, it forms C 3-12 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is separated by one or more R u Optional substitution;

[0388] R X2 and R Z2 Each occurrence is independently hydrogen or replaced by one or more R u Optionally substituted C 1-6 alkyl;

[0389] m' and n' are independently integers selected from 0-3, wherein m' and n' are not both 0;

[0390] When valence permits, s is an integer selected from 0 to 8, and

[0391] 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R uOptionally substituted,

[0392] The condition is that when both m' and n' are not 0, then ring A 1 It is a 4- to 9-membered heterocyclic ring.

[0393] In certain embodiments, Ring A is: 1)

[0395]

[0396] where o is 0 or 1; or 2)

[0398]

[0399] Where ** indicates attachment to L.

[0400] In certain embodiments, Ring A IV C 3-8 carbocycle (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]heptyl (C7), or bicyclo[2.2.2]octyl (C8)) or a 3- to 8-membered heterocycle (e.g., a heterocyclyl group comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S).

[0401] In certain embodiments, each X is independently -C(R X1 )2-、-NR X2 -, -O-, -S-, -S(=O)-, or -S(=O)2-. In certain embodiments, each X is independently -C(R X1 )2-、-NR X2 -and-O-.

[0402] In certain embodiments, each Z is independently -C(R Z1 )2-、-NR Z2 -, -O-, -S-, -S(=O)-, or -S(=O)2-. In certain embodiments, each Z is independently -C(R Z1 )2-、-NR Z2 -or-O-.

[0403] In certain embodiments, R X1 and R Z1Each occurrence is independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 1-6 Alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentyloxy (C5), or hexyloxy (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 propyl-n-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 3-12Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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)2NR 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)Ra 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution.

[0404] In certain embodiments, R X1 and R Z1 Each occurrence 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 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0405] In certain embodiments, R X1 and R Z1 Each occurrence 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, 3 to 6 membered heterocyclyl, C6 aryl or 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0406] In certain embodiments, R X1 and R Z1 Each occurrence 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, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0407] In certain embodiments, R X1 and R Z1 Each occurrence 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, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0408] In certain embodiments, two geminal R X1 or two R Z1 Together they form an oxo group.

[0409] In certain embodiments, both R X1 or two R Z1 Together with the intervening carbon atom, it forms C 3-12 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is separated by one or more R u Optional substitution.

[0410] In certain embodiments, two geminal R X1 or two R Z1 Together with the carbon atom to which they are attached, they form C 3-12 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is separated by one or more R u Optional substitution.

[0411] In certain embodiments, R X2 and R Z2 Each occurrence is independently hydrogen or replaced by one or more R u Optionally substituted 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)).

[0412] 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.

[0413] 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.

[0414] In certain embodiments, m' and n' are not both zero.

[0415] In certain embodiments, Ring A is replaced by one or more R u Optional substitution.

[0416] In certain embodiments, R u R X1 In certain embodiments, R u R X2 In certain embodiments, R u R Z1 In certain embodiments, R u R Z2 In certain embodiments, R u R i .

[0417] In certain embodiments, Ring A is an optionally substituted 5- to 6-membered heterocyclic ring.

[0418] In certain embodiments, Ring A is

[0419]

[0420] in:

[0421] ** indicates attachment to L;

[0422] R 5 is hydrogen or is replaced by one or more R u Optionally substituted C 1-6 alkyl;

[0423] 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- to 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 cS(=O)2OR b 、-NR c S(=O)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u optionally substituted; and

[0424] s is an integer selected from 0 to 8 when valence permits.

[0425] In certain embodiments, Ring A is replaced by one or more R u Optional substitution.

[0426] In certain embodiments, R u R 5 In certain embodiments, R u R i .

[0427] In certain embodiments, R 5 is hydrogen or is replaced by one or more R u Optionally substituted 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)).

[0428] In certain embodiments, each R i are independently oxo, halogen (e.g., -F, -Cl, -Br or -I), -CN, -NO2, -OH, -NH2, C1-6 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), pentyloxy (C5), or hexyloxy (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 propyl-n-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 3-12 Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9),10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution.

[0429] 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 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0430] 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, 3 to 6 membered heterocyclyl, C6 aryl or 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0431] 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, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0432] 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, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0433] 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.

[0434] In certain embodiments, X T1 、X T2 、X T3 and X T4 Each of them is CR T .

[0435] In certain embodiments, X T1 、X T2 、X T3 and X T4 In certain embodiments, each of X is CH. T1 and X T4 Each of CH, X T2 and X T3 One of them is CH, and X T2 and X T3 The other of X is CF. In certain embodiments, X T1 and X T4 One of them is CF or C(OCH3), X T1 and X T4 The other one of them is CH, and X T2 and X T3 In certain embodiments, each of X is CH. T1 is C(OCH3), X T3 is CF, and X T2 and X T4 In certain embodiments, each of X is CH. T2 CF, X T4 is C(OCH3), and X T1 and X T3 In certain embodiments, each of X is CH. T1 is C(OCH3), X T2 is CF, and X T3 and X T4 Each of them is CH.

[0436] In certain embodiments, X T1 、X T2 、X T3 and X T4 One of them is N.

[0437] In certain embodiments, X T1 and X T4 One of them is N, X T1 and X T4 The other one of them is CH, and X T2 and X T3 In certain embodiments, each of X is CH. T2 and X T3 One of them is N, X T2 and X T3 The other one of them is CH, and X T1 and X T4 Each of them is CH.

[0438] In certain embodiments, X T1 、X T2 、X T3 and X T4 Both of them are N.

[0439] In certain embodiments, X T1 and X T4 Each of is CH, and X T2 and X T3 Each of them is N.

[0440] In certain embodiments, T is

[0441]

[0442] 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, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 Carbocyclyl, 3 to 12 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0443] In certain embodiments, each R T are independently hydrogen, C 1-6 Alkoxy or halogen.

[0444] In certain embodiments, each R E are independently halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C1-6 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 carbocyclyl or 3 to 12 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0445] In certain embodiments, R E It is a halogen.

[0446] 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.

[0447] In certain embodiments, L has the formula I'-3:

[0448]

[0449] in:

[0450] * indicates attachment to T, and ** indicates attachment to C;

[0451] Each L ’ Independently C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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-, wherein the alkylene, heteroalkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene or heteroarylene is replaced by one or more R u Optional substitution;

[0452] R L Each occurrence is independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, -S(=O)2R a 、-S(=O)2ORb 、-S(=O)2NR c R d 、-C(=O)R a 、-C(=O)OR b or -C(=O)NR c R d wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u optionally substituted; and

[0453] l is an integer selected from 0 to 10;

[0454] 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., containing 1-5 C 1-6 Heteroalkylene), C 2-6 alkenylene (e.g., vinylene (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 Alkynylidene (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]heptylene (C7), bicyclo[2.2.2]octylene (C8), cyclononylene (C9), cyclononenylene (C9), cyclodecylene (C9), 10 ), cyclodecenylene (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthylene (C 10) or spiro[4.5]decylene (C 10 )), a 3- to 12-membered heterocyclylene group (e.g., a heterocyclylene group comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C 6-10 Arylene (e.g., phenylene or naphthylene), 5- to 10-membered heteroarylene (e.g., heteroarylene containing one or two 5- or 6-membered rings and 1-5 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-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene or heteroarylene is replaced by one or more R u Optional substitution.

[0455] 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-, wherein the alkylene, carbocyclylene or heterocyclylene is replaced by one or more R u Optional substitution.

[0456] In certain embodiments, R L Each occurrence 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 3-12Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C8), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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)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 wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0457] In certain embodiments, R L Each occurrence is independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic or 3- to 6-membered heterocyclic, 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 wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution.

[0458] In certain embodiments, R L Each occurrence is independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group, -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 wherein the alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is replaced by one or more R u Optional substitution.

[0459] In certain embodiments, R L Each occurrence is independently hydrogen, C 1-6 Alkyl, C 3-6 Carbocyclic group or 3 to 6 membered heterocyclic group, -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 wherein the alkyl, carbocyclic or heterocyclic group is replaced by one or more R u Optional substitution.

[0460] 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.

[0461] In certain embodiments, L has Formula I-3:

[0462]

[0463] in:

[0464] * indicates attachment to T and ** indicates attachment to C;

[0465] W does not exist; or

[0466] W is C 1-3 Alkylene, -O-, -NR W - or -(C=O)-, wherein the alkylene group is replaced by one or more R u Optional substitution;

[0467] Cy 1 does not exist; or

[0468] 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 separated by one or more R u Optional substitution;

[0469] Z' does not exist; or

[0470] 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 separated by one or more R u Optional substitution;

[0471] R W is hydrogen or is replaced by one or more R u Optionally substituted C 1-6 alkyl; and

[0472] p is an integer selected from 0 to 8.

[0473] In certain embodiments, W is absent.

[0474] 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)-, wherein the alkylene group is replaced by one or more R u Optional substitution.

[0475] In certain embodiments, Cy 1 Does not exist.

[0476] In certain embodiments, Cy 1 is C6 arylene (ie, phenylene), 6-membered heteroarylene (eg, heteroarylene containing a 6-membered ring and 1-4 heteroatoms selected from N, O and S), C 3-12Carbocyclylene (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]heptylene (C7), bicyclo[2.2.2]octylene (C8), cyclononylene (C9), cyclononenylene (C9), cyclodecylene (C9), 10 ), cyclodecenylene (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthylene (C 10 ) or spiro[4.5]decylene (C 10 )) or a 3 to 12 membered heterocyclylene (e.g., a heterocyclylene comprising one or two 3 to 8 membered rings and 1 to 5 heteroatoms selected from N, O, and S), wherein the arylene, heteroarylene, carbocyclylene, or heterocyclylene is replaced by one or more R u Optional substitution.

[0477] In certain embodiments, Cy 1is a 3- to 12-membered heterocyclylene group selected from the group consisting of 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-8-azaspiro[4.5]decenylene, 1 ... -Oxa-2-azaspiro[3.4]octanylene, 6-oxa-2-azaspiro[3.4]octanylene, 3,9-diazaspiro[5.5]undecylene, 5-oxa-2-azaspiro[3.5]nonanylene, 1-oxa-9-azaspiro[5.5]undecylene, 1-oxa-4,9-diazaspiro[5.5]undecylene, 2,6-diazaspiro[3.3]heptylene alkyl, 2-azaspiro[3.3]heptylene, 1,5-dioxa-9-azaspiro[5.5]undecylene, 1,4-dioxa-9-azaspiro[5.5]undecylene, 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 replaced by one or more R u Optional substitution.

[0478] In certain embodiments, Cy 1 is a 3- to 12-membered heterocyclylene group selected from the following:

[0479]

[0480] wherein the heterocyclylene group is replaced by one or more R u Optional substitution.

[0481] In certain embodiments, Z' is absent.

[0482] 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 3-12Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl (C 10 )) or a 3 to 12 membered heterocyclyl (e.g., a heterocyclyl comprising 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 replaced by one or more R u Optional substitution.

[0483] In certain embodiments, R W is hydrogen or is replaced by one or more R u Optionally substituted 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)).

[0484] 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.

[0485] 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)-(C1-6 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 1-6 alkylene)-(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)-, wherein the alkylene or heterocyclylene is replaced by one or more R u Optionally substituted, and * indicates attachment to C.

[0486] 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 to 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 separated by one or more R u Optionally substituted, and * indicates attachment to C.

[0487] In certain embodiments, L' is W. In certain embodiments, L' is Cy 1 In certain embodiments, L' is Z'.

[0488] In certain embodiments, l is p. In certain embodiments, l is p+1. In certain embodiments, l is p+2.

[0489] In certain embodiments,

[0490] C has the formula I-1-i

[0491]

[0492] in:

[0493] R 1 and R 2 Together with the intervening carbon atom, it forms Ring A to which L is attached; or

[0494] R 2 and R 3 Together with the intervening carbon atom, it forms Ring A to which L is attached; and

[0495] Ring A is an optionally substituted 7- to 16-membered fused heterocyclic ring or an optionally substituted 7- to 16-membered spiroheterocyclic ring,

[0496] T has the formula I-2:

[0497]

[0498] in:

[0499] X T1 、X T2 、X T3 and X T4 Each of them is CR T ,in

[0500] i)X T1 is C(OCH3), X T3 is CF, and X T2 and X T4 each of which is CH; or

[0501] ii)X T1 is C(OCH3), X T2 is CF, and X T3 and X T4 Each of is CH, and

[0502] L has the formula I-3:

[0503]

[0504] in:

[0505] W does not exist;

[0506] Cy 1 C 3-12 Carbocyclylene or 3 to 12 membered heterocyclylene, wherein the carbocyclylene or heterocyclylene is separated by one or more R u Optional substitution;

[0507] Each Z' is independently one or more R u Optionally substituted C 1-3 an alkylene group; and

[0508] p is an integer selected from 0 to 6.

[0509] In certain embodiments, Ring A is

[0510]

[0511] wherein ** denotes attachment to L; s is an integer selected from 0 to 8 when valence permits; and

[0512] Ring A 2 C 3-8 carbocyclic ring or 3- to 8-membered heterocyclic ring.

[0513] 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 Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C8), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl(C 10)), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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 comprising 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 replaced by one or more R u Optional substitution.

[0514] In certain embodiments, each R a Independently C 1-6 Alkyl, 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.

[0515] In certain embodiments, each R a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 a carbocyclic group or a 3- to 6-membered heterocyclic group.

[0516] In certain embodiments, each R a Independently C 1-6 Alkyl, C 3-6 carbocyclyl or 3 to 6 membered heterocyclyl, wherein the alkyl, carbocyclyl or heterocyclyl is separated by one or more R u Optional substitution.

[0517] In certain embodiments, each R b are independently hydrogen, C 1-6 Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C8), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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 comprising 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 replaced by one or more R u Optional substitution.

[0518] In certain embodiments, each R b are independently hydrogen, C 1-6 Alkyl, 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.

[0519] In certain embodiments, each R b are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 a carbocyclic group or a 3- to 6-membered heterocyclic group.

[0520] In certain embodiments, each R b are independently hydrogen, C 1-6 Alkyl, C 3-6 Carbocyclic or 3 to 6 membered heterocyclic or C 2-6 Alkynyl, wherein the alkyl, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

[0521] In certain embodiments, each R c and each R d are independently hydrogen, C 1-6Alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C 2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C 2-6 Alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C 3-12 Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C8), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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 comprising 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 replaced by one or more R u Optional substitution.

[0522] 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, wherein the alkyl, carbocyclyl or heterocyclyl is separated by one or more R u Optional substitution.

[0523] In certain embodiments, R c and R dTogether with the nitrogen atom to which they are attached, they form a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclic group is surrounded by one or more R u Optional substitution.

[0524] In certain embodiments, R a 、R b 、R c and R d By one or more R z are independently and optionally substituted.

[0525] 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 a carbocyclic group or a 3- to 6-membered heterocyclic group.

[0526] 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), pentyloxy (C5), or hexyloxy (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 propyl-n-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 3-12 Carbocyclic groups (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]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ) or spiro[4.5]decyl(C 10 )), a 3- to 12-membered heterocyclic group (e.g., a heterocyclic group comprising 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), -SRb 、-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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl and 3- to 6-membered heterocyclyl.

[0527] 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, C2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl and 3- to 6-membered heterocyclyl.

[0528] 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, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl and 3- to 6-membered heterocyclyl.

[0529] 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, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 carbocyclyl and 3- to 6-membered heterocyclyl.

[0530] 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, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl and 3- to 6-membered heterocyclyl.

[0531] In certain embodiments, both R u Together with the carbon atom to which they are attached, they form C 3-6 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 comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O and S).

[0532] In certain embodiments, two geminal R u Together with the carbon atom to which they are attached, they form C 3-6 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 comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O and S).

