Compounds and compositions as smarca2 / 4 degraders and uses thereof

Abstract

Described herein are compounds of Formula T-L-C and their pharmaceutically acceptable salts, solvates, or stereoisomers, as well as their uses (e.g., as SMARCA2 or SMARCA4 degraders), wherein T is of formula (I-1) and C is of formula (I-3').

Description

COMPOUNDS AND COMPOSITIONS AS SMARCA2 / 4 DEGRADERS AND USES THEREOF RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No.63 / 598,455, filed November 13, 2023, the contents of which are incorporated herein by reference in their entireties. BACKGROUND

[0002] One of the most significant findings from the cancer genome profiling is the discovery offrequent mutations in various subunits of the mammalian SWI / SNF (SWItch / Sucrose Non- Fermentable) chromatin remodeling complex. Approximately 20% of human cancers are associated with somatic mutations in subunits of the SWI / SNF complex, a chromatin remodeling complex that influences gene regulation by disrupting histone-DNA contacts ( PNAS February 25, 2014. Ill (8) 3128-3133 ).

[0003] SWI / SNF complexes contain either of two closely related and evolutionarily conservedcatalytic ATPase subunits: Brahma (BRM / SMARCA2) or Brahma-related gene 1 (BRG1 / SMARCA4). They share approximately 75% identity at the protein level. Although BRG1- and BRM-containing complexes show some redundancy, they may function distinctively. In human cancer, BRG1 seems to be one of the most frequently mutated subunit genes, whereas the BRM gene is rarely mutated. BRG1 / SMARCA4 mutations occurring in 10-15% of lung adenocarcinomas. BRM / SMARCA2, is essential for the growth of tumor cells that harbor loss of function mutations in BRG1 / SMARCA4. Depletion of BRM in BRG1-deficient cancer cells leads to a cell cycle arrest, induction of senescence, and increased levels of global H3K9me3l.

[0004] In some tumor types, mutations within the SWI / SNF complex lead to context specificvulnerabilities such as the requirement of SMARCA2 for survival of tumor cells lacking SMARCA4. This finding of SMARCA2 / 4 synthetic lethal relationship translates in vivo which emphasizes SMARCA2 as a promising therapeutic target for the treatment SMARCA4-deficient cancers. Moreover, the SMARCA4-deficient patient population generally lacks targetable oncogenes (such as mutant EGFR or ALK translocations), which further emphasizes the potentialof developing SMARCA2 inhibitors. Characterization of SMARCA4 function in tumors with high SMARCA4 levels, shows effects on signaling pathways that result in increased proliferation and survival. SMARCA4 knockdown in tumors that show elevated levels known to inhibit proliferation and other cancer cell properties. Studies have also shown that SMARCA4 knock down / modulation increases sensitivity to known chemotherapeutic agents, thereby indicating that SMARCA4 targeting could also be an adjuvant therapy to existing chemotherapeutic approaches.

[0005] Contrary to genetic silencing of SMARCA2 leading to potent anti-proliferative activity inSMARCA4-deficient cancer cell lines, PFI-3, a selective cell permeable SMARCA2 / 4 bromodomain inhibitor capable of binding to SMARCA2 and SMARCA4 bromodomain, pharmacological studies fail to display an antiproliferative phenotype indicating that bromodomain function of SMARCA2 / 4 is dispensable for tumor cell proliferation, while the catalytic ATPase activity is essential. Therefore, in order to mimic the phenotype achieved by genetic silencing, approaches that lead to reduction or complete elimination of SMARCA2 / 4 may be needed.

[0006] The ubiquitin-proteasome system (UPS) is a major pathway that regulates the levels ofintracellular proteins and provides a fine balance between protein synthesis and degradation required for normal maintenance of cellular function, including proliferation, differentiation, and cell death. Ubiquitination is a post-translational modification, where a small protein, ubiquitin, is covalently attached to lysine residues on a substrate protein carried out sequentially by a cascade of enzymatic reactions involving an intimate collaboration between El activating, E2 conjugating and E3 ligating enzymes and subsequent degradation of the tagged proteins.

[0007] Proteolysis targeting chimeras are the heterobifunctional molecules containing a ligand fora target protein of interest connected via a linker to a ligand for an E3 ubiquitin ligase. Upon such bi-functional molecule-mediated heterodimerization of the two bound proteins, the target protein is ubiquitinated and degraded by the proteasome in cells. Many such bi-functional molecules have been developed to recruit E3 ubiquitin ligases to a variety of substrates using high-affinity ligands for the protein of interest. Proteins effectively degraded using these approaches include RIPK2 and ERRa, BRD4, BRD9, BCR / Abl and Abl and Era. E3 ubiquitin ligases (of which over 600 are known in humans) confer substrate specificity for ubiquitination and are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates.SUMMARY

[0008] In certain aspects, the present disclosure provides compounds of Formula IT-L-C (I), and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: T is of Formula I-1 ,L is of Formula I-2C is of Formula I-3 , wherein each of the variables inembodied, and exemplified herein.

[0009] In certain aspects, the present disclosure provides pharmaceutical compositions comprisinga compound disclosed herein, and a pharmaceutically acceptable excipient.

[0010] In certain aspects, the present disclosure provides methods of degrading a SMARCA2and / or SMARCA4 protein in a subject, comprising administering to the subject a compound disclosed herein.

[0011] In certain aspects, the present disclosure provides uses of a compound disclosed herein inthe manufacture of a medicament for degrading a SMARCA2 and / or SMARCA4 protein in a subject.

[0012] In certain aspects, the present disclosure provides compounds disclosed herein for use indegrading a SMARCA2 and / or SMARCA4 protein in a subject.

[0013] In certain aspects, the present disclosure provides methods of reducing the amount of aSMARCA2 and / or SMARCA4 protein in a subject (e.g., in a biological sample (e.g., a cell or a tissue) obtained from the subject), comprising administering to the subject a compound disclosed herein.

[0014] In certain aspects, the present disclosure provides uses of a compound disclosed herein inthe manufacture of a medicament for reducing the amount of a SMARCA2 and / or SMARCA4 protein in a subject (e.g., in a biological sample (e.g., a cell or a tissue) obtained from the subject).

[0015] In certain aspects, the present disclosure provides compounds disclosed herein for use inreducing the amount of a SMARCA2 and / or SMARCA4 protein in a subject (e.g., in a biological sample (e.g., a cell or a tissue) obtained from the subject).

[0016] In certain aspects, the present disclosure provides methods of treating or preventing adisease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount).

[0017] In certain aspects, the present disclosure provides methods of treating a disease or disorderin a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount).

[0018] In certain aspects, the present disclosure provides uses of a compound disclosed herein inthe manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0019] In certain aspects, the present disclosure provides uses of a compound disclosed herein inthe manufacture of a medicament for treating a disease or disorder in a subject in need thereof.

[0020] In certain aspects, the present disclosure provides compounds disclosed herein for use intreating or preventing a disease or disorder in a subject in need thereof.

[0021] In certain aspects, the present disclosure provides compounds disclosed herein for use intreating a disease or disorder in a subject in need thereof.DETAILED DESCRIPTION

[0022] The present disclosure relates to compounds and compositions that are useful asSMARCA2 and / or SMARCA4 protein degraders. The present disclosure also relates to methods of degrading a SMARCA2 and / or SMARCA4 protein comprising contacting the SMARCA2 and / or SMARCA4 protein with a SMARCA2 and / or SMARCA4 protein degrader disclosed herein. The invention also relates to methods of treating a SMARCA2 and / or SMARCA4 protein- mediated disease or condition in a subject in need thereof by administering (e.g., in a therapeutically effective amount) a SMARCA2 and / or SMARCA4 protein degrader disclosed herein. The invention further relates to methods of treating a SMARCA2 and / or SMARCA4 protein-mediated disease or condition in a subject in need thereof, comprising administering (e.g., in a therapeutically effective amount) a pharmaceutical composition comprising an amount of a SMARCA2 and / or SMARCA4 protein degrader disclosed herein. Compounds of the Application

[0023] In certain aspects, the present disclosure provides compounds of Formula IT-L-C (I), and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: T is of Formula I-1 , wherein:A1is CRA1or N; A2is CRA2or N; A3is CRA3or N; A4is CRA4or N; RA1, RA2, RA3, and RA4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS -NRbC -NRbC -NRbC -OS - -each RCis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - - -heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; two RCtogether form an oxo; or two RC, together with the carbon atom to which they are attached, form Ring D ; Ring D is C3-12 carbocycle or 3- to 12-each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 10, as valency permits; E1is CRE1or N; E2is CRE2or N; E3is CRE3or N;E4is CRE4or N; one of RE2, RE3, or RE4is ; RE1, RE2, and RE4, RE1, RE3, and RE4,are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, - NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; * denotes attachment to L; Ring F is C3-12carbocyclyl or 3- to 12-membered heterocycle; each RFis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - - -- C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and f is an integer selected from 0 to 10, as valency permits, L is of Formula I-2 , wherein:* denotes attachment to T and ** denotes attachment to C; each L’ is independently C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C6-10 arylene, 5- to 10-membered heteroarylene, -C(=O)-, -C(=O)N(RL’)-, -C(=O)O-, -N(RL’)-, -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more Ru; each occurrence of RL’is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and l is an integer selected from 0 to 5, C is of Formula I-3 , wherein:H2is N or CRH2; H3is N or CRH3; H4is N or CRH4; H5is N or CRH5; RH2, RH3, RH4, and RH5are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru, wherein one of RH2, RH3, RH4, and RH5 is ;** denotes RJ1is 6 6 3- to 6-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; K1is N or CRK1; RK1is hydrogen, deuterium, or C1-6alkyl optionally substituted with one or more Ru; q is an integer from 0 to 2, each RKis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10aryl, 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 Ru; and k is an integer selected from 0 to 5, wherein: each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; ortwo Ru, together with the one or more intervening atoms, form C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; each Rais independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rbis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl; and each Rcand Rdis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz; and each Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

[0024] In certain embodiments, T is of Formula I-1, wherein:A1is CRA1or N; A2is CRA2or N; A3is CRA3or N; A4is CRA4or N; RA1, RA2, RA3, and RA4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RCis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - - - - - - - -heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; two RCtogether form an oxo; or two RC, together with the carbon atom to which they are attached, form Ring D ; Ring D is C3-12carbocycle or 3- to 12-each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 10, as valency permits; E1is CRE1or N; E2is CRE2or N; E3is CRE3or N; E4is CRE4or N; one of RE2, RE3, and RE4isRE2, RE3, and RE4, RE1, RE2, and RE4, o RE4are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, - NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; * denotes attachment to L; Ring F is C3-12 carbocyclyl or 3- to 12-membered heterocycle; each RFis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - - -- C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and f is an integer selected from 0 to 10, as valency permits.

[0025] In certain embodiments, T is of Formula I-1-i or I-1-ii.

[0026] In certain embodiments, T is of Formula I-1-i-1, I-1-i-2, I-1-i-3, I-1-ii-1, I-1-ii-2, or I-1-ii-3 , 3).or I-1-ii-6, , 6),

[0028] In certain embodiments, A1 is CRA1 or N. In certain embodiments, A1 is N. In certainembodiments, A1is CRA1.

[0029] In certain embodiments, A2 is CRA2 or N. In certain embodiments, A2 is N. In certainembodiments, A2is CRA2.

[0030] In certain embodiments, A3 is CRA3 or N. In certain embodiments, A3 is N. In certainembodiments, A3is CRA3.

[0031] In certain embodiments, A4 is CRA4 or N. In certain embodiments, A4 is N. In certainembodiments, A4is CRA4.

[0032] In certain embodiments, none of A1, A2, A3, and A4 is N. In certain embodiments, one ofA1, A2, A3, and A4is N. In certain embodiments, two of A1, A2, A3, and A4are N. In certainembodiments, three of A1, A2, A3, and A4are N. In certain embodiments, each of A1, A2, A3, and A4is N.

[0033] In certain embodiments, RA1, RA2, RA3, and RA4 are independently hydrogen, halogen (e.g.,-F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (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)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i- butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, orpentylhexylamino), C2-6alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (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), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0034] In certain embodiments, RA1, RA2, RA3, and RA4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0035] In certain embodiments, RA1, RA2, RA3, and RA4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0036] In certain embodiments, RA1, RA2, RA3, and RA4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru.

[0037] In certain embodiments, RA1, RA2, RA3, and RA4 are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru.

[0038] In certain embodiments, RA1 is hydrogen. In certain embodiments, RA1 is halogen. Incertain embodiments, RA2is hydrogen. In certain embodiments, RA3is hydrogen. In certain embodiments, RA4is hydrogen.

[0039] In certain embodiments, each RC is independently hydrogen, 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)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t- butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, orpentylhexylamino), 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)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 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), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, - OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0040] In certain embodiments, each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0041] In certain embodiments, each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0042] In certain embodiments, each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru.

[0043] In certain embodiments, each RC is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru.

[0044] In certain embodiments, each RC is independently C1-6 alkyl optionally substituted with oneor more Ru. In certain embodiments, at least one RCis C1-6 alkyl optionally substituted with one or more Ru.

[0045] In certain embodiments, two RC together form an oxo.

[0046] In certain embodiments, two RC, together with the carbon atom to which they are attached,form Ring D .

[0047] In certain embodiments, Ring(e.g., cyclopropyl (C3), cyclopropenyl(C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) or3- to 12-membered heterocycle (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S).

[0048] In certain embodiments, Ring D is cyclopentane ring, cyclohexane ring, or tetrahydropyranring.

[0049] In certain embodiments, each RD is independently oxo, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (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)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t- butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i- propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, 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)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 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), -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein thealkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0050] In certain embodiments, each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2,C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0051] In certain embodiments, each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2,C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0052] In certain embodiments, each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2,C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru.

[0053] In certain embodiments, each RD is independently oxo, halogen, -CN, -NO2, -OH, -NH2,C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru.

[0054] In certain embodiments, d is 0. In certain embodiments, d is 1. In certain embodiments, dis 2. In certain embodiments, d is 3. In certain embodiments, d is 4. In certain embodiments, d is 5. In certain embodiments, d is 6. In certain embodiments, d is 7. In certain embodiments, d is 8. In certain embodiments, d is 9. In certain embodiments, d is 10.

[0055] In certain embodiments, E1 is CRE1 or N. In certain embodiments, E1 is N. In certainembodiments, E1is CRE1.

[0056] In certain embodiments, E2 is CRE2 or N. In certain embodiments, E2 is N. In certainembodiments, E2is CRE2.

[0057] In certain embodiments, E3 is CRE3 or N. In certain embodiments, E3 is N. In certainembodiments, E3is CRE3.

[0058] In certain embodiments, E4 is CRE4 or N. In certain embodiments, E4 is N. In certainembodiments, E4is CRE4.

[0059] In certain embodiments, none of E1, E2, E3, and E4 is N. In certain embodiments, one of E1,E2, E3, and E4is N. In certain embodiments, two of E1, E2, E3, and E4are N. In certain embodiments, three of E1, E2, E3, and E4are N. In certain embodiments, each of E1, E2, E3, and E4is N.

[0060] In certain embodiments, RE1, RE2, RE3, and RE4 are independently hydrogen, 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)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i- butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, orpentylhexylamino), C2-6alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (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), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, - OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0061] In certain embodiments, RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, -CN,-NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0062] In certain embodiments, RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, -CN,-NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0063] In certain embodiments, RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, -CN,-NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru.

[0064] In certain embodiments, RE1, RE2, RE3, and RE4 are independently hydrogen, halogen, -CN,-NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru.

[0065] In certain embodiments, RE1 is hydrogen. In certain embodiments, RE2 is hydrogen. Incertain embodiments, RE3is hydrogen. In certain embodiments, RE4is hydrogen.

[0066] In certain embodiments, one of RE2, RE3, or RE4 is.

[0067] In certain embodiments, Ring F yclyl (e.g., cyclopropyl (C3), cyclopropenyl(C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) or 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S).

[0068] In certain embodiments, Ring F is piperidinyl, 2,7-diazaspiro[3.5]nonanyl, or 3,9-diazaspiro[5.5]undecanyl.

[0069] In certain embodiments, each RF is independently oxo, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (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)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), n-propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t- butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i- propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, 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)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl(e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (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), -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0070] In certain embodiments, each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2,C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0071] In certain embodiments, each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2,C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6- membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0072] In certain embodiments, each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2,C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru.

[0073] In certain embodiments, each RF is independently oxo, halogen, -CN, -NO2, -OH, -NH2,C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl,wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru.

[0074] In certain embodiments, f is 0. In certain embodiments, f is 1. In certain embodiments, f is2. In certain embodiments, f is 3. In certain embodiments, f is 4. In certain embodiments, f is 5. In certain embodiments, f is 6. In certain embodiments, f is 7. In certain embodiments, f is 8. In certain embodiments, f is 9. In certain embodiments, f is 10.

[0075] In certain embodiments, L is of Formula I-2, wherein:* denotes attachment to T, and ** to C; each L’ is independently C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C6-10arylene, 5- to 10-membered heteroarylene, -C(=O)-, -C(=O)N(RL’)-, -C(=O)O-, -N(RL’)-, -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more Ru; each occurrence of RL’is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and l is an integer selected from 0 to 5.

[0076] In certain embodiments, L is of Formula I-2-ii).

[0077] In certain embodiments,(e.g., heterocyclylenecomprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S) optionally substituted with one or more Ru.

[0078] In certain embodiments, L’’ is 6- to 12-membered spiro heterocyclylene (e.g., spiroheterocyclylene comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S) optionally substituted with one or more Ru.

