Compounds and compositions as smarca2 / 4 degraders and uses thereof

Abstract

Described herein are compounds of Formula (I) and their pharmaceutically acceptable salts, solvates, or stereoisomers, as well as their uses (e.g., as SMARCA2 or SMARCA4 degraders).

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 / 598,451, 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 of frequent 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 conserved catalytic 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 specific vulnerabilities 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 in SMARCA4-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 of intracellular 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 for a 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 I T-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-i or I-3-ii 3-ii), wherein eachembodied, and exemplified herein.

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

[0010] In certain aspects, the present disclosure provides methods of degrading a SMARCA2 and / 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 in the 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 in degrading a SMARCA2 and / or SMARCA4 protein in a subject.

[0013] In certain aspects, the present disclosure provides methods of 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), comprising administering to the subject a compound disclosed herein.

[0014] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the 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 in 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).

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

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

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

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

[0022] The present disclosure relates to compounds and compositions that are useful as SMARCA2 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 I T-L-C (I), and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: T is of Formula I-1 , or a pharmaceutically acceptablethereof, wherein: each RAis independently 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 Ru; a is an integer selected from 0 to 4; B1is CRB1or N; RB1and RB2are 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; and RB3is ; wherein * denotes attachment to L; or RB3together with the intervening carbon atoms, form Ring C, wherein Ring C is optionally substituted 7- to 18-membered fused heterocycle attached to L, RB4is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, 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; 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, C6-10arylene, 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, C1-6alkyl, 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-i or I-3-ii 3-ii), wherein:H1is N or CRH1; H2is N or CRH2; H3is N or CRH3; H4is N or CRH4; H5is N or CRH5; RH1, RH2, RH3, RH4, and RH5are , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino,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(=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 RH1, RH2, RH3, RH4, and RH5is ; ** denotes attachment to L;RJ1is 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 CRK1or N; 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- 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, C2-6 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 substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6alkynyl, C3-6carbocyclyl, 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, 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 C1-6 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, C6-10aryl, or 5- to 10-membered heteroaryl; andeach Rcand Rdis independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 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, each RAis independently halogen, -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), 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, 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 ortwo 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.

[0025] In certain embodiments, each RAis independently halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, 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.

[0026] In certain embodiments, each RAis 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.

[0027] In certain embodiments, each RAis independently halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0028] In certain embodiments, each RAis independently halogen. In certain embodiments, at least one RAis halogen.

[0029] In certain embodiments, a is 0. In certain embodiments, a is 1. In certain embodiments, a is 2. In certain embodiments, a is 3. In certain embodiments, a is 4.

[0030] In certain embodiments, B1is N. In certain embodiments, B1is CRB1.

[0031] In certain embodiments, RB1is hydrogen, 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)), C2-6alkynyl (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), 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.

[0032] In certain embodiments, RB1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0033] In certain embodiments, RB1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, 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.

[0034] In certain embodiments, RB1is 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.

[0035] In certain embodiments, RB1is hydrogen.

[0036] In certain embodiments, RB2is hydrogen, halogen, -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), 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, 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 ortwo 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.

[0037] In certain embodiments, RB2is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, 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.

[0038] In certain embodiments, RB2is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, 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.

[0039] In certain embodiments, RB2is 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.

[0040] In certain embodiments, RB2is hydrogen.

[0041] In certain embodiments, RB3is ; wherein * denotes attachment to L

[0042] In certain embodiments, RB3and RB4, together with the intervening carbon atoms, form Ring C attached to L, wherein Ring C is optionally substituted 7- to 18-membered fused heterocycle (e.g., fused heterocycle comprising two 3- to 10-membered rings and 1-5 heteroatoms selected from N, O, and S).

[0043] In certain embodiments, Ring C attached to L is optionally substituted with one or more substituents selected from 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, and -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- 6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6- membered heterocyclyl.

[0044] In certain embodiments, Ring C attached to L is optionally substituted with one or more Ru. In certain embodiments, Ring C attached to L is optionally substituted with one or more substituents selected from RCxor RC. In certain embodiments, Ruis RC. In certain embodiments, Ruis RCx.

[0045] In certain embodiments, 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, C6-10arylene, 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.

[0046] In certain embodiments, L is I-2-i or I-2-ii (I-2-ii),wherein: L’’ is 3- to 12-membered heterocyclylene optionally substituted with one or more Ru.

[0047] In certain embodiments, L’’ is 6- to 12-membered spiro heterocyclylene optionally substituted with one or more Ru..

[0048] 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-)), C1-6heteroalkylene (e.g., C1-6 heteroalkylene comprising 1-7 heteroatoms selected from N, O, and S), C2-6 alkenylene (e.g., ethenylene (C2), 1-propenylene (C3), 2-propenylene (C3), 1-butenylene (C4), 2-butenylene (C4), butadienylene (C4), pentenylene (C5), pentadienylene (C5), or hexenylene (C6)), C2-6alkynylene (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), C6-10arylene (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.

[0049] In certain embodiments, 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.

[0050] In certain embodiments, 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, carbocyclylene, or heterocyclylene is optionally substituted with one or more Ru.

[0051] 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)), C3-12 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), -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.

[0052] In certain embodiments, each occurrence of RL’is independently hydrogen, C1-6alkyl, 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.

[0053] 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.

[0054] In certain embodiments, each occurrence of RL’is independently hydrogen, C1-6 alkyl, C3-6carbocyclyl, 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.

[0055] In certain embodiments, each occurrence of RL’is hydrogen.

[0056] In certain embodiments, l is 0. In certain embodiments, l is 1. In certain embodiments, l is 2. In certain embodiments, l is 3. In certain embodiments, l is 4. In certain embodiments, l is 5. In certain embodiments, l is an integer selected from 1 to 4.