[0533] The following describes embodiments of the variables in any formula described herein (e.g., Formula I and Formula I'), where applicable. Any variable can be any moiety as described in the embodiments below. In addition, combinations of any moiety described for any variable with any moiety described for any remaining variable are also contemplated.

[0534] Without wishing to be limited by this statement, although various options for variables are described herein, it should be understood that the present disclosure is intended to encompass operable embodiments having combinations of options. The present disclosure can be interpreted as excluding inoperable embodiments resulting from certain combinations of options. For example, although various options for variables X and Z are described herein, the present disclosure can be interpreted as excluding structures of inoperable compounds resulting from certain combinations of options (e.g., when both X or both Z are nitrogen or both are oxygen; or when one of the two X or one of the two Z is nitrogen and the other is oxygen).

[0535] When a numerical range is listed, each discrete value and subrange within that range is also considered. For example, "C 1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0536] In certain embodiments, the compound is selected from the compounds in Table X below or a pharmaceutically acceptable salt thereof.

[0537] In certain embodiments, the compound is selected from the compounds in Table X below.

[0538] Table X

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558] In certain embodiments, the compound is selected from the compounds in Tables 1-3 or pharmaceutically acceptable salts thereof.

[0559] In certain embodiments, the compound is selected from the compounds in Tables 1-3.

[0560] In certain embodiments, the compound is selected from the compounds in Table 1 and Table 2, or pharmaceutically acceptable salts thereof.

[0561] In certain embodiments, the compound is selected from the compounds in Table 1 and Table 2.

[0562] In certain embodiments, the compound is selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof.

[0563] In certain embodiments, the compound is selected from the compounds in Table 1.

[0564] In certain embodiments, the compound is selected from the compounds in Table 2 or a pharmaceutically acceptable salt thereof.

[0565] In certain embodiments, the compound is selected from the compounds in Table 2.

[0566] In certain embodiments, the compound is selected from the compounds in Table 3 or a pharmaceutically acceptable salt thereof.

[0567] In certain embodiments, the compound is selected from the compounds in Table 3.

[0568] Table 1.

[0569] *Specifies for the warhead (tetralin) which is enantiomerically pure but of undetermined absolute configuration; the relative configuration of the two stereocenters is cis.

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673] Table 2.

[0674] *Specifies that it is racemic with respect to the two stereocenters on the warhead (tetralin); the relative configuration of the two stereocenters is cis.

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763] Table 3.

[0764] *Specifies that it is racemic with respect to the two stereocenters on the warhead (tetralin); the relative configuration of the two stereocenters is cis.

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838] Compared to known compounds, such as known estrogen receptor degraders, the compounds of the present disclosure may have advantageous characteristics. For example, the compounds of the present disclosure may exhibit stronger estrogen receptor activity, more favorable pharmacokinetic properties (e.g., as measured by C max 、T max and / or AUC measurements), and / or less interaction with other cellular targets (e.g., hepatocyte transporters such as OATP1B1), and accordingly exhibit improved safety (e.g., drug-drug interactions). These beneficial properties of the compounds of the present disclosure can be measured according to methods generally available in the art, such as the methods exemplified herein.

[0839] Due to the presence of double bonds, the compounds of the present disclosure may be in cis or trans configuration, or in Z or E configuration. It should be understood that although one configuration may be depicted in the structure of the compounds or formulas of the present disclosure, other configurations are also encompassed by the present disclosure. For example, the compounds or formulas of the present disclosure may be depicted in cis or trans configuration, or in Z or E configuration.

[0840] In certain embodiments, the compounds of the present disclosure (e.g., compounds of any formula disclosed herein or any individual compound) are pharmaceutically acceptable salts. In certain embodiments, the compounds of the present disclosure (e.g., compounds of any formula disclosed herein or any individual compound) are solvates. In certain embodiments, the compounds of the present disclosure (e.g., compounds of any formula disclosed herein or any individual compound) are hydrates.

[0841] Pharmaceutically acceptable salts

[0842] In certain embodiments, the compounds disclosed herein exist as pharmaceutically acceptable salts thereof. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0843] In certain embodiments, the compounds described herein possess acidic or basic groups and, therefore, 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 thus formed.

[0844] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with mineral acids, organic acids, or inorganic bases, such salts including acetates, acrylates, adipates, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphor, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate salt, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propionate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, undecylenic tosylate, and xylenesulfonate.

[0845] In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to 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, 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, glucoheptanoic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0846] In certain embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base, such as a pharmaceutically acceptable hydroxide, carbonate, bicarbonate, or sulfate of a metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl)4, etc.

[0847] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In certain embodiments, water- or oil-soluble or dispersible products are obtained by such quaternization.

[0848] Solvates

[0849] "Solvate" refers to a form of a compound that is associated with a solvent or water, typically by a solvolysis reaction (also referred to as a "hydrate"). This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the present disclosure can be prepared, for example, in crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and also include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of separation (e.g., when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid). "Solvate" encompasses both solution-phase and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0850] Those skilled in the art of organic chemistry will recognize that many organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates." For example, a complex with water is referred to as a "hydrate." Solvates are within the scope of the present disclosure.

[0851] Those skilled in the art of organic chemistry will also recognize that many organic compounds can exist in more than one crystalline form. For example, the crystalline form can vary depending on the solvate. Therefore, all crystalline forms or pharmaceutically acceptable solvates thereof are contemplated and within the scope of this disclosure.

[0852] 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 also provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0853] Solvates contain stoichiometric or non-stoichiometric amounts of solvents, such as water, ethanol, and the like. 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 methods described herein. In addition, the compounds provided herein can exist in unsolvated forms as well as solvated forms. In general, for the purposes of the compounds and methods provided herein, solvated forms are considered equivalent to unsolvated forms.

[0854] Isomers (stereoisomers, geometric isomers, tautomers, etc.)

[0855] It is also understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0856] Stereoisomers that are not mirror images of each other are called "diastereomers", and those that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, when the asymmetric center 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 are described and designated as right-handed or left-handed (i.e., (+) or (-) isomers, respectively) by the R and S sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light. A chiral compound can exist as an individual enantiomer or a mixture thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0857] As used herein, an enantiomerically pure compound is substantially free of the other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains greater than 95% by weight, greater than 96% by weight, greater than 97% by weight, greater than 98% by weight, greater than 98.5% by weight, greater than 99% by weight, greater than 99.2% by weight, greater than 99.5% by weight, greater than 99.6% by weight, greater than 99.7% by weight, greater than 99.8% by weight, or greater than 99.9% by weight of the enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0858] 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 no more than about 5% by weight of the (S)-compound, at least about 99% by weight of the (R)-compound and no more than about 1% by weight of the (S)-compound, or at least about 99.9% by weight of the (R)-compound and no more than about 0.1% by weight of the (S)-compound. In certain embodiments, the weight is based on the total weight of the compound.

[0859] 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 no more than about 5% by weight of the (R)-compound, at least about 99% by weight of the (S)-compound and no more than about 1% by weight of the (R)-compound, or at least about 99.9% by weight of the (S)-compound and no more than about 0.1% by weight of the (R)-compound. In certain embodiments, the weight is based on the total weight of the compound.

[0860] In the compositions provided herein, enantiomerically pure compounds or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure (R)-compound can include, for example, about 90% excipients and about 10% enantiomerically pure (R)-compounds. In certain embodiments, by the total weight of the compound, the enantiomerically pure (R)-compound in such compositions can, for example, include at least about 95% by weight of the (R)-compound and up to about 5% by weight of the (S)-compound. For example, a pharmaceutical composition comprising an enantiomerically pure (S)-compound can include, for example, about 90% excipients and about 10% enantiomerically pure (S)-compound. In certain embodiments, by the total weight of the compound, the enantiomerically pure (S)-compound in such compositions can, for example, include at least about 95% by weight of the (S)-compound and up to about 5% by weight of the (R)-compound. In certain embodiments, the active ingredient can be formulated with almost no excipients or carriers.

[0861] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and racemic or other mixtures thereof.Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0862] 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, cis, trans, entgegen (E) and zusammen (Z) isomers and their corresponding mixtures. All geometric forms of the compounds disclosed herein are considered and are within the scope of the present disclosure.

[0863] In certain embodiments, the compounds disclosed herein have one or more chiral centers, and each center exists in the R configuration or the S configuration. The compounds disclosed herein include all diastereoisomers, enantiomers, and epimeric forms and their corresponding mixtures. All diastereoisomers, enantiomers, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the present disclosure.

[0864] In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination or interconversion can be used for applications as described herein. In certain embodiments, the racemic mixture of the compound is reacted with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and reclaiming the optically pure enantiomers to prepare the compounds described herein as their individual stereoisomers. In certain embodiments, dissociable complexes are preferred. In certain embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In certain embodiments, diastereomers are separated by chiral chromatography, or preferably separated by separation / resolving techniques based on solubility differences. In certain embodiments, optically pure enantiomers and resolving agents are then recovered.

[0865] Tautomers

[0866] In certain embodiments, the compounds described herein exist as tautomers.The compounds described herein include all possible tautomers of the formulae described herein.

[0867] Tautomers are compounds that can be converted to each other by the migration of hydrogen atoms, accompanied by the conversion of single bonds and adjacent double bonds. In the bonding arrangement where tautomerism may occur, there will be a chemical equilibrium of tautomers. For example, enols and ketones are tautomers because they are rapidly converted to each other by treatment with acid or base. Another example of tautomerism is the acid- and nitro- forms of phenylnitromethane, which are also formed by treatment with acid or base. Tautomeric forms can be relevant to obtaining the optimal chemical reactivity and biological activity of the target compound. All tautomeric forms of the compounds disclosed herein are considered and are within the scope of this disclosure. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH.

[0868] Pharmaceutical composition

[0869] In certain embodiments, the compounds described herein are administered as pure chemicals. In some embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), which is selected based on the selected route of administration and standard pharmaceutical practice, such as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed., Mack Pub. Co., Easton, PA (2005)).

[0870] 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.

[0871] In certain embodiments, a compound provided herein is substantially pure in that it contains less than about 5%, less than about 1%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthesis by-products produced, for example, in one or more steps of a synthetic method.

[0872] Pharmaceutical composition is used in the mode of the disease that is suitable for drug treatment (or prevention).Suitable dosage and suitable duration of application and frequency will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of active ingredient and the method of administration.In general, suitable dosage and treatment regimen provide the composition of the amount that is enough to provide treatment and / or prevention benefit (for example, improved clinical outcome, such as more frequent complete or partial remission, or longer disease-free survival and / or total survival, or the alleviating of symptom severity).Optimal dose is usually determined using experimental model and / or clinical trial.Optimal dose depends on the patient's body mass, body weight or blood volume.

[0873] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and 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 ophthalmic 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 into tablets, pills, capsules, liquids, inhalants, nasal spray solutions, suppositories, suspensions, gels, colloids, dispersions, suspensions, solutions, emulsions, ointments, lotions, eye drops, or ear drops. In some embodiments, the pharmaceutical composition is formulated into tablets.

[0874] Preparation and characterization of compounds

[0875] Compound of the present disclosure can be prepared by many methods well known to those skilled in the art of organic synthesis.For example, compound of the present disclosure can be synthesized using the following method, as well as synthetic methods known in the field of synthetic organic chemistry, or its modification method recognized by those skilled in the art. Compound of the present disclosure (that is, compound of the application (for example, compound of any formula disclosed herein or any single compound)) can be synthesized by following the steps outlined in the following general synthesis scheme and embodiments described herein, scheme, program and / or synthesis (for example, embodiment).

[0876] General synthetic methods

[0877] The compounds of the present disclosure can generally be prepared by first preparing a library of intermediates (including a library of cerebellin ligands, a library of linkers, and a library of inhibitors, as detailed in the Examples section), followed by subsequent reactions to attach the linker to the inhibitor and cerebellin ligand via metal-catalyzed coupling reactions and reductive amination. By selecting different combinations of cerebellin ligands, linkers, and inhibitors from each library, large libraries of compounds can be prepared. The following summarizes a general synthetic route for preparing inhibitor-linker conjugates via metal-catalyzed coupling reactions, which are further coupled to the cerebellin ligand via reductive amination.

[0878] Solution 1

[0879]

[0880] Option 2

[0881]

[0882] Those skilled in the art will recognize whether there is a stereocenter in the compounds of the present disclosure (for example, compounds of any formula disclosed herein or any single compound). Therefore, the present disclosure includes two possible stereoisomers (unless otherwise stated in the synthesis), and not only includes racemic compounds, but also includes independent enantiomers and / or diastereomers. When it is necessary to obtain a compound as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by splitting the final product or any convenient intermediate. The splitting of the final product, intermediate or starting material can be affected by any suitable method known in the art. Referring to, for example, " Stereochemistry of Organic Compounds " (Wiley-Interscience, 1994) by E.L. Eliel, S.H. Wilen and L.N. Mander.

[0883] The compounds used in the reactions described herein are prepared 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. “Commercial chemicals” were obtained from standard commercial sources, including 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).

[0884] Suitable reference books and treatises that detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide references to articles describing their preparation, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions," 2nd ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, "Heterocyclic Chemistry," 2nd ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and papers detailing the synthesis of reactants that can be used to prepare the compounds described herein, or providing references to articles describing their preparation, include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", 2nd revised 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, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, 73 volumes.

[0885] Specific and similar reactants are optionally identified by indexes of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, which are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis agencies, many of which provide custom synthesis services. A reference for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein is P.H. Stahl & C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0886] Analytical methods, materials, and instruments

[0887] Unless otherwise noted, the reagents and solvents received from commercial suppliers are used as is. Proton nuclear magnetic resonance (NMR) spectra are obtained on Bruker or Varian spectrometers at 400 MHz. Spectra are given in ppm (δ) and coupling constants J are reported in Hertz. Tetramethylsilane (TMS) is used as internal standard. Liquid chromatography-mass spectrometry (LC / MS) is collected using Shimadzu SHIMADZU LCMS-2020EV or Agilent 1260-6125B LCMS. Purity and low-resolution mass spectral data are measured using an Agilent 1260-6125B LCMS system (with diode array detector and Agilent G6125BA mass spectrometer) or using a Waters Acquity UPLC system (with diode array detector and Waters 3100 mass detector). Purity is characterized by ultraviolet wavelengths of 214 nm, 220 nm, 254 nm and ESI. Column: Poroshell 120EC-C18 2.7 μm 4.6 × 100 mm; flow rate 0.8 mL / min; solvent A (100 / 0.1 water / formic acid), solvent B (100 acetonitrile); gradient: hold 5% B for 0.3 minutes, 5%-95% B from 0.3 minutes to 2 minutes, hold 95% B for 4.8 minutes, 95%-5% B from 4.8 to 5.4 minutes, then hold 5% B for 6.5 minutes. 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 minutes, 5%-95% B from 0.2 minutes to 2.0 minutes, hold 95% B for 3.1 minutes, then hold 5% B for 3.5 minutes.

[0888] Bioassay

[0889] The biological activity of the compounds of the present invention can be assessed using methods and assays known in the art.

[0890] The CRBN-DDB1 binding potency of the present disclosure was determined using HTRF assay technology (Perkin Elmer). Compounds were serially diluted and transferred to a multiwell plate. The reaction was performed by adding His-tagged (e.g., CRBN+DDB-DLS7+CXU4), followed by the addition of 60 nM fluorescent probe (e.g., Cy5-labeled thalidomide) and MAb anti-6HIS Tb cryptate gold in assay buffer. After incubation at room temperature for one hour, the HTRF signal was read, for example, on an Envision reader (Perkin Elmer).