[0079] In certain embodiments, each L’ is independently C1-6 alkylene (e.g., methylene (-CH2-),ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (- CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-)), C1-6 heteroalkylene (e.g., C1-6heteroalkylene comprising 1-7 heteroatoms selected from N, O, and S), C2-6alkenylene (e.g., ethenylene (C2), 1-propenylene (C3), 2-propenylene (C3), 1-butenylene (C4), 2-butenylene (C4), butadienylene (C4), pentenylene (C5), pentadienylene (C5), or hexenylene (C6)), C2-6 alkynylene (e.g., ethynylene (C2), 1-propynylene (C3), 2-propynylene (C3), 1-butynylene (C4), 2-butynylene (C4), pentynylene (C5), or hexynylene (C6)), C3-12 carbocyclylene (e.g., cyclopropylene (C3), cyclopropenylene (C3), cyclobutylene (C4), cyclobutenylene (C4), cyclopentylene (C5), cyclopentenylene (C5), cyclohexylene (C6), cyclohexenylene (C6), cyclohexadienylene (C6), cycloheptylene (C7), cycloheptenylene (C7), cycloheptadienylene (C7), cycloheptatrienylene (C7), cyclooctylene (C8), cyclooctenylene (C8), bicyclo[2.2.1]heptanylene (C7), bicyclo[2.2.2]octanylene (C8), cyclononylene (C9), cyclononenylene (C9), cyclodecylene (C10), cyclodecenylene (C10), octahydro-1H-indenylene (C9), decahydronaphthalenylene (C10), or spiro[4.5]decanylene (C10)), 3- to 12-membered heterocyclylene (e.g., heterocyclylene comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 arylene (e.g., phenylene or naphthylene), 5- to 10-membered heteroarylene (e.g., heteroarylene comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -C(=O)-, - N(RL2)-, -O-, -S-, or -S(=O)2-, wherein the alkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more Ru.

[0080] In certain embodiments, each L’ is independently C1-6 alkylene, C1-6 heteroalkylene, C3-12carbocyclylene, 3- to 12-membered heterocyclylene, -C(=O)-, -C(=O)N(RL’)-, -C(=O)O-, -N(RL’)- , or -O-, wherein the alkylene, heteroalkylene, carbocyclylene, or heterocyclylene is optionally substituted with one or more Ru.

[0081] In certain embodiments, each L’ is independently C1-6 alkylene, C3-12 carbocyclylene, 3- to12-membered heterocyclylene, O, or -C(=O)-.

[0082] In certain embodiments, each occurrence of RL’ is independently hydrogen, 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)), 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)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4),pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 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), -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0083] In certain embodiments, each occurrence of RL’ is independently hydrogen, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, C6aryl, 5- to 6- membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0084] In certain embodiments, each occurrence of RL’ is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0085] In certain embodiments, each occurrence of RL’ is independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0086] In certain embodiments, each occurrence of RL’ is hydrogen.

[0087] In certain embodiments, l is 0. In certain embodiments, l is 1. In certain embodiments, l is2. In certain embodiments, l is 3. In certain embodiments, l is 4. In certain embodiments, l is 5. In certain embodiments, l is an integer selected from 1 to 4.

[0088] In certain embodiments, L is *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(3- to 12-membered heterocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C1-6alkylene)-(3- to 12-membered heterocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *- (C1-6 alkylene)-(3- to 12-membered heterocyclylene)-C(=O)-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(C3-12 carbocyclylene)-O-(3- to 12-membered heterocyclylene)-, *-(C1-6alkylene)-(3- to 12-membered heterocyclylene)-O-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-(3- to 12-membered heterocyclylene)-, *-(3- to 12-membered heterocyclylene)-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C1-6alkylene)-(3- to 12-membered heterocyclylene)-(C1-6alkylene)-(3- to 12-membered heterocyclylene)-, wherein each alkylene, carbocyclylene, or heterocyclylene is independently optionally substituted with one or more Ru, and *denotes attachment to T.

[0089] In certain embodiments, C is of Formula I-3, wherein:H2is N or CRH2; H3is N or CRH3; H4is N or CRH4; H5is N or CRH5; RH2, RH3, RH4, and RH5are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru, wherein one of RH2, RH3, RH4, and RH5 is ;** denotes JR1is 3- to 6-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; K1is N or CRK1; RK1is hydrogen, deuterium, or C1-6alkyl optionally substituted with one or more Ru; q is an integer from 0 to 2, each RKis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 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 Ru; and k is an integer selected from 0 to 5.

[0090] In certain embodiments, H2 is N or CRH2. In certain embodiments, H2 is N. In certainembodiments, H2is CRH2.

[0091] In certain embodiments, H3 is N or CRH3. In certain embodiments, H3 is N. In certainembodiments, H3is CRH3.

[0092] In certain embodiments, H4 is N or CRH4. In certain embodiments, H2 is N. In certainembodiments, H4is CRH4.

[0093] In certain embodiments, H5 is N or CRH5. In certain embodiments, H2 is N. In certainembodiments, H5is CRH5.

[0094] In certain embodiments, one of H2, H3, H4, and H5 is N. In certain embodiments, two ofH2, H3, H4, and H5are N.

[0095] In certain embodiments, RH2, RH3, RH4, and RH5 are independently , hydrogen, halogen(e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (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)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g.,dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i- butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, orpentylhexylamino), C2-6alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (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), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, - OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0096] In certain embodiments, RH2, RH3, RH4, and RH5 are independently , hydrogen,halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 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 Ru.

[0097] In certain embodiments, RH2, RH3, RH4, and RH5 are independently , hydrogen,halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, 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 Ru.

[0098] In certain embodiments, RH2, RH3, RH4, and RH5 are independently , hydrogen,halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0099] In certain embodiments, RH2, RH3, RH4, and RH5 are independently , hydrogen,halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0100] In certain embodiments, RH3 is .

[0101] In certainI-3-ii).

[0102] In certainhydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0103] In certain embodiments, RH2, RH4, and RH5 are independently hydrogen or halogen.

[0104] In certain embodiments, RJ1 is hydrogen, 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)), C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0105] In certain embodiments, RJ1 is C1-6 alkyl or C3-6 carbocyclyl.

[0106] In certain embodiments, K1 is N. In certain embodiments, K1 is CRK1.

[0107] In certain embodiments, RK1 is hydrogen, deuterium, or 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)) optionally substituted with one or more Ru.

[0108] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, qis 2.

[0109] In certain embodiments, each RK is independently halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (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)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n- propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i- propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, 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)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3),2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 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, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0110] In certain embodiments, each RK is independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 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 Ru.

[0111] In certain embodiments, each RK is independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0112] In certain embodiments, each RK is independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl, is optionally substituted with one or more Ru.

[0113] In certain embodiments, k is 0. In certain embodiments, k is 1. In certain embodiments, kis 2. In certain embodiments, k is 3. In certain embodiments, k is 4. In certain embodiments, k is 5.

[0114] In certain embodiments, each Ra is independently 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)), C2-6alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), or 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 optionally substituted with one or more Ru.

[0115] In certain embodiments, each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl.

[0116] In certain embodiments, each Ra is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl.

[0117] In certain embodiments, each Ra is independently C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0118] In certain embodiments, each Rb is independently hydrogen, 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)), 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), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 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 optionally substituted with one or more Ru.

[0119] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl.

[0120] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

[0121] In certain embodiments, each Rb is independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or3- to 6-membered heterocyclyl, or C2-6alkynyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0122] In certain embodiments, each Rc and each Rd is independently hydrogen, 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)), 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), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 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 optionally substituted with one or more Ru.

[0123] In certain embodiments, each Rc and each Rd is independently hydrogen, C1-6 alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclylis optionally substituted with one or more Ru.

[0124] In certain embodiments, Rc and Rd, together with the nitrogen atom to which they areattached, form 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8- membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocyclyl is optionally substituted with one or more Ru.

[0125] In certain embodiments, Ra, Rb, Rc, and Rd is independently and optionally substituted withone or more Rz.

[0126] In certain embodiments, Rz is independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

[0127] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2,C1-6alkyl (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)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di- i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n- butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t- butylamino, propylpentylylamino, 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)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), orspiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 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), -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, and 3- to 6-membered heterocyclyl.

[0128] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2,C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 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 oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, and 3- to 6-membered heterocyclyl.

[0129] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2,C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6- membered heterocyclyl, C6aryl, 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 oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, and 3- to 6-membered heterocyclyl.

[0130] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2,C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, - CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, and 3- to 6-membered heterocyclyl.

[0131] In certain embodiments, each Ru is independently oxo, halogen, -CN, -NO2, -OH, -NH2,C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

[0132] In certain embodiments, two Ru, together with the carbon atom(s) to which they areattached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6- membered ring and 1-3 heteroatoms selected from N, O, and S), C6aryl (i.e., phenyl), or 5- to 6- membered heteroaryl (e.g., heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz.

[0133] In certain embodiments, two Ru, together with the carbon atom(s) to which they areattached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S) , wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Rz.

[0134] In certain embodiments, two geminal Ru, together with the carbon atom to which they areattached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S) , wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Rz.

[0135] Embodiments of the variables in any of the Formulae described herein, e.g., Formulae I-1,I-2, and I-3, as applicable, are described below. Any of the variables can be any moiety asdescribed in the embodiments below. In addition, the combination of any moieties described for any of the variables, as applicable, with any moieties described for any of the remaining variables, are also contemplated.

[0136] Without wishing to be limited by this statement, while various options for variables aredescribed herein, it is understood that the present disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.