[0057] In certain embodiments, L is *-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C3-12carbocyclylene)-O-(3- to 12-membered heterocyclylene), *-(C1-12 alkylene)-(3- to 12-membered heterocyclylene)-C(=O)-(3- to 12-membered heterocyclylene), *-(C1-12 alkylene)-(3- to 12- membered heterocyclylene)-C(=O)-(C1-12alkylene)-(3- to 12-membered heterocyclylene), *-(3- to 12-membered heterocyclylene)-C(=O)-(3- to 12-membered heterocyclylene), *-(C1-12alkylene)- (3- to 12-membered heterocyclylene)-(C1-12 alkylene)-(3- to 12-membered heterocyclylene), *-(3- to 12-membered heterocyclylene)-(C1-12 alkylene)-(3- to 12-membered heterocyclylene), wherein the alkylene, heterocyclylene, or carbocyclylene is optionally substituted with one or more Ru, and *denotes attachment to T.

[0058] In certain embodiments, Formula I-3-i or I-3-ii 3-ii), wherein:H1is N or CRH1; H2is N or CRH2; H3is N or CRH3; H4is N or CRH4; H5is N or CRH5; RH1, 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 RH1, RH2, RH3, RH4, and RH5is ; ** denotesRJ1is 6 6 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 CRK1or N; 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, C2-6alkenyl, 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; and k is an integer selected from 0 to 5.

[0059] In certain embodiments, H1is N or CRH1. In certain embodiments, H1is N. In certain embodiments, H1is CRH1.

[0060] In certain embodiments, H2is N or CRH2. In certain embodiments, H2is N. In certain embodiments, H2is CRH2.

[0061] In certain embodiments, H3is N or CRH3. In certain embodiments, H3is N. In certain embodiments, H3is CRH3.

[0062] In certain embodiments, H4is N or CRH4. In certain embodiments, H2is N. In certain embodiments, H4is CRH4.

[0063] In certain embodiments, H5is N or CRH5. In certain embodiments, H2is N. In certain embodiments, H5is CRH5.

[0064] In certain embodiments, one of H2, H3, H4, and H5is N. In certain embodiments, two of H2, H3, H4, and H5are N.

[0065] In certain embodiments, RH1, RH2, RH3, RH4, and RH5are independently , hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., , 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), 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), C2-6alkenyl (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.

[0066] In certain embodiments, RH1, RH2, RH3, RH4, and RH5are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 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.

[0067] In certain embodiments, RH1, RH2, RH3, RH4, and RH5are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6C2-6alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0068] In certain embodiments, RH1, RH2, RH3, RH4, and RH5are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6C2-6alkynyl, 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.

[0069] In certain embodiments, RH1, RH2, RH3, RH4, and RH5are , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0070] In certain .

[0071] In certainI-3-i-1 or I-3-ii-11).

[0072] In .

[0073] In certain 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.

[0074] In certain embodiments, RH1, 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.

[0075] In certain embodiments, RH1and RH5are independently halogen, and each of RH2and RH4is hydrogen.

[0076] In certain embodiments, each of RH1and RH5is fluro, and each of RH2and RH4is hydrogen.

[0077] In certain embodiments, 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.

[0078] In certain embodiments, RH2, RH4, and RH5are independently hydrogen or halogen.

[0079] In certain embodiments, RJ1is 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)),C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), 3- to 6-membered heterocyclyl (e.g., heterocyclyl 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.

[0080] In certain embodiments, RJ1is C1-6alkyl or C3-6carbocyclyl.

[0081] In certain embodiments, K1is N. In certain embodiments, K1is CRK1.

[0082] In certain embodiments, RK1is 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.

[0083] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.

[0084] In certain embodiments, each RKis independently 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), 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, or pentylhexylamino), 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), C6-10 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.

[0085] In certain embodiments, each RKis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0086] In certain embodiments, each RKis independently halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, 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.

[0087] In certain embodiments, each RKis independently 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.

[0088] In certain embodiments, k is 0. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4. In certain embodiments, k is 5.

[0089] In certain embodiments, each Rais independently 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)), 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), orhexynyl (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, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0090] In certain embodiments, each Rais 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.

[0091] In certain embodiments, each Rais independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

[0092] In certain embodiments, each Rais 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.

[0093] In certain embodiments, each Rbis 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)), C2-6alkenyl (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), 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.

[0094] In certain embodiments, each Rbis independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl.

[0095] In certain embodiments, each Rbis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl.

[0096] In certain embodiments, each Rbis independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, or C2-6 alkynyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0097] In certain embodiments, each Rcand each Rdis independently hydrogen, 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)), 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), 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.

[0098] In certain embodiments, each Rcand each Rdis independently hydrogen, C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclylis optionally substituted with one or more Ru.

[0099] In certain embodiments, Rcand Rd, together with the nitrogen atom to which they are attached, 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.

[0100] In certain embodiments, Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz.

[0101] In certain embodiments, Rzis 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.

[0102] In certain embodiments, each Ruis independently oxo, halogen, -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), 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, or pentylhexylamino), 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., phenylor 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, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

[0103] In certain embodiments, 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, 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, C1-6alkyl, C1-6alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

[0104] In certain embodiments, each Ruis 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, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from 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.

[0105] In certain embodiments, each Ruis 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 substituents selected from oxo, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

[0106] In certain embodiments, each Ruis 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 substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

[0107] In certain embodiments, two Ru, together with the carbon atom(s) to which they are attached, 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), C6 aryl (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.

[0108] In certain embodiments, two Ru, together with the carbon atom(s) to which they are attached, form C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., 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.

[0109] In certain embodiments, two geminal Ru, together with the carbon atom to which they are attached, form C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., 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.

[0110] 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 as described 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.

[0111] Without wishing to be limited by this statement, while various options for variables are described herein, it is understood that the present disclosure intends to encompass operableembodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.

[0112] When a range of values is listed, each discrete value and sub-range within the range are also contemplated. For example, “C1-6alkyl” 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.