[0891] The ERa degradation activity of the compound can be evaluated in MCF-7 and T47D cells. MCF-7 and T47D cells are seeded and then treated with a certain concentration (e.g., 0.02nM to 300nM) of the compound. DMSO can be used as a vehicle control. The cells are fixed and 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 in a cold room (e.g., 4°C) overnight. Secondary antibodies (e.g., IRDye 800CW goat anti-rabbit IgG) and CellTag 700 stain are added to Intercept (PBS) blocking buffer. Finally, the cell plate is placed in an incubator to dry. Images and signals were captured on the DLx imaging system.

[0892] In vitro assays can be performed using the MCF-7 and T47D Cell Titer Glo (CTG) assays. MCF-7 and T47D cells (from HDB) are cultured in white multi-well plates with RPMI1640 + 10% CS-FBS + 1% P / S medium without phenol red (e.g., 1,000 cells / well). On day 0, cells are treated with a compound at a concentration (e.g., 0.5 nM to 10,000 nM) (DMSO and staurosporine are used as controls). On day 0 and day 6, the Cell Titer Glo reagent is added and read on the EnVision after a 30-minute incubation for data generation.

[0893] For intracellular protein blot analysis, cells were seeded in multiwell plates (e.g., 40,000 or 10,000 cells / well). A certain concentration of diluted compound (final 0.5% DMSO) was added and the cells were incubated for a certain time (e.g., 16 hours). Formaldehyde (e.g., PBS:FA=9:1) was added, followed by washing with PBS. The cells were blocked with Licor blocking buffer (Li-Cor). The relative ER percentage in the treated cells was obtained by comparing the values of the treated wells with the values of the untreated wells and DMSO-treated wells as 100%.

[0894] For western blot analysis, cells treated with the compound were lysed in a 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 lauryl sulfate) containing a protease inhibitor cocktail. After determining protein concentration by BCA assay, equal amounts of total protein were electrophoresed through a 10% SDS-polyacrylamide gel. The separated protein bands were transferred to a PVDF membrane and blotted for different antibodies. The blots were scanned and the band intensities were quantified (e.g., by using the GelQuant.NET software provided by biochemlabsolutions.com). The relative average intensity of the target protein was expressed after normalization relative to the intensity of the glyceraldehyde-3-phosphate dehydrogenase band.

[0895] For cell growth assays, cells are seeded in multi-well plates at a certain concentration (e.g., 1500 cells / well) overnight. Cells are subsequently treated with compounds. After a period of time (e.g., 4 days) after compound treatment, 10% WST-8 reagent is added to the culture medium and incubated under certain conditions (e.g., incubated in a CO2 incubator at 37°C for 2.5 hours). The absorbance of each sample is measured using a microplate reader at a certain wavelength (e.g., 450 nm). Relative absorbance is calculated relative to the vehicle control from three separate repetitions.

[0896] To conduct in vivo pharmacodynamic and efficacy studies, breast cancer cell line xenografts were developed as follows: mice were given 17β-estradiol in their drinking water for a period of time. A certain number (e.g., 5 million) of cells in 50% Matrigel were injected subcutaneously into SCID mice to induce tumor formation. When the tumors reached a certain size (e.g., 100-400 mm 3 ), mice were treated with vehicle control (e.g., 5% DMSO, 10% solutol, 85% water) or compound and sacrificed at different time points. Tumor tissues were harvested for analysis. Tumor size and animal weight were measured 2-3 times per week. Tumor volume (mm 3 ) = (length × width2) / 2. Tumor growth inhibition was calculated using TGI (%) = (Vc-Vt) / (Vc-Vo) × 100, where Vc and Vt are the median values of the control and treatment groups at the end of the study, and Vo is the median value at the beginning.

[0897] How to use

[0898] In certain aspects, the present disclosure provides methods of degrading an estrogen receptor in a subject, the method comprising administering to the subject a compound disclosed herein.

[0899] In certain aspects, the present disclosure provides use of a compound disclosed herein in the manufacture of a medicament for degrading an estrogen receptor in a subject.

[0900] In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading an estrogen receptor in a subject.

[0901] In certain aspects, the present disclosure provides methods of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject a compound disclosed herein (eg, in a therapeutically effective amount).

[0902] In certain aspects, the present disclosure provides methods of treating a disease or condition in a subject in need thereof, comprising administering to the subject a compound disclosed herein (eg, in a therapeutically effective amount).

[0903] In certain aspects, the present disclosure provides 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.

[0904] In certain aspects, the present disclosure provides use of a compound disclosed herein in the manufacture of a medicament for treating a disease or condition in a subject in need thereof.

[0905] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.

[0906] In certain aspects, the present disclosure provides a compound disclosed herein for use in treating a disease or disorder in a subject in need thereof.

[0907] In certain embodiments, the disease or condition is an estrogen receptor mediated disease or condition.

[0908] In certain embodiments, the disease or condition is cancer.

[0909] In certain embodiments, the disease or condition is breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or esophageal cancer.

[0910] In certain embodiments, the cancer includes, but is not limited to, one or more of the cancers listed in Table A.

[0911] Table A

[0912]

[0913]

[0914]

[0915]

[0916] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a blood cancer. Exemplary blood cancers include, but are not limited to, the cancers listed in Table B. In certain embodiments, the blood cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.

[0917] Table B

[0918]

[0919]

[0920] In certain embodiments, the subject is a mammal.

[0921] In certain embodiments, the subject is a human.

[0922] definition

[0923] As used in the specification and appended claims, unless indicated otherwise, the following terms have the meanings indicated below.

[0924] Chemical definition

[0925] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described herein. In addition, the general principles of organic chemistry and 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, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0926] The compounds described herein may contain one or more asymmetric centers and therefore can exist in various isomeric forms, for example, 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 stereoisomer mixtures, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture 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 may be prepared by asymmetric synthesis. See, e.g., 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., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0927] Additionally, the present disclosure encompasses the compounds as described herein as single isomers, substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0928] When a numerical range is listed, it is intended to include every value and sub-range within that range. For example, "C 1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0929] The following terms are intended to have the meanings presented below with them, and can be used to understand the description and expected scope of the present disclosure. When describing the disclosure that may include compounds, pharmaceutical compositions containing such compounds, and methods using such compounds and compositions, unless otherwise stated, the following terms, if present, have the following meanings. It should also be understood that when described in this article, any part defined below can be substituted by various substituents, and each definition is intended to include such substituted parts within the scope shown below. Unless otherwise stated, the term "substituted" is defined as follows. It should also be understood that the terms "group" and "atomic radical" can be considered to be interchangeable when used herein. The articles "one" and "a (kind)" can be used in this article to refer to one or more (i.e., at least one) grammatical objects of the article. For example, "an analogue" means an analogue or more than one analogue.

[0930] As used herein, "alkyl" refers to a straight-chain or branched saturated hydrocarbon group ("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 1-7 In certain embodiments, an alkyl group has 1 to 6 carbon atoms ("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, an alkyl group has 1 carbon atom ("C1 alkyl"). 1-6Examples 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-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise indicated, each example of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent). In certain embodiments, an alkyl group is an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-10 Alkyl. Common alkyl abbreviations include Me(-CH3), Et(-CH2CH3), i-Pr(-CH(CH3)2), n-Pr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0931] As used herein, "alkylene" refers to an alkyl group in which two hydrogen atoms are removed to provide a divalent radical. When a range or number of carbon atoms is provided for a particular "alkylene" group, it should be understood that the range or number refers to the range or number of carbon atoms in a linear carbon divalent chain. As described herein, an "alkylene" group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted divalent alkylene groups (e.g., substituted with one or more alkyl(methyl) groups) include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-), and the like.

[0932] As used herein, "alkenyl" refers to a straight or branched chain hydrocarbon group ("C"). 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). 2-20 In certain embodiments, an alkenyl group does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In certain embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In certain embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In certain embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In certain embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In certain embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In certain embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In certain embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2-3 In certain embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 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 aforementioned C 2-4 In some embodiments, an alkenyl group is an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, an unsubstituted C 1-4 alkenyl group, 2-10 In certain embodiments, an alkenyl group is a substituted C 2-10 Alkenyl.

[0933] As used herein, "alkenylene" refers to an alkenyl group in which two hydrogen atoms are removed to provide a divalent radical. When a range or number of carbon atoms is provided for a particular "alkenylene" group, it is understood that the range or number refers to the range or number of carbon atoms in a linear carbon divalent chain. As described herein, an "alkenylene" group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted divalent alkenylene groups (e.g., substituted with one or more alkyl(methyl) groups) include, but are not limited to, substituted ethylene groups (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene groups (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.

[0934] As used herein, "alkynyl" refers to a straight or branched chain hydrocarbon group ("C") 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). 2-20 In certain embodiments, an alkynyl group does not contain any double bonds. In certain embodiments, an alkynyl group has 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 ("C 2-6 In certain embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In certain embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In certain embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In certain embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2-4Examples 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 aforementioned C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl groups include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent) (a “substituted alkynyl”). In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 Alkynyl.

[0935] As used herein, "alkynylene" refers to an alkynyl group in which two hydrogen atoms are removed to provide a divalent radical. When a range or number of carbon atoms is provided for a particular "alkynylene" group, it is understood that the range or number refers to the range or number of carbon atoms in a linear carbon divalent chain. As described herein, an "alkynylene" group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0936] 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, wherein the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group ("C 1-10 In certain embodiments, a heteroalkyl group is a saturated group ("C 1-9 In certain embodiments, a heteroalkyl group is a saturated group ("C 1-8 In certain embodiments, a heteroalkyl group is a saturated group ("C 1-7 In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("C 1-6In certain embodiments, a heteroalkyl group is a saturated group ("C 1-5 In certain embodiments, a heteroalkyl group is a saturated group ("C 1-4 In certain embodiments, a heteroalkyl group is a saturated group ("C 1-3 In certain embodiments, a heteroalkyl group is a saturated group ("C 1-2 In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("C1 heteroalkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("C1 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, a heteroalkyl group is a substituted C 1-10 Heteroalkyl.

[0937] As used herein, the term "heteroalkenyl" refers to an alkenyl 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), wherein the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a 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, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("C 2-9 In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("C 2-8 In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("C 2-7 In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("C 2-6 In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("C 2-5In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("C 2-4 In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom ("C 2-3 In certain embodiments, a heteroalkenyl group has 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, a heteroalkenyl group is a substituted C 2-10 Heteroalkenyl.

[0938] As used herein, the term "heteroalkynyl" refers to an alkynyl 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), wherein the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a 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 2-10 In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("C 2-9 In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("C 2-8 In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("C 2-7 In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("C 2-6 In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("C 2-5 In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("C 2-4 In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom ("C 2-3In certain embodiments, a heteroalkynyl group has 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, a heteroalkynyl group is a substituted C 2-10 Heteroalkynyl.

[0939] Similar to the definitions of "alkylene," "alkenylene," and "alkynylene" as described above, "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" as used herein refer to divalent radicals of heteroalkyl, heteroalkenyl, and heteroalkynyl groups, respectively. When a range or number of carbon atoms is provided for a particular "heteroalkylene," "heteroalkenylene," or "heteroalkynylene" group, it is understood that the range or number refers to the range or number of carbon atoms in a linear divalent chain. "Heteroalkylene," "heteroalkenylene," and "heteroalkynylene" groups may be unsubstituted or substituted with one or more substituents as described herein.

[0940] "Aryl" refers to 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 the ring array) radical, wherein 6-14 ring atoms and zero heteroatoms ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 Typical aryl groups include, but are not limited to, groups derived from aceanthrene, acenaphthylene, acephenanthren, anthracene, azulene, benzene, Coronene, fluoranthene, hexacene, hexalene, unsymmetrical indacene, symmetrical indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentadiene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Specific aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group may independently be optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 Aryl.

[0941] "Heteroaryl" refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons in common in the ring array) in which ring carbon atoms and 1-8 ring heteroatoms are provided, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.

[0942] "Heteroaryl" also includes ring systems in which a heteroaryl group as defined above is fused to one or more aryl groups, wherein the point of attachment is on the heteroaryl group or on the one or more aryl groups, and in such cases, the number of ring members specifies the number of ring members in the fused (aryl / heteroaryl) ring system. When substitution is indicated in such cases, unless otherwise indicated, substitution may occur on 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, quinolyl, carbazolyl, etc.), the point of attachment may be on either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0943] In certain embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is 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 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In certain embodiments, 5 to 6 membered heteroaryls have 1-3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, 5 to 6 membered heteroaryls have 1-2 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, 5 to 6 membered heteroaryls have 1 ring heteroatom selected from nitrogen, oxygen and sulfur. In certain embodiments, 5 to 6 membered heteroaryls have 1 ring heteroatom selected from nitrogen, oxygen and sulfur. Unless otherwise indicated, each example of a heteroaryl group can be independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. 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.

[0944] 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, aza Examples of heteroaryl groups include, but are not limited to, benzophenone, benzothiophene, benzothiobenzothiophene, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Examples of heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0945] "Carbocyclyl" refers to a non-aromatic cyclic hydrocarbon radical having from 3 to 12 ring carbon atoms ("C 3-12 In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3-10 In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms ("C 5-12 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms ("C 5-8 In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms ("C 5-6 Carbocyclyl”). Exemplary C 3-6 Carbocyclic groups 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 Carbocyclic groups include but are not limited to the aforementioned C 3-6 Carbocyclyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclic groups include but are not limited to the aforementioned C 3-8 Carbocyclyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C10 )wait.

[0946] In certain embodiments, a "carbocyclyl" group is a monocyclic saturated carbocyclyl group ("C 3-12 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group ("C 3-10 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group ("C 3-8 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group ("C 3-6 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group ("C 5-12 In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms ("C 5-8 In certain embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group ("C 5-6 carbocyclyl”). C 5-6 Examples of carbocyclic groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of the carbocyclic group include the aforementioned C 5-6 Carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of the carbocyclic group include the aforementioned C 3-6 In some embodiments, a carbocyclyl group is an unsubstituted C or C-substituted carbocyclyl group, and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, a carbocyclyl group is an unsubstituted C or C-substituted carbocyclyl group. 3-12 In certain embodiments, a carbocyclyl group is a substituted C 3-12 Carbocyclic group.

[0947] In certain embodiments, a carbocyclyl group is a monocyclic ring ("monocyclic carbocyclyl") or polycyclic ring ("polycyclic carbocyclyl") containing a fused, bridged, or spirocyclic ring system and may be saturated or partially unsaturated. Unless otherwise indicated, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") with one or more substituents. In certain embodiments, a carbocyclyl group is an unsubstituted C 3-12In certain embodiments, a carbocyclyl group is a substituted C 3-12 Carbocyclic group.

[0948] "Fused carbocyclyl" or "fused carbocycle" refers to a ring system in which a carbocyclyl group as defined above is fused to, i.e., shares a common bond with, one or more carbocyclyl groups as defined above, with the point of attachment being on any fused ring. In such cases, the number of carbons specifies the total number of carbons in the fused carbocyclyl ring system. When substitution is indicated, unless otherwise specified, substitution may occur on any fused ring.

[0949] "Spirocarbocyclyl" or "spirocarbocycle" means a carbocyclyl group as defined above that forms a spiro ring structure with one or more carbocyclyl groups as defined above, i.e., shares a common atom therewith, wherein the point of attachment is on any carbocyclyl ring in which the spiro ring structure is embedded. In such cases, the number of carbons specifies the total number of carbons of the carbocyclyl ring in which the spiro ring structure is embedded. When substitution is indicated, unless otherwise indicated, substitution may occur on any carbocyclyl ring in which the spiro ring structure is embedded.

[0950] "Bridged carbocyclyl" or "bridged carbocycle" refers to a carbocyclyl group as defined above that forms a bridge structure with one or more carbocyclyl groups as defined above, i.e., shares more than one atom (and therefore, more than one bond) therewith, wherein the point of attachment is on any carbocyclyl ring in which the bridge structure is embedded. In such cases, the number of carbons specifies the total number of carbons in the bridged ring. When substitution is indicated, unless otherwise indicated, substitution may occur on any carbocyclyl ring in which the bridge structure is embedded.