[0137] When a range of values is listed, each discrete value and sub-range within the range arealso contemplated. For example, “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0138] In certain embodiments, the compound is selected from the compounds in Tables 1 and 2,or a pharmaceutically acceptable salt thereof.T CaobA A NmlAe3 2 1 op .1o.und S tructure PR SC -097 / 001W O 3 431 3y 3 17 y- l -( 0ml)m1, (6)m1 6-(yl)1 -(6 -23e 7-(th e '-yt i7e ,77mm,7-(-th '-i -( e e '-i713 -3lh n-1yl d ( y) o (4 il)n- l -( nd -2d (o 4 tl -(h t4ylh-y nd (01l) o (42 7- l -(5H2o[4'a - o['-m H 2o[4' / 5-i-naz1a,2 -cz-ho al za 1, -2 a1-e -inza ,2 -c98- h1dsp a lo-3 spath 2 ds a loC1az ]o qr -ly ir]qo ,4 az p ]qrh -i3rouo[in-5 l) op [3uixny(-1H oli- 3-rouion-5 emy .l 5az'-oi)x pe.5]az5'-o,33[H- 3.5az'-oxicp ]noip o lio rn-5 idno onlixoy)- l) ]odno lio-a5l ne nr aidn]-1'H ine ann-]-- 15'Hdioih n nan]-1'Hami-2-0' --sp -2,206-y'- -nysd -pero 2-0' --spene- y2 ly)l i)pro,6 -5 ip[ -c dli )o -y1l)piro py yly)l i)pro[-d -f e n - ip[rim-5 ipci l rycl e mercy-f eryco u id oeneoro in hethid ci lidlu id lon ohinor in he-1 -1 xy- -aln-1 -1eee -x- o -a-1 1 x-a-Hn-ne-e- -C o A A A A Nm76 5 4 op .ound S tructure PR SC -097 / 001W O 3 43y1 y1 y37in ld)am1 -, ( l) sppil)zoe 7 6-1-ip ro 3m1 -, ( y 3-( 0-276- ml)m1, 6- 31l-th '3y -(in7 m-eter [i cy -( e5 th '-(in7-e 7t 'h et -(in23 -30- ly )-l2d (o (l 4hd- yin cl-fyl- oh luin)-2d (o (4ylh-yl d (o (42 75)d -a o[ (4'l-i- 1H 1-y e o dx roa - la o -[ (41')- H-7-lo -[ (4'- / 5h zy a 1s,2 cd- h ll-i)man -6 z-ol za 1s,2 c- hl-inaz1a,2 c98- hl1 1rpaoipryo]q onr[ o d ea et -1(2-3 pa--y ir]q ordo az sp a] oC 3ui on- zoh ,7 ( iqroh a5'l-yl '- ( li 4 ) opi[3uin-5'l-3rou[in-5 e'mrim.5]i nzo-ox 3-)y -7-n -d(4 p.'edolo r5]anzo-ox- 3y .5azo-oxicainneain-5'l)apzoalo-m ied oin nalion-5l)p ]n loio in-5 l n-n]2 -, 2-1Hi4 -- psp[1,te n]-'Hp n ]-'Hamse i2ho-2 -21 -ser an1 -( y01 l'-ypri i ro-ax-0'pid-70'speH )-1l)pr d []qy ,6yl-y ir in-y-y iio i[ n 3c e- .5 u- ]in5'--di )o -1l)pio[e-2 l)-l)prio[,3-H mpe) eryc 2l-o ,6 n a ox n -mp- on zo o e ecryc ,l 65- pcyo-d fl er clod tihidoyin he dx ioanln l--i -n 5et]'Hhidyin he ix o u idnor in hexe1 -H 1-anne7- -1-l-1 -1ae o--1a-e y- l)-0'- H -n1 -n-e--e-C A AoNm11A A 9op 1 08.ound S tructure PR SC -097 / 001W O 3 431 3y y7 a-mzas( l6)m3-(me 1 - y 3 l, ( l) )76- m1 -, (m3-( 0-276-e 1,7 6- 31ep 4e th '-(yi7eth '-(7thy '-(93th ilr 1 -( th y n -( 1 y in -( l in -( 30-o[,7 (1 3'- 7y -l-l1)- d (2 o 1H-- l) d- o (1 )- ind-3-do (42 -75H.5i- ] nd (4'i- H,7-lo[ (4i1'-n 2 ld ,7n nd o-o[ (4 1'-azazlo[ (4'- / 59 nolochal-india ,2 c- hlazz aodi ,a 2 c- hloal-sp1,2 c 8- hl1 1o n[1, od2ro azz a a] oo s qr lz ao-3as ]q or3 io -y roa]q or C o hl--32-- ya]-5'l p- u3irin-5 -' ylp uiin-5 l' ) [pi5.u5in-5 e'm-yll) q)mu- ioxoapo-y [3zo-ox)p ri oap[3zo-ox per]u an zo-oxicai enp taz -5l)p .5 loi]nin-5 eri.5]e hnlion-5 id di eclion-5 l nr yi lo 'Hpo]-'H dd )p lin -i o]'H ne a]'Hamseprindan10' -snp e n- -a1n0' -sp -2 n-- 13 0' -speinei-p ]- i in-2-y i2, --y i ,6 - -y i2e,r 16id0'r-o[e-2-y l)prio[6- 2d- l)prio[ -diyol)-l)pro[- id n yl)cyc ,i - l 6-l)-pc5eryc il oynl)- pecryc n 1 ipcle-meryco 1 -2 on -y - h di-id o 1h e - id oeid loe l) e onflu in e min heth in he- x1-ae onre o -4 xaeth-4 xayl-1 xa --1 -ny -n -1 -n-e- l- e- H e- -C A A A AoNm11 1 1 op 6 4 3 2.ound S tructure PR SC -097 / 001W O 3 431 ssy b 37 0l)ypml) ip r inpod c ir ip 1-( yl)1 -(6 -23ei [ a ar o[mip 6e 1-( m,7-(413i t p cn h er yczol3dy -lb- li3onyy cl ycel1 th rid ,74-e' -( t '-h ind -( 3(02 )di on he(6- -y l))p op ip h-(6 y-l-i1neind4- y( l) o 4 7p lo -(5az po il p-1- e- x (a4l- )d ip eerix (a4 H]- o 4'-1' lo-chy ip [4 e1, '- / 5c983 riyl)ne ((1 ih ey ri dd in n -e (4 i- 2 n -d ca [1lol)p ri2d-a hl1 o C1-y dl i) nm-1 -, (( dp 4roin-1--1, (( ,4 4(1azorb ,2o - raoii-pen ]- qurohi-1-eth 7'-i-( p- 4y1-yl)7'- -(4H l- n ]3 y qu5'-rid1-y in-5 e'mpe yr li )yld -5) n-6do'- rnlc ih myl) mii-n5e d '-t o c ,3H-yl)p in olh lip azx io ne l) a- - zo-oxic21lo-ali - -aolod-fh o lo)e f- )de o-5 -min5 n- lu za[1,2roineluoyl) [1r,2 o-dioihryidli'nH ,6-de ]-1'Ham2 o,r so p -a-5 -'2, rp4o-ipe -a 5'-nd inoero -]- -s 1p iotnhy 0' --spe6-d-i 1ir]on-mo[q2u-o.xo (1 1-mri ]d qu xo p 1y -y0 i'- re l-yo[1Hyl i)proeet5 in - H ih] a n in -5 ri l)z 5',3 ete az 'H m-5 l)-cy i[ c-inp[ecycyo o H Hl-1ctlin-h)-y -l 1 o- - li-indin-fl1 lu,4 odri'heazd loi heHan- ]-dio 1H]- e-oro - x ol n- -1 x-6-10n'-1 -an 3 -a-e 0'- 1-e- -ne-C A A A AoNm22 1 1 op 2 1 8 7.ound S tructure PR SC -097 / 001W O 3 43flu 3 y y f1 3 7o yrol)m1 -, (6y-l l) ) sp ppli ir y )l)p spluipir o y -rol)m1, ( 06- -23-17'-(3ippehro[cmero[-17'(313-met in -er idyceidcyc3-et -in - 30e yth l d (() ol 4i-diin n- lo3h- t( h i6 inydyl n-loh-(mh6 e yl d (() ol 42 -75l-1- -o (1 o[1 4'--11-yex -(4a )z p 1i-y e -(tlx 4hyl-1-o[ (4 / 1'- 598H x ,a 2 b-a royl -) yll))man - o p)a -e (6 l- ermne ((- 61 oH x ,a 2 c-a hl1 1 --9 ] mpi -5 e -1 -( 3- id e -1 - --9 ] oCin -quo p - th , (4 y in th , (( in -qurohda aza in -5e' rf idluoyl 7) '-i -( l4 )pi-1-yl 7 4) '-i-(4da aza in-5 e'mzosl-p az3 io-ox ine ro--3 n- d 'p yo-cer l)- -3- ndo'-czoslp azo-oxoica- ry o lol [ in-5 -2, 1a6-mza lo hlo ir di 5a) 5 ]n -fza lohlo-3 i- ro l[ in-5 l np .5 -1'H--de bic[1,2 o-5 e- lub oic[y1,2roy 5 ]- l)p .5 -1'Ha-mipe]ur n0'-siyp iionthyyl c -l a] '- 2o,6ro- cl -o a]5'-ipe]un0'-s ypeid di en cl)prioe[-1 oH [ q3 u xi- no-di 1 [ qo-m3. uoinxo rid decl)prio[e a- n p2 -, 9 ecrycl-i.1n.0 a 5zo 'H nee1th.1 a -z 5 in ao 'H e- n p-9 ecrycl6--idyd ohda ]hlli)n i-yl]hli-2,i- ex zo ex n] -1epn] 6--iyd ohlin exo-5 1n -al-3a-1 Htan -1 d) i-5 -1-ae -ne--n-3-0'---30 o-ne- '-ne -C A A A AoNm22 2 2p 6 5 4 3o.ound S tructure PR SC -097 / 001W O 3 43y 1 l3 s s71)m-me 1 -( azpai aza pia szp0ai -23t,7 6'-(3 spro[spro[spro[13ethhy -y l i) nd -( i( r co y[ycllo3 ir- o cy 3 ir cy 3 3([5ycl 0o-( o[ycl- 2- -11 -oH oxl 4o - i[ (4nd 5.' 5l)phe6-( .5l)phe6-(ind 5.5l)oph(e6-(75 / - -a ] ix (R]u ix (Ra ] ix (R 5ia1,n-d82 chzo un pe a y n pe a zo un pe a 981a --a lol-3 de rid n )ie -3 l)p decrid n )ie -3 l-3 de rid n )ie -3C1zoaz]l a quro -yc- sp in-5 lan n--1, -7 (( ipean n--1, -7 (( -ycan n--1, -7 ((h ')pi -91-y'- 4i -(4rid-91-y'- 4-(l4)pi -91-y'- 4- e(4 m3-yiral ozo-ox pe-yl)mnd'-bine-yll)imnd'- pb e-yl)imnd'-cica) [p 4 lioi . n- r5 idli)-5e oloro -p 5m 2)-, 1-e oloro ridli)-5e olohl lo ne ] ]-r d 1'H ne -fltuhy [1,6 mt2o-dhy [1m,n -2oe fltuhy [1,2 roamid ec 0' -i -sp -2,o lr )-1 -a-5'ioen an nth l)-1 -a-5- '2l, or )-1 -a-5' ee- -yl i 62 8)prio[ -d o-1 -o ]x qu-ox eyl-1 -o ]x qu-ox6-d o-1 -o ]qu-ox, -6 y p- l ecyioc n-ma- i9 n oa -5 H-a- i9 n o ia -5 on-mxa- i9 n oa -5d )- r l eet -zo 'Hin-zo 'H eet -z 'Hio 5 in - d of i h hylin-dali-h oyli-e lu n- eo1 xl-1 ]-zo nl ]-l-n1 ]-r -aone H 1- --0-'- 3 1-0H 1'--0'-C A A A AoNm32 2 2p 0 9 8 7o.ound S tructure PR SC -097 / 001W O 3 431 y y17-y l) sp1 y- l) spyl)l p)- ip ir ylm3- l)m3- 0-2)pi ir 1-1, (6-e 1, (6- 35-ferol iu d[c- y1p-meroid[cmet 7y ethy '-(i3t- h 7y '-(i313 -3o in cro - l4 o3h-(6 ein c- lo3-(hl nd (( 16 y )-1o 4Hl) nd ((02 --1o 4 75-1 -ex -(4thy4 hl-ex -(4l-1 -H oxlo[ (4 -'-in--y doxlo -[ (4'- / 5ml)man -(- (1yHl)man -(( -ia-18,2 b- roazao-81,2 b98- ro1 1e e e- 1- - e e- 1- nd -ah] ml- -aa] mCt tylh 1, (( in th 1, (( a azquo 3 za qoh-yl 7 1) '-i-(4da y 7 1z l) '-i-(zo a4 l- sp in -5-' yls up in -5e'm1Hpi-pndi o'-cop ln-ipdo'-c 3-yiraozo-o )x p iraz-o ioip ooxocanerdiadloh[lo3- ey ridloh[lol) [p 4. lin-5 e' ri[d4. l5 in-5 l' nz io n 1,2ro l)l -- -piin 1,2roi-- p 5e ] ]d -1H0-i] ]-Hamsnede 10 -s- 43 -- ya]5q'-p-oer4-ya]5q'- ro id ec 'i an-ypi - r2,can'-ypeiyll))pouinxo i- dil)ouinxo-ne- -l28-)pio[6 -c-d 8-l)prio[cixpy) a 5e p zo 'Hne-xa 52y)p zo 'H ,6 y p- l) eryic il o yn l p)- eryclri id p li e in-,6 i]-n rdp le in-d -5 d o] io i h e 1- id ohn -fl n- ex min- exe id -1i- inorid -1 e uo1-an et1-an-0'- ne in-0'-ro- e-hyl e- -C A A AoNm33p 3 231o.ound S tructure PR SC -097 / 001W O 3 43y 1 l)1m3-me 1 - 37 -3- 0-t , (7 6-(myl)1m, (76-(7myl)1m, (7 62-( 313ethhy '-i7-et '-i - et '-i73y l) nl- -5d ( h1 -o (4yelth nd ( ho (4yelth nd -(0o(42 7H oxlo -[ (4-1yHl) l -- o[ (4-1y' Hl) l -5-o[ (4 / 5-ian-1'-c 5d2 ,2-a hl-in-o1,2 -b 5r-in-o1, '2 -ch981a -z a]q ooza ur do ax -a oz a- ]q mdax -a lz a- ]q or C1hl- s3 p in-5ol 2- uo- o3-ain 5 l 2- uo3-ain-5 em-yiraoz'o-ox- zyas a'pzo-o zx -yas az'o-oxicl) [p 3. lion-5l)pi iro lio n-5l)ppiro lion -a5l nip 5 ]e ]nrio-1'Hp [ ]- -'Hip [ ]'Hamser 3. 1 - er 3. -1 -dnina0'-ypii d 5 0in ]no'-s ypii d 5 0i ]no'-s ypeien- -2 2l)prio[e,c-2 nal)prio n[e-2 nal)prio[c6--ypdli)eryc ,l 6 n-d - pc2eryc ,l 6 n-d - p2 eryclo-5 in - d of in he io- nyild o)in he io-id onyl)in hee lu -1 x e -1 -1 x e -1 -1 xo -an- -a- -aro enene- - - -C A A A AoNm33 3 3p 7 6 5 4o.ound S tructure PR SC -097 / 001W O 3 43yy y17y ll)) smppli 3)m3-( azp iro - e 1, 6- aspl)m3sir -o 1-e 1, ( 06- -231e ethriyd[ (c 6y-th 7c(4'1 y -(3 plin - ir [o cmtych 7'3 ety -(in73 -30li)np- loh-((H)i1 (- -1-d (o (4[ -5.5yl)loh-(hl6 y )-5d (o (42 -75p -e yex 1Rindoxlo (4rl a[1'-]u pipe -x ((l- R1 -H oxlo[ (1 4'- / 598i)dman ,ine e 5-Saz, o- l8 ,2 c-a hly n e aol) de ri ne )- -ian-2 ,2 b-a ro1 11- -a]picadin- 3- d -a] mC-t-h 1, 6s 3 za quro pn -1, (( a zquohyyl 7))'-i-6-ylsp in- a5 e' rid-9 1-y7'- 4 zo ai-(4 l- sp in -5e'ml)--13 n --- d ( )( pi ip rozo-oxoine-yllmaz o ))mnd'- 3c -yiraozo-ox icaa l 4o -(e[4ri4. l5 in-5 -2 -, 1o6-et lohlol) [p 3. lio n-5 l ne b [tic1,2 '-c dh in]d ]e -1'H-- mdh [e y 1rl ,2 oi 5 ]- pe ]no-1'Ha-mhyyl- c -l a] lo er -2ca0s n'-yp iionth )y -1 -- a]5'- ridna0'-s ype1H o[ q-3 u o ,i 6 -l ri. n--d 8-)pio[e l-1 o qH xa uioxoinen- -2l)pirio[n1d.0 a5zao'-oio y pn l)- ecryc -l-in9 na -5 2- z 'H ,6-ypcleryclzo]hl e l- x ixno e 1 id ohdol--d)-5 id oh] -5 -min exazin] io -f in ex3-an-- 1 'He3t-1 o-al- -1 ne lu -1-a-0'--hynle 30 o ne- - - '-ro- -C A A A AoNm44 3 3p 1 0 9 8o.ound S tructure PR SC -097 / 001W O 3 43flu 3 f1 l3 y7o a -roza-1 s( up6-o a - 3(4roza(6 --a -mza(6-y l) sl)ppi3 0-21 sp (4esp (4 mp irero -(31 oi[c 6-(3-mir 1 --mir 1 -( th ir 1 -( etdyc 430e[th3,7 ('- (7 o- e[3,7'- (7yo-l-[,7 (y.5i1 3'- 7 h- in yiln- loh-(2 ((75l-1] nn d (4'-thy.5il] nd (4.'-H5i] nd (4d'-a )1zpi -yex 1R / 59Honoloch -l 1nHonolobro-in n obo pldonlorol- er)man ,81 e5S1-an[1, o-an[1maan[1m3- id e - ,Cin -2ro in -,2ozo-,2o y in th 1, 6shd 2a -- ya]- q5' d 2a -- ya -] 5 l2-a -5lq'-3-y]q' )pi-1-yl 7))'-i-6emzoll)-mu-3inoxzl)oolmui- nox -yl)mui-oxpe yr l)--3 n -- do (( i4 ca- ey tl haz -5-)'3- ethao z-5l)'pi enthao z-5 id 5a'in -fza lo -l[(4np ylo Hy) li -sl)p ylo Hp) li - er ylo H)li -e- lub2o ic1y ,2 '-cahmipepri nip ]-p ide 1 ipepi np ]s -pid p nsp r1i in ip ]-1 i ,6o- c -l a lo ]q oerinrid0'r-o[re i yciderid0'r-o[e-2erid0'r-o -[ di 1o-m[3 u oin-5- n2 - l)-yc in i yl e n- l)c-yc ,l 6- in y- l)c-yc nl ee.t1.0 az'-o, 16 - 2 oh -2 1- 2 oh di 1- 2 ohhy ]olxo- y - ,d l e 6- y - e on y - e l-1hex in -5i)o- xn5ad l)- x5ae l)- x ]1aHa-1 'He -ne-ione -ne- -ne- -n-3-0'--C A A A AoNm44 4 4 op 5 4 3 2.ound S tructure PR SC -097 / 001W O 3 43yl) y y y y y17- l5 ) s- ppfli i lr )upe o - l) spl) s- l)psyp0-2[3 5 p- -fli ip re o[ 3 5 p- -fli ip re o[ 3 l-)my il r) o[ 33- 1 ( 3o rr aco zyc(6uor cy (6uor cy (6 e pi cy 6 30- i1 n lo -( ridh4 o- i cn l -o ( ridcl -(th4 o- in oh 4in hy pecrl -o (42 75- -m1-ex-((( 1- -m1-y ex-((( 1 -11-m- ex-((d(a l)p idhiex-(((1 / 59e ytlh)yman1er,4 etl)mane ry,4 etl)man1er z, o ip4 l- e n- r1-aR 81 yne , 11e -1 r hy e -1 r) hy e -1 r 3- idl- 5SCl-Hthy ,7 )-l-th , -4l-t , )- y in)-1, )- h l' 4-i -(1(dHy 7l '-i -(1h( dHy 7l ' 4-i -( l) -( pi 1 3-7y-a'-i8e-m-i )n cd y nd 4-( ion-i )n cy nd4-(ion-i )n cy nd 4-p(er l) za c o- abnd (4-(icaz lo lo 4'- ecda cz l oo lo4'- ebda cz l oo lo 4'- ic di 5on-fic lo4'l-nol-hex[1,2 hloo hl- ex[1,2 romo hl- ex[1,2 hlo e- luy2oc [l 1,2ch alm3-y yl l -) ) a rp o ]x q o 3u - - y5 y l) -a 3' l) o ]qopx u-- y5y ll ) -a r) o ]q o r-,6oo-[3-a]o eqro px u 5'-d1.2. u -5ip y in -o i y in'-i y in -o io-m1e) ] in '-orp aid ip z xo o p )p a-eri ip zoxo o p )p a-eri ip z xo o n-eeto ahct z xia o o-n erle ii-2dn5i] 'H delin 5' delin5'yl n lin5'n -1-in re i-2din ] H--in rid] H --1 -3 ] H- 1e-2in -1 H-- -1-,6 -- 1-0'- ,6- 1-0'- ,6 -- 1-0'-0'-C A A A AoNm49484746op .ound S tructure PR SC -097 / 001W O 3 43f 17 y3- yml)m1 ( l),6- m31 -(6 y 3- ml)m1 - l( u 36-o y -rol)m1 ( 06- -231e 7'(3et ,7'(7e e ,7'(7 -1,7(33th eyt -lh i - hy -i - th t -i --et '-i - 30-1y nl d (o (4lH)-1- in)-n2d (o (4yh-l-y n (l do (4mh- e y n (l do (42 75-i-lo ([4d'-a -a lo ([41')- H-2-lo (4'-th )y -1-lo -(4'- / 59nodxaa1,2 chzlol za 1s,2 chl-inaz[a1,2 ch l- o[l1H xa1,2 ch 81 1z -o 9 -a] o-l qr 3 p--- o -y ira] odqro az sp -a o - -a loC i]qro -i9 ]qroh3azua in-5 l' ) opi[3uin-5o'l-3ro[uin-5 nd -a azua in-5 em-yslp a)z-p iroox p.oer5]naz- ooxo- 3y .5az'-ooxzos a'-o ilp zo xcai op [ lin-5 id oie 5n nalin-5l)p ]ni o loin-5-3 i- roo[lin-5 l nr .5 ]-'9H-e n]'Hps-2 -2-9 -se nr an]-'9Hy- l) 5 ]'Hap .5 -9 -mid ] '-p -'-pid-2'-sp ip] '-spein ue n- dyl i ,6ylyl i in-yy ul ie ny i2 e, c)pir6 a po[ -di )o -1)pirpo[e-2 l)-)pirpo[rid delc)pirpo[-d ni - erciyc n -l e merciyc ,l 65- -f eclriyc in al e- n- erciyclo 9 dn-eyi oln he)- -1 etdi oh di u di oh 2, 9 di oh- xhynal- - e onor n- e 61 1 --yn- e- xae o 1- xadl)- 1 x1-ne- Hn -1n i-e--e-o5 -ane -ne-C A A A AoNm53525150op .ound C l O N N N S tructure F NOH NOP NNR SC -097 / 001W O 3 43y 1 l 7 )y- l s5 )- pp3i y - 3- 3- 0fll)1 (6yl)1 (6 yml)1 (6 -23uip ro 3m,7-(4 m,7-( m,7-(313 oerr [c -(6 e '-oi - e '-4-et et '- - 3-di1 nycl -o (4i tn h iy nd ((4 i tn h iy nd (( h4ylh i-y n (02 ld (4 75- -m1- he-((d(a l) op lo -(4d'l-a ) op lo -(41'H)-1o-lo -(4'- / 5eytl xh) 1zman r, o il p [e 1,2 brzoo il p [e 1, -2 ch-inox[1,2 br98o1 1yl-1e et - 4 -3 ri- 1r)- -y dia] m- q3 r- i- ydia l] oda- -a mC qr az 9 ]qh dHhy ,7 4' -( l) np -1 uo- i- in 5l) np -1 uo-in-5ol-- 3azuo-a in 5emon- li )c -y in (d 4i-pe yl) az'-oixpe yl) az'-ox-ysp az'-ox icenda cz lo o (l 4' r- id -oh oi 5 o-lori-5 id -5 o o-l l ii-5)p rool oai-5 l nl- ex[1ch n fl ln'H in fln'Hioe- uo]-e- uo]- p [e 5 n.'5]-Ham3- y,yl)2-a ro 2,6ro9-'- -ysp 2,6ro9-'- -srypid ] 9i un'- -yspel) o ]p xip y q -) u 5i 'n -- odi 1lxon-m) ipirpo -e[ dci 1lon-m) ipirpo ne[ec- del) ipy2, ca irpoe[cepri i ad p z o eetrycl eetr cl 6- n- ryclien ro-5 hyid oeilin 'H l- i hh1n eyil d o- in h de io 9 id on-yin he-2di -, n ]--H 1- x 1H -1- xael)- -1 x6 - 9-an-n1 -an-1- '- e- e- - e-C A A AoNm565554op .ound S tructure PR SC -097 / 001W O 3 4y 3 y 3 y3175 l) 5 l) y l) s 0-f clu y -(6 - cy -(6 l) pippi -23o crol- o(flh2u c-- orl- o(-2erh7o13 --ox rid[c 3 31 e- x(myl1 (4o-1 e(-xy1 (4 1H oi yc-(02 -etn-lo6-75e)tm,7 -'- (4' ml,-)m7 -'- (4'-inh1d y-y he (hx 4- / 59ye il-t ndchelth inca l) yet dhlzo-4 l)ma (n 28-(1 11hy oHl l) oo l[ro-1hy ol lool -[ ro -3 hy et e6C h-1 -(h- - 1 -H)- 1 - -i2,,25' -i2,,25' yd lroyl ,) 7('4e-mn 7d-ad -a]-oxdion 7 -zi nd-d a]-ox)pixy-3 -i (- nd 4' icoa qlz u o-i -5 eazioa q oz upi-5 eripi ap za o -l c ahl n3as n-p a 'yz Hla--3s np a 'z H di en ribodic[1 lo a, roml iro ol s ip-i yl iro o-lseipi-2iny2-clo -a -5'-e)pip[e3 n rr.5 ]-1o )[ pip[3 n r. ]-1o,[6-d1-y[ ]3 qu oxid]no 0'c-yc er5id]no 0'c-yc io l) .- 1 in o1 .1 a -5in n loh in n lo n zh e -m]o 'He a-2 n-ex e a- n ehlxe epin-,67--y a2- l)ne ,62-a thytan ]-9- --yl)ne l - '- - - 3- -

[0139] The compounds of the present disclosure may possess advantageous characteristics, ascompared to known compounds, such as known SMARCA2 / 4 degraders. For example, the compounds of the present disclosure may display more SMARCA2 / 4 activity, more favorable pharmacokinetic properties (e.g., as measured by Cmax, Tmax, and / or AUC), and / or less interaction with other cellular targets (e.g., hepatic cellular transporter such as OATP1B1) and accordingly improved safety (e.g., drug-drug interaction). These beneficial properties of the compounds of the present disclosure may be measured according to methods commonly available in the art, such as methods exemplified herein.