[0113] In certain embodiments, the compound is selected from the compounds in Tables 1 and 2, or a pharmaceutically acceptable salt thereof.-)ly-8 -)l- - -)86,ly- - -)6ly- ne-n yne-n2-ne8-n,2- ne8-nhpiz-7h izenhpiz enihpiz-7-yx-adi -pne y adidyxaddiyxad neorrHan x-iriroedy8y -pnoiorHyep r-irr odHye r-iran nd Hyoh o] noirc-ond-dy8-po]rc-ip y8h-po]pirc-p) y8-po]c-]5d- m -a2(dy3,]5. 6,32-h-dy3,)ly -n2(dy3,lyh- 2r(dy3,.36,[2- n-l2ha2[a-)xo [oen2(-2ha2[oeh-2- ha2[noe-2- ha2[oorienciS(enhi-zriidi -)xenizp) en)Sxenizhp)e )xnln S e izpsidi0arpsareS( h-0arly-oi(d(- h-o ( h0ary-id(-- araz reme((- h21(,y -9,pz p]a-ip((-41,y p1]-n2(1,y p1- 2( 01,yapi pdip75,7-)ly(-9,75,id-4(-9, ] n-7 5,iz 2(-9, ] -)7 5,7, lC 40-,oa1r89 o 64:,')l62,'yn4 ht e -,oa64: 'ire 4,-a64: 'ar4,-a64: '2-yne ehp5)ro,62,' piopro,62,'epioro,62,')lyt hp) / ul,57fi 51[d-onmi)llyul,yfi 51[d-on)l,i yhul 51[fiopn)lul,51[oeclyiytfi ni a)206, zazr6,arted- zaecd- zaly3 2 2 m 6, ra)6, r2(1y(y)23 -(y l 2(y2 3 p-3 ply-p y p-3-3071343O W100 / 60930-CSR P erutcurtS dn .uo1 p.o 1 2 3 4m N A A A A elboaC T-)-l-)l- - - - -lyne8y- 8 - hnnH8013, yhpi-eh-n- ,i-- 8- ni9,2[ teyz2- p z1- 2xadnoayxadni(-or z-1 7,r - 2d ad-n a o6,nim- enz1- oid Hirytpeny8-p]ehoior- dyHir8 ydien-p]reoi-) ySh(airyidep]in a )roi6,5-rylyd--16,eh-o c ] d-h o cpd- (xec epd-)lp]- 2- ma2r - 3(d 3-y ,.36, -2r -(id 3, p)l6,-4((h- -3,ip6,yn5,n24nihdena2[[o2- eln-2 yha2[yh2- en-401, 2[)l2y- eeh : '2,iridia -)xociS(enriip(sid-)Sxo t-henieid(- 9oh n4,7 ni teidpy'1epirep-zarazire((-h-zarm)ire - or,a zarmirx[e or o p)lipme2( 01,y h -6p ai pi3 0p((1,ylpy-pipo6,6,y)ly- pipd niyzayh)ly C(-9, ]5,d- 6,)l-4( 9, ]51,-n)lulfi5-p]5,1-)lh-ryte -3-047,y1 -8oa 4: '2- ne -47,a4: 'idyned-)ly4: 'niyd9r6,i n262,')l h- e(- p-m)l lopo 6r,62,'ilor h6p,2n(e 2,'re hp2-)H8y-8za5o / u5l,51[yte)cly o7fiona ul,51[ry )lhy-3p 1[pi )lyS-(( or -ndni-20d-iz )l fionizp)l -) yonp)yS(xoizly(- diz4yhadH13 6,ar yd-a ry 6, r da (yr -6axir2123(2-p-32(y-p hyp (e y3 -3 h p]c071343O W100 / 61930-CSR P erutcurtS dn uop.o 5 6 7 8m N A A A A o C-)ly--1-n e- - - 7,-27- e-)971--)n eidnol e-7i no-9irid2-lno,)y-id 3n-o,)yh-id 2 d-)irid-6,3e-pi -p6,(-ly hte6,2- -6-2lyte6,2- -6-2lyepi ,2-2 )l2y)l-ee6--4m)l,2(- - 6-4m)l)l,2(- - 6-4 p)l-e(-6-4yhnimo-nanii )lyzy- e- - yno ni y- - e- - nno ni yh i- - tdo niedirna-72- nidlini z7a 3- -nidini zate ireni za m)lepama dir -nacai-3n rema dirna anrema dirm)lpima diry-ip(ypnoon pi-3( ypce onpi-3( ypy-p)-3( yp3-)lym-e7()ln]]5p)l- 9()ldn ]5p)l- 7()l2-ly -9()lna ne h(-yn5.C 2.3[yne(-ynu].53[yn(-ynnaney ch (- n e hdp0(-eh 3[o2 orih (-eh.5 ori eh 4(-ehno p4eo (- h n ouro14(p89-y3xorip pspor4(py[oripspor4(pyn] r5o 4(py ]5ulrsaazaou-3xorpazou-3xor .3 ulf-3xo.r5[ fi5 / 5d7y2hzalifidsya ahzalfidy[hoiri d-dyod-hri6,0d didp6,p2-3ds2a 2sa )ly1z3az2ia-did071343O W100 / 62930-CSR P erutcurtS dn uop.o 90N A11121m A A A o C-)ly- -)lny- -)- ly2- - e 8))- -n8nlly -1 y-7n8- nhn eh-n e --n e-n apiyz piz- h 8-h i nx or-ad-1ir-ni enyxor-ad 1ir-pnidenyxnor-iid p zzairepenyxaoodn]r-ir5.endyH 8 ydi oidHyiroidHdi i oiHy3[oieh--po]cr-epd- y8h--po]cepd- y8h- r po y)ld-dy8h-po]c orid- ma2r(-n2dy3,i2p6, r -i[)l2-2(-2dy3, p62[), - rl -p2 2(-2dy ]c-yh6t, - r -e2-2(- dy3,p2[ s6,a2- l-)hay en- hayhen- ha3,men 2ha zenaSxoenihzteid )xoiSenizteid )x i Se 2[)lid-)Sxoeni a-z7 idci((-h-r0arm)e ((-h-0arm)rle ((-h-0onyi-ire((-h- ar -)lirem3e((1,y h -4p ly pi3p((1,y py- pi7p((1, z2a- prnai3p(0(1,y pyh pip(9, ]-7 5, 1- )l-y4( 9, ]75,1-)l-y4( 9,7 y pno)l-2( 9, ]5,te)lC -04,a 1 -8o 64: ' nid ne -4,a64: 'nidi ne -4,a]y5,n] ne -47,a4: 'm)lyne9r ,62,'it h-p5o ) or ,62,'re h-po 6r,64:'5.3 h-po 6r,62,'y- hp / 57ul,51[ezfiona)lly oul,51[pi )lfy oionp)ull,52,fi'1[o )l[ ri y oul,51[1- fionn)ildy2i0d3- zayd-iz yd- op nsad-izite26, r12 y3( p6,ar2(yp6,i2z(arza6,ar2(yzpa)2- - - l-3 3 3yp-3 y071343O W100 / 63930-CSR P erutcurtS dn uop.o3 4 5 6N1 1 1 1m A A A A o C- 2(- - - -)86,l- y -83- -l- - -8e- -3-H 2 --n-2-ne-n-o)8-iz3-e h iz3-za2(- H 28- -niz-n3o- 8 -l-id2(H-- 8- niz-o3zaSor((d a nnipa n dn-)ora n -6 2- ora- ndn(- y dhir a dyxeiryxor-dir axei- S H((d(y