[0951] "Heterocyclyl" refers to a group ("3 to 12 membered heterocyclyl") of a 3 to 12 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as valence permits. Exemplary 3 membered heterocyclyls containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4 membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetane, and thiirane. Exemplary 5 membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic radicals containing two heteroatoms include but are not limited to dioxolanyl, oxathiolanyl, dithiolanyl and oxazolidin-2-one. Exemplary 5-membered heterocyclic radicals containing three heteroatoms include but are not limited to triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic radicals containing one heteroatom include but are not limited to piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl. Exemplary 6-membered heterocyclic radicals containing two heteroatoms include but are not limited to piperazinyl, morpholinyl, dithiolanyl and dioxanyl. Exemplary 6-membered heterocyclic radicals containing two heteroatoms include but are not limited to triazinyl. Exemplary 7-membered heterocyclic radicals containing one heteroatom include but are not limited to azepanyl, oxepanyl and thienyl. Exemplary 8-membered heterocyclic radicals containing one heteroatom include but are not limited to azocanyl, oxepanyl and thianyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0952] In certain embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is 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 1-4 ring heteroatoms, wherein each heteroatom is 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 1-4 ring heteroatoms, wherein each heteroatom is 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 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a “5- to 6-membered heterocyclyl”). In certain embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0953] In certain embodiments, the heterocyclyl group can be a monocycle ("monocyclic heterocyclyl") or polycycle ("polycyclic heterocyclyl") containing a fused, bridged or spirocyclic ring system, and can be saturated or can be partially unsaturated. The heterocyclyl polycyclic ring system can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which the heterocyclyl group as defined above is fused to one or more carbocyclyl groups, wherein the attachment point is on the carbocyclyl or heterocyclyl ring, and in such cases, the number of ring members specifies the total number of ring members in the entire ring system. When substitution is indicated in such cases, unless otherwise stated, substitution can occur on the heterocyclyl or one or more carbocyclyl groups. Unless otherwise stated, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3 to 12 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 12-membered heterocyclyl.

[0954] "Fused heterocyclyl" or "fused heterocycle" refers to a ring system in which a heterocyclyl group, as defined above, is fused to, i.e., shares a common bond with, one or more heterocyclyl or carbocyclyl groups, as defined above, with the point of attachment being on any fused ring. In such cases, the number of carbon atoms specifies the total number of ring members in the fused ring system. When substitution is indicated, substitution may occur on any fused ring unless otherwise specified.

[0955] "Spiroheterocyclyl" or "spiroheterocycle" means a heterocyclyl group as defined above that forms a spiro ring structure with one or more heterocyclyl or carbocyclyl groups as defined above, i.e., shares a common atom therewith, wherein the point of attachment is on any carbocyclyl ring in which the spiro ring structure is embedded. In such cases, the number of ring members specifies the total number of ring members of the heterocyclyl or carbocyclyl ring in which the spiro ring structure is embedded. When substitution is indicated, unless otherwise indicated, substitution may occur on any heterocyclyl or carbocyclyl ring in which the spiro ring structure is embedded.

[0956] "Bridged heterocyclyl" or "bridged heterocycle" means a heterocyclyl group as defined above that forms a bridge structure with one or more heterocyclyl groups as defined above, i.e., shares more than one atom (and therefore, more than one bond) therewith, wherein the point of attachment is on any heterocyclyl or carbocyclyl ring in which the bridge structure is embedded. In such cases, the number of ring members specifies the total number of ring members of the heterocyclyl or carbocyclyl ring in which the bridge structure is embedded. When substitution is indicated, substitution may occur on any bridged ring unless otherwise indicated.

[0957] "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 have been replaced by nitrogen, oxygen, sulfur, boron, phosphorus or silicon heteroatoms, where valence permits. Hetero can apply to any of the above hydrocarbyl groups having 1 to 5 heteroatoms, and particularly 1 to 3 heteroatoms.

[0958] As used herein, "alkoxy" refers to a group -OR, wherein R is an alkyl group as defined herein. 1-6 Alkoxy refers to a group -OR, wherein each R is C as defined herein. 1-6 Alkyl. Exemplary C 1-6 The alkyl group is as described above.

[0959] As used herein, "alkylamino" refers to the group -NHR or -NR2, wherein each R is independently an alkyl group, as defined herein. 1-6 Alkylamino refers to the group -NHR or -NR2, where each R is independently C 1-6 Alkyl is as defined herein. Exemplary C 1-6 The alkyl group is as described above.

[0960] "Oxo" refers to =0. When a group or atom other than an aryl or heteroaryl group is substituted with an oxo group, it means that two geminal groups on the group or atom form a double bond with the oxygen group. When a heteroaryl group is substituted with an oxo group, it means that the resonance structure / tautomer involving the heteroatom provides a carbon atom capable of forming two geminal groups, which form a double bond with the oxygen group.

[0961] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In certain embodiments, the halo group is fluorine or chlorine.

[0962] As used herein, "protecting group" is well-known in the art 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 require protection include, but are not limited to, hydroxyl, amino, thiol, and carboxylic acid. Therefore, protecting groups are referred to as hydroxyl protecting groups, amino protecting groups, thiol protecting groups, and carboxylic acid protecting groups, respectively.

[0963] Common types of hydroxy protecting groups include, but are not limited to, ethers (e.g., methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p-methoxyphenyl (PMP), tert-butyl, triphenylmethyl (trityl), allyl, and benzyl ether (Bn)), silyl ethers (e.g., t-tert-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), triisopropylsiloxymethyl (TOM), and tert-butyldimethylsilyl (TBDMS)), and esters (e.g., valerate (Piv) and benzoate (benzoate; Bz)).

[0964] Common types of amino protecting groups include, but are not limited to, carbamates (e.g., tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), p-methoxybenzylcarbonyl (Moz or MeOZ), 2,2,2-trichloroethoxycarbonyl (Troc), and benzylcarbamate (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)).

[0965] Common types of thiol protecting groups include, but are not limited to, sulfides (eg, p-methylbenzyl (Meb), tert-butyl, acetamidomethyl (Acm), and triphenylmethyl (trityl)).

[0966] Common types of carboxylic acid protecting groups include, but are not limited to, esters (eg, methyl, triphenylmethyl (trityl), tert-butyl, benzyl (Bn), S-tert-butyl, silyl, and orthoesters) and oxazolines.

[0967] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims.This disclosure is not intended to be limited in any way by the foregoing exemplary list of substituents.

[0968] Other definitions

[0969] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or equivalent agency in a country outside the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0970] "Pharmaceutically acceptable salts" refer 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. Specifically, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with 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 The present invention also includes acid addition salts formed with methylbenzene, ...

[0971] "Subjects" contemplated for administration include, but are not limited to, humans (i.e., males or females 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.

[0972] "Effective amount" means the amount of a compound that, when administered to a subject to treat or prevent 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 to be treated. A "therapeutically effective amount" refers to an amount effective for therapeutic treatment. A "prophylactically effective amount" refers to an amount effective for preventative treatment.

[0973] "Preventing," "prevention," or "prophylactic treatment" refers to reducing the risk of acquiring or developing a disease or condition (i.e., preventing the development of at least one clinical symptom of the disease in a subject who has not been exposed to the disease-causing agent, or in a subject who is susceptible to the disease before onset of the disease).

[0974] The term "prophylaxis," which is related to "prevention," refers to measures or procedures whose purpose is to prevent, rather than to treat or cure, a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospitalized patients who are at risk of thrombosis due to immobilization before visiting geographic areas where malaria is prevalent or the risk of contracting malaria is high; and the administration of antimalarial agents such as chloroquine.

[0975] In certain embodiments, "treating" or "treatment" or "therapeutic treatment" of any disease or condition refers to ameliorating the disease or condition (i.e., arresting the disease or lessening the manifestation, extent, or severity of at least one clinical symptom thereof). 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 condition, physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In another embodiment, "treating" or "treatment" involves slowing the progression of a disease.

[0976] When mentioning numeral or numerical range, term " about " means that the numeral or numerical range mentioned is the approximate value within experimental variability or within statistical experimental error, and thus this numeral or numerical range will change between 1% to 15% of the numeral or numerical range stated in some cases. In certain embodiments, the change of numeral or numerical range is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% of the numeral or numerical range stated. In certain embodiments, the change of numeral or numerical range is 1%, 2%, 3%, 4% or 5% of the numeral or numerical range stated. In certain embodiments, the change of numeral or numerical range is 1%, 2% or 3% of the numeral or numerical range stated.

[0977] The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude certain other embodiments, e.g., embodiments of any composition of matter, composition, method or process, etc. described herein, "consisting of" or "consisting essentially of" the described features.

[0978] As used herein in the specification and claims, the phrase "and / or" should be understood to mean "either or both" of the elements so combined, i.e., elements that are present in combination in some cases and separately in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" of the elements are so connected. In addition to the elements explicitly identified with the "and / or" clause, other elements may optionally be present, whether related or unrelated to those elements explicitly identified. Thus, as a non-limiting example, when used in conjunction with open language such as "comprising," reference to "A and / or B" may, in certain embodiments, refer to only A (optionally including elements other than B); in certain embodiments, to only B (optionally including elements other than A); in certain embodiments, to both A and B (optionally including other elements); and so on.

[0979] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one, but also including a number or series of elements, and optionally, more than one of other unlisted items. Only when a term to the contrary is explicitly indicated, such as "only one" or "exactly one", or when used in a claim, "consisting of..." will mean including exactly one element of a number or series of elements. In general, the term "or" as used herein, when preceded by an exclusive term, such as "any one", "one of...", "only one of..." or "only one of...", should only be interpreted as indicating an exclusive alternative (i.e., "one or the other, but not both"). When used in a claim, "consisting essentially of..." should have the ordinary meaning used in the field of patent law.

[0980] As used herein in the specification and claims, the phrase "at least one" with respect to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements, whether related or unrelated to those specifically identified elements, in addition to the elements specifically identified in the list of elements to which the phrase "at least one" refers. Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B," or equivalently, "at least one of A and / or B") can, in certain embodiments, refer to at least one (optionally including more than one) A, with no B (and optionally including elements other than B); in certain embodiments, refer to at least one (optionally including more than one) B, with no A (and optionally including elements other than A); in certain embodiments, refer to at least one (optionally including more than one) A and at least one (optionally including more than one) B (and optionally including other elements); and so on.

[0981] Although the present teaching has been described in conjunction with various embodiments and examples, it is not intended that the present teaching be limited to such embodiments or examples. On the contrary, as will be appreciated by those skilled in the art, the present teaching encompasses various alternatives, modifications, and equivalents.

[0982] Although various invention embodiments have been described and illustrated herein, a person of ordinary skill in the art will readily conceive of various other means and / or structures for performing the functions and / or obtaining the results and / or one or more advantages described herein, and each such variation and / or modification is considered to be within the scope of the invention embodiments described herein. More generally, a person of ordinary skill in the art will readily recognize 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 specific application or applications for which the present invention is used. Those skilled in the art will recognize many equivalents to the specific invention embodiments described herein. Therefore, it should be understood that the foregoing embodiments are presented by way of example only, and within the scope of the appended claims and their equivalents, the invention embodiments may be practiced in ways other than those specifically described and claimed. The invention embodiments of the present disclosure relate to each individual feature, system, article, material, kit, and / or method described herein. In addition, if such features, systems, articles, materials, kits, and / or methods are not inconsistent with each other, any combination of two or more such features, systems, articles, materials, kits, and / or methods is included within the scope of the invention disclosed herein.

[0983] Unless otherwise stated, the claims should not be construed as limited to the described order or elements. It should be understood that various changes in form and details may be made by one skilled in the art without departing from the spirit and scope of the appended claims. Protection is claimed for all embodiments within the spirit and scope of the following claims and their equivalents.

[0984] Example

[0985] In order that the invention described herein may be more completely understood, the following examples are listed.The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be interpreted in any way as limiting the scope thereof.

[0986] It is understood that the values presented in the examples are approximate and that they may be subject to instrumental and / or experimental variations.

[0987] The following abbreviations are used in the specification and examples:

[0988] ACN (acetonitrile); AIBN (azobisisobutyronitrile); BINAP ([1,1'-binaphthyl]-2,2'-diyl)bis(diphenylphosphine); 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); hrs (hours); hrs (hours); IPA (isopropyl alcohol); IPE (diisopropyl ether); K2CO3 (potassium carbonate); m-CPBA (3-chlorophenylcarbonyl peroxyacid); LC / MS (liquid chromatography-mass spectrometry); MeOH (methanol); MS (mass spectrometry); mL (milliliters); NaBH3CN (sodium cyanoborohydride); NBS (N-bromosuccinimide); NCS N-chlorosuccinimide; NMP; N-methylpyrrolidone; NMR; PE; parts per million; T3P; propylphosphonic anhydride; TEA; triethylamine; THF; tetrahydrofuran

[0989] I. Synthesis and Characterization of Intermediates and Compound "A"

[0990] Chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI, and Shanghai Chemical Reagent Company) and used without further purification.

[0991] Unless otherwise stated, the following experimental and analytical protocols were followed in obtaining the compounds and corresponding analytical data described in the following examples.

[0992] A summary of the LC-MS method is shown below.

[0993] Method A:

[0994] Waters SunFire C18 50*4.6mm 5um 2.000ml / min 2.6 minutes Column temperature: 40℃

[0995] Gradient: 5% B held for 0.2 min, increasing to 95% B in 1.40 min, holding at 95% B for 0.9 min, then back to 5% B in 0.01 min

[0996] Pump A: 0.1% formic acid (FA) and 10% acetonitrile (ACN) in H2O

[0997] Pump B: 0.1% FA and 10% H2O in ACN.

[0998] Method B:

[0999] Waters SunFire C18 50*4.6mm 5um 2.000ml / min 2.6 minutes Column temperature: 40℃

[1000] Gradient: 5% B held for 0.2 min, increasing to 95% B in 1.40 min, holding at 95% B for 0.9 min, then back to 5% B in 0.01 min

[1001] Pump A: 0.03% trifluoroacetic acid (TFA) in H2O

[1002] Pump B: 0.03% TFA in ACN

[1003] Method C:

[1004] Column: Sunfire C18 150*4.6mm 5um 1.00ml / min Column temperature: 40℃

[1005] Gradient: 10% B held for 1.8 minutes, increasing to 95% B in 10.2 minutes, held at 95% B

[1006] 3.0 minutes, then back to 10% B in 0.01 minutes

[1007] Pump A: 0.03% TFA in H2O

[1008] Pump B: 0.03% TFA in ACN

[1009] Method D:

[1010] Column: Luna C18 30*2.0mm 3um 1.200ml / min 1.5 minutes Column temperature: 50℃, 5% B increases to 95% B in 0.7 minutes, maintains at 95% B for 0.4 minutes, and returns to 5% B in 0.01 minutes

[1011] Pump A: 0.03% TFA in H2O

[1012] Pump B: 0.03% TFA in ACN

[1013] Method E:

[1014] SunFire C18 50*4.6mm 5um 2.6 minutes 2.0ml / minute

[1015] Temperature: 40℃

[1016] Gradient: 10% B to 30% B in 0.40 min, to 95% B in 1.60 min, 95% B for 0.90 min, back to 10% B in 0.01 min, A70B30

[1017] Method F:

[1018] SunFire C18 50*4.6mm 5um 2.6 minutes 2.0ml / minute

[1019] Temperature: 40℃

[1020] Gradient: 10% B to 30% B in 0.40 min, to 95% B in 1.60 min, 95% B for 0.90 min, back to 10% B in 0.01 min, A50B50.