[0140] Due to the existence of double bonds, the compounds of the present disclosure may be incis or trans, or Z or E, configuration. It is understood that although one configuration may be depicted in the structure of the compounds or formulae of the present disclosure, the present disclosure also encompasses the other configuration. For example, the compounds or formulae of the present disclosure may be depicted in cis or trans, or Z or E, configuration.

[0141] In one embodiment, a compound of the present disclosure (e.g., a compound of any of theformulae or any individual compounds disclosed herein) is a pharmaceutically acceptable salt. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a solvate. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a hydrate. Pharmaceutically acceptable salts

[0142] In certain embodiments, the compounds disclosed herein exist as their pharmaceuticallyacceptable salts. 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.

[0143] In certain embodiments, the compounds described herein possess acidic or basic groupsand therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In certain embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or byseparately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0144] Examples of pharmaceutically acceptable salts include those salts prepared by reaction ofthe compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6- dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

[0145] Further, the compounds described herein can be prepared as pharmaceutically acceptablesalts formed 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, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0146] In certain embodiments, those compounds described herein which comprise a free acidgroup react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like.

[0147] Representative organic amines useful for the formation of base addition salts includeethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In certain embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates

[0148] “Solvate” refers to forms of the compound that are associated with a solvent or water (alsoreferred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the disclosure may be prepared e.g., in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution- phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0149] Those skilled in the art of organic chemistry will appreciate that many organic compoundscan form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates are within the scope of the disclosure.

[0150] It will also be appreciated by those skilled in organic chemistry that many organiccompounds can exist in more than one crystalline form. For example, crystalline form may varyfrom solvate to solvate. Thus, all crystalline forms or the pharmaceutically acceptable solvates thereof are contemplated and are within the scope of the present disclosure.

[0151] In certain embodiments, the compounds described herein exist as solvates. The presentdisclosure provides for methods of treating diseases by administering such solvates. The present disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0152] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such aswater, 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 processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Isomers (stereoisomers, geometric isomer, tautomer, etc.)

[0153] It is also to be understood that compounds that have the same molecular formula but differin the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”

[0154] Stereoisomers that are not mirror images of one another are termed “diastereomers” andthose that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R - and S - sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)- isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is termed a “racemic mixture” or “racemate”.

[0155] As used herein a pure enantiomeric compound is substantially free from other enantiomersor stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that thecompound comprises more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0156] As used herein and unless otherwise indicated, the term “enantiomerically pure (R)-compound” refers to at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, at least about 99% by weight (R)-compound and at most about 1% by weight (S)- compound, or at least about 99.9 % by weight (R)-compound and at most about 0.1% by weight (S)-compound. In certain embodiments, the weights are based upon total weight of compound.

[0157] As used herein and unless otherwise indicated, the term “enantiomerically pure (S)-compound” refers to at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, at least about 99% by weight (S)-compound and at most about 1% by weight (R)- compound or at least about 99.9% by weight (S)-compound and at most about 0.1% by weight (R)-compound. In certain embodiments, the weights are based upon total weight of compound.

[0158] In the compositions provided herein, an enantiomerically pure compound or apharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure (R)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)- compound in such compositions can, for example, comprise, at least about 95% by weight (R)- compound and at most about 5% by weight (S)-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure (S)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0159] Unless indicated otherwise, the description or naming of a particular compound in thespecification and claims is intended to include both individual enantiomers and mixtures, racemicor otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0160] In certain embodiments, the compounds described herein exist as geometric isomers. Incertain embodiments, the compounds described herein possess one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. All geometric forms of the compounds disclosed herein are contemplated and are within the scope of the disclosure.

[0161] In certain embodiments, the compounds disclosed herein possess one or more chiral centersand each center exists in the R configuration or S configuration. The compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the disclosure.

[0162] In additional embodiments of the compounds and methods provided herein, mixtures ofenantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In certain embodiments, dissociable complexes are preferred. In certain embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In certain embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In certain embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Tautomers

[0163] In certain embodiments, compounds described herein exist as tautomers. The compoundsdescribed herein include all possible tautomers within the formulas described herein.

[0164] Tautomers are compounds that are interconvertible by migration of a hydrogen atom,accompanied by a switch of a single bond and an adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with eitheracid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest. All tautomeric forms of the compounds disclosed herein are contemplated and are within the scope of the disclosure. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Pharmaceutical Compositions

[0165] In certain embodiments, the compound described herein is administered as a pure chemical.In some embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0166] Accordingly, the present disclosure provides pharmaceutical compositions comprising acompound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0167] In certain embodiments, the compound provided herein is substantially pure, in that itcontains less than about 5%, less than about 1%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0168] Pharmaceutical compositions are administered in a manner appropriate to the disease to betreated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined usingexperimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0169] 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, nasal 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 as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet. Preparation and Characterization of the Compounds

[0170] The compounds of the present disclosure can be prepared in a number of ways well knownto those skilled in the art of organic synthesis. By way of example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. The compounds of the present disclosure (i.e., a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein)) can be synthesized by following the general synthetic scheme below as well as the steps outlined in the examples, schemes, procedures, and / or synthesis described herein (e.g., Examples). General Synthetic Method

[0171] Those skilled in the art will recognize if a stereocenter exists in the compounds of thepresent disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and / ordiastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[0172] The compounds used in the reactions described herein are made according to organicsynthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. “Commercially available chemicals” are 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, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), 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, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), 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).

[0173] Suitable reference books and treatises that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. 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 treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and PenzlinG. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471- 60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527- 29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

[0174] Specific and analogous reactants are optionally identified through the indices of knownchemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002. Analytical Methods, Materials, and Instrumentation

[0175] Unless otherwise noted, reagents and solvents were used as received from commercialsuppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker or Varian spectrometers at 400 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Liquid chromatography-mass spectrometry (LC / MS) were collected using a SHIMADZU LCMS- 2020EV or Agilent 1260-6125B LCMS. Purity and low-resolution mass spectral data were measured using Agilent 1260-6125B LCMS system (with Diode Array Detector, and AgilentG6125BA Mass spectrometer) or using Waters Acquity UPLC system (with Diode Array Detector, and Waters 3100 Mass Detector). The purity was characterized by UV wavelength 214 nm, 220 nm, 254 nm and ESI. Column: poroshell 120 EC-C18 2.7 μm 4.6 X 100 mm; Flow rate 0.8 mL / min; Solvent A (100 / 0.1 water / formic acid), Solvent B (100 acetonitrile); gradient: hold 5% B to 0.3 min, 5-95% B from 0.3 to 2 min, hold 95% B to 4.8 min, 95-5% B from 4.8 to 5.4 min, then hold 5% B to 6.5 min. Or, column: Acquity UPLC BEH C181.7 µm 2.1 X 50 mm; Flow rate 0.5 mL / min; Solvent A (0.1%formic acid water), Solvent B (acetonitrile); gradient: hold 5%B for 0.2 min, 5-95% B from 0.2 to 2.0 min, hold 95% B to 3.1 min, then 5% B at 3.5 min. Biological Assays

[0176] The biological activities of the compounds of the present application can be assessed withmethods and assays known in the art.

[0177] In certain embodiments, protein degradation is measured using HiBiT Assay. For example,Hela cells are genetically modified via CRISPR / Cas9 to fuse HiBiT to the carboxy terminus of SMARCA2 (Promega CS302365) or SMARCA4 (Promega CS3023225). Cells are cultured and subsequently treated with serial dilutions of test compounds. Levels of SMARCA2 or SMARCA4 expression are assessed with Nano-Glo® HiBiT Lytic Detection Assay (Promega N3050). IC50 is obtained using the GraphPad Prism data analysis software. Methods of Use

[0178] In certain aspects, the present disclosure provides methods of degrading a SMARCA2and / or SMARCA4 protein in a subject, comprising administering to the subject a compound disclosed herein.

[0179] In certain aspects, the present disclosure provides uses of a compound disclosed herein inthe manufacture of a medicament for degrading a SMARCA2 and / or SMARCA4 protein in a subject.

[0180] In certain aspects, the present disclosure provides compounds disclosed herein for use indegrading a SMARCA2 and / or SMARCA4 protein in a subject.

[0181] In certain aspects, the present disclosure provides methods of reducing the amount of aSMARCA2 and / or SMARCA4 protein in a subject (e.g., in a biological sample (e.g., a cell or a tissue) obtained from the subject), comprising administering to the subject a compound disclosed herein.

[0182] In certain aspects, the present disclosure provides uses of a compound disclosed herein inthe manufacture of a medicament for reducing the amount of a SMARCA2 and / or SMARCA4 protein in a subject (e.g., in a biological sample (e.g., a cell or a tissue) obtained from the subject).

[0183] In certain aspects, the present disclosure provides compounds disclosed herein for use inreducing the amount of a SMARCA2 and / or SMARCA4 protein in a subject (e.g., in a biological sample (e.g., a cell or a tissue) obtained from the subject).

[0184] In certain aspects, the present disclosure provides methods of treating or preventing adisease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount).

[0185] In certain aspects, the present disclosure provides methods of treating a disease or disorderin a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount).

[0186] In certain aspects, the present disclosure provides uses of a compound disclosed herein inthe manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0187] In certain aspects, the present disclosure provides uses of a compound disclosed herein inthe manufacture of a medicament for treating a disease or disorder in a subject in need thereof.

[0188] In certain aspects, the present disclosure provides compounds disclosed herein for use intreating or preventing a disease or disorder in a subject in need thereof.

[0189] In certain aspects, the present disclosure provides compounds disclosed herein for use intreating a disease or disorder in a subject in need thereof.

[0190] In certain embodiments, the disease or disorder is a SMARCA2 and / or SMARCA4 protein-mediated disease or disorder.

[0191] In certain embodiments, the disease or disorder is cancer.

[0192] In certain embodiments, the cancer is non-small cell lung cancer, small-cell lung cancer,colorectal cancer, bladder cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinalstromal tumor, CNS cancer, thymic tumor, Adrenocortical carcinoma, appendiceal cancer, small bowel cancer, or penile cancer.

[0193] In certain embodiments, the cancer is selected from NSCLC adenocarcinoma (LUAD),NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), uterine corpus endometrial carcinoma (UCEC), esophageal carcinoma (ESCA), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), bladder urothelial carcinoma (BLCA), and uterine carcinosarcoma (UCS).

[0194] In certain embodiments, the cancer is selected from NSCLC adenocarcinoma (LUAD),NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC).

[0195] In certain embodiments, the cancer includes, but is not limited to, one or more of thecancers of Table A. Table A. adrenal cancer acinic cell carcinoma acoustic neuroma acral lentigious melanoma acrospiroma acute eosinophilic acute erythroid acute lymphoblastic leukemia leukemia leukemia acute megakaryoblastic acute monocytic acute promyelocytic leukemia adenocarcinoma leukemia leukemia adenoid cystic adenomatoid adenosquam rcinoma ade ous ca noma odontogenic tumor carcinoma adipose tissue adrenocortical adult T-cell aggressive NK-cell neoplasm carcinoma leukemia / lymphoma leukemia AIDS-related alveolar alveolar soft part lymphoma rhabdomyosarcoma sarcoma ameloblastic fibroma anaplastic large cell anaplastic thyroid angioimmunoblastic lymphoma cancer T-cell lymphoma angiomyolipoma atypical teratoi B-cell chronic angiosarcoma astrocytoma d rhabdoid tumor lymphocytic leukemia B-cell prolymphocytic B-cell lymphoma basal cell carcinoma biliary tract cancer leukemia bladder cancer blastoma bone cancer Brenner tumor Brown tumor Burkitt's lymphoma breast cancer brain cancercarcinoma carcinoma in situ carcinosarcoma cartilage tumor cementoma myeloid sarcoma chondroma chordoma choriocarcinoma choroid plexus clear-cell sarcoma of papilloma the kidney craniopharyngioma cutaneous T-cell lymphoma cervical cancer colorectal cancer Degos disease desmoplastic small diffuse large B-cell dysembryoplastic round cell tumor lymphoma neuroepithelial tumor dysgerminoma endocrine gland end enteropathy- embryonal carcinoma odermal sinus neoplasm tumor associated T-cell lymphoma esophageal cancer fetus in fetu fibroma fibrosarcoma follicular lymphoma follicular thyroid gastrointestinal cancer ganglioneuroma cancer germ cell tumor gestational giant cell giant cell tumor of choriocarcinoma fibroblastoma the bone glial tumor glioblastoma multiforme glioma gliomatosis cerebri glucagonoma gonadoblastoma granulosa cell tumor gynandroblastoma gallbladder cancer gastric cancer hairy cell leukemia hemangioblastoma head and neck cancer hemangiopericytoma hematological cancer hepatoblastoma hepatosplenic T-cell Hodgkin's lympho non-Hodgkin's invasive lobular lymphoma ma lymphoma carcinoma intestinal cancer kidney cancer laryngeal cancer lentigo maligna lethal midline carcinoma leukemia leydig cell tumor liposarcoma lung cancer lymphangioma lymphangiosarcoma lymphoepithelioma lymphoma acute lymphocytic acute myelogeous chronic lymphocytic leukemia leukemia leukemia liver cancer small cell lung cancer non-small cell lung cancer MALT lymphoma malignant fibrous malignant peripheral malignant triton mantle cell histiocytoma nerve sheath tumor tumor lymphoma marginal zone B-cell mast cell leukemia mediastinal germ cell medullary carcinoma lymphoma tumor of the breastmedullary thyroid cancer medulloblastoma melanoma meningioma merkel cell cancer mesothelioma metastatic urothelial mixed Mullerian carcinoma tumor mucinous tumor multiple myeloma muscle tissue neoplasm mycosis fungoides myxoid liposarcoma myxoma myxosarcoma nasopharyngeal carcinoma neurinoma neuroblastoma neurofibroma neuroma nodular melanoma ocular cancer oligoastrocytoma oligodendroglioma oncocytoma optic nerve sheath meningioma optic nerve tumor oral cancer osteosarcoma ovarian cancer Pancoast tumor papillary thyroid cancer paraganglioma pinealoblastoma pineocytoma pituicytoma pituitary adenoma pituitary tumor plasmacytoma polyembryoma precursor T- primary central lymphoblastic nervous system primary effusion primary peritoneal lymphoma lymphoma lymphoma cancer prostate cancer pancreatic cancer pharyngeal cancer pseudomyxoma periotonei renal cell carcinoma renal medullary carcinoma retinoblastoma rhabdomyoma rhabdomyosarcoma Richter's transformation rectal cancer sarcoma Schwannomatosis seminoma Sertoli cell tumor sex cord-gonadal stromal tumor signet ring cell carcinoma skin cancer small blue round cell tumors small cell carcinoma soft tissue sarcoma somatostatinoma soot wart spinal tumor splenic marginal zone squamous cell lymphoma carcinoma synovial sarcoma Sezary's disease small intestine cancer squamous carcinoma stomach cancer T-cell lymphoma testicular cancer thecoma thyroid cancer transitional cell carcinoma throat cancer urachal cancer urogenital cancer urothelial carcinomauveal melanoma uterine cancer verrucous carcinoma visual pathway glioma vulvar cancer vaginal cancer Waldenstrom's macroglobulinemia Warthin's tumor Wilms' tumor

[0196] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer isa hematological cancer. Exemplary hematological cancers include, but are not limited to, the cancers listed in Table B. In certain embodiments, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia. Table B. acute lymphocytic leukemia (ALL) acute eosinophilic leukemia acute myeloid leukemia (AML) acute erythroid leukemia chronic lymphocytic leukemia (CLL) acute lymphoblastic leukemia small lymphocytic lymphoma (SLL) acute megakaryoblastic leukemia multiple myeloma (MM) acute monocytic leukemia Hodgkins lymphoma (HL) acute promyelocytic leukemia non-Hodgkin's lymphoma (NHL) acute myelogeous leukemia mantle cell lymphoma (MCL) B-cell prolymphocytic leukemia marginal zone B-cell lymphoma B-cell lymphoma splenic marginal zone lymphoma MALT lymphoma follicular lymphoma (FL) precursor T-lymphoblastic lymphoma Waldenstrom's macroglobulinemia (WM) T-cell lymphoma diffuse large B-cell lymphoma (DLBCL) mast cell leukemia marginal zone lymphoma (MZL) adult T cell leukemia / lymphoma hairy cell leukemia (HCL) aggressive NK-cell leukemia Burkitt's lymphoma (BL) angioimmunoblastic T-cell lymphoma Richter's transformation

[0197] In certain embodiments, the subject is a mammal.

[0198] In certain embodiments, the subject is a human.Definitions

[0199] As used in the specification and appended claims, unless specified to the contrary, thefollowing terms have the meaning indicated below. Chemical Definitions

[0200] Definitions of specific functional groups and chemical terms are described in more detailbelow. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, 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, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0201] Compounds described herein can comprise one or more asymmetric centers, and thus canexist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.F. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0202] The invention additionally encompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures of various isomers.

[0203] When a range of values is listed, it is intended to encompass each value and sub-rangewithin the range. For example, “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0204] The following terms are intended to have the meanings presented therewith below and areuseful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e., at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

[0205] “Alkyl” as used herein, refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C1-20alkyl”). In certain embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In certain embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, which is also referred to herein as “lower alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3- pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C1-10alkyl. 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).

[0206] “Alkylene” as used herein, refers to an alkyl group wherein two hydrogens are removed toprovide a divalent radical. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. 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-, -CH2CH2C(CH3)2-), and the like.

[0207] “Alkenyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbongroup having from 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) (“C2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (suchas in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-10 alkenyl.

[0208] “Alkenylene” as used herein, refers to an alkenyl group wherein two hydrogens areremoved to provide a divalent radical. When a range or number of carbons is provided for a particular “alkenylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. 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, ethenylene (-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 (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, - CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-,-C(CH3)2- CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0209] “Alkynyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbongroup having from 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) (“C2-20alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In certain embodiments, an alkynyl group has 2 to3 carbon atoms (“C2-3alkynyl”). 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). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2-10alkynyl. In certain embodiments, the alkynyl group is substituted C2-10alkynyl.

[0210] “Alkynylene” as used herein, refers to a linear alkynyl group wherein two hydrogens areremoved to provide a divalent radical. When a range or number of carbons is provided for a particular “alkynylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. 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.