d a,)dh irxe 2- S(y d aih irxe -H 6- ae)rxep]hc]epdH 0ip y8y -p]h]10-le - ay n6-xep]h] e (0ni(- ay xep]h]1-len6,h- -3.,1.)lh-orc- 3. y o,1.hid)sh-c- 3.,1.di6r-)rh-c-03.1. yhoimaS0n 5, 1, 2[3[yn2(dyoe -2ha2[3[tem-66,S01, 2[3[ epi6,01 ,,2[3[te dm-6laR9,7oni lc hpc) e-)oo Sxni1(i lc-1,2- 5, 9eoo R,7 ni lcp)S l5, 9,7onolc-1,2-( ,a zaryci lynoi ((eh-zaryc-i)l ni 1((,a zaryc ynR1,aizaryc-)lenim(e-46,h(-6,yb-a1C5 p] z-d(-n60-) 1,yb9,p]ayz-1di--nre-46,(-6,yibaeh((65 p] z p) (,ib y-46,y p]az-1di-re4-5,a-id r5,a-pi4-5,a- l5-5,a- npi0 o)ly4: '3-1r8o n) ir6,S7,a4: '3-idirp)-o)rly4: '3-y-(- 6-)ly4: '3-idirp)9u eh2,' leyphi 5, 6,62,')lyheply ounle 2,')l1y-hniorne2,')lyheply5l / fip5y1[7d-o te p)lR1,(51[(o teip)lfi h1d py [otedi o h1r ulpy [oteip)l206,xo n3 2(r idzm)yarlhyte(- n4izm)l yh -xnt6, or izm) efl pi -5(xo nmr iz )l yhm(-ar y e2( dar yp)-3 dar yte21 -33yhyp )ly6(ypm)-3yhyplyyhypm)2--3lyly071343O W100 / 64930-CSR P erutcurtS dn uop.o71819102m N A A A A o C- -l-l- - - 8y-8y 013na- -l6 -yh-)h h), , ce,2-)8tH --lnt -nt92-n e3,yinz eeame -)l iz ee,7[od-elyizm- hd-1 n yHn am d -n,aninuninea 11p- y Hiroi e- y -)l d-h ir 1-)oid-6,6,za]r5.5direhp-dir -)l(4,2x8-p] y-26, pH 2-yx8y -p]ly-76,25- y[) p] or piyxH o8y -p]y- 1- -eeororcmadyd-y3,-nenororcd- 3,-n -elnyn5, ipsp)lryd orcd- 3,ninidin hha2[ani dodiy yhha2[anidi eh4: '2,az-3 yh- yha2[diremilra-2ci(- xoenin]r25ep-2(xoenoin]r5eppy'1a- -l3oz e2(- xoni piyp e( h-zar.3ip -2h-zar.3ipx[or o -)ladnoi 2(eh-zarp)lonroime(- 01,y[h 7 C(-96,p] o)rl (iy-(- 021,y[po)lniydyzayhnid- -4(0-1,yynd doy-7,5,ps3-(-9, ]ri -75,ps3-h-ryteH14(-9,p] h75,brid0oa1r64: 'azlo6z- ,oa64: 'azlo2z(- p-m) ,Hly-l6-a64: 'ac)-ly89 o,62, ,'a- 2a5-d ro,62, / ul,'a- 7a 2d-)8- -8yho tro,62, ,' 1- -e3-57f- 51[on)l ni-ulf- 51[o- nSo-n en)li-((rdizmulf51[onilo25(i yhH 5(i yhH (-y0 -33 zra -a te 1- a1 - n3 zte 19i diza(h d-)5( zredn21y mrym- 6(axiryly-1arypii-3p ) p )eh p-3 pp)2lyly-3]clyH1-071343O W100 / 65930-CSR P erutcurtS dn uop.o1 2 3 4N2 2 2 2m A A A A o C- - -1) 8 -)l -lny-- -)- ely-83-l -)- l -3- -l-1-en -n o y8 n-n-o-)l8-n)lynyneizhp-a 1-nidirnidi ehpizza eiaz3 dmiyx-d-i6dnhpr-ni-y-ad- za ynn iz -9oidiratdnie-hp-ad-in -ra 6,yxHyireoeryorHyatHxo HypeHyxHyce2-r8-pd o]cpipody8-po]cco1-le rynody8-po]hc]11-leyn or8-p] dec nu nimy rahn-d-y3,p)rld ehy noh- rd - 3,]5.ht idh- rd - 3.,1.hotiddyord - 3,]d5ira2[ ynhil 2( did2( y-ha2[ 2[eom-6, 2( y-ha2[3[ e- h- yom6, 2 ha2[.5e[pia - xoci 2((en ohi br)l-) 2-)xoeni ri-1 2-2e-)xoeni lc-1 2-(e-2xoniori p)l-zaracy- H 3,S(( h-zarps-a)l niS(( h-zaryc-)l ni-)eh-zarpsy- me-40h(-1,y -13C 4(-9,p]- -loH1(- 01,yzay--1dir (- 01,yib ya-1diS0r((1,yaz3-l7,5, enizda(41(( 9,p]5,6- -n epi6(( 9,p]5z,a- -n ep(-39,p]5,a- oz06 d ,2 -7,)lid -7,id i(-7,9- aa4: ' n4a 4: 'y i p)4a 4: '3-i p)a 4: 'a d1 -8o6,9r62,'irei-(- 66,62,' htreply(- 66, 2,')l reply6-o6, 2,x n'o-i-5o / ul,51[ pipH1 --lor ,51[ em)ip - 6,)lor51[yhteipr6,)o 51[1-) H157f-on)lyoonlyyoonmlyulf on ly-l2053(izy-h h1arteteulf-iz ht ulf iz )lht-iz hyh5(ar e -5ar y e5(- artete21ypm)myl -3 pm) (yl -3 pm)l3ypm)lm32-y y y y071343O W100 / 66930-CSR P erutcurtS dn uop.o52627282m N A A A A o C- - 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-n oi- -2- -3-l8- -onzH8-idia8- niid- re6,(- H8 2- 2 - - 2oz-)8- ni-)l aor zdyad-i2dn-)i-or zdyadpieSor zay-dnip) ni ((dy d3-i-e-hryl2yH1m( ap hryly dir(-h iryn H1a-2xe ]- -cl- -6- y 2( ap- xe ]hcteep6- api )sxe ] a-c xe lyn -)h- n h03,atte 2-)h- - o p603,xo)l ,Sh- -h03, ] h0.telaS ci(( 1(-,92[c, oon]5m- S12[- y1 ((,9o2- - 3-5, 12[R,9o 1.m- 1me1( 7,aiz.2 -)l(-e,4( 7,niz )lylo1,(( 7,niz3[o-)l eh -26, ar[yoriy- 1no-2 a6, ary -1z-a-aad26,rlycyy- 1noC(-046-,5p-])5,ps -aniid(d --646-,5p-] n)5,id niri-(- 46-,5p-] ci)5, b -aniidd-61y8x9l 4: z i,2yxl 4:H yxl 4: z i,25 / or yn'5e2,a-r6epi-eor yn'ee2,pi1-lor yn'e2,a-r3ep-e7dyh' -2p 1[)lp)nididyh' pp1[)lyht dyh'1[ -)l ip)nidi0h-34yxony2(-ihltyhtreh-4yxonyehihtm -p4yxony lihtyhre13 6o(rz edarp2meo i(p- 6orz edar-m1(-- 6orz e tdarpmeo ip -0-3yhy)plyx)ol(y-3yhy)pl)yl(y-3y) )hyplyxoly71343O W100 / 61940-CSR P erutcurtS dn uop.o647484m N A A A o C