[1021] Unless otherwise stated, the reaction mixtures were stirred magnetically at room temperature (rt) under a nitrogen atmosphere. In the case of "dried" solutions, they were typically dried over a drying agent such as Na2SO4 or MgSO4. In the case of "concentrated" mixtures, solutions and extracts, they were typically concentrated under reduced pressure on a rotary evaporator.

[1022] Compounds are purified as needed using various conventional methods including, but not limited to, preparative chromatography using normal or reverse phase HPLC or flash columns or Prep-TLC plates under acidic, neutral or basic conditions.

[1023] Flash chromatography was performed on a Biotage Isolera One via column using 200-300 mesh silica gel particles. Analytical and preparative thin layer chromatography were performed using silica gel 60GF254 plates. Normal phase silica gel chromatography (FCC) was also performed on silica gel (SiO2) using pre-packed cartridges.

[1024] Preparative reverse phase high performance liquid chromatography (RP HPLC) was performed using either:

[1025] Method 1. Prep-HPLC using a Waters-Sunfire C18 21.2x250mmx10um with a mobile phase of 10%-20% acetonitrile (0.1% HCOOH) in water over 15 minutes, followed by 100% ACN for 5 minutes at a flow rate of 20 mL / min. Or

[1026] Method 2.

[1027] Preparative supercritical fluid high performance liquid chromatography (SFC) was performed on a Waters 150 Prep-SFC system from Waters. The ABPR was set to 100 bar to keep the CO2 under SF conditions, and the flow rate was verified according to the compound characteristics and ranged from 70 g / min to 140 g / min. The column temperature was ambient temperature.

[1028] Unless otherwise indicated, 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, double of doublet; ddd, double of two doublets; dt, double of three triplet; bs, broad signal. Chemical shifts are reported in parts per million (ppm, δ) downfield from tetramethylsilane. It should be understood that for compounds containing exchangeable protons, the protons may or may not be visible in the NMR spectrum, depending on the choice of solvent used to run the NMR spectrum and the concentration of the compound in solution.

[1029] Unless otherwise stated, mass spectra (MS) were obtained on a SHIMADZU LC-MS-2020MSD using electrospray ionization (ESI) in positive mode. Calculated (calcd.) masses correspond to accurate masses.

[1030] 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).

[1031] Compounds designated as R* or S* are enantiomerically pure compounds whose absolute configuration has not been determined.

[1032] Intermediate 1: 1-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine

[1033]

[1034] Step 1: 6-(Benzyloxy)-3,4-dihydronaphthalen-1(2H)-one

[1035] To a solution of 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (25 g, 154.14 mmol, 1 eq) and K2CO3 (46.2 g, 308.28 mmol, 2 eq) in CH3CN (350 mL) was added BnBr (3.1 g, 184.96 mmol, 1.2 eq) and stirred at 50°C for 2 hours. LCMS showed the reaction was complete. The reaction was concentrated under vacuum 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] + .

[1036] Step 2: 6-(Benzyloxy)-1-(4-bromo-2-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1037] To a solution of 4-bromo-1-iodo-2-methoxybenzene (14.9 g, 47.6 mmol, 1.2 eq) in THF (100 mL) cooled to -80°C was added n-BuLi (2.5 M, 19.1 mL, 47.6 mmol, 1.2 eq) and stirred under N for 1 hour. 6-(Benzyloxy)-3,4-dihydronaphthalen-1(2H)-one (10 g, 39.6 mmol, 1.2 eq) in THF (30 mL) was then added and stirred at -80°C for 3 hours. Once the reaction was complete, the mixture was quenched with H2O (200 mL) and extracted with EA (400 mL) to give the crude product. The residue was purified by silica gel column chromatography (PE:EA=10:1) to give 6-(benzyloxy)-1-(4-bromo-2-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-ol (7.3 g, 42%) as an oil.

[1038] LC-MS purity: 100% (UV at 254 nm), 439, 451 [M+H] + .

[1039] Step 3: 7-(Benzyloxy)-4-(4-bromo-2-methoxyphenyl)-1,2-dihydronaphthalene

[1040] To a mixture of 6-(benzyloxy)-1-(4-bromo-2-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-ol (7 g, 15.98 mmol, 1 eq) in MeOH (70 mL) was added TsOH (60 mg, 0.32 mmol, 0.02 eq) and stirred at 50 ° C for 0.5 hours. LCMS showed that 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] + .

[1041] Step 4: 1-(4-(6-(Benzyloxy)-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine

[1042] Ruphos (134.0 mg, 0.286 mmol, 0.2 eq), Ruphos Pd G3 (240.0 mg, 0.286 mmol, 0.2 eq) and t-BuONa (550.0 mg, 5.72 mmol, 4.0 eq) 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 eq) and 4-(dimethoxymethyl)piperidine (340.2 mg, 2.14 mmol, 1.5 eq) in 1,4-dioxane (30 mL). The reaction mixture was heated to 100° C. for 2 hours. LC-MS showed the reaction was complete. The reaction mixture was cooled to rt, filtered, and the precipitate was washed with THF (30 mL x 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(400M Hz, CDCl3) δ7.43-7.32(m,5H),7.03(d,J=8.0Hz,1H),6.80(d,J=2.4Hz,1H),6.69- 6.62(m,2H),6.55-6.53(m,2H),5.86(t,J=4.4Hz,1H),5.03(s,2H),4.10(d,J=7.6H z,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).

[1043] Step 5: 11-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine

[1044] 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 eq) in DMF (20 mL) was slowly added dropwise PyBr3 (1.18 g, 3.7 mmol, 1 eq) in DMF (10 mL) at 0 ° C over 30 minutes, and then stirred at 0 ° C for 1 hour. LC-MS showed that the reaction was complete. 10 mL of saturated NH4Cl 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 Na2SO4, 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.

[1045] LC-MS purity: 88.4% (UV at 254 nm), 580.2 [M+H] + .

[1046] Step 6: 1-(4-(6-(Benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-4-(dimethoxymethyl)piperidine

[1047] Pd(dppf)Cl2 (227 mg, 0.311 mmol, 0.1 equiv) and Na2CO3 (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 heated to 90°C for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature, filtered, the precipitate was washed with THF (40 mL x 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.

[1048] LC-MS purity: 99.4% (UV at 254 nm), 576.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.43-7.32(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,2H),2.68-2.62(m,2H),1.87-1.84(m,2H),1.77-1.73(m,1H),1.51-1.44(m,2H).

[1049] Step 7: 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol

[1050] 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 equivalent) and Pd / C (700 mg) in MeOH (150 mL) was degassed under reduced pressure and purged with H2 atmosphere. The reaction mixture was heated to 40 ° C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was cooled to room temperature, filtered, and the precipitate was washed with EtOAc (20 mLx2). 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.

[1051] LC-MS purity: 99.4% (UV at 254 nm), 488.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.10-7.03(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) ,3.60-3.57(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).

[1052] 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

[1053] 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).

[1054] 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

[1055] 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 dark red oils, which were used directly without further purification.

[1056] LC-MS purity: 99.5% (UV at 254 nm), 442.2 [M+H] + .

[1057] Intermediate 2: 5-(4-(3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]dec-8-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol

[1058]

[1059] Step 2-1:

[1060] 8-(4-(6-(Benzyloxy)-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decane

[1061] To a solution of 7-(benzyloxy)-4-(4-bromo-2-methoxyphenyl)-1,2-dihydronaphthalene (1.1 g, 2.61 mmol, 1 eq), 3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decane (562.1 mg, 2.61 mmol, 1 eq), t-BuONa (752.7 mg, 7.83 mmol, 3.0 eq) and Ruphos (121.6 mg, 0.26 mmol, 0.1 eq) in 1,4-dioxane (20 mL) was added Ruphos Pd G3 (218.2 mg, 0.26 mmol, 0.1 eq) under N2 atmosphere. The mixture was heated to 100°C for 2 hours. LC-MS showed the reaction was complete. The reaction mixture was cooled to rt, filtered, the precipitate was washed with THF (30 mL×2), the filtrate was evaporated, and the residue was purified by SiO2 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.

[1062] LC-MS purity: 100% (UV at 254 nm), LC-MS: 556.2 [M+H] + .

[1063] Step 2-2:

[1064] 8-(4-(6-(Benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decane

[1065] 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 eq) in DMF (20 mL) was slowly added dropwise PyBr3 (686.3 mg, 2.16 mmol, 1 eq) in DMF (10 mL) at 0°C over 30 minutes, then stirred at 0°C for 1 hour. LC-MS showed the reaction was complete. 10 mL of saturated NH4Cl solution was added, followed by 110 mL of water and extracted with EtOAc (120 mL x 3). The combined organic layers were washed with water (120 mL x 2), brine (120 mL), dried over Na2SO4, 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.

[1066] LC-MS purity: 100% (UV at 254 nm), LC-MS: 634.1, 636.3 [M+H] + .

[1067] Steps 2-3:

[1068] 8-(4-(6-(Benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decane

[1069] To a solution of compound 1 (900 mg, 1.42 mmol, 1 eq) in dioxane (20 mL) was added compound 2 (207.98 mg, 1.70 mmol, 1.2 eq), H2O (2 mL), K2CO3 (386.73 mg, 2.84 mmol, 2 eq) and Pd(dppf)Cl2 (51.9 mg, 0.07 mmol, 0.05 eq) under N2 atmosphere. The mixture was heated to 100°C for 2 hours. The solution was red and turbid. 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] + .

[1070] Steps 2-4:

[1071] 5-(4-(3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]dec-8-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol

[1072] 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 eq) in MeOH (15 mL) was added Pd / C (82 mg, 0.38 mmol, 0.3 eq) under an atmosphere of H (15 Psi). The mixture was heated to 40 ° C for 16 hours. The solution was black and turbid. 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]dec-8-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (640 mg, yellow oil, 91.25% yield).

[1073] LC-MS purity: 100% (UV at 254 nm), LC-MS: 544.2 [M+H] +

[1074] Intermediate 3: 5-(4-(2-(dimethoxymethyl)-7-azaspiro[3.5]nonan-7-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol

[1075]

[1076] Step 3-1:

[1077] 7-(4-(6-(benzyloxy)-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane

[1078] Ruphos (332.0 mg, 0.712 mmol, 0.2 eq), Ruphos Pd G3 (596.0 mg, 0.712 mmol, 0.2 eq) and t-BuONa (1.37 g, 14.2 mmol, 4.0 eq) 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 eq) and 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane (710.0 mg, 3.56 mmol, 1.0 eq) in 1,4-dioxane (20 mL). The reaction mixture was heated to 100 ° C and stirred for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was cooled to rt, the mixture was diluted with water and washed with EA, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by SiO2 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.

[1079] LC-MS purity: 100% (UV at 254 nm), MS: 540.3 [M+H] + .

[1080] Step 3-2:

[1081] 7-(4-(6-(Benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane

[1082] 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 eq) in DMF (20 mL) was slowly added dropwise PyBr (507.8 mg, 1.59 mmol, 1 eq) in DMF (10 mL) at 0°C over 30 minutes, then stirred at 0°C for 1 hour. LC-MS showed the reaction was complete. 10 mL of saturated NH4Cl solution was added, followed by water, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, 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.

[1083] LC-MS purity: 100% (UV at 254 nm), MS: 618.2 [M+H] + .

[1084] Step 3-3:

[1085] 7-(4-(6-(benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-3-methoxyphenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane

[1086] Pd(dppf)Cl2 (88.4 mg, 0.121 mmol, 0.1 eq) and Na2CO3 (384.7 mg, 3.63 mmol, 3.0 eq) 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 eq) and phenylboronic acid (177 mg, 1.452 mmol, 1.2 eq) in 1,4-dioxane / H2O (30 mL / 3 mL). The reaction mixture was heated to 90°C for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was cooled to rt, the mixture was diluted with water and 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=1:5) 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.

[1087] LC-MS purity: 100% (UV at 254 nm), MS: 616.4 [M+H] + .

[1088] Steps 3-4

[1089] 5-(4-(2-(dimethoxymethyl)-7-azaspiro[3.5]nonan-7-yl)-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol

[1090] 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 H2 atmosphere. The reaction mixture was heated to 40 ° C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was cooled to room temperature, filtered, the precipitate was washed with MeOH, the filtrate was evaporated, and the residue was 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.

[1091] LC-MS purity: 100% (UV at 254 nm), LC-MS: 528.4 [M+H] + .

[1092] 1 H NMR(400M Hz,DMSO-d6)δ9.04(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).

[1093] Intermediate 4: 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (two isomers)

[1094]

[1095] Step 1: 1-(4-bromo-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine

[1096] To a mixture of 1-bromo-4,5-difluoro-2-methoxybenzene (8.5 g, 38.1 mmol, 1 equivalent) and 4-(dimethoxymethyl)piperidine (6.1 g, 38.1 mmol, 1 equivalent) in NMP (50 mL) was added CsCO (37.3 g, 114 mmol, 3 equivalents). The mixture was purged with nitrogen and stirred at 145 ° C overnight. The mixture was cooled to room temperature and then poured into H O (500 mL). The mixture was extracted with EtOAc (150 mL). The organic phase was dried over Na SO and concentrated. The residue was purified by silica gel column chromatography, eluted with 0-20% EtOAc / hexane to obtain 1- (4-bromo-2-fluoro-5-methoxyphenyl) -4- (dimethoxymethyl) piperidine (2.5 g, 18% yield) as a yellow oil.

[1097] LC-MS purity: 100% (UV at 254 nm), 362.1 / 364.1 [M+H] + .

[1098] Step 2: 6-(Benzyloxy)-1-(4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-ol

[1099] To a mixture of 1-(4-bromo-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine (5.0 g, 13.8 mmol, 1 equivalent) in anhydrous THF (25 mL) was added dropwise n-BuLi (2.50 M, 6.6 mL, 1.2 equivalents) under argon. The mixture was stirred at -75 ° C for 1.5 hours and 6-(benzyloxy)-3,4-dihydronaphthalene-1(2H)-one (4.2 g, 16.6 mmol, 1.1 equivalents) in anhydrous THF (10 mL) was added dropwise. The mixture was stirred at -75 ° C for 3 hours. The mixture was quenched by adding saturated NH4Cl aqueous solution. The mixture was poured into H2O (40 mL) and extracted with EtOAc (2x30 mL). The combined organic layer was washed with brine (40 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 0-30% EtOAc / hexanes to afford 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.

[1100] LC-MS purity: 100% (UV at 254 nm), 536.1 [M+H] + .

[1101] Step 3: 1-(4-(6-(Benzyloxy)-3,4-dihydronaphthalen-1-yl)-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine

[1102] 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 eq) in MeOH (8 mL) was added TsOH (171 mg, 0.9 mmol, 0.2 eq). The mixture was stirred at 70 ° C for 3 hours and concentrated. The residue was purified by silica gel column chromatography eluting with 0-30% EtOAc / hexanes 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.

[1103] LC-MS purity: 100% (UV at 254 nm), 518.3 [M+H] + .

[1104] Step 4: 1-(4-(6-(Benzyloxy)-2-bromo-3,4-dihydronaphthalen-1-yl)-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine

[1105] 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 eq) and DIEA (0.8 g, 6.2 mmol, 2 eq) in DMA (10 mL) was added pyridinium tribromide (1.2 g, 3.7 mmol, 1.2 eq) at 0 ° C. The mixture was stirred at room temperature for 3 hours. The mixture was poured into H2O (50 mL) and extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 0-20% EtOAc / hexanes to afford 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.

[1106] LC-MS purity: 100% (UV at 254 nm), 598.2 [M+H] + .