[0211] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, whichfurther comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-10 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-8 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-7 alkyl”). In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1-6alkyl”). In certain embodiments, a heteroalkyl group is a saturatedgroup having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-5alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and / or 2 heteroatoms (“heteroC1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1-3alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC1-2 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6 alkyl”). 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, the heteroalkyl group is an unsubstituted heteroC1-10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10 alkyl.

[0212] The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein,which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-5alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms (“heteroC2-4 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC2-3alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-6alkenyl”). Unless otherwisespecified, 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, the heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10alkenyl.

[0213] The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein,which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC2-6alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-5 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (“heteroC2-4alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC2-3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-6 alkynyl”). 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, the heteroalkynyl group is an unsubstituted heteroC2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10alkynyl.

[0214] Analogous to “alkylene,” “alkenylene,” and “alkynylene” as defined above,“heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” as used herein, refer to a divalent radical of heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively. When a range or number of carbons is provided for a particular “heteroalkylene,” “heteroalkenylene,” or“heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear divalent chain. “Heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein.

[0215] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). 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 (“C10 aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl).

[0216] Typical aryl groups include, but are not limited to, groups derived from aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-14aryl. In certain embodiments, the aryl group is substituted C6-14aryl.

[0217] “Arylene” as used herein, refers to an aryl group wherein two hydrogens are removed toprovide a divalent radical. When a range or number of carbons is provided for a particular “arylene” group, it is understood that the range or number refers to the range or number of carbons in the aryl group. An “arylene” group may be substituted or unsubstituted with one or more substituents as described herein.

[0218] “Heteroaryl” refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-8 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 14-membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachmentcan be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.

[0219] “Heteroaryl” also includes ring systems wherein the heteroaryl group, as defined above, isfused with one or more aryl groups wherein the point of attachment is either on the heteroaryl or the one or more aryl groups, and in such instances, the number of ring members designates the total number of ring members in the fused (aryl / heteroaryl) ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heteroaryl or the one or more aryl groups. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0220] In certain embodiments, a heteroaryl is a 5- to 10-membered aromatic ring system havingring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In certain embodiments, a heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, 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 provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6- membered heteroaryl”). In certain embodiments, the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certainembodiments, the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5- to 14-membered heteroaryl.

[0221] Exemplary 5-membered heteroaryl containing one heteroatom include, without limitation,pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0222] “Heteroarylene” as used herein, refers to a heteroaryl group wherein two hydrogens areremoved to provide a divalent radical. When a range or number of ring members is provided for a particular “heteroarylene” group, it is understood that the range or number refers to the number of ring members in the heteroaryl group. A “heteroarylene” group may be substituted or unsubstituted with one or more substituents as described herein.

[0223] “Carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from3 to 12 ring carbon atoms (“C3-12 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms (“C5-12carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”). Exemplary C3-6 carbocyclyl include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.

[0224] In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group havingfrom 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C5-8carbocyclyl”). In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having 5 or 6 ring carbon atoms (“C5-6 carbocyclyl”). Examples of C5-6 carbocyclyl include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 carbocyclyl include the aforementioned C5-6carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 carbocyclyl include the aforementioned C3-6 carbocyclyl groups as well as 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, the carbocyclyl group is unsubstituted C3-12 carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C3-12carbocyclyl.

[0225] As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group iseither monocyclic (“monocyclic carbocyclyl”) or polycyclic (“polycyclic carbocyclyl”) that contains a fused, bridged or spiro ring system and can be saturated or can be partially unsaturated. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-12carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-12 carbocyclyl.

[0226] “Fused carbocyclyl” or “fused carbocycle” refers to ring systems wherein the carbocyclylgroup, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond), one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of carbons designates the total number of carbons in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings.

[0227] “Spiro carbocyclyl” or “spiro carbocycle” refers to ring systems wherein the carbocyclylgroup, as defined above, form spiro structure with, i.e., share one common atom with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on the carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on the carbocyclyl rings in which the spiro structure is embedded.

[0228] “Bridged carbocyclyl” or “bridged carbocycle” refers to ring systems wherein thecarbocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the carbocyclyl rings in which the bridged structure is embedded.

[0229] “Carbocyclylene” as used herein, refers to a carbocyclyl group wherein two hydrogens areremoved to provide a divalent radical. The divalent radical may be present on different atoms orthe same atom of the carbocycle group. When a range or number of carbons is provided for a particular “carbocyclyl” group, it is understood that the range or number refers to the range or number of carbons in the carbocyclyl group. A “carbocyclyl” group may be substituted or unsubstituted with one or more substituents as described herein.

[0230] “Heterocyclyl” refers to a radical of a 3- to 12-membered non-aromatic ring system havingring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0231] In certain embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“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 (“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 (“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 (“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.

[0232] As the foregoing examples illustrate, in certain embodiments, a heterocyclyl group caneither be monocyclic (“monocyclic heterocyclyl”) or polycyclic (“polycyclic heterocyclyl”) that contains a fused, bridged or spiro ring system, and can be saturated or can be partially unsaturated. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl group, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, and in such instances, the number of ring members designates the total number of ring members in the entire ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heterocyclyl or the one or more carbocyclyl groups. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3- to 12-membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3- to 12-membered heterocyclyl.

[0233] “Fused heterocyclyl” or “fused heterocycle” refers to ring systems wherein the heterocyclylgroup, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of ring members designates the total number of ring members in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings.

[0234] “Spiro heterocyclyl” or “spiro heterocycle” refers to ring systems wherein the heterocyclylgroup, as defined above, form spiro structure with, i.e., share one common atom with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded.

[0235] “Bridged heterocyclyl” or “bridged heterocycle” refers to ring systems wherein theheterocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded.

[0236] “Heterocyclylene” as used herein, refers to a heterocyclyl group wherein two hydrogensare removed to provide a divalent radical. The divalent radical may be present on different atoms or the same atom of the heterocycle group. When a range or number of ring members is provided for a particular “heterocyclylene” group, it is understood that the range or number refers to the number of ring members in the heterocyclylene group. A “heterocyclylene” group may be substituted or unsubstituted with one or more substituents as described herein.

[0237] “Alkoxy” as used herein, refers to the group -OR, wherein R is alkyl as defined herein. C1-6alkoxy refers to the group -OR, wherein each R is C1-6alkyl, as defined herein. Exemplary C1-6alkyl is set forth above.

[0238] “Alkylamino” as used herein, refers to the group -NHR or -NR2, wherein each R isindependently alkyl, as defined herein. C1-6 alkylamino refers to the group -NHR or -NR2, wherein each R is independently C1-6 alkyl, as defined herein. Exemplary C1-6 alkyl is set forth above.

[0239] “Oxo” refers to =O. When a group other than aryl and heteroaryl or an atom is substitutedwith an oxo, it is meant to indicate that two geminal radicals on that group or atom form a double bond with an oxygen radical. When a heteroaryl is substituted with an oxo, it is meant to indicate that a resonance structure / tautomer involving a heteroatom provides a carbon atom that is able to form two geminal radicals, which form a double bond with an oxygen radical.

[0240] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certainembodiments, the halo group is either fluoro or chloro.

[0241] “Protecting group” as used herein is art-recognized and refers to a chemical moietyintroduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction. Common functional groups that need to be protected include but not limited to hydroxyl, amino, thiol, and carboxylic acid. Accordingly, the protecting groups are termed hydroxyl- protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid- protecting groups, respectively.

[0242] Common types of hydroxyl-protecting groups include but not limited to ethers (e.g.,methoxymethyl (MOM), β-Methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p- methoxyphenyl (PMP), t-butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn)), silyl ethers(e.g., t-butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), triisopropylsilyl (TIPS), tri-iso-propylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalic acidester (Piv) and benzoic acid ester (benzoate; Bz)).

[0243] Common types of amino-protecting groups include but not limited to carbamates (e.g., t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyl carbonyl (Moz or MeOZ), 2,2,2-trichloroehtoxycarbonyl (Troc), and benzyl carbamate (Cbz)), esters (e.g., acetyl (Ac); benzoyl (Bz), trifluoroacetyl, and phthalimide), amines (e.g., benzyl (Bn), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), and triphenylmethyl (trityl)), and sulfonamides (e.g., tosyl (Ts), N-alkyl nitrobenzenesulfonamides (Nosyl), and 2-nitrophenylsulfenyl (Nps)).

[0244] Common types of thiol-protecting groups include but not limited to sulfide (e.g., p-methylbenzyl (Meb), t-butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)).

[0245] Common types of carboxylic acid-protecting groups include but not limited to esters (e.g.,methyl ester, triphenylmethyl (Trityl), t-butyl ester, benzyl ester (Bn), S-t-butyl ester, silyl esters, and orthoesters) and oxazoline.

[0246] These and other exemplary substituents are described in more detail in the DetailedDescription, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents. Other Definitions

[0247] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency ofthe Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0248] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that ispharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic 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, and the like; or formed 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, camphorsulfonic acid, 4-methylbicyclo [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid , gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion , an alkaline earth ion , or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like.Salts further include, by way of example only, sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0249] A “subject” to which administration is contemplated includes, but is not limited to, humans(i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or an adult subject (e.g., young adult, middle aged adult or senior adult) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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.

[0250] An “effective amount” means the amount of a compound that, when administered to asubject for treating or preventing a disease, is sufficient to affect such treatment or prevention. The “effective amount” can 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 the effective amount for therapeutic treatment. A “prophylactically effective amount” refers to the effective amount for prophylactic treatment.

[0251] “Preventing”, “prevention” or “prophylactic treatment” refers to a reduction in risk ofacquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject not yet exposed to a disease-causing agent, or in a subject who is predisposed to the disease in advance of disease onset).

[0252] The term “prophylaxis” is related to “prevention,” and refers to a measure or procedure thepurpose of which 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 hospital patients at risk for thrombosis due, for example, to immobilization, and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0253] “Treating” or “treatment” or “therapeutic treatment” of any disease or disorder refers, inone embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment, “treating” or “treatment” refers to ameliorating at least one physical parameter,which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.

[0254] The term “about” when referring to a number or a numerical range means that the numberor numerical range referred to is an approximation within experimental variability or within statistical experimental error, and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, or 5% of the stated number or numerical range. In certain embodiments, the number or numerical range vary by 1%, 2%, or 3% of the stated number or numerical range.

[0255] The term “comprising” (and related terms such as “comprise” or “comprises” or “having”or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

[0256] The phrase “and / or,” as used herein in the specification and in the claims, should beunderstood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” may refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0257] As used herein in the specification and in the claims, “or” should be understood to havethe same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but alsoincluding more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0258] As used herein in the specification and in the claims, the phrase “at least one,” in referenceto a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) may refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, 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); etc.

[0259] While the present teachings have been described in conjunction with various embodimentsand examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art.

[0260] While various inventive embodiments have been described and illustrated herein, those ofordinary skill in the art will readily envision a variety of other means and / or structures for performing the function and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein aremeant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the inventive teachings is / are used. Those skilled in the art will recognize many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

[0261] The claims should not be read as limited to the described order or elements unless statedto that effect. It should be understood that various changes in form and detail may be made by one of ordinary skill in the art without departing from the spirit and scope of the appended claims. All embodiments that come within the spirit and scope of the following claims and equivalents thereto are claimed. EXEMPLARY EMBODIMENTS

[0262] EXEMPLARY EMBODIMENT 1. A compound of Formula IT-L-C (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: T is of Formula I-1 , wherein:A1is CRA1or N; A2is CRA2or N; A3is CRA3or N;A4is CRA4or N; RA1, RA2, RA3, and RA4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RCis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - - -- C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; two RCtogether form an oxo; or two RC, together with the carbon atom to which they are attached, form Ring D ; Ring D is C3-12carbocycle or 3- to 12-each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;d is an integer selected from 0 to 10, as valency permits; E1is CRE1or N; E2is CRE2or N; E3is CRE3or N; E4is CRE4or N; one of RE2, RE3, or RE4is ; RE1, RE2, and RE4, RE1, RE3, and RE4, or are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, - NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; * denotes attachment to L; Ring F is C3-12carbocycle or 3- to 12-membered heterocycle; each RFis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - - -- C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and f is an integer selected from 0 to 10, as valency permits, L is of Formula I-2, wherein: * denotes attachment to T, and **each L’ is independently C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, C6-10 arylene, 5- to 10-membered heteroarylene, -C(=O)-, -C(=O)N(RL’)-, -C(=O)O-, -N(RL’)-, -O-, -S-, or -S(=O)2-, wherein the alkylene, heteroalkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more Ru; each occurrence of RL’is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and l is an integer selected from 0 to 5, C is of Formula I-3 , wherein:H2is N or CRH2; H3is N or CRH3; H4is N or CRH4; H5is N or CRH5; RH2, RH3, RH4, and RH5are , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru, wherein one of RH2, RH3, RH4, and RH5 is ;** denotesRJ1is 6 6 3- to 6-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; K1is N or CRK1; RK1is hydrogen, deuterium, or C1-6 alkyl optionally substituted with one or more Ru; q is an integer from 0 to 2, each RKis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10aryl, 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 Ru; and k is an integer selected from 0 to 5, wherein: each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selectedfrom oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; each Rais independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl; each Rbis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rcand Rdis independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl; or Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz; and each Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl.

[0263] EXEMPLARY EMBODIMENT 2. The compound of any one of the precedingembodiments, wherein T is of Formula I-1-i or I-1-ii ii), wherein eachC1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 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 Ru.

[0264] EXEMPLARY EMBODIMENT 3. The compound of any one of the precedingembodiments, wherein T is of Formula I-1-i-1, I-1-i-2, I-1-i-3, I-1-ii-1, I-1-ii-2, or I-1-ii-3 , 3),C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 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 Ru.

[0265] EXEMPLARY EMBODIMENT 4. The compound of any one of the precedingembodiments, wherein RA1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 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 Ru.

[0266] EXEMPLARY EMBODIMENT 5. The compound of any one of the precedingembodiments, wherein RA1is halogen or C1-6alkoxy.

[0267] EXEMPLARY EMBODIMENT 6. The compound of any one of the precedingembodiments, wherein T is of Formula I-1-i-4, I-1-i-5, I-1-i-6, I-1-ii-4, or I-1-ii-5, or I-1-ii-66),each RCis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 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 Ru; andRA1is halogen or C1-6alkoxy.

[0268] EXEMPLARY EMBODIMENT 7. The compound of any one of the precedingembodiments, wherein Ring F is 4- to 6-membered heterocycle or C4-6 carbocycle.

[0269] EXEMPLARY EMBODIMENT 8. The compound of any one of the precedingembodiments, wherein each RFis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 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 Ru.

[0270] EXEMPLARY EMBODIMENT 9. The compound of any one of the precedingembodiments, wherein f is 0.

[0271] EXEMPLARY EMBODIMENT 10. The compound of any one of the precedingembodiments, wherein RE1, RE2, and RE4, RE1, RE3, and RE4, or RE1, RE2, and RE3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 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 Ru.

[0272] EXEMPLARY EMBODIMENT 11. The compound of any one of the precedingembodiments, wherein each of RE1, RE2, and RE4, each of RE1, RE3, and RE4, or each of RE1, RE2, and RE3is hydrogen.

[0273] EXEMPLARY EMBODIMENT 12. The compound of any one of the precedingembodiments, wherein one or two of E1, E2, and E4, one or two of E1, E3, and E4, or one or two of E1, E2, and E3are N.

[0274] EXEMPLARY EMBODIMENT 13. The compound of any one of the precedingembodiments, wherein one or two of RE1, RE2, and RE4, one or two of RE1, RE3, and RE4, or one or two of RE1, RE2, and RE3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 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 Ru.

[0275] EXEMPLARY EMBODIMENT 14. The compound of any one of the precedingembodiments, wherein one or two of RE1, RE2, and RE4, one or two of RE1, RE3, and RE4, or one or two of RE1, RE2, and RE3are hydrogen.

[0276] EXEMPLARY EMBODIMENT 15. The compound of any one of the precedingembodiments, wherein RA2, RA3, and RA4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 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 Ru.

[0277] EXEMPLARY EMBODIMENT 16. The compound of any one of the precedingembodiments, wherein each of RA2, RA3, and RA4is hydrogen.

[0278] EXEMPLARY EMBODIMENT 17. The compound of any one of the precedingembodiments, wherein Ring D is C3-12 carbocycle.

[0279] EXEMPLARY EMBODIMENT 18. The compound of any one of the precedingembodiments, wherein Ring D is C5-7 carbocycle.

[0280] EXEMPLARY EMBODIMENT 19. The compound of any one of the precedingembodiments, wherein Ring D is 3- to 12-membered heterocycle.

[0281] EXEMPLARY EMBODIMENT 20. The compound of any one of the precedingembodiments, wherein Ring D is 5- to 7-membered heterocycle.

[0282] EXEMPLARY EMBODIMENT 21. The compound of any one of the precedingembodiments, wherein each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 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 Ru.

[0283] EXEMPLARY EMBODIMENT 22. The compound of any one of the precedingembodiments, wherein d is 0.

[0284] EXEMPLARY EMBODIMENT 23. The compound of any one of the precedingembodiments, wherein each RCis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 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 Ru.

[0285] EXEMPLARY EMBODIMENT 24. The compound of any one of the precedingembodiments, wherein at least one RCis C1-6alkyl.

[0286] EXEMPLARY EMBODIMENT 25. The compound of any one of the precedingembodiments, wherein each of RCis independently C1-6 alkyl.

[0287] EXEMPLARY EMBODIMENT 26. The compound of any one of the precedingembodiments, wherein L is of Formula I-2-i i), wherein:L’’ is 3- to 12-membered heterocyclylene optionally substituted with one or more Ru.

[0288] EXEMPLARY EMBODIMENT 27. The compound of any one of the precedingembodiments, wherein L’’ is 6- to 12-membered spiro heterocyclylene

[0289] EXEMPLARY EMBODIMENT 28. The compound of any one of the precedingembodiments, wherein each L’ is independently C1-6 alkylene, C1-6 heteroalkylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, -C(=O)-, -C(=O)N(RL’)-, -C(=O)O-, -N(RL’)- , or -O-, wherein the alkylene, heteroalkylene, carbocyclylene, or heterocyclylene is optionally substituted with one or more Ru, and l is an integer selected from 0 to 4.