[0114] The compounds of the present disclosure may possess advantageous characteristics, as compared 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.

[0115] Due to the existence of double bonds, the compounds of the present disclosure may be in cis 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.

[0116] In one embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae 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

[0117] In certain embodiments, the compounds disclosed herein exist as their pharmaceutically acceptable 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.

[0118] In certain embodiments, the compounds described herein possess acidic or basic groups and 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.

[0119] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the 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.

[0120] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, 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.

[0121] In certain embodiments, those compounds described herein which comprise a free acid group 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.

[0122] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In certain embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates

[0123] “Solvate” refers to forms of the compound that are associated with a solvent or water (also referred 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.

[0124] Those skilled in the art of organic chemistry will appreciate that many organic compounds can 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.

[0125] It will also be appreciated by those skilled in organic chemistry that many organic compounds 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.

[0126] In certain embodiments, the compounds described herein exist as solvates. The present disclosure 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.

[0127] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the 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.)

[0128] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”

[0129] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those 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”.

[0130] As used herein a pure enantiomeric compound is substantially free from other enantiomers or 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.

[0131] 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.

[0132] 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.

[0133] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically 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.

[0134] Unless indicated otherwise, the description or naming of a particular compound in the specification 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.

[0135] In certain embodiments, the compounds described herein exist as geometric isomers. In certain 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.

[0136] In certain embodiments, the compounds disclosed herein possess one or more chiral centers and 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.

[0137] In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers 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

[0138] In certain embodiments, compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein.

[0139] 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

[0140] 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)).

[0141] Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0142] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, less than about 1%, or less than about 0.1% of other 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.

[0143] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (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.

[0144] 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

[0145] The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. 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

[0146] Those skilled in the art will recognize if a stereocenter exists in the compounds of the present 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).

[0147] The compounds used in the reactions described herein are made according to organic synthesis 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).

[0148] 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, “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.

[0149] Specific and analogous reactants are optionally identified through the indices of known chemicals 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

[0150] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. 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

[0151] The biological activities of the compounds of the present application can be assessed with methods and assays known in the art.

[0152] For example, protein degradation may be 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

[0153] In certain aspects, the present disclosure provides methods of degrading a SMARCA2 and / or SMARCA4 protein in a subject, comprising administering to the subject a compound disclosed herein.

[0154] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for degrading a SMARCA2 and / or SMARCA4 protein in a subject.

[0155] In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading a SMARCA2 and / or SMARCA4 protein in a subject.

[0156] In certain aspects, the present disclosure provides methods of 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), comprising administering to the subject a compound disclosed herein.

[0157] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the 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).

[0158] In certain aspects, the present disclosure provides compounds disclosed herein for use in 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).

[0159] In certain aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount).

[0160] In certain aspects, the present disclosure provides methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., in a therapeutically effective amount).

[0161] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0162] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof.

[0163] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.

[0164] In certain aspects, the present disclosure provides compounds disclosed herein for use in treating a disease or disorder in a subject in need thereof.

[0165] In certain embodiments, the disease or disorder is a SMARCA2 and / or SMARCA4 protein- mediated disease or disorder.

[0166] In certain embodiments, the disease or disorder is cancer.

[0167] 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.

[0168] 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).

[0169] 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).

[0170] In certain embodiments, the cancer includes, but is not limited to, one or more of the cancers 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

[0171] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a hematological cancer. Exemplary hematological cancers include, but are not limited to, 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

[0172] In certain embodiments, the subject is a mammal.

[0173] In certain embodiments, the subject is a human. Definitions

[0174] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. Chemical Definitions

[0175] Definitions of specific functional groups and chemical terms are described in more detail below. 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.