[1107] Step 5: 1-(4-(6-(Benzyloxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-2-fluoro-5-methoxyphenyl)-4-(dimethoxymethyl)piperidine

[1108] 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 H₂O (2 mL) was added phenylboronic acid (522 mg, 4.5 mmol, 1.5 equiv), K₂CO₃ (636 mg, 3 mmol, 2 equiv), followed by Pd(dppf)Cl₂ (137 mg, 0.15 mmol, 0.05 equiv). The mixture was stirred at 100° C. under argon for 16 hours. The mixture was cooled to room temperature, poured into H₂O (50 mL), and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (40 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0-20% EtOAc / hexanes to afford 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.

[1109] LC-MS purity: 100% (UV at 254 nm), 594.3 [M+H] + .

[1110] Step 6: 5-(4-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol

[1111] 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, moistened with approximately 55% water). The mixture was stirred at room temperature under H. The catalyst was removed by filtration and 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.

[1112] LC-MS purity: 68.0% (UV at 254 nm), 506.5 [M+H] + .

[1113] 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

[1114] 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), and the two structures were tentatively assigned.

[1115] 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

[1116]

[1117] Step 5-1:

[1118] 7-(4-((1R,2S)-6-(tert-Butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2-(dimethoxymethyl)-7-azaspiro[3.5]nonane

[1119] 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 hours. LC-MS showed the reaction was complete. The reaction mixture was cooled to rt, the mixture was diluted with water and washed with EtOAc, 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.

[1120] LC-MS purity: 62.1% (UV at 254 nm), LC-MS: 554.3 [M+H] + .

[1121] Step 5-2:

[1122] 7-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-7-azaspiro[3.5]nonane-2-carbaldehyde

[1123] 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.

[1124] LC-MS purity: 100% (UV at 254 nm), LC-MS: 452.2 [M+H] + .

[1125] 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

[1126]

[1127] Step 1: (R)-tert-Butyl 1-((9H-fluoren-9-yl)methyl)4-2-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate

[1128] To a mixture of methyl 5-bromo-6-oxo-1,6-dihydropyridine-2-carboxylate (2.5 g, 10.7 mmol, 1 eq) in THF (50 mL) were added tert-butyl (R)-1-((9H-fluoren-9-yl)methyl)4-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (5.7 g, 12.9 mmol, 1.2 eq) and PPh3 (8.4 g, 32.1 mmol, 3 eq) and the mixture was stirred at 60° C. DIAD (6.5 g, 32.1 mmol, 3 eq) was added dropwise to the mixture and the mixture was stirred at room temperature for 12 h. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography eluting with 0-30% EtOAc / hexanes to give (R)-tert-butyl 1-((9H-fluoren-9-yl)methyl)4-2-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate (5.0 g, 70% yield) as a yellow solid.

[1129] Step 2: (R)-tert-Butyl 3-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1-carboxylate

[1130] To a mixture of (R)-tert-butyl 1-((9H-fluoren-9-yl)methyl)4-2-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate (5 g, 7.6 mmol, 1 eq) in DMF (50 mL) was added piperidine (1.1 g, 15.2 mmol, 2 eq). The mixture was stirred at room temperature for 1 hour, 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 product was purified by silica gel column chromatography eluting with 0-5% DCM in methanol to give tert-butyl (R)-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]+ .

[1131] Step 3: (R)-tert-Butyl 3-8-methyl 1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate

[1132] 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 eq), XantPhos (486 mg, 0.84 mmol, 0.15 eq) and CsCO (5.4 g, 16.8 mmol, 3 eq) in dioxane (50 mL) was added Pd(dba) (511 mg, 0.56 mmol, 0.1 eq) under Ar flow and the mixture was stirred at 100° C. for 16 hours. 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 mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography using 0-50% EtOAc / hexanes as eluent to give (R)-tert-butyl 3-8-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] + .

[1133] 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

[1134] To a mixture of (R)-3-8-methyl 1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylic acid tert-butyl ester (1.3 g, 3.7 mmol, 1 eq) in THF (10 mL) and water (10 mL) was added sodium hydroxide (590 mg, 14.8 mmol, 4 eq) and the mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 5-6 with HCl (1 M) aqueous solution 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 product) as a white solid. LC-MS purity: 100% (UV at 254 nm), 336.3 [M+H]+ .

[1135] Step 5: (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

[1136] 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 eq) in DMF (10 mL) were added HATU (1.7 g, 4.6 mmol, 1.2 eq) and DIPEA (980 mg, 7.6 mmol, 2 eq) and the mixture was stirred at room temperature for 1 hour. The mixture was purified directly by reverse phase column chromatography (0-90% acetonitrile / 0.05% formic acid) to give tert-butyl (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 (1.3 g, 76% yield) as a white solid. LC-MS purity: 100% (UV at 254 nm), 446.2 [M+H] + .

[1137] 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

[1138] 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 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 (1.0 g, 91% yield) as a white solid.

[1139] LC-MS purity: 100% (UV at 254 nm), ms: 346.2 [M+1] + .

[1140] 1H NMR (400MHz, DMSO): δ10.84(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,2H),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).

[1141] 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

[1142]

[1143] Step 1: (S)-tert-Butyl 1-((9H-fluoren-9-yl)methyl)4-2-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate

[1144] To a mixture of methyl 5-bromo-6-oxo-1,6-dihydropyridine-2-carboxylate (2.5 g, 10.7 mmol, 1 eq) in THF (50 mL) were added tert-butyl (R)-1-((9H-fluoren-9-yl)methyl)4-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (5.7 g, 12.9 mmol, 1.2 eq) and PPh3 (8.4 g, 32.1 mmol, 3 eq) and the mixture was stirred at 60° C. DIAD (6.5 g, 32.1 mmol, 3 eq) was added dropwise to the mixture and the mixture was stirred at room temperature for 12 h. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography eluting with 0-30% EtOAc / hexanes to give (R)-tert-butyl 1-((9H-fluoren-9-yl)methyl)4-2-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate (3.0 g, 50% yield) as a yellow solid.

[1145] Step 2: (S)-tert-Butyl 3-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1-carboxylate

[1146] To a mixture of (R)-tert-butyl 1-((9H-fluoren-9-yl)methyl)4-2-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate (3 g, 5.6 mmol, 1 eq) in DMF (50 mL) was added piperidine (1.1 g, 15.2 mmol, 3 eq). The mixture was stirred at room temperature for 1 hour, 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 silica gel column chromatography eluting with 0-5% DCM in methanol to give tert-butyl (R)-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] + .

[1147] Step 3: (S)-tert-Butyl 3-8-methyl 1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate

[1148] 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 eq), XantPhos (486 mg, 0.84 mmol, 0.15 eq) and CsCO (5.4 g, 16.8 mmol, 3 eq) in dioxane (50 mL) was added Pd(dba) (511 mg, 0.56 mmol, 0.1 eq) under Ar flow and the mixture was stirred at 100° C. for 16 hours. 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 mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography eluting with 0-50% EtOAc / hexanes to give (R)-tert-butyl 3-8-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] + .

[1149] 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

[1150] To a mixture of (R)-3-8-methyl 1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylic acid tert-butyl ester (1.3 g, 3.7 mmol, 1 eq) in THF (10 mL) and water (10 mL) was added sodium hydroxide (590 mg, 14.8 mmol, 4 eq) and the mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 5-6 with HCl (1 M) aqueous solution 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 product) as a white solid. LC-MS purity: 100% (UV at 254 nm), 336.3 [M+H] + .

[1151] 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

[1152] 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 eq) in DMF (10 mL) was added T3P (3.2 mL, 5.2 mmol, 2 eq) and DIPEA (0.64 mL, 5.2 mmol, 2 eq). The mixture was stirred at room temperature for 1 hour, quenched with water (10 mL) and purified directly by reverse phase column chromatography (0-90% acetonitrile / 0.05% formic acid) to give (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] + .

[1153] 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

[1154] 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.

[1155] LC-MS purity: 100% (UV at 254 nm), 346.2 [M+H] + .

[1156] 1 H NMR (400MHz, DMSO): δ10.84(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,2H),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).

[1157] Intermediate 8: 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[1158]

[1159] Step 1: tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate

[1160] To a mixture of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (1.5 g, 5.4 mmol 1.0 equivalent) in DMA (8 mL) was added 3-bromopiperidine-2,6-dione (1.0 g, 5.428 mmol, 1.0 equivalent) and NaHCO (456 mg, 5.4 mmol, 1.0 equivalent). The mixture was stirred at 80 ° C overnight and cooled to room temperature. The mixture was concentrated and the residue was purified by silica gel column chromatography, eluting with 0-100% EtOAc / hexane to give tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (1.6 g, 76.0% yield) as a light blue solid. LC-MS purity: 100% (UV at 254 nm), 388.0 [M+H] + :

[1161] Step 2: 3-((4-(Piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[1162] 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] + 1HNMR (400 MHz, DMSO) δ10.83 (s, 1H), 9.11–8.76 (m, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 4.33 (dd, J = 11.6, 4.8 Hz, 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). Intermediate 9: (R or S)-3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[1163]

[1164] Step 1: (R / S)-tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate

[1165] tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (1.9 g, 5 mmol) was purified by SFC to give tert-butyl (R / S)-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] + .

[1166] Step 2: (R / S)-3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[1167] A mixture of tert-butyl (R / S)-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 afford (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) δ10.83(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=1 1.6,4.8Hz,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).

[1168] 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

[1169]

[1170] Step 1: 5-Fluoro-6-nitroisobenzofuran-1(3H)-one

[1171] To a solution of 5-fluoroisobenzofuran-1(3H)-one (10 g, 65.8 mmol, 1.0 equiv) in HSO (50 mL) was added KNO (9.97 g, 98.7 mmol, 1.5 equiv) portionwise. The reaction mixture was stirred at room temperature for 3 hours and slowly poured into ice water. The organic phase was washed with brine, dried over NaSO and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 0-50% EtOAc / hexane to give 5-fluoro-6-nitroisobenzofuran-1(3H)-one (10.4 g, 80% yield) as a white solid.

[1172] Step 2: (S)-tert-Butyl 3-(hydroxymethyl)-4-(6-nitro-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate

[1173] To a solution of 5-fluoro-6-nitroisobenzofuran-1(3H)-one (1 g, 5.0 mmol, 1 eq) and (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.7 g, 7.5 mmol, 1.5 eq) in acetonitrile (10 mL) was added DIPEA (2.2 mL, 12.5 mmol, 2.5 eq) and the mixture was stirred at 60° C. for 6 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with 0-5% MeOH / DCM to give (S)-tert-butyl 3-(hydroxymethyl)-4-(6-nitro-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate (1.3 g, 66% yield) as a yellow foam.

[1174] Step 3: (S)-tert-Butyl 4-(6-amino-1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

[1175] 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 equivalent) in MeOH (15 mL) was added Pd / C (300 mg, 10% on carbon, moistened with approximately 55% water). The mixture was degassed and purged with H2 three times and stirred at room temperature for 4 hours. 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 (860 mg, 93% yield) as a light yellow foam.

[1176] Step 4: (S)-tert-Butyl 4-(6-bromo-1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

[1177] To a solution of (S)-tert-butyl 4-(6-amino-1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (468 mg, 1.3 mmol, 1 eq) in acetonitrile (25 mL) cooled in an ice bath was added t-BuONO (0.2 mL, 1.7 mmol, 1.3 eq) and the mixture was stirred for 30 minutes. A solution of CuBr (300 mg, 1.3 mmol, 1 eq) in acetonitrile (6 mL) was then added dropwise to the solution and the mixture was stirred at room temperature for 3 hours. 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 silica gel column chromatography 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 (415 mg, 75% yield) as a brown oil.

[1178] 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

[1179] 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 eq), Pd(OAc)2 (36.8 mg, 0.15 mmol, 0.5 eq), JohnPhos (118 mg, 0.36 mmol, 1.2 eq) and Cs2CO3 (214 mg, 0.7 mmol, 2 eq) in toluene was degassed and purged with N2 three times, and then the mixture was stirred at 90° C. for 3 hours. 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 (90 mg, 80% yield) as a yellow solid.

[1180] 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

[1181] To a solution of (S)-8-oxo-1,2,4a,5,8,10-hexahydroisobenzofuro[5,6-b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (87 mg, 0.25 mmol, 1 eq) in THF (3 mL) was added a solution of NaOH (60 mg, 1.3 mmol, 6 eq) in H O (1 mL) and the mixture was stirred at 40 ° C for 6 hours. The mixture was then concentrated and the residue was diluted with water (4 mL) and acidified to pH 3-4 with 2N HCl. The mixture was extracted with DCM (10 mL) and the organic phase was washed with brine, dried over Na SO 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 (76 mg, 83% yield) as a white powder.

[1182] 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

[1183] 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 eq) in DCM (10 mL) cooled at 0 ° C. DMP (93.7 mg, 0.23 mmol, 1.5 eq) was added in small portions and the mixture was stirred at 0 ° C. for 30 minutes. The mixture was then diluted with DCM and washed with brine. The organic phase was dried over Na2SO4 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 (50 mg, crude) as a yellow solid.

[1184] 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

[1185] 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 eq), 3-aminopiperidine-2,6-dione (47.6 mg, 0.3 mmol, 1.5 eq) and NaOAc (23.7 mg, 0.3 mmol, 1.5 eq) diluted in MeOH (6 mL) was added NaBH3CN (36 mg, 0.6 mmol, 3 eq) 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 (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 (35 mg, 38% yield) as a white powder after lyophilization.

[1186] 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)-carboxylic acid tert-butyl ester

[1187] 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 eq) in DMF (2.5 mL) was added HATU (54 mg, 0.15 mmol, 1.5 eq) followed by DIPEA (40 mg, 0.3 mmol, 3 eq) and the mixture was stirred at room temperature for 1 hour. 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 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, 66% yield) as a white powder.

[1188] 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

[1189] 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 equiv) 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 (26 mg, crude) as a white solid. LC-MS: [M+H] + =356.90. 1 H NMR (400MHz, methanol-d4) δ7.15(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)δ174.68,172.52,172.49,171.63,171.59,146.42,146.37,139.22,139.20,138.12,138.08,123.85,123.7 8,111.88,108.70,108.65,66.94,53.72,53.57,50.79,50.75,48.90,48.68,44.36,44.17,44.10,43.63,43.61,32.35,24.08.

[1190] Intermediate 11: N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)picolinamide hydrochloride

[1191]

[1192] Step 1: tert-Butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate

[1193] To a mixture of methyl 5-bromopicolinate (15 g, 69.4 mmol 1 eq), tert-butyl piperazine-1-carboxylate (12.9 g, 69.4 mmol, 1 eq) and CsCO (45 g, 139 mmol, 2 eq) in dioxane (150 mL) was added Ruphos-G-Pd (2.2 g, 3.5 mmol, 0.05 eq) under an Ar stream. The mixture was stirred at 100° C. for 16 hours and cooled to room temperature. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc / hexane to give tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (22 g, crude product).

[1194] Step 2: 5-(4-(tert-Butoxycarbonyl)piperazin-1-yl)picolinic acid

[1195] To a mixture of tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (22 g, 68.5 mmol, 1 eq) in MeOH (40 mL) / THF (100 mL) / HO (40 mL) was added LiOH (5.5 g, 137 mmol, 2 eq) and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated and the residue was adjusted to pH 6 with 1N HCl. The precipitate was collected by filtration and dried under vacuum to give 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid (16.3 g, 76.4% yield).

[1196] Step 3: tert-Butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[1197] To a mixture of 5-(4-(tert-butoxycarbonyl)piperazine-1-yl)picolinic acid (1 g, 3.2 mmol, 1 equivalent), 3-aminopiperidine-2,6-dione (537 mg, 3.2 mmol, 1 equivalent) in DMA (5 ml) was added TEA (0.8 mL, 6.4 mmol, 2 equivalents) and T3P (3 mL, 4.8 mmol, 1.5 equivalents). The reaction mixture was stirred at room temperature for 2 hours, 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 silica gel column chromatography, eluted with 0-100% EtOAc / hexane 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.