[0290] EXEMPLARY EMBODIMENT 29. The compound of any one of the precedingembodiments, wherein each L’ is independently C1-6alkylene, C3-12carbocyclylene, 3- to 12- membered heterocyclylene, -O-, or -C(=O)-.

[0291] EXEMPLARY EMBODIMENT 30. The compound of any one of the precedingembodiments, wherein L is *-(C1-6alkylene)-(3- to 12-membered heterocyclylene)-, *-(3- to 12- membered heterocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)- (3- to 12-membered heterocyclylene)-C(=O)-(C1-6alkylene)-(3- to 12-membered heterocyclylene)-, *-(C1-6alkylene)-(C3-12carbocyclylene)-O-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-O-(3- to 12-membered heterocyclylene)-, *-(C1-6alkylene)-(3- to 12-membered heterocyclylene)-(3- to 12-membered heterocyclylene)-, *-(3- to 12-membered heterocyclylene)-(C1-6alkylene)-(3- to 12-memberedheterocyclylene)-, *-(C1-6alkylene)-(3- to 12-membered heterocyclylene)-(C1-6alkylene)-(3- to 12-membered heterocyclylene)-, wherein each alkylene, carbocyclylene, or heterocyclylene is independently optionally substituted with one or more Ru, and *denotes attachment to T.

[0292] EXEMPLARY EMBODIMENT 31. The compound of any one of the precedingembodiments, wherein C is of Formula I-3-i i).

[0293] EXEMPLARY of any one of the precedingembodiments, wherein RJ1is C1-6alkyl or C3-4carbocyclyl.

[0294] EXEMPLARY EMBODIMENT 33. The compound of any one of the precedingembodiments, wherein RH2, RH4, and RH5are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0295] EXEMPLARY EMBODIMENT 34. The compound of any one of the precedingembodiments, wherein RH2, RH4, and RH5are independently hydrogen or halogen

[0296] EXEMPLARY EMBODIMENT 35. The compound of any one of the precedingembodiments, wherein K1is CRK1.

[0297] EXEMPLARY EMBODIMENT 36. The compound of any one of the precedingembodiments, wherein RK1is hydrogen.

[0298] EXEMPLARY EMBODIMENT 37. The compound of any one of the precedingembodiments, wherein K1is N

[0299] EXEMPLARY EMBODIMENT 38. The compound of any one of the precedingembodiments, wherein q is 1.

[0300] EXEMPLARY EMBODIMENT 39. The compound of any one of the precedingembodiments, wherein k is 0.

[0301] EXEMPLARY EMBODIMENT 40. A compound selected from the compounds in Table1, or a pharmaceutically acceptable salt thereof.

[0302] EXEMPLARY EMBODIMENT 41. A pharmaceutical composition comprising thecompound of any one of the preceding embodiments, and a pharmaceutically acceptable excipient.

[0303] EXEMPLARY EMBODIMENT 42. A method of degrading a SMARCA2 or SMARCA4protein in a patient or biological sample comprising contacting said patient or biological sample with a compound of any one of the preceding embodiments.

[0304] EXEMPLARY EMBODIMENT 43. Use of a compound of any one of the precedingembodiments in the manufacture of a medicament for degrading a SMARCA2 or SMARCA4 protein in a patient or biological sample.

[0305] EXEMPLARY EMBODIMENT 44. A compound of any one of the precedingembodiments for use in degrading a SMARCA2 or SMARCA4 protein in a patient or biological sample.

[0306] EXEMPLARY EMBODIMENT 45. A method of treating a disease or disordercomprising administering to a patient in need thereof a compound of any one of the preceding embodiments.

[0307] EXEMPLARY EMBODIMENT 46. Use of a compound of any one of the precedingembodiments in the manufacture of a medicament for treating a disease or disorder.

[0308] EXEMPLARY EMBODIMENT 47. A compound of any one of the precedingembodiments for use in treating a disease or disorder.

[0309] EXEMPLARY EMBODIMENT 48. The method, use, or compound for use of any one ofthe preceding embodiments, wherein the disease or disorder is a SMARCA2 or SMARCA4 protein-mediated disease or disorder.

[0310] EXEMPLARY EMBODIMENT 49. The method, use, or compound for use of any one ofthe preceding embodiments, wherein the disease or disorder is cancer.

[0311] EXEMPLARY EMBODIMENT 50. The method, use, or compound for use of any one ofthe preceding embodiments, wherein the cancer is selected from NSCLC adenocarcinoma (LUAD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), uterine corpus endometrial carcinoma (UCEC), esophageal carcinoma (ESCA), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), bladder urothelial carcinoma (BLCA), and uterine carcinosarcoma (UCS).

[0312] EXEMPLARY EMBODIMENT 51. The method, use, or compound for use of any one ofthe preceding embodiments, wherein the cancer is selected from NSCLC adenocarcinoma (LUAD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC). EXAMPLES

[0313] In order that the invention described herein may be more fully understood, the followingexamples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. I. Synthesis and Characterization Synthesis of 4'-chloro-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one (SMD-1074).

[0314] The synthesis of SMD-1074 is illustrated below. Compound 1 is treated with compound 2under Suzuki conditions to produce compound 3, which is further hydrogenated to give Saturated compound 4. Compound 4 is treated with LiHMDS and 1,5-dibromo pentane, which contracts the spirocyclic ring, resulting in the formation of compound 6. Subsequently, compound 6 undergoes SNAr reaction with 2-chloro-6-fluorobenzonitrile (7) to give compound 8. The cyano group in compound 7 is then transformed into an amide using base-catalyzed oxidation conditions with H2O2. The resulting amide is subjected to base-catalyzed cyclization using sodium methoxide as a base, which constructs the tetracyclic spiro core (10). Finally, Boc deprotection of compound 10 under acidic conditions yields the desired SMARCA inhibitor SMD-1074..92g, 9.40 mmol, 1.0 eq), Pd(dppf)Cl2(692 mg, 0.94 mmol, 0.1 eq), K2CO3(2.61 g, 18.80 mmol, 2.0 eq). Then a mixture solvent of dioxane and water (50 mL and 10 mL) was added to the flask. The suspension was protected by nitrogen and heated to reflux for 10 h. LC-MS showed the reaction completed. The reaction mixture was diluted by ethyl acetate (the formed solid was removed by celite filtration) and washed with brine. After removing the solvent, the residue was purified directly by C-18 reversal column chromatography (elution solvents: CH3CN / H2O from 10% to 100%, 0.1%TFA) to get target product 3 (2.45 g, 86%) as a slightly yellow solid. ESI MS m / z: 315.16 [M+H]+.

[0316] Step 2: Under nitrogen protection, to a solution of 3 (2.40 g, 7.63 mmol, 1.0 eq) inmethanol (50 mL) was added palladium on carbon (0.6 g, 50% wt water, 10% wt palladium) cautiously. Then the mixture was stirred overnight under a hydrogen atmosphere (1 atm). After the reaction, the mixture was filtered through celite and concentrated. The residue was purified by silica-gel column chromatography (ethyl acetate / hexane = 1 / 1) to obtain product 4 (2.10 g, 87%) as a white solid. ESI MS m / z: 317.18 [M+H]+.

[0317] Step 3: Under nitrogen protection, a solution of 4 (500 mg, 1.58 mmol, 1.0 eq) in dry THF(40 mL) was added LiHMDS (5.2 mL, 5.2 mmol, 3.3 eq) slowly at -78 °C. Then mixture was stirred for 30 min. After that, 5 (363 mg, 1.58 mmol, 1.0 eq) was added. The mixture was warmed to rt and kept for 12 h, the mixture was quenched by NH4Cl solution, diluted with ethyl acetate (50 mL). The organic phase was collected, dried by anhydrous Na2SO4. After removing solvent, theresidue was purified by silica-gel column chromatography (ethyl acetate / hexane = 1 / 1) to obtained product 6 (410 mg, 67%) as a white solid. ESI MS m / z: 385.24 [M+H]+.

[0318] Step 4: To a flask was added 6 (400 mg, 1.04 mmol, 1.0 eq), 7 (178 mg, 1.11 mmol, 1.1eq) and Cs2CO3(678 g, 2.08 mmol, 2.0 eq), then CH3CN (30 mL) was added to the flask. The suspension was refluxed overnight. After concentration, the residue was redissolved into a mixture of ethyl acetate and water. The organic layer was collected. After concentration, the residue was purified directly by C-18 reversal column chromatography (elution solvents: CH3CN / H2O from 10% to 100%, 0.1%TFA) to get target product 8 (470 mg, 87%) as a light-yellow solid. ESI MS m / z: 520.23 [M+H]+.

[0319] Step 5: To a solution of DMSO (10 mL) was added 8 (200 mg, 0.38 mmol, 1 eq), K2CO3(106 mg, 0.76 mmol, 2 eq) and H2O2(2 mL). The mixture was warmed to 60 °C and stirred for 16 h. After the reaction, the mixture was transferred to the C-18 reversal column (elution solvents: CH3CN / H2O from 10% to 100%, 0.1%TFA) to purify directly to get the product 9 (170 mg, 82%). ESI MS m / z: 538.24 [M+H]+.

[0320] Step 6: The compound 9 (100 mg, 0.19 mmol, 1.0 eq) was dissolved into dry methanol (20mL), then MeONa (103 mg, 1.91 mmol, 10 eq) was added. Followed by refluxing overnight under anhydrous condition. The reaction solution was cooled by dry ice, then TFA (0.5 mL) was added to neutralize the MeONa. The solvent was removed under rotatory evaporator and the received residue was dissolved into a mixture of DCM and water, the DCM layer was collected and dried by anhydrous Na2SO4. After removing solvent, the residue was purified by C-18 reversal column (elution solvents: CH3CN / H2O from 10% to 100%, 0.1%TFA) directly to get product 10 (38 mg, 39 %). ESI MS m / z: 520.23 [M+H]+.

[0321] Step 7: To a solution of 10 (30 mg, 0.57 mol, 1 eq) in DCM (2 mL) was added TFA (2mL). After stirring 30 min, the solvent was removed and the residue was purified by pre-HPLC directly to get product SMD-1074 (18 mg, 74 %). ESI MS m / z: 420.18 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.42 (dd, J = 8.6, 1.0 Hz, 1H), 8.02 – 7.97 (s, 1H), 7.92 – 7.81 (m, 2H), 7.66 (dd, J = 8.0, 0.8 Hz, 1H), 7.36 (dd, J = 7.9, 1.4 Hz, 1H), 3.59 (d, J = 12.6 Hz, 2H), 3.28 – 3.09 (m, 3H), 2.22 (d, J = 14.2 Hz, 2H), 2.15 – 2.01 (m, 6H), 1.95 – 1.87 (m, 3H), 1.77 (q, J = 6.7, 5.7 Hz, 3H). Synthesis of 4'-bromo-9'-(piperidin-4-yl)-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]- 5'-one.D-1074. 7-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-7-azaspiro[3.5]nonane-2- carbaldehyde (7).ag, werepowered KOH (1.5 eq) at 0° C, followed by the addition of Me2SO4(1 mL, 1.2 eq) at 0 °C. The resulting mixture was stirred at 0° C for 15 min-30 min. The reaction mixture was quenched with water and the reaction mixture was transferred to a separatory funnel and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water and brine,and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was subjected to flash column chromatography on silica gel (Ethyl acetate / Hexane = 0% to 10%). The title compound 2 (2.2 g) was obtained as an off-white solid.

[0324] Step 2: To a solution of compound 2 (3 g, 1.0 eq.) and compound 3 (1.0 eq) in THF:H2O(1:5 mL) were degassed with N2 for 10 min. Then added Cs2CO3 (2.0 eq) and PdCl2(dppf)DCM adduct (0.03 eq) at room temperature. The resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated and added water and ethyl acetate. The reaction mixture was transferred to a separatory funnel and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was subjected to flash column chromatography on silica gel (Ethyl acetate / Hexane = 0% to 20%). The title compound 4 (2.2 g) was obtained as an off-white solid.

[0325] Step 3: To a solution of compound 4 (300 mg, 1.0 eq) and compound 5 (1.2 eq) in dry 1,4Dioxane (5 mL) were degassed with N2for 10 min. Then added Cs2CO3(2.0 eq), X-Phos (0.05 eq) and Pd2(dba)3 (0.05 eq) at room temperature. The resulting mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated and added water and ethyl acetate. The reaction mixture was transferred to a separatory funnel and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was subjected to flash column chromatography on silica gel (Ethyl acetate / Hexane = 0% to 40%). The title compound 6 (200 mg) was obtained as an off-white solid.

[0326] Step 4: To a solution of compound 6 (200 mg, 1.0 eq) in MeOH (5 mL) were added Pd / C(20 mg) and the obtained reaction mixture was stirred under H2 gas for 5 h at 40oC. After completion of the starting material, the reaction mixture was filtered and concentrated. The crude compound was dissolved in DCM and then added TFA at room temperature. The obtained reaction mixture stirred at r.t for 2 h. After completion of the starting material the reaction mixture was concentrated and lyophilized to get dry compound 7 (80 mg) for the next step. 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole (4).

[0327] As showed in the scheme 4, cereblon ligand 4 was synthesized by similar procedure asshown above.1-(6-(7-(dimethoxymethyl)-2-azaspiro[3.5]nonan-2-yl)-5-fluoro-1-methyl-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (6).

[0328] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (200mg, 1.0 eq) and amine compound (1.2 eq) in 1,4 dioxane (5 mL) was degassed with N2 for 5 mins, then added Pd2(dba)3 (0.05 eq), X-Phos (0.05 eq) and Cs2CO3 (2.0 eq) at room temperature. Themixture was stirred at 100 °C for 16 h, diluted with water (10 mL), and extracted with EtOAc (10 mL x 3). The organic layer was dried over Na2SO4, filtered, and concentrated under a vacuum. The crude product was purified by flash silica gel chromatography (Biotage, 40 g SepaFlash® Silica Flash Column, Eluent of 30-40% EtOAc / hexane gradient @ 40 mL / min) to afford the title compound (30-45%) as an oil. General Procedure For the Reductive amination:

[0329] To a solution of desired amine (1 equiv.) and aldehyde (1 equiv.) in DMF (10 mL / mol)was added NaOAc (35 mg, 0.42 mmol, 3 equiv.) at room temperature. The mixture was stirred for 30 min. Then Na(OAc)3BH (3 equiv.) was added. The reaction mixture was stirred for additional 1 h. The solvent was removed by air. The residue was purified by C-18 reversal column (elution solvents: CH3CN / H2O from 10% to 100%, 0.1%TFA) to get the desired product in 60-70% yield. General Procedure for Synthesis of Amines.

[0330] The commercially available spirocyclic ketones (1.1) were subjected to Boc groupdeprotection, followed by Cbz protection, to obtain compounds (1.2) in quantitative yield. Next, the Cbz-protected ketone spirocycles were transformed into corresponding aldehydes (1.3) using the Wittig reaction. Finally, the aldehydes were protected with acetal and subjected to Cbz deprotection under hydrogenation conditions to yield the desired dimethyl acetal functionalized

[0331] To a stirred solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (A.1, 24 g,0.1 mol, 1 eq.) in ethyl acetate (50 mL) at room temperature was added conc. HCl (45 mL, 0.5 mol, 5 eq.) slowly and the reaction mixture was stirred at room temperature for 1 h. Once the reaction was completed, the mixture was diluted with ethyl acetate (150 mL), poured into Na2CO3suspension (106 g, 1 mol, 10 eq., in 500 mL of water) and the mixture was stirred for 20 min. To the mixture was added CbzOSu (25 g, 0.1 mmol, 1 eq.) and the mixture was stirred for 1 h. The organic phase was separated, washed with brine, dried, concentrated and the residue was purified by silica column chromatography eluting with 50% ethyl acetate in hexane to give compound benzyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (A.2, 27 g, 0.1 mol, 100%) as a light yellow oil. LCMS: 274.10 [M+H]+.

[0332] To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (68 g, 0.2 mol, 2eq) in dried THF (300 mL) cooled at -70oC was added NaHMDS (200 mL, 0.2 mol, 2 eq.) dropwise and the mixture was warmed to 0oC slowly and stirred for 2 h. Then the mixture wascooled at -78 oC and a solution of benzyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (A.2, 27 g,0.1 mol, 1eq.) in THF (50 mL) was added. The mixture was warmed to rt slowly and stirred for 2 h. TLC was done to detect the process of the reaction. Once no starting material was left, the mixture was quenched by NH4Cl solution (500 mL) and diluted with ethyl acetate (200 mL). The organic phase was separated, washed with brine, dried, concentrated. LCMS: 302.18 [M+H]+.

[0333] The crude solution of benzyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate(24 g, 0.67 mol, 1 eq.) in formic acid (50 mL) was stirred at room temperature for 4 h. TLC was done to detect the process of the reaction and the residue was purified by silica column chromatography eluting with 30% ethyl acetate in hexane to give compound benzyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate (A.3, 20 g, 0.067 mol, 67%) as a light yellow oil. LCMS:288.10 [M+H]+.

[0334] A solution of benzyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate (A.3) was dissolvedin MeOH (120 mL). To the mixture was added CH(OMe)3 (10.6 g, 0.1 mol, 1.5 eq.) followed by TsOH·H2O (1.5 g, 0.07 mol, 0.1 eq.) and the mixture was stirred at 70oC for 12 h. Once the reaction was completed, the mixture was concentrated and the residue was purified by silica column chromatography eluting with 20% ethyl acetate in hexane to give compound benzyl 2- (dimethoxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (14.6 g, 0.44 mol, 67%) as light yellow oil. LCMS: 334.22 [M+H]+.

[0335] To a solution of benzyl 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (14.6g, 0.44 mol, 1 eq.) in MeOH (100 mL) was added Pd / C (4 g, 10% on Carbon) and the mixture was stirred at room temperature for 12 h under H2 (balloon). Once the reaction was completed, 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.1H NMR (400 MHz, Methanol-d4) δ 4.32 (d, J = 6.7 Hz, 1H), 3.33 (s, 6H), 2.95 – 2.83 (m, 2H), 2.83 – 2.74 (m, 2H), 2.58 (pd, J = 8.7, 6.8 Hz, 1H), 1.97 – 1.81 (m, 2H), 1.78 – 1.64 (m, 4H), 1.64 – 1.49 (m, 2H); LCMS: 200.12 [M+H]+.

[0336] Following the similar procedure, other spirocycle amine was prepared.7-(dimethoxymethyl)-2-azaspiro[3.5]nonane.