[0176] Compounds described herein can comprise one or more asymmetric centers, and thus can exist 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).

[0177] The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0178] When a range of values is listed, it is intended to encompass each value and sub-range within 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.

[0179] The following terms are intended to have the meanings presented therewith below and are useful 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.

[0180] “Alkyl” as used herein, refers to a radical of a straight-chain or branched saturated hydrocarbon 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).

[0181] “Alkylene” as used herein, refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in 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.

[0182] “Alkenyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group 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.

[0183] “Alkenylene” as used herein, refers to an alkenyl group wherein two hydrogens are removed 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.

[0184] “Alkynyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group 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.

[0185] “Alkynylene” as used herein, refers to a linear alkynyl group wherein two hydrogens are removed 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.

[0186] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 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).

[0191] 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.

[0192] “Arylene” as used herein, refers to an aryl group wherein two hydrogens are removed to provide 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.

[0193] “Heteroaryl” refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons 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.

[0194] “Heteroaryl” also includes ring systems wherein the heteroaryl group, as defined above, is fused 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).

[0195] In certain embodiments, a heteroaryl is a 5- to 10-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 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.

[0196] 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.

[0197] “Heteroarylene” as used herein, refers to a heteroaryl group wherein two hydrogens are removed 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.

[0198] “Carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 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.

[0199] In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 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.

[0200] As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either 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.

[0201] “Fused carbocyclyl” or “fused carbocycle” refers to ring systems wherein the carbocyclyl group, 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.

[0202] “Spiro carbocyclyl” or “spiro carbocycle” refers to ring systems wherein the carbocyclyl group, 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.

[0203] “Bridged carbocyclyl” or “bridged carbocycle” refers to ring systems wherein the carbocyclyl 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.

[0204] “Carbocyclylene” as used herein, refers to a carbocyclyl group wherein two hydrogens are removed 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.

[0205] “Heterocyclyl” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring 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.

[0206] In certain embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“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.

[0207] As the foregoing examples illustrate, in certain embodiments, a heterocyclyl group can either 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.

[0208] “Fused heterocyclyl” or “fused heterocycle” refers to ring systems wherein the heterocyclyl group, 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.

[0209] “Spiro heterocyclyl” or “spiro heterocycle” refers to ring systems wherein the heterocyclyl group, 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.

[0210] “Bridged heterocyclyl” or “bridged heterocycle” refers to ring systems wherein the heterocyclyl 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.

[0211] “Heterocyclylene” as used herein, refers to a heterocyclyl group wherein two hydrogens are 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.

[0212] “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.

[0213] “Alkylamino” as used herein, refers to the group -NHR or -NR2, wherein each R is independently 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.

[0214] “Oxo” refers to =O. When a group other than aryl and heteroaryl or an atom is substituted with 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.

[0215] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

[0216] “Protecting group” as used herein is art-recognized and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction. Common functional groups that need to be protected include but 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.

[0217] 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 acid ester (Piv) and benzoic acid ester (benzoate; Bz)).

[0218] 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)).

[0219] Common types of thiol-protecting groups include but not limited to sulfide (e.g., p- methylbenzyl (Meb), t-butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)).

[0220] 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.

[0221] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents. Other Definitions

[0222] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the 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.

[0223] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically 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.

[0224] 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.

[0225] An “effective amount” means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to affect such treatment or prevention. The “effective amount” 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.

[0226] “Preventing”, “prevention” or “prophylactic treatment” refers to a reduction in risk of acquiring 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).

[0227] The term “prophylaxis” is related to “prevention,” and refers to a measure or procedure the purpose 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.

[0228] “Treating” or “treatment” or “therapeutic treatment” of any disease or disorder refers, in one 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.

[0229] The term “about” when referring to a number or a numerical range means that the number or 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.

[0230] 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.

[0231] The phrase “and / or,” as used herein in the specification and in the claims, should be understood 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.

[0232] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” 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.

[0233] As used herein in the specification and in the claims, the phrase “at least one,” in reference to 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.

[0234] While the present teachings have been described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art.

[0235] While various inventive embodiments have been described and illustrated herein, those of ordinary 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.

[0236] The claims should not be read as limited to the described order or elements unless stated to 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. EXAMPLARY EMBODIMENTS

[0237] EXAMPLARY EMBODIMENT 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 , or a pharmaceutically acceptablethereof, wherein: each RAis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to10-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; a is an integer selected from 0 to 4; B1is CRB1or N; RB1and RB2are independently 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, 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; and-CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, 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; or RB3and RB4, together with the intervening carbon atoms, form Ring C, wherein Ring C is optionally substituted 7- to 18-membered fused heterocycle attached to L, 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, 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, C6-10aryl, 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-i or I-3-ii 3-ii), wherein:H1is N or CRH1; H2is N or CRH2; H3is N or CRH3; H4is N or CRH4; H5is N or CRH5; RH1, RH2, RH3, RH4, and RH5are , hydrogen, halogen, -CN, -NO2, -OH, -NH2,C1-6alkyl, C1-6alkoxy, C1-6alkylamino, 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 RH1, RH2, RH3, RH4, and RH5is ; ** denotes attachment to L; RJ1is 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, Ru; 1K or 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, C2-6alkenyl, 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; 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, C2-6 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 substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6alkynyl, C3-6carbocyclyl, 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.

[0238] EXAMPLARY EMBODIMENT 2. The compound of any one of the preceding examplary embodiments, wherein Ring C is , wherein:* denotes attachment to L; Ring CIand Ring CIIare independently C4-8 carbocycle or 4- to 8-membered heterocycle; wherein at least one of Ring CIand Ring CIIis 4- to 8-membered heterocycle; C3and C4are independently C, CRCx, or N; RCxis 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;each RCis 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, - 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; and c is an integer selected from 0 to 8, as valency permits, wherein each RCindependently may be present on either Ring CIor Ring CII.

[0239] EXAMPLARY EMBODIMENT 3. The compound of any one of the preceding examplary embodiments, wherein Ring C is ,RNis hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 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.

[0240] EXAMPLARY EMBODIMENT 4. The compound of any one of the preceding examplary embodiments, wherein T is of Formula I-1-i: i).