[1198] Step 4: N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)picolinamide hydrochloride

[1199] 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 (950 mg, crude) as a white solid.

[1200] Intermediate 12: N-(2,6-dioxopiperidin-3-yl)-6-methoxy-5-(piperazin-1-yl)picolinamide hydrochloride

[1201]

[1202] Step 1: tert-Butyl 4-(2-methoxy-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate

[1203] To a mixture of methyl 5-bromo-6-methoxypicolinate (900 mg, 3.7 mmol, 1 eq), tert-butyl piperazine-1-carboxylate (818 mg, 4.4 mmol, 1.2 eq) and CsCO (1.4 g, 4.4 mmol, 1.2 eq) in dioxane (15 mL) was added Ruphos-G-Pd (153 mg, 0.18 mmol, 0.05 eq) under an Ar flow. The mixture was stirred at 100° C. for 16 hours and cooled to room temperature. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc / hexane to give tert-butyl 4-(2-methoxy-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (770 mg, 50%).

[1204] Step 2: 5-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-6-methoxypicolinic acid

[1205] To a mixture of tert-butyl 4-(2-methoxy-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (70 mg, 0.2 mmol, 1 eq) in MeOH (1 mL) / THF (1 mL) / H O (1 mL) was added LiOH (14 mg, 0.6 mmol, 3 eq) and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated and the residue was adjusted to pH = 6 with 1N HCl. The precipitate was collected by filtration and dried under vacuum to give 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methoxypicolinic acid (65 mg, crude).

[1206] Step 3: tert-Butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-methoxypyridin-3-yl)piperazine-1-carboxylate

[1207] To a mixture of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methoxypicolinic acid (80 mg, 0.24 mmol, 1 eq), 3-aminopiperidine-2,6-dione (46 mg, 0.28 mmol, 1.2 eq) in DMA (3 ml) was added TEA (48 mg, 0.48 mmol, 2 eq) and T3P (152 mg, 0.48 mmol, 2 eq). The reaction mixture was stirred at room temperature for 2 hours, 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 silica gel column chromatography 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.

[1208] Step 4: N-(2,6-dioxopiperidin-3-yl)-6-methoxy-5-(piperazin-1-yl)picolinamide hydrochloride

[1209] 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 (950 mg, crude) as a white solid.

[1210] Intermediate 13: N-(2,6-dioxopiperidin-3-yl)-4-methoxy-5-(piperazin-1-yl)picolinamide hydrochloride.

[1211]

[1212] Step 1: tert-Butyl 4-(4-methoxy-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate

[1213] To a mixture of methyl 5-bromo-4-methoxypicolinate (1 g, 4.0 mmol, 1 eq), tert-butyl piperazine-1-carboxylate (818 mg, 4.4 mmol, 1.2 eq) and CsCO (1.4 g, 4.4 mmol, 1.2 eq) in dioxane (15 mL) was added Ruphos-G-Pd (153 mg, 0.18 mmol, 0.05 eq) under an Ar stream. The mixture was stirred at 100° C. for 16 hours and cooled to room temperature. The residue was purified by silica gel column chromatography 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).

[1214] Step 2: 5-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-4-methoxypicolinic acid

[1215] To a mixture of tert-butyl 4-(2-methoxy-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (70 mg, 0.2 mmol, 1 eq) in MeOH (1 mL) / THF (1 mL) / H O (1 mL) was added LiOH (14 mg, 0.6 mmol, 3 eq) and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated and the residue was adjusted to pH = 6 with 1N HCl. The precipitate was collected by filtration and dried under vacuum to give 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-methoxypicolinic acid (65 mg, crude).

[1216] Step 3: tert-Butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)-4-methoxypyridin-3-yl)piperazine-1-carboxylate

[1217] To a mixture of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-methoxypicolinic acid (160 mg, 0.48 mmol, 1 eq), 3-aminopiperidine-2,6-dione (92 mg, 0.56 mmol, 1.2 eq) in DMA (3 ml) was added TEA (97 mg, 0.97 mmol, 2 eq) and T3P (152 mg, 0.48 mmol, 1 eq). The reaction mixture was stirred at room temperature for 2 hours, 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 silica gel column chromatography 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.

[1218] Step 4: N-(2,6-dioxopiperidin-3-yl)-4-methoxy-5-(piperazin-1-yl)picolinamide hydrochloride

[1219] 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 (90 mg, crude) as a white solid.

[1220] Intermediate 14. 3-(6-Oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione trifluoroacetate

[1221]

[1222] Step 1: tert-Butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate

[1223] 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 aqueous toluene (300 mL) was heated at reflux for 36 hours. 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 (Na2SO4) and then concentrated under reduced pressure. Chromatography of the residue gave the title compound 2 (12 g, 48%) as a colorless oil.

[1224] Step 2: Methyl 4-bromo-2-formyl-3-hydroxybenzoate

[1225] To a solution of 4-bromo-3-hydroxybenzoic acid methyl ester 3 (18g, 77.9mmol) in TFA (150mL) was added HMTA (41.5g, 296mmol). The solution was stirred at 90°C overnight. 2N HCl was added, and a yellow solid was formed. The mixture was stirred for 10 minutes, and then 1L of water was added and stirred for 1 hour. The mixture was filtered. The filter cake was dissolved in DCM and filtered on diatomaceous earth, dried, and most of the solvent was removed in vacuo. The resulting mixture was ground with MeOH and filtered to give 4-bromo-2-formyl-3-hydroxybenzoic acid methyl ester 4 (12g, 59%) as a yellow solid.

[1226] Step 3: tert-Butyl 4-((6-bromo-2-formyl-3-(methoxycarbonyl)phenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate

[1227] To a solution of compound 2 (6 g, 23.2 mmol, 1.0 equivalent) in anhydrous THF (50 ml), compound 4 (5.9 g, 27.8 mmol, 1.2 equivalents) and PPh3 (7.9 g, 30.1 mmol, 1.3 equivalents) were added. The reaction mixture was cooled to 0 ° C and DIAD (6.6 g, 32.4 mmol, 1.4 equivalents) was added dropwise. The resulting mixture was then stirred at room temperature for 1 hour. 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 (4 g, 38%) was obtained as a yellow oil.

[1228] Step 4: 1'-(tert-Butyl)6-7-formyl-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1',6-dicarboxylic acid methyl ester

[1229] 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), Et4NCl.HO (1.95 g, 10.6 mmol, 1.2 equiv), Pd(OAc)2 (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 (720 mg, 24% yield) as a yellow oil.

[1230] 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

[1231] To a solution of compound 6 (780 mg, 2.09 mmol, 1 eq) and compound 6 (344 mg, 2.09 mmol, 1 eq) in MeOH (10 mL) was added TEA (211 mg, 2.09 mmol, 1 eq) and AcOH (627 mg, 10.5 mmol, 5 eq), followed by the addition of NaBHCN (395 mg, 6.27 mmol, 3 eq). The mixture was stirred at room temperature for 16 hours, diluted with EA, and washed with brine, 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 / hexane to give compound 8 (400 mg, 42%) as a white solid.

[1232] 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

[1233] To a solution of compound 8 (400 mg, 0.88 mmol, 1 equivalent) in MeOH was added Pd / C (200 mg, 10% on carbon, moistened with about 55% water) and Pd(OH)2 (200 mg). The mixture was purged with H2 and stirred overnight at rt under H2. The mixture was filtered through celite and the filtrate was concentrated. The crude product was purified by silica gel chromatography. Compound 7-(2,6-dioxopiperidin-3-yl)-6-oxo-7,8-dihydro-2H, 6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-1'-tert-butyl carboxylate (220 mg, 55%) was obtained as a white solid. LC / MS(ESI)m / z:356.2[M+H] + . 1 H NMR (400MHz, DMSO) δ10.97(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,1H),1.98–1.96(m,1H),1.83-1.77(m,2H),1.71-1.65(m,2H),1.42(s,9H).

[1234] Step 7: 3-(6-Oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindol-3,4'-piperidin]-7-yl)piperidine-2,6-dione trifluoroacetate

[1235] Compound 9 was treated with TFA in DCM at room temperature to deprotect the N-Boc group, providing intermediate 1- 14. LC / MS (ESI) m / z: 356.15. 1 H NMR (400MHz, CDCl3) δ8.00 (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).

[1236] Intermediate 15: 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane

[1237]

[1238] Step 1: Benzyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate

[1239] To the stirred solution of 2- oxo -7- azaspiro [3.5] nonane -7- tert-butyl formates (24g, 0.1mol, 1 equivalent) in EA (50mL) at room temperature, concentrated HCl (45mL, 0.5mol, 5 equivalents) is slowly added and the reaction mixture is stirred at rt for 1 hour. Once the reaction is complete, the mixture is diluted with EA (150mL), poured into Na2CO3 suspension (106g, 1mol, 10 equivalents in 500mL water) and the mixture is stirred for 20 minutes. CbzOSu (25g, 0.1mmol, 1 equivalent) is added to the mixture and the mixture is stirred for 1 hour. Separate the organic phase, wash with salt water, dry, concentrate and pass through silica gel column chromatography residue, eluted with 50% EA in PE, obtain compound 2- oxo -7- azaspiro [3.5] nonane -7- benzyl formates (27g, 0.1mol, 100%) as light yellow oil.

[1240] Step 2: Benzyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate

[1241] To the stirred solution of (methoxymethyl) triphenylphosphonium chloride (68g, 0.2mol, 2 equivalents) in anhydrous THF (300mL) cooling at-70 ℃, drip NaHMDS (100mL, 0.2mol, 2 equivalents) and the mixture is slowly warming up to 0 ℃ and stirred 2 hours.Then the mixture is cooled at-70 ℃ and is added into 2-oxo-7-azaspiro [3.5] nonane-7-benzyl formate (27g, 0.1mol, 1 equivalent) in THF (50mL).The mixture is slowly warming up to rt and stirred 2 hours.Carry out TLC to detect reaction process.In case there is no starting material remaining, just use NH Cl solution (500mL) cancellation mixture and dilute with EA (200mL). The organic phase was separated, washed with brine, dried, concentrated and the residue was purified by column chromatography on silica gel eluting with 30% EA in PE to give compound benzyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate (20 g, 0.067 mol, 67%) as a light yellow oil.

[1242] Step 3: Benzyl 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate

[1243] A solution of benzyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate (24 g, 0.67 mol, 1 eq) in FA (50 mL) was stirred at rt for 4 h. TLC was performed to monitor the progress of the reaction. Once the reaction was complete, the mixture was concentrated and the residue was dissolved in MeOH (120 mL). CH(OMe) (10.6 g, 0.1 mol, 1.5 eq) was added to the mixture, followed by TsOH·H2O (1.5 g, 0.07 mol, 0.1 eq) and the mixture was stirred at 70°C for 12 h. TLC was performed to monitor the progress of the reaction. Once the reaction was complete, the mixture was concentrated and the residue was purified by silica gel column chromatography eluting with 20% EA in PE to give compound benzyl 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (14.6 g, 0.44 mol, 67%) as a light yellow oil.

[1244] Step 4: 2-(Dimethoxymethyl)-7-azaspiro[3.5]nonane

[1245] To a solution of benzyl 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (14.6 g, 0.44 mol, 1 equivalent) in MeOH (100 mL) was added Pd / C (4 g, 10% on carbon, wetted with about 55% water) and the mixture was stirred at rt under H (balloon) for 12 hours. TLC was performed to monitor the progress of the reaction. Once the reaction was complete, the catalyst was removed by filtration and the filtrate was concentrated to give compound 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane (8.9 g, 0.44 mol, 100%) as a white paste.

[1246] LCMS[M+H]:200.0. 1 H NMR (400MHz, DMSO-d6) δ4.57(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).

[1247] Intermediate 16: 4-(dimethoxymethyl)piperidine

[1248]

[1249] Steps 1 and 2: Benzyl 4-formylpiperidine-1-carboxylate

[1250] At room temperature, concentrated HCl (600mL, 6.6mol, 3 equivalents) is slowly added to the stirred solution of compound tert-butyl 4-formyl piperidine-1-formate (500g, 2.2mol, 1 equivalent) in EA (500mL) and the reaction mixture is stirred at rt for 1 hour. Once the reaction is complete, the mixture is diluted with EA (500mL), poured into Na CO suspension (1160g, 11mol, 5 equivalents, in 3000mL water) and the mixture is stirred for 20 minutes. In the mixture, CbzOSu (550g, 2.2mmol, 1 equivalent) is added and the mixture is stirred for 1 hour. Separate organic phase, wash with salt water, dry, concentrate and pass through silica gel column chromatography residue, elute with 50% EA in PE, obtain compound 4-formyl piperidine-1-benzyl formate (550g, 2.1mol, 95%) as light yellow oil.

[1251] Step 3: Benzyl 4-(dimethoxymethyl)piperidine-1-carboxylate

[1252] To a solution of benzyl 4-formylpiperidine-1-carboxylate (150 g, 0.5 mol, 1 eq) in MeOH (500 mL) was added CH(OMe) (212 g, 1 mol, 2 eq) followed by TsOH.HO (19 g, 0.1 mol, 0.1 eq) and the mixture was stirred at 70° C. for 12 h. Once the reaction was complete, the mixture was concentrated and the residue was purified by silica gel 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 light yellow oil.

[1253] Step 4: 4-(Dimethoxymethyl)piperidine

[1254] To a solution of compound 4-(dimethoxymethyl)piperidine-1-carboxylic acid benzyl ester (120 g, 0.44 mol, 1 eq) in MeOH (400 mL) was added Pd / C (20 g, 10% on carbon, wetted with about 55% water) and the mixture was stirred at rt under H (balloon) for 12 h. Once the reaction was complete, 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.

[1255] Intermediate 17: 7-(dimethoxymethyl)-2-azaspiro[3.5]nonane

[1256]

[1257] Step 1: Benzyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate

[1258] To the stirred solution of compound 7- oxo -2- azaspiro [3.5] nonane -2- tert-butyl formate (2.4g, 10mmol, 1 equivalent) in EA (5mL) at room temperature, concentrated HCl (4.5mL, 50mol, 5 equivalents) is slowly added and the reaction mixture is stirred at rt for 1 hour. Once the reaction is complete, the mixture is diluted with EA (15mL), Na is poured into a suspension (10.6g, 0.1mol, 10 equivalents in 50mL water) and the mixture is stirred for 20 minutes. CbzOSu (2.5g, 10mmol, 1 equivalent) is added to the mixture and the mixture is stirred for 1 hour. The organic phase is separated, washed with salt water, dried, concentrated and passed through silica gel column chromatography to purify the residue, eluted with 50% EA in PE to obtain compound 7- oxo -2- azaspiro [3.5] nonane -2- benzyl formate (2.7g, 0.1mol, 100%) as a light yellow oil.

[1259] Step 2: Benzyl 7-(methoxymethylene)-2-azaspiro[3.5]nonane-2-carboxylate

[1260] To the stirred solution of (methoxymethyl) triphenylphosphonium chloride (6.8g, 20mol, 2 equivalents) in anhydrous THF (30mL) cooling at-70 ℃, drip NaHMDS (10mL, 20mol, 2 equivalents) and the mixture is slowly warming up to 0 ℃ and stirred 2 hours.Then the mixture is cooled at-70 ℃ and is added into 7-oxo-2-azaspiro [3.5] nonane-2-benzyl formate (2.7g, 0.1mol, 1 equivalent) in THF (5mL).The mixture is slowly warming up to rt and stirred 2 hours.Carry out TLC to detect reaction process.In case there is no starting material remaining, just use NH4Cl solution (50mL) cancellation mixture and dilute with EA (20mL). The organic phase was separated, washed with brine, dried, concentrated and the residue was purified by column chromatography on silica gel eluting with 30% EA in PE to give compound benzyl 7-(methoxymethylene)-2-azaspiro[3.5]nonane-2-carboxylate (2.2 g, 7.3 mmol, 73%) as a light yellow oil.