[0337] 1H NMR (400 MHz, Methanol-J = 6.8 Hz, 1H), 3.36 (s, 6H), 2.42-2.35 (m,2H), 2.17 – 2.00 (m, 3H), 1.97 – 1.81 (m, 4H), 1.74 (d, J = 13.5 Hz, 2H), 1.16 – 0.97 (m, 2H); LCMS: 200.10 [M+H]+. 2-(dimethoxymethyl)-8-azaspiro[4.5]decane

[0338] 1H NMR (400 MHz, Methanol-= 7.6 Hz, 1H), 3.35 (d, J = 0.9 Hz, 6H), 2.81(q, J = 7.2, 6.5 Hz, 4H), 2.35 (dt, J = 9.4, 7.9 Hz, 1H), 1.83 – 1.66 (m, 2H), 1.58 – 1.44 (m, 8H); LCMS: 214.25 [M+H]+. 9-(dimethoxymethyl)-3-azaspiro[5.5]undecane

[0339] 1H NMR (400 MHz, CDCl3) δ 4.1 m, 1H), 3.48 (d, J = 4.3 Hz, 4H), 3.35 (s, 6H),1.60 (dddd, J = 39.4, 35.6, 13.4, 8.8 Hz, 7H), 1.40 – 1.00 (m, 6H); LCMS: 228.15 [M+H]+. 3-(dimethoxymethyl)-1,5-dioxa-9-azaspiro[5.5]undecane

[0340] 1H NMR (400 MHz, Methanol-J = 8.2, 2.7 Hz, 1H), 4.05 – 3.89 (m, 2H),3.84 (ddd, J = 12.0, 10.2, 6.6 Hz, 2H), 3.38 (s, 6H), 3.04 (dt, J = 9.4, 3.6 Hz, 3H), 2.71 (td, J = 5.7, 3.3 Hz, 1H), 2.07 – 1.94 (m, 4H), 1.89 (t, J = 5.8 Hz, 1H); LCMS: 232.20 [M+H]+. 3-(dimethoxymethyl)-1-oxa-8-azaspiro[4.5]decane

[0341] 1H NMR (400 MHz, Methanol-(m, 2H), 3.71 (s, 6H), 3.40 – 3.22 (m, 2H),3.00 (td, J = 10.5, 9.8, 5.3 Hz, 2H), 2.90 (dd, J = 11.5, 6.4 Hz, 2H), 2.16 – 1.99 (m, 2H), 1.80 – 1.56 (m, 4H); LCMS: 216.26 [M+H]+. Synthesis of Ether Linker:1.0eq) in THF (20 mL) was added TMSCl (1.5 g, 13.93 mmol, 1.1 eq) and TEA (2.2 mL, 15.19 mmol, 1.2 eq) at 00C, and the reaction mixture was stirred at 250C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. Then a stirred solution of above residue and benzyl 4-oxopiperidine-l-carboxylate (3.4 g, 14.56 mmol, 1.15 eq) in DCM (30 mL) was added EtsSiH (2.2 g, 18.99 mmol, 1.5 eq) and TMSOTf (1.6 g, 6.96 mmol, 0.55 eq) dropwise at -750C under N2, and the reaction mixture was stirred at O0C under N2 for 3 hours. TLC (Petroleum ether: Ethyl acetate=3: l, PMA, Rf =0.43) showed new spots formed. The reaction mixture was quenched by the addition water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography eluent of 0-20% Ethyl acetate / Petroleum ether to give benzyl 4-(4- methoxycarbonylcyclohexoxy)piperidine-l-carboxylate (4.2 g, 90% yield) was obtained as a colorless oil.

[0343] Step 2: To a solution of benzyl 4-(4-methoxycarbonylcyclohexoxy)piperidine-l-carboxylate (3.0 g, 8.00 mmol, 1.0 eq) in DCM (30 mL) was added DIBAL-H (16 mL, 16.00 mmol, 2.0 eq) at -78oC, then the solution was stirred at -78oC under N2 for 4 hours. TLC (Petroleum ether: Ethyl acetate=3: l) showed a new spot formed. The reaction mixture was quenched with sodium tartrate tetrahydrate and heated to room temperature. The reaction mixture was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography eluent of 0-20% Ethyl acetate / Petroleumether to give benzyl 4-((4-formylcyclohexyl)oxy)piperidine-1-carboxylate (1.2 g, 63% yield) was obtained as a colorless oil.

[0344] Step 3: To a solution of benzyl 4-((4-formylcyclohexyl)oxy)piperidine-1-carboxylate (1.2g, 3.50 mmol, 1.0 eq) in MeOH (20 mL) was added PTSA.H2O (66 mg, 0.35 mmol, 0.1 eq) and trimethoxy methane (553 mg, 5.22 mmol, 1.5 eq) at 25oC. The obtained reaction mixture was stirred at 70oC for 12 h and then quenched with aq. NaHCO3. The reaction mixture was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography eluent of 0-20% Ethyl acetate / Petroleum to give benzyl 4-((4-(dimethoxymethyl)cyclohexyl)oxy)piperidine-1-carboxylate (1.2 g, 92% yield) was obtained as a colorless oil.

[0345] Step 4: To a solution of benzyl 4-((4-(dimethoxymethyl)cyclohexyl)oxy)piperidine-1-carboxylate (1.2 g, 3.00 mmol, 1.0 eq) in MeOH (20 mL) was added Pd / C (3200 mg, 10% purity wet) under N2. The suspension was degassed under vacuum and purged with H2. The mixture was stirred under H2 at 250C for 2 hour. TLC (petroleum ether: ethyl acetate=l:l) showed the reaction completed. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 4-((4-(dimethoxymethyl)cyclohexyl)oxy)piperidine (700 mg, 90% yield) as a white gum. methyl 1-oxa-9-azaspiro[5.5]undecane-3-carboxylate (5)bromide (15.2 g, 2.5 eq) to a solution of N-Boc-4-piperidone (1, 10.0 g, 50 mmol) in THF (40 mL). Then added sat. aq. NH4Cl (40 mL), after that the Zn powder (6.6 g, 2.0 eq.) was added at room temperature by three batches, then warmed to 40oC and stirred for 16 h. The mixture was diluted in water (200 mL) and extracted by ethyl acetate (100 mL×3). The organic layers were washed with water and brine, dried (Na2SO4) and concentrated. Purify the crude by flash chromatography0-30% ethyl acetate in hexane to obtain the compound 2 (10.5 g).1H NMR: (400 MHz, CDCl3) δ 5.94 - 5.77 (m, 1 H), 5.19 (dd, J = 10.4, 1.8 Hz, 1 H), 5.14 (dd, J = 17.1, 1.9 Hz, 1 H), 3.81 (dt, J = 13.4, 3.3 Hz, 2 H), 3.24 -3.08 (m, 2 H), 2.23 (d, J = 7.6 Hz, 2 H), 1.53 (dd, J = 10.4, 4.8 Hz, 4 H), 1.46 (s, 9 H); LCMS: 242.14 [M+H]+.

[0347] Step 2: tert-butyl 4-allyl-4-((2-(methoxycarbonyl)allyl)oxy)piperidine-1-carboxylate (3).A 60% oil dispersion of sodium hydride (2.9 g, 2.0 eq.) was added to a solution of tert-butyl 4- allyl-4-hydroxypiperidine-1-carboxylate (2, 8.8 g, 1 eq.) in anhydrous DMF (100 mL) and the mixture cooled to 0 °C. The mixture was warmed to room temperature for 1 h and methyl 2- (bromomethyl)acrylate (9.8 g, 1.5 eq.) was added dropwise to the solution over 5 minutes. The mixture was aged for 18 h. A saturated solution of ammonium chloride was added to the reaction mixture and the mixture was diluted with ethyl acetate. The organic phase was separated and washed twice with water then brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified using column chromatography on silica gel (0%-100% ethyl acetate in hexanes). Yield: 4.3 g of tert-butyl 4-{[2-(methoxycarbonyl)prop-2-en-1-yl]oxy}- 4-(prop-2-en-1-yl)piperidine-1-carboxylate as a colorless oil (3). LCMS: 340.23 [M+H]+.

[0348] Step 3: 9-(tert-butyl) 3-methyl 1-oxa-9-azaspiro[5.5]undec-3-ene-3,9-dicarboxylate (4).tert-butyl 4-{[2-(methoxycarbonyl)prop-2-en-1-yl]oxy}-4-(prop-2-en-1-yl)piperidine-1- carboxylate (3, 2.4 g, 1 eq.) in anhydrous 1,2-dichloroethane (75 mL) was combined with benzylidene [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro- (tricyclohexylphosphine)ruthenium (G-II, 0.61 g, 10 mol%) and the mixture was heated at 85°C for overnight. The mixture was cooled to room temperature, then diluted with ethyl acetate and washed with water twice with brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to offer compound 4 as an oil (1.97 g).1H NMR (400 MHz, Chloroform-d) δ 6.99 (dt, J = 4.3, 2.3 Hz, 1H), 4.30 (m, 2H), 3.76 (m, 2H), 3.74 (s, 3H), 3.15 (m, 2H), 2.14 (dt, J = 4.3, 2.9 Hz, 2H), 1.74 (m, 2H), 1.60 (m, 2H), 1.46 (s, 9H); LCMS: 312.18 [M+H]+.Step 4: 9-(tert-butyl) 3-methyl 1-oxa-9-azaspiro[5.5]undecane-3,9-dicarboxylate (5). A MeOHsolution of the compound 4 was added palladium on activated carbon catalyst (0.15 eq., 10% purity) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was heated at 40 °C for overnight, then filtered and concentrated in vacuo to offer compound 5 as an oil. LCMS: 314.20 [M+H]+.Compoud A17.3-(6-(3-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)-1-oxa-9-azaspiro[5.5]undecan-9-yl)-5-fluoro-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione.

[0349] Scheme 10 depicts the synthesis of A17. First, the cereblon ligand (1) was preparedfollowing the literature procedure starting from commercially available material 1.1. The 6,6- oxygen-containing spiro-ring-linker (2) was prepared following the procedure as described below. Compound 2.1 undergoes O-alkylation with bromomethyl methacrylate to yield the diene 2.2, which is then treated with Grubbs second-generation catalyst and heated at 85oC in 1,2- dichloroethane for 18 hours to provide the desired spiro-dihydropyran 2.3 in 93% yield. Palladium- catalyzed hydrogenation of 2.3 provides the target spiropiperidine 2.4. The racemic ester on Boc deprotection in acidic condition results in the desired amine 2. Then, intermediate 1 is coupled with amine 2 using Buchwald coupling, yielding the desired intermediate 3. Further, intermediate 3 is converted to the desired aldehyde 5 by reducing the ester to alcohol, followed by oxidizing the alcohol to aldehyde using DMP oxidation. The benzyl protection of the glutarimide part is removed in the hydrogenation condition, yielding the desired aldehyde 8. Finally, the reductive amination of aldehyde 8 with SMI-1074 results in the title compound A17.Compoud A21. 3-(6-(4-((1R,5S,6s)-6-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'- indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexan-3- yl)piperidin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dioneCompoud A33.3-(6-(7-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)-5-oxa-2-azaspiro[3.5]nonan-2-yl)-5-fluoro-1- methyl-1H-indazol-3-yl)piperidine-2,6-dioneCompound A43. 3-(6-(4-(((1r,4r)-4-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2-a]quinazolin]-10'-yl)piperidin-1-yl)methyl)cyclohexyl)oxy)piperidin-1-yl)-5- fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dioneCompound A5.3-(6-(7-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dioneCompound A1.1-(6-(7-((4-(4'-chloro-5'-oxo-5'H-spiro[cyclohexane-1,7'-indolo[1,2- a]quinazolin]-10'-yl)piperidin-1-yl)methyl)-2-azaspiro[3.5]nonan-2-yl)-5-fluoro-1-methyl- 1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneTable E1. Compound No. Synthetic procedure used A1 Scheme 16 A2 Scheme 15 A3 Scheme 15 A4 Scheme 15Compound No. Synthetic procedure used A5 Scheme 15 A6 Scheme 15 A7 Scheme 16 A8 Scheme 15 A9 Scheme 17 A10 Scheme 17 A11 Scheme 15 A12 Scheme 15 A13 Scheme 18 A14 Scheme 18 A16 Scheme 15 A17 Scheme 13 A18 Scheme 15 A21 Scheme 15 A22 Scheme 13 A23 Scheme 13 A24 Scheme 13 A25 Scheme 13 A26 Scheme 13 A27 Scheme 13 A28 Scheme 13 A29 Scheme 14 A30 Scheme 14 A31 Scheme 13 A32 Scheme 13 A33 Scheme 13Compound No. Synthetic procedure used A34 Scheme 13 A35 Scheme 13 A36 Scheme 13 A37 Scheme 15 A38 Scheme 15 A39 Scheme 15 A40 Scheme 15 A41 Scheme 15 A42 Scheme 15 A43 Scheme 14 A44 Scheme 14 A45 Scheme 14 A46 Scheme 20 A47 Scheme 20 A48 Scheme 20 A49 Scheme 20 A50 Scheme 20 A51 Scheme 20 A52 Scheme 20 A53 Scheme 14 A54 Scheme 18 A55 Scheme 19 A56 Scheme 19 Table E2. Characterization DataCompound LC-MS: [M1No. + H]+H NMR 1H NMR (400 MHz, Methanol-d4) δ 8.42 (dd, J = 8.6, 1.0 Hz, 1H), 8.01 (d, J = 1.4 Hz, 1H), 7.95 – 7.79 (m, 2H), 7.68 (dd, J = 7.9, 0.9 Hz, 1H), 7.37 (dd, J = 8.0, 1.3 Hz, 1H), 7.24 (d, J = 12.5 A1 817.48 Hz, 1H), 6.41 (d, J = 7.3 Hz, 1H), 4.01 (dd, J = 7.7, 5.8 Hz, 2H), 3.92 (s, 3H), 3.87 – 3.71 (m, 5H), 3.41 – 3.35 (m, 1H), 3.28 (p, J = 1.7 Hz, 1H), 3.25 – 3.08 (m, 4H), 2.87 (t, J = 6.8 Hz, 2H), 2.33 –1.63 (m, 21H), 1.27 (d, J = 12.2 Hz, 2H).A2 794.64 1H NMR (400 MHz, Methanol-d4) δ 8.42 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 3.9 Hz, 1H), 7.97 – 7.76 (m, 2H), 7.68 (d, J = 7.8 A3 816.41 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 12.4 Hz, 1H), 6.43 (d, J = 7.2 Hz, 1H), 4.30 – 4.21 (m, 1H), 3.92 (d, J = 3.4 Hz, 3H), 3.85 – 3.69 (m, 6H), 3.25 – 3.06 (m, 6H), 2.86 – 2.63 (m, 3H), 2.48 – 1.62 (m, 21H), 1.36 – 1.19 (m, 2H).A4 816.71 1H NMR (400 MHz, Methanol-d4) δ 8.40 (dd, J = 8.7, 1.0 Hz, 1H), 8.02 – 7.96 (m, 1H), 7.97 – 7.75 (m, 3H), 7.73 – 7.61 (m, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 8.0, 1.3 Hz, 1H), A5 798.70 6.51 (d, J = 8.8 Hz, 1H), 4.30 (dd, J = 9.1, 5.1 Hz, 1H), 3.91 (s, 3H), 3.77 (s, 3H), 3.70 (s, 2H), 3.24 – 3.09 (m, 5H), 2.82 – 2.70 (m, 2H), 2.50 – 2.41 (m, 1H), 2.35 – 2.19 (m, 5H), 2.15 – 1.98 (m, 7H), 1.95 – 1.67 (m, 11H), 1.33 – 1.20 (m, 2H).A6 812.77 1H NMR (400 MHz, Methanol-d4) δ 8.46 – 8.36 (m, 1H), 8.05 – 7.97 (m, 1H), 7.97 – 7.79 (m, 3H), 7.67 (dt, J = 7.9, 1.1 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.41 – 7.30 (m, 1H), 6.48 (d, J = 8.8 A7 799.20 Hz, 1H), 4.01 (dd, J = 7.3, 6.2 Hz, 2H), 3.91 (d, J = 4.5 Hz, 3H), 3.80 (d, J = 12.3 Hz, 2H), 3.74 (s, 2H), 3.67 (s, 2H), 3.24 – 3.09 (m, 5H), 2.87 (t, J = 6.7 Hz, 2H), 2.27 – 2.01 (m, 11H), 1.94 – 1.71 (m, 11H), 1.34 – 1.24 (m, 2H).1H NMR (400 MHz, Methanol-d4) δ 8.50 – 8.30 (m, 1H), 8.09 – 7.76 (m, 5H), 7.72 – 7.58 (m, 1H), 7.38 (ddd, J = 12.0, 8.4, 1.6 A8 826.66 Hz, 2H), 4.43 (dd, J = 9.5, 5.1 Hz, 1H), 4.09 (s, 3H), 3.88 – 3.59 (m, 6H), 3.18 (dd, J = 17.7, 5.7 Hz, 5H), 2.91 – 2.69 (m, 2H), 2.62 – 2.46 (m, 1H), 2.41 – 1.66 (m, 24H), 1.54 – 1.31 (m, 4H).A9 799.40 A10 817.42 A11 798.25 1 A12 758.21 H NMR (400 MHz, Methanol-d4) δ 8.42 (d, J = 8.3 Hz, 1H), 8.01 (s, 1H), 7.95 – 7.81 (m, 2H), 7.75 (d, J = 8.8 Hz, 1H), 7.66Compound LC-MS: [M1No. + H]+H NMR (d, J = 7.7 Hz, 1H), 7.44 – 7.23 (m, 2H), 7.17 (d, J = 9.0 Hz, 1H), 4.37 (dd, J = 9.3, 5.1 Hz, 1H), 4.01 (s, 3H), 3.87 (t, J = 13.2 Hz, 4H), 3.27 (dd, J = 14.4, 5.4 Hz, 6H), 2.87 – 2.67 (m, 2H), 2.48 (dd, J = 9.2, 4.9 Hz, 1H), 2.41 – 2.21 (m, 6H), 2.21 – 1.98 (m, 7H), 1.82 (dd, J = 48.2, 11.5 Hz, 8H).A13 874.64 A14 888.60 1H NMR (400 MHz, Methanol-d4) δ 8.67 (d, J = 8.6 Hz, 1H), 8.25 (s, 1H), 8.10 – 7.97 (m, 2H), 7.91 – 7.76 (m, 2H), 7.72 (dd, J = 11.8, 1.9 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 4.39 (dd, J = 9.6, A16 900.08 5.1 Hz, 1H), 3.99 – 3.50 (m, 9H), 3.49 – 3.34 (m, 2H), 3.31 – 3.12 (m, 5H), 2.89 – 2.67 (m, 2H), 2.63 – 2.19 (m, 12H), 2.19 – 1.80 (m, 13H), 1.68 (dd, J = 30.2, 12.9 Hz, 3H), 1.44 – 1.24 (m, 2H), 1.13 – 0.98 (m, 1H), 0.89 – 0.70 (m, 1H).1H NMR (400 MHz, Methanol-d4) δ 8.41 (d, J = 8.5 Hz, 1H), 8.00 (s, 1H), 7.94 – 7.79 (m, 2H), 7.72 – 7.57 (m, 1H), 7.57 – 7.43 (m, 1H), 7.36 (d, J = 7.9 Hz, 2H), 4.33 (dd, J = 9.3, 5.1 Hz, A17 846.60 1H), 4.02 (s, 3H), 3.93 (dd, J = 11.9, 3.8 Hz, 1H), 3.81 (t, J = 13.0 Hz, 2H), 3.56 (dd, J = 11.9, 8.7 Hz, 1H), 3.46 – 3.33 (m, 5H), 3.31 – 3.04 (m, J = 5.8 Hz, 5H), 2.90 – 2.67 (m, 2H), 2.48 (dq, J = 9.1, 4.5 Hz, 1H), 2.42 – 2.29 (m, 2H), 2.29 – 1.56 (m, 21H). 1H NMR (400 MHz, Methanol-d4) δ 8.50 – 8.33 (m, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.95 – 7.76 (m, 2H), 7.66 (dd, J = 8.0, 0.8 Hz, 1H), 7.47 – 7.30 (m, 2H), 7.05 (dd, J = 6.9, 2.5 Hz, 1H), A18 885.65 4.30 (ddd, J = 9.2, 5.1, 1.7 Hz, 1H), 4.24 – 4.04 (m, 1H), 3.98 (d, J = 2.0 Hz, 4H), 3.81 (d, J = 12.0 Hz, 2H), 3.54 (d, J = 51.3 Hz, 6H), 3.30 – 3.07 (m, 3H), 2.99 – 2.59 (m, 7H), 2.53 – 2.19 (m, 7H), 2.19 – 1.95 (m, 8H), 1.95 – 1.48 (m, 9H).1H NMR (400 MHz, Methanol-d4) δ 8.48 – 8.34 (m, 1H), 8.01 (s, 1H), 7.94 – 7.76 (m, 2H), 7.67 (dd, J = 7.9, 0.9 Hz, 1H), 7.38 (dd, J = 15.7, 10.0 Hz, 2H), 7.04 (d, J = 6.8 Hz, 1H), 4.30 (dd, J A21 857.42 = 9.2, 5.1 Hz, 1H), 3.99 (s, 5H), 3.82 (d, J = 12.0 Hz, 2H), 3.64 (dd, J = 23.6, 11.5 Hz, 4H), 3.30 – 3.08 (m, 6H), 2.79 (dddd, J = 23.2, 14.4, 9.3, 4.3 Hz, 4H), 2.45 (dq, J = 9.0, 4.5, 4.0 Hz, 1H), 2.37 – 1.68 (m, 23H).A22 890.35 A23 846.57 A24 872.46 A25 890.48Compound LC-MS: [M1No. + H]+H NMR A26 832.58 A27 857.33 A28 875.32 A29 857.51 A30 875.60 1H NMR (400 MHz, Methanol-d4) δ 8.49 – 8.36 (m, 1H), 8.00 (s, 1H), 7.95 – 7.78 (m, 3H), 7.68 (dd, J = 7.9, 0.9 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 8.8 Hz, A31 800.36 1H), 4.34 – 4.26 (m, 1H), 4.00 – 3.94 (m, 2H), 3.92 (s, 3H), 3.82 (t, J = 7.0 Hz, 4H), 3.49 (dd, J = 11.8, 8.5 Hz, 2H), 3.29 – 3.07 (m, 5H), 2.85 – 2.68 (m, 2H), 2.43 (ddd, J = 14.1, 9.3, 5.2 Hz, 1H), 2.35 – 2.21 (m, 4H), 2.19 – 1.58 (m, 16H).A32 844.31 1H NMR (400 MHz, Methanol-d4) δ 8.41 (dd, J = 8.7, 1.0 Hz, 1H), 8.00 (d, J = 1.3 Hz, 1H), 7.96 – 7.78 (m, 2H), 7.67 (dd, J = 7.9, 0.9 Hz, 1H), 7.40 – 7.21 (m, 2H), 6.49 (d, J = 7.2 Hz, 1H), A33 818.35 4.27 (dd, J = 9.1, 5.2 Hz, 1H), 4.07 – 3.76 (m, 10H), 3.48 (dd, J = 11.9, 8.5 Hz, 1H), 3.30 – 3.09 (m, 5H), 2.85 – 2.66 (m, 2H), 2.43 (ddd, J = 14.1, 9.2, 5.0 Hz, 1H), 2.37 – 1.99 (m, 12H), 1.99 –1.58 (m, 8H).A34 862.30 1H NMR (400 MHz, Methanol-d4) δ 8.42 (d, J = 8.6 Hz, 1H), 8.00 (s, 1H), 7.96 – 7.73 (m, 4H), 7.65 (d, J = 7.9 Hz, 1H), 7.36 A35 828.43 (dd, J = 8.1, 3.8 Hz, 2H), 4.43 (dd, J = 9.5, 5.2 Hz, 1H), 4.06 – 3.95 (m, 1H), 3.82 (t, J = 14.9 Hz, 4H), 3.61 (ddd, J = 20.8, 11.6, 8.4 Hz, 4H), 3.31 – 3.03 (m, 5H), 2.92 – 2.69 (m, 2H), 2.66 – 2.44 (m, 2H), 2.44 – 1.54 (m, 25H).1H NMR (400 MHz, Methanol-d4) δ 8.41 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.92 – 7.78 (m, 3H), 7.65 (d, J = 7.9 Hz, 1H), 7.60 (s, 1H), 7.42 – 7.31 (m, 1H), 7.28 (d, J = 8.8 Hz, A36 814.43 1H), 4.40 (dd, J = 9.5, 5.1 Hz, 1H), 4.26 (t, J = 8.0 Hz, 1H), 4.05 (s, 3H), 3.69 (ddd, J = 44.5, 18.9, 13.6 Hz, 7H), 3.40 – 3.35 (m, 2H), 3.30 – 3.07 (m, 4H), 2.83 – 2.75 (m, 1H), 2.57 – 2.44 (m, 1H), 2.39 – 2.31 (m, 2H), 2.17 (d, J = 61.9 Hz, 12H), 1.94 – 1.64 (m, 8H). A37 853.12 A38 871.23Compound LC-MS: [M1No. + H]+H NMR A39 842.49 A40 860.33 A41 816.47 A42 885.46 A43 874.42 A44 918.36 A45 875.42 A46 846.4 A47 816.1 A48 798.2 A49 828.2 A50 872.3 A51 776.1 A52 821.9 A53 874.4 A54 911.5 A55 816.37 A56 816.37 II. Biological Activity HiBiT Assays for protein degradation of SMARCA2 and SMARCA4