[0241] EXAMPLARYany one of the preceding examplary embodiments, wherein RNis hydrogen, C1-6 alkyl, C3-4 carbocyclyl, 3- to 4-memberedheterocyclyl, -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.

[0242] EXAMPLARY EMBODIMENT 6. The compound of any one of the preceding examplary embodiments, wherein each RCis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0243] EXAMPLARY EMBODIMENT 7. The compound of any one of the preceding examplary embodiments, wherein c is 0.

[0244] EXAMPLARY EMBODIMENT 8. The compound of any one of the preceding examplary embodiments, wherein T is of Formula I-1-ii: .

[0245] EXAMPLARYany one of the preceding examplary embodiments, wherein RB4is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, 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.

[0246] EXAMPLARY EMBODIMENT 10. The compound of any one of the preceding examplary embodiments, wherein B1is N.

[0247] EXAMPLARY EMBODIMENT 11. The compound of any one of the preceding examplary embodiments, wherein RB2is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0248] EXAMPLARY EMBODIMENT 12. The compound of any one of the preceding examplary embodiments, wherein RB2is hydrogen.

[0249] EXAMPLARY EMBODIMENT 13. The compound of any one of the preceding examplary embodiments, wherein each RAis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0250] EXAMPLARY EMBODIMENT 14. The compound of any one of the preceding examplary embodiments, wherein at least one RAis independently halogen.

[0251] EXAMPLARY EMBODIMENT 15. The compound of any one of the preceding examplary embodiments, wherein a is 0 or 1.

[0252] EXAMPLARY EMBODIMENT 16. The compound of any one of the preceding examplary embodiments, wherein L is I-2-i or I-2-ii (I-2-ii), wherein:L’’ is 3- to 12-membered heterocyclylene optionally substituted with one or more Ru.

[0253] EXAMPLARY EMBODIMENT 17. The compound of any one of the preceding examplary embodiments, wherein L’’ is 6- to 12-membered spiro heterocyclylene optionally substituted with one or more Ru.

[0254] EXAMPLARY EMBODIMENT 18. The compound of any one of the preceding examplary embodiments, wherein each L’ is independently C1-6alkylene, C1-6heteroalkylene, 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.

[0255] EXAMPLARY EMBODIMENT 19. The compound of any one of the preceding examplary embodiments, wherein L is *-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C3-12 carbocyclylene)-O-(3- to 12-membered heterocyclylene), *-(C1-12alkylene)-(3- to 12-membered heterocyclylene)-C(=O)-(3- to 12-membered heterocyclylene), *-(C1-12alkylene)-(3- to 12- membered heterocyclylene)-C(=O)-(C1-12 alkylene)-(3- to 12-membered heterocyclylene), *-(3- to 12-membered heterocyclylene)-C(=O)-(3- to 12-membered heterocyclylene), *-(C1-12alkylene)- (3- to 12-membered heterocyclylene)-(C1-12alkylene)-(3- to 12-membered heterocyclylene), *-(3- to 12-membered heterocyclylene)-(C1-12 alkylene)-(3- to 12-membered heterocyclylene), whereinthe alkylene, heterocyclylene, or carbocyclylene is optionally substituted with one or more Ru, and *denotes attachment to T.

[0256] EXAMPLARY EMBODIMENT 20. The compound of any one of the preceding examplary embodiments, wherein C is of Formula I-3-i-1 .

[0257] EXAMPLARY any one of the precedingexamplary embodiments, are 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.

[0258] EXAMPLARY EMBODIMENT 22. The compound of any one of the preceding examplary embodiments, wherein RH1and RH5are independently halogen, and each of RH2and RH4is hydrogen.

[0259] EXAMPLARY EMBODIMENT 23. The compound of any one of the preceding examplary embodiments, wherein C is of Formula I-3-i-2 .

[0260] EXAMPLARYany one of the preceding examplary embodiments, wherein C is of Formula I-3-ii-1 3-ii-1).

[0261] EXAMPLARY EMBODIMENT 25. The compound of any one of the preceding examplary embodiments, wherein RJ1is C1-6 alkyl or C3-4 carbocyclyl.

[0262] EXAMPLARY EMBODIMENT 26. The compound of any one of the preceding examplary embodiments, 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.

[0263] EXAMPLARY EMBODIMENT 27. The compound of any one of the preceding examplary embodiments, wherein RH2, RH4, and RH5are independently hydrogen or halogen.

[0264] EXAMPLARY EMBODIMENT 28. The compound of any one of the preceding examplary embodiments, wherein K1is CRK1.

[0265] EXAMPLARY EMBODIMENT 29. The compound of any one of the preceding examplary embodiments, wherein RK1is hydrogen.

[0266] EXAMPLARY EMBODIMENT 30. The compound of any one of the preceding examplary embodiments, wherein K1is N.

[0267] EXAMPLARY EMBODIMENT 31. The compound of any one of the preceding examplary embodiments, wherein q is 1.

[0268] EXAMPLARY EMBODIMENT 32. The compound of any one of the preceding examplary embodiments, wherein k is 0.

[0269] EXAMPLARY EMBODIMENT 33. A compound selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

[0270] EXAMPLARY EMBODIMENT 34. A pharmaceutical composition comprising the compound of any one of the preceding examplary embodiments, and a pharmaceutically acceptable excipient.

[0271] EXAMPLARY EMBODIMENT 35. A method of degrading a SMARCA2 and / or SMARCA4 protein in a patient or biological sample comprising contacting said patient or biological sample with a compound of any one of the preceding examplary embodiments.

[0272] EXAMPLARY EMBODIMENT 36. Use of a compound of any one of the preceding examplary embodiments in the manufacture of a medicament for degrading a SMARCA2 and / or SMARCA4 protein in a patient or biological sample.

[0273] EXAMPLARY EMBODIMENT 37. A compound of any one of the preceding examplary embodiments for use in degrading a SMARCA2 and / or SMARCA4 protein in a patient or biological sample.

[0274] EXAMPLARY EMBODIMENT 38. A method of treating a disease or disorder comprising administering to a patient in need thereof a compound of any one of the preceding examplary embodiments.