[1261] Step 3: Benzyl 7-(dimethoxymethyl)-2-azaspiro[3.5]nonane-2-carboxylate

[1262] A solution of 7-(methoxymethylene)-2-azaspiro[3.5]nonane-2-formate (2.2 g, 7.3 mol, 1 equivalent) in FA (5 mL) was stirred at rt for 4 hours. TLC was carried out to detect the reaction process. Once the reaction was complete, the mixture was concentrated and the residue was dissolved in MeOH (12 mL). CH(OMe) was added to the mixture (1.06 g, 10 mol, 1.5 equivalents), followed by addition of TsOH H2O (190 mg, 1 mol, 0.1 equivalents) and the mixture was stirred at 70 ° C for 12 hours. TLC was carried out to detect the reaction process. Once the reaction was complete, the mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with 20% EA in PE to obtain compound 7-(dimethoxymethyl)-2-azaspiro[3.5]nonane-2-formate benzyl ester (1.5 g, 4.4 mmol, 67%) as a light yellow oil.

[1263] Step 4: 7-(Dimethoxymethyl)-2-azaspiro[3.5]nonane

[1264] To a solution of compound 7-(dimethoxymethyl)-2-azaspiro[3.5]nonane-2-carboxylic acid benzyl ester (1.5 g, 4.4 mol, 1 equivalent) in MeOH (10 mL) was added Pd / C (400 mg, 10% on carbon, moistened with about 55% water) and the mixture was stirred at rt under H2 (balloon) for 12 hours. TLC was carried out to detect the progress of the reaction. Once the reaction was complete, the catalyst was removed by filtration and the filtrate was concentrated to give compound 7-(dimethoxymethyl)-2-azaspiro[3.5]nonane (810 mg, 4 mol, 90%) as a white paste. LCMS: 200 [M+H] + .

[1265] Intermediate 18. 2-(Dimethoxymethyl)-7-azaspiro[3.5]nonane

[1266]

[1267] Step 1: Benzyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

[1268] To a stirred solution of tert-butyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-formate (10 g, 40 mmol, 1 equivalent) in EA (50 mL) was slowly added concentrated HCl (20 mL, 0.2 mol, 5 equivalents) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was then diluted with EA (150 mL), and NaCO suspension (40 g, 0.4 mol, 10 equivalents in 500 mL of water) was poured into the mixture and the mixture was stirred for 20 minutes. CbzOSu (10 g, 40 mmol, 1 equivale...

Claims

1. A compound of formula I: TLC(I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, in: C has the formula I'-1 in: R 1 For 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution; R 2 *-Cy 2 -, where * indicates attachment to L; -Cy 2 - for C 3-12 Carbocyclylene or 3 to 12 membered heterocyclylene, wherein the carbocyclylene or heterocyclylene is separated by one or more R u optionally substituted; or R 1 and R 2 Together with the intervening carbon atom, it forms Ring A to which L is attached, wherein Ring A is an optionally substituted C 3-12 carbocyclic ring or 5- to 16-membered heterocyclic ring; Y" is N or CR 3 ; R 3 For 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u optionally substituted; or R 2 and R 3 together with the intervening carbon atoms, form Ring A to which L is attached, wherein Ring A is an optionally substituted 5- to 16-membered heterocyclic ring; The condition is R 1 and R 2 and R 2 and R 3 Not all form ring A attached to L; Y' is N or CR Y’ ; R Y’ For 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- to 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 replaced by one or more R u Optional substitution; --- represents an optional covalent bond between Y and U; i) When the bond between Y and U does not exist: r is 0 or 1; Y is N or CR Y ; R Y For 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- to 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 replaced by one or more R u Optional substitution; U is hydrogen or is replaced by one or more R u Optionally substituted C 1-6 alkyl; ii) When a bond between Y and U exists: r is 1; Y is C; U is -CH2-, -C(=O)-, -(C=O)-N(R U )-*or-N=C(R U )-*; R U H or one or more R u Substituted C 1-6 alkyl, and * indicates attachment to ring B; R 4 For hydrogen, deuterium, C 1-6 Haloalkyl or C 1-6 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- to 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 replaced by one or more R u Optional substitution; d is an integer from 0 to 4; and q is an integer from 0 to 2, T has the formula I-2: in: X T1 、X T2 、X T3 and X T4 Each of is independently N or CR T ; R T Each occurrence 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution; Each R E are independently 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u optionally substituted; and m is an integer selected from 0 to 5; L has the formula I'-3: in: * indicates attachment to T, and ** indicates attachment to C; Each L ’ Independently C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, 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-, wherein the alkylene, heteroalkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene or heteroarylene is replaced by one or more R u Optional substitution; R L Each occurrence is independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 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 wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u optionally substituted; and l is an integer selected from 0 to 10; in: 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of oxo, halogen, -CN, -NO2, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl and 3- to 6-membered heterocyclyl; or Two R's u Together with one or more intervening atoms, it forms C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-12 a carbocyclyl group or a 3- to 12-membered heterocyclyl group; Each R a Independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, 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 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; and Each R c and R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl; or R c and R d together with the nitrogen atom to which they are attached, form a 3- to 12-membered heterocyclic group, where R a 、R b 、R c and R d Each occurrence is followed by one or more R z are independently and optionally substituted; and 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 a carbocyclic group or a 3- to 6-membered heterocyclic group.

2. The compound of claim 1, wherein 1) When a bond between Y and U exists, U is -CH2- 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, it forms Ring A to which L is attached; and ii) Ring A is not Where ** indicates attachment to L; and 2) The compound is not or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

3. The compound of claim 1 or 2, wherein C has the formula I'-1-i The compound according to claim 3 , wherein U is —CH 2 — or —C(═O)—.

5. The compound of claim 1 or 2, wherein C has the formula I'-1-ii The compound according to claim 5 , wherein Y is N.

7. The compound of claim 5, wherein Y is CR Y , and R Y is hydrogen, halogen or C 1-6 Alkoxy.

8. The compound of any one of claims 1 to 7, wherein R 1 and R 2 Together with the intervening carbon atoms, they form Ring A to which L is attached, wherein said Ring A is an optionally substituted 5- to 16-membered heterocyclic ring.

9. The compound of claim 8, wherein Y" is N.

10. The compound of claim 8, wherein Y" is CR 3 , and R 3 For 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- to 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 replaced by one or more R u Optional substitution.

11. The compound of claim 10, wherein R 3 is hydrogen, halogen or C 1-6 Alkoxy.

12. The compound of any one of claims 1 to 7, wherein R 2 and R 3 Together with the intervening carbon atoms, they form Ring A to which L is attached, wherein said Ring A is an optionally substituted 5- to 16-membered heterocyclic ring.

13. The compound of claim 12, wherein R 1 For 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- to 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 replaced by one or more R u Optional substitution.

14. The compound of claim 13, wherein R 1 is hydrogen, halogen or C 1-6 Alkoxy.

15. The compound of any one of claims 1 to 14, wherein Ring A is an optionally substituted 7- to 16-membered fused heterocyclic ring.

16. The compound according to any one of claims 1 to 14, wherein ring A is in: ** indicates attachment to L; Ring A I and Ring A II Independently C 4-8 Carbocyclic or 4- to 8-membered heterocyclic ring; wherein Ring A III and Ring A IV At least one of is a 4- to 8-membered heterocycle; A 1 and A 2 Independently C, CR Ax or N; R Ax For 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 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is replaced by one or more R u Optional substitution; 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 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6-10 Aryl, 5- to 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)2R a 、-NR c S(=O)R a 、-NR c S(=O)2OR b 、-NR c S(=O)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optional substitution; and When valence permits, s is an integer selected from 0 to 8, Each R i Can exist independently in ring A I or ring II superior.

17. The compound according to any one of claims 1 to 14, wherein ring A is in: ** indicates attachment to L; R 5 is hydrogen or is replaced by one or more R u Optionally substituted C 1-6 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u optionally substituted; and s is an integer selected from 0 to 8 when valence permits.

18. The compound of any one of claims 1-14, wherein Ring A is an optionally substituted 7- to 16-membered spiroheterocycle.

19. The compound of any one of claims 1 to 14, wherein Ring A is: in: ** indicates attachment to L; Ring A IV C 3-8 Carbocyclic or 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 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- to 10-membered heteroaryl, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, -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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u optionally substituted; or Two R X1 or two R Z1 Together they form an oxo group; R X2 and R Z2 Each occurrence is independently hydrogen or replaced by one or more R u Optionally substituted C 1-6 alkyl; m' and n' are independently integers selected from 0 to 3, wherein m' and n' are not both 0; When valence permits, s is an integer selected from 0 to 8, and 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u Optionally substituted, The condition is that when both m' and n' are not 0, then ring A 1 is a 4- to 9-membered heterocyclic ring, and Each R i Can exist independently in ring A III or Ring A IV superior.

20. The compound of any one of claims 1 to 14, wherein Ring A is: 1) where o is 0 or 1; or 2) Where ** indicates attachment to L.

21. The compound of any one of claims 1-14, wherein Ring A is an optionally substituted 5- to 6-membered heterocycle.

22. The compound of any one of claims 1 to 14, wherein ring A is in: ** indicates attachment to L; R 5 is hydrogen or is replaced by one or more R u Optionally substituted C 1-6 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- to 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)2NR 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 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl group is replaced by one or more R u optionally substituted; and s is an integer selected from 0 to 8 when valence permits.

23. The compound of any one of claims 16-17, 19-20 and 22, wherein 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- to 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 replaced by one or more R u Optional substitution.

24. The compound of claim 23, wherein s is 0.

25. The compound of claim 1, wherein C has the formula I'-1-ii 26. The compound of claim 25, wherein R 2 *-Cy 2 -, where * indicates attachment to L.

27. The compound of claim 26, wherein -Cy 2 - for C 5-12 A fused carbocyclylene or a 5- to 12-membered fused heterocyclylene, wherein the carbocyclylene or heterocyclylene is surrounded by one or more R u Optional substitution.

28. A compound as described in any one of claims 25-27, wherein R 1 For 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- to 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 replaced by one or more R u Optional substitution.

29. The compound of claim 28, wherein R 1 is hydrogen, halogen or C 1-6 Alkoxy.

30. The compound of any one of claims 25-29, wherein Y is N.

31. The compound of any one of claims 25-29, wherein Y is CR Y , and R Y is hydrogen, halogen or C 1-6 Alkoxy.

32. A compound as described in any one of claims 25-31, wherein Y" is CR 3 , and R 3 For 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- to 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 replaced by one or more R u Optional substitution.

33. The compound of claim 32, wherein R 3 is hydrogen, halogen or C 1-6 Alkoxy.

34. The compound of any one of claims 1 to 33, wherein Y' is CR Y’ , and R Y’ For 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- to 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 replaced by one or more R u Optional substitution.

35. The compound of claim 34, wherein Y' is CR Y’ , and R Y’ is hydrogen, halogen or C 1-6 Alkoxy.

36. A compound as described in any one of claims 1 to 35, wherein R 4 For hydrogen.

37. The compound of any one of claims 1-36, wherein q is 1.

38. A compound as described in any one of claims 1 to 37, wherein X T1 、X T2 、X T3 and X T4 Each of them is CR T .

39. The compound of claim 38, wherein X T1 、X T2 、X T3 and X T4 Each of them is CH.

40. The compound of claim 38, wherein X T1 is C(OCH3), X T3 is CF, and X T2 and X T4 Each of CH; X T2 CF, X T4 is C(OCH3), and X T1 and X T3 Each of CH; X T1 and X T4 One of them is CF or C(OCH3), X T1 and X T4 The other one of them is CH, and X T2 and X T3 Each of CH, or X T1 is C(OCH3), X T2 is CF, and X T3 and X T4 Each of them is CH.

41. The compound of any one of claims 1 to 37, wherein X T1 、X T2 、X T3 and X T4 One of them is N.

42. The compound of claim 41, wherein X T1 and X T4 One of them is N, X T1 and X T4 The other one of them is CH, and X T2 and X T3 Each of is CH, or X T2 and X T3 One of them is N, X T2 and X T3 The other one of them is CH, and X T1 and X T4 Each of them is CH.

43. A compound as described in any one of claims 1-37, wherein X T1 、X T2 、X T3 and X T4 Both of them are N.

44. The compound of claim 43, wherein X T1 and X T4 Each of is CH, and X T2 and X T3 Each of them is N.

45. A compound as described in any one of claims 38, 41 or 43, wherein 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, C 6-10 Aryl, 5- to 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 replaced by one or more R u Optional substitution.

46. The compound of claim 45, wherein each R T are independently hydrogen or halogen.

47. A compound as described in any one of claims 38-46, wherein each R E are independently 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- to 10-membered heteroaryl, C 3-6 carbocyclyl or 3 to 6 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl or heterocyclyl is replaced by one or more R u Optional substitution.

48. The compound of claim 47, wherein R E It is a halogen.

49. The compound of any one of claims 38-48, wherein m is 0.

50. The compound of any one of claims 1-49, wherein L has formula I-3: in: * indicates attachment to T and ** indicates attachment to C; W does not exist; or W is C 1-3 Alkylene, -O-, -NR W - or -(C=O)-, wherein the alkylene group is replaced by one or more R u Optional substitution; Cy 1 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 separated by one or more R u Optional substitution; 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 separated by one or more R u Optional substitution; R W is hydrogen or is replaced by one or more R u Optionally substituted C 1-6 alkyl; and p is an integer selected from 0 to 8.

51. The compound of claim 50, wherein Cy 1 C 3-12 Carbocyclylene or 3 to 12 membered heterocyclylene, wherein the carbocyclylene or heterocyclylene is separated by one or more R u Optional substitution.

52. The compound of claim 50, wherein Cy 1 is a 3- to 12-membered heterocyclylene group, wherein the heterocyclylene group is surrounded by one or more R u Optional substitution.

53. The compound of any one of claims 50-52, wherein W is absent.

54. The compound of any one of claims 50-52, wherein Z' is absent.

55. A compound as described in any one of claims 50-52, wherein -[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 1-6 alkylene)-(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)-, wherein the alkylene or heterocyclylene is replaced by one or more R u Optionally substituted, and * indicates attachment to C.

56. The compound of claim 55, wherein -[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 to 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 separated by one or more R u Optionally substituted, and * indicates attachment to C.

57. A compound selected from the group consisting of compounds in Table 1 and Table 2 or pharmaceutically acceptable salts thereof.

58. A compound selected from Table X or a pharmaceutically acceptable salt thereof, Table X 59. A pharmaceutical composition comprising a compound according to any one of claims 1 to 58 and a pharmaceutically acceptable excipient.

60. A method of degrading estrogen receptor protein in a patient or a biological sample, the method comprising administering to the patient a compound according to any one of claims 1-58, or contacting the biological sample with a compound according to any one of claims 1-58.

61. Use of a compound as claimed in any one of claims 1 to 58 in the manufacture of a medicament for degrading estrogen receptor protein in a patient or biological sample.

62. The compound of any one of claims 1-58, for use in degrading estrogen receptor protein in a patient or biological sample.

63. A method of treating a disease or condition comprising administering to a patient in need thereof a compound of any one of claims 1-58.

64. Use of a compound as described in any one of claims 1-58 in the manufacture of a medicament for treating a disease or condition.

65. A compound as described in any one of claims 1-58 for use in treating a disease or condition.

66. The method, use or compound for use of any one of claims 63-65, wherein the disease or condition is an estrogen receptor mediated disease or condition.

67. The method, use, or compound for use of any one of claims 63-65, wherein the disease or condition is breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or esophageal cancer.

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