[0350] Hela cells were genetically modified via CRISPR / Cas9 to fuse HiBiT to the carboxyterminus of SMARCA2 (Promega CS302365) or SMARCA4 (Promega CS3023225). Cells were cultured in DMEM containing 10% FBS and 1% (Vol : Vol) penicillin-streptomycin. At the time of experiment, cells were seeded at a density of 20,000 cells per well in a 96-well plate (Corning Cat. #3903) and treated with serial dilutions of testing compounds for 24 hours. At the end of experiment, levels of SMARCA2 or SMARCA4 expression were assessed with Nano-Glo® HiBiTLytic Detection Assay (Promega N3050). IC50 was obtained using the GraphPad Prism data analysis software. The results of the HiBiT Assay are summarized in Table E3 below. Table E3. Compound SMARCA2 SMARCA4 No. DC50 (nM) Dmax(%) DC50 (nM) Dmax(%) A1 A A A BA2 D D D DA3 A A B BA4 A B D DA5 A A A BA6 D D D DA7 A B B BA8 A A A BA9 A B A BA10 A B A BA11 A B D CA12 A B D NAA13 A A A AA14 A B A BA16 A A A AA17 A B A BA18 A B A BA21 A A A AA22 A A A BCompound SMARCA2 SMARCA4 No. DC50 (nM) Dmax(%) DC50 (nM) Dmax(%) A23 A B A BA24 A A B BA25 A A A BA26 A B B CA27 ND ND ND NDA28 A A A BA29 A C D DA30 A C D DA31 A A A BA32 A A A BA33 A A A BA34 A A A AA35 A A B BA36 A A B BA37 A A A BA38 C B D DA39 A B A BA40 A A A AA41 A B A BA42 B B C CA43 A B D DA44 A A A BCompound SMARCA2 SMARCA4 No. DC50 (nM) Dmax(%) DC50 (nM) Dmax(%) A45 A A D DA46 A B D D A47 A B D D A48 A B D D A49 B B B B A50 B B B B A51 A A A A A52 A A A A A53 A A A A A54 ND - - - A55 A B A B A56 A B A B Note: DC50: A (<10 nM), B (10-100 nM), C (101-500 nM), and D (>500 nM). Dmax: A (>90% degradation), B (70-90% degradation), C (50-69% degradation), and D (<50% degradation).INCORPORATION BY REFERENCE

[0351] All publications and patents mentioned herein are hereby incorporated by reference in theirentirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS

[0352] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” includeplural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth.

[0353] While specific embodiments of the subject invention have been discussed, the abovespecification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula I T-L-C (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: T is of Formula I-1 , wherein:A1is CRA1or N; A2is CRA2or N; A3is CRA3or N; A4is CRA4or N; RA1, RA2, RA3, and RA4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RCis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;two RCtogether form an oxo; or two RC, together with the carbon atom to which they are attached, form Ring D ; Ring D is C3-12 carbocycle or 3- to 12-each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - - - -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; d is an integer selected from 0 to 10, as valency permits; E1is CRE1or N; E2is CRE2or N; E3is CRE3or N; E4is CRE4or N; one of RE2, RE3, or RE4is ; RE1, RE2, and RE4, RE1, RE3, and RE4, orare independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, - NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; * denotes attachment to L; Ring F is C3-12carbocycle or 3- to 12-membered heterocycle; each RFis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - - - - - - - -heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and f is an integer selected from 0 to 10, as valency permits, L is of Formula I-2 , wherein:* denotes attachment to T, and ** denotes attachment to C; each L’ is independently C1-6alkylene, C1-6heteroalkylene, C2-6alkenylene, C2-6alkynylene, C3-12carbocyclylene, 3- to 12-membered heterocyclylene, C6-10 arylene, 5- to 10-membered heteroarylene, -C(=O)-, -C(=O)N(RL’)-, -C(=O)O-, -N(RL’)-, -O-, -S-, or -S(=O)2-, wherein the alkylene, heteroalkylene, alkenylene, carbocyclylene, heterocyclylene, arylene, or heteroarylene is optionally substituted with one or more Ru; each occurrence of RL’is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and l is an integer selected from 0 to 5,C is of Formula I-3 , wherein:H2is N or CRH2; H3is N or CRH3; H4is N or CRH4; H5is N or CRH5; RH2, RH3, RH4, and RH5are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - - -carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru, wherein one of and RH5 is ;** denotesRJ1is hydrogen, C1-6alkyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; K1is N or CRK1; RK1is hydrogen, deuterium, or C1-6alkyl optionally substituted with one or more Ru; q is an integer from 0 to 2,each RKis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 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 Ru; and k is an integer selected from 0 to 5, wherein: each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rz; each Rais independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each Rbis independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and each Rcand Rdis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl; or Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz; andeach Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

2. The compound of claim 1, wherein T is of Formula I-1-i or I-1-ii ii), wherein each C1-6alkyl, C1-6alkoxy, 6 6 6 12 to 12-membered heterocyclyl, C6-10 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 Ru.

3. The compound of claim 1, wherein T is of Formula I-1-i-1, I-1-i-2, I-1-i-3, I-1-ii-1, I-1-ii- 2, or I-1-ii-3, ),3), wh l, C1-6alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 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 Ru.

4. The compound of any one of claims 1-3, wherein RA1is hydrogen, halogen, -CN, -NO2, - OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 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 Ru.

5. The compound of any one of claims 1-3, wherein RA1is halogen or C1-6 alkoxy.

6. The compound of claim 1, wherein T is of Formula I-1-i-4, I-1-i-5, I-1-i-6, I-1-ii-4, or I-1-ii-5, or I-1-ii-6 6),each RCis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6- 10aryl, 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 Ru; and RA1is halogen or C1-6alkoxy.

7. The compound of any one of claims 1-6, wherein Ring F is 4- to 6-membered heterocycle or C4-6 carbocycle.

8. The compound of any one of claims 1-7, wherein each RFis independently oxo, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 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 Ru; and f is 0.

9. The compound of any one of claims 1-8, wherein RE1, RE2, and RE4, RE1, RE3, and RE4, or RE1, RE2, and RE3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 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 Ru.

10. The compound of claim 9, wherein each of RE1, RE2, and RE4, each of RE1, RE3, and RE4, or each of RE1, RE2, and RE3is hydrogen.

11. The compound of any one of claims 1-8, wherein one or two of E1, E2, and E4, one or two of E1, E3, and E4, or one or two of E1, E2, and E3are N.

12. The compound of claim 11, wherein one or two of RE1, RE2, and RE4, one or two of RE1, RE3, and RE4, or one or two of RE1, RE2, and RE3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 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 Ru.

13. The compound of claim 12, wherein one or two of RE1, RE2, and RE4, one or two of RE1, RE3, and RE4, or one or two of RE1, RE2, and RE3are hydrogen.

14. The compound of any one of claims 1-13, wherein RA2, RA3, and RA4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 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 Ru.

15. The compound of any one of claims 1-13, wherein each of RA2, RA3, and RA4is hydrogen.

16. The compound of any one of claims 1-15, wherein Ring D is C3-12 carbocycle or 3- to 12- membered heterocycle.

17. The compound of claim 16, wherein Ring D is C5-7 carbocycle or 5- to 7-membered heterocycle.

18. The compound of any one of claims 1-17, wherein each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 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 Ru; and d is 0.

19. The compound of any one of claims 1-15, wherein each RCis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 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 Ru.

20. The compound of any one of claims 1-15, wherein at least one RCis C1-6alkyl; or each of RCis independently C1-6alkyl.

21. The compound of any one of claims 1-20, wherein L is of Formula I-2-i i), wherein:L’’ is 3- to 12-membered with one or more Ru.

22. The compound of claim 21, wherein L’’ is 6- to 12-membered spiro heterocyclylene optionally substituted with one or more Ru.

23. The compound of any one of claims 1-22, wherein each L’ is independently C1-6alkylene, C1-6 heteroalkylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, -C(=O)-, - C(=O)N(RL’)-, -C(=O)O-, -N(RL’)-, or -O-, wherein the alkylene, heteroalkylene, carbocyclylene, or heterocyclylene is optionally substituted with one or more Ru, and l is an integer selected from 0 to 4.

24. The compound of claim 23, wherein each L’ is independently C1-6alkylene, C3-12carbocyclylene, 3- to 12-membered heterocyclylene, -O-, or -C(=O)-.

25. The compound of any one of claims 1-20, wherein L is *-(C1-6alkylene)-(3- to 12- membered heterocyclylene)-, *-(3- to 12-membered heterocyclylene)-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-C(=O)-(3- to 12- membered heterocyclylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-C(=O)-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-, *-(C1-6alkylene)-(C3-12carbocyclylene)-O-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-O-(3- to 12-membered heterocyclylene)-, *-(C1-6 alkylene)-(3- to 12-membered heterocyclylene)-(3- to 12- membered heterocyclylene)-, *-(3- to 12-membered heterocyclylene)-(C1-6alkylene)-(3- to 12- membered heterocyclylene)-, *-(C1-6alkylene)-(3- to 12-membered heterocyclylene)-(C1-6alkylene)-(3- to 12-membered heterocyclylene)-, wherein each alkylene, carbocyclylene, or heterocyclylene is independently optionally substituted with one or more Ru, and *denotes attachment to T.

26. The compound of claim 1, wherein C is of Formula I-3-i i).

27. The compound of any one is C1-6alkyl or C3-4carbocyclyl.

28. The compound of any one of claims 1-32, wherein RH2, RH4, and RH5are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

29. The compound of claim 28, wherein RH2, RH4, and RH5are independently hydrogen or halogen.

30. The compound of any one of claims 1-29, wherein K1is CRK1; and RK1is hydrogen.

31. The compound of any one of claims 1-29, wherein K1is N 32. The compound of any one of claims 1-31, wherein q is 1; and k is 0.

33. A compound selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising the compound of any one of claims 1-33, and a pharmaceutically acceptable excipient.

35. A method of treating a disease or disorder comprising administering to a patient in need thereof a compound of any one of claims 1-33.

36. Use of a compound of any one of claims 1-33 in the manufacture of a medicament for treating a disease or disorder.

37. A compound of any one of claims 1-33 for use in treating a disease or disorder.

38. The method, use, or compound for use of any one of claims 35-37, wherein the disease or disorder is a SMARCA2 or SMARCA4 protein-mediated disease or disorder.

39. The method, use, or compound for use of any one of claims 35-37, wherein the disease or disorder is cancer.

40. The method, use, or compound for use of claim 39, wherein the cancer is selected from NSCLC adenocarcinoma (LUAD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), uterine corpus endometrial carcinoma (UCEC), esophageal carcinoma (ESCA), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), bladder urothelial carcinoma (BLCA), and uterine carcinosarcoma (UCS).

41. The method, use, or compound for use of claim 40, wherein the cancer is selected from NSCLC adenocarcinoma (LUAD), NSCL squamous cell carcinoma (LUSC), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC).

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