[0275] EXAMPLARY EMBODIMENT 39. Use of a compound of any one of the preceding examplary embodiments in the manufacture of a medicament for treating a disease or disorder.

[0276] EXAMPLARY EMBODIMENT 40. A compound of any one of the preceding examplary embodiments for use in treating a disease or disorder.

[0277] EXAMPLARY EMBODIMENT 41. The method, use, or compound for use of any any one of the preceding examplary embodiments, wherein the disease or disorder is a SMARCA2 and / or SMARCA4 protein-mediated disease or disorder.

[0278] EXAMPLARY EMBODIMENT 42. The method, use, or compound for use of any any one of the preceding examplary embodiments, wherein the disease or disorder is cancer.

[0279] EXAMPLARY EMBODIMENT 43. The method, use, or compound for use of any one of the preceding examplary 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).

[0280] EXAMPLARY EMBODIMENT 44. The method, use, or compound for use of any one of the preceding examplary 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

[0281] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are 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 compound I-6

[0282] 1.5 eq.), Cs2CO3(5.4 g, 2 eq), and CuI (273 mg, 0.15 eq.). The resulting mixture was stirred at 130° C for 3 h. The reaction was quenched with water and ethyl acetate was added. 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 (DCM / MeOH = 0% to 5%). The title compound 3 was obtained as a yellow solid (1.4 g).

[0283] Step 2: To 3 (330 mg) in dry THF (9 mL) was slowly added LiAlH4 (1 M in THF, 4 mL) at 0° C. The resulting mixture was stirred at 0° C. for 1~2 h. Excess reagent was quenched carefully with water, and then stirred until the solution was clear and transparent. 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 brine, and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was subjected to flash column chromatography on silica gel (DCM / MeOH = 0% to 10%). The title compound 4 was obtained as a yellow solid (114 mg).

[0284] Step 3: To 4 (72 mg, 1 eq.) in 1,4-dioxane (2.7 mL) were added (2-hydroxyphenyl)boronic acid (76 mg, 2.5 eq.), potassium carbonate (76mg, 2.5 eq), XPhosPdG3 (18.6 mg, 0.1 eq.) and water (0.54 mL). The resulting mixture was purged with nitrogen and stirred at 95° C for 6 h. Thereaction mixture was concentrated in vacuo and purified by silica gel chromatography (eluting with 0-5% MeOH in DCM).) to provide the title compound 5 (94 mg).

[0285] Step 4: To 5 (94 mg) in dry DCM (2 mL) was added HCl / dioxrane (4M, 0.1 mL) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure and the title compound I-6 was obtained.1H NMR (400 MHz, MeOD) δ 7.59 (dd, J = 8.2, 1.5 Hz, 1H), 7.50 – 7.42 (m, 1H), 7.35 (s, 1H), 7.12 – 7.04 (m, 2H), 4.54 – 4.42 (m, 1H), 4.09 – 3.98 (m, 1H), 3.79 (dd, J = 12.5, 4.2 Hz, 1H), 3.71 – 3.54 (m, 4H), 3.46 (dd, J = 12.5, 7.2 Hz, 1H), 3.18 (t, J = 12.4 Hz, 1H). UPLC-MS m / z: 284.15 [M+H]. Synthesis of compound CRBN-ligand 7added 2 (5.0 g, 12 mmol, 1.0 eq), Pd(dppf)Cl2 (438 mg, 0.6 mmol, 0.05 eq) and K2CO3 (5.8 g, 42 mmol, 3.5 eq). The mixture was refluxed for 6 h. The mixture was diluted by adding EA (80 mL), washed by brine once. After dried by anhydrous Na2SO4 and concentrated, the crude product was purified by silica-gel column chromatography (elution with EA / hexane = 1 / 1) to get product 3 (4.0 g, 70%) as a colorless oil.

[0287] Step 2: To a solution of 3 (460 mg, 0.95 mmol, 1.0 eq) in dioxane (10 mL) was added 4 (0.32 mL, 1.9 mmol, 2.0 eq), Pd2(dba)3 (87 mg, 0.095 mmol, 0.1 eq), Xphos (91 mg, 0.19 mmol, 0.2 eq) and Cs2CO3 (929 mg, 2.85 mmol, 3.0 eq). The mixture was refluxed for 12 h. The mixture was diluted by adding EA (80 mL), washed by brine once. After dried by anhydrous Na2SO4and concentrated, the crude product was purified by silica-gel column chromatography (elution with EA / hexane = 1 / 1) to get product 3 (400 mg, 75%) as a yellow oil.

[0288] Step 3: To a solution of 5 (400 mg, 0.71 mmol, 1.0 eq) in MeOH (30 mL) was added Pd / C (200 mg, 10% Wt., 50% water contained), The mixture was stirred for 20 h under hydrogen atmosphere. The mixture was filtered, and filtrate was concentrated to get product 6.

[0289] Step 4: The received 6 was dissolved into DCM (30 mL), then TFA (5 mL) was added. The mixture was stirred for 3 h at rt. the mixture was purified by reversal C-18 column chromatography (elution with CH3CN / H2O from 10% to 100%, 0.1% TFA) to get product 7 (205 mg, 86% 2 steps) as a colorless solid. UPLC-MS m / z: 337.14 [M+H].1H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 9.61 (s, 1H), 6.62 (dd, J = 12.6, 9.0 Hz, 2H), 3.05 – 2.84 (m, 1H), 2.84 – 2.48 (m, 4H), 2.17 – 2.00 (m, 2H), 2.00 – 1.85 (m, 2H), 1.81 – 1.64 (m, 2H), 1.59 – 1.42 (m, 2H), 1.43 – 1.28 (m, 1H). General Procedure for Synthesis of Amines.

[0290] The commercially available spirocyclic ketones (1.1) were subjected to Boc group deprotection, 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 spirocyclic amines (1.4).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 Na2CO3 suspension (106 g, 1 mol, 10 eq., in 500 mL of water) and the mixture was stirred for 20 min. Tothe 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]+.

[0292] To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (68 g, 0.2 mol, 2 eq) 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 was cooled at -78oC 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]+.

[0293] 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]+.

[0294] A solution of benzyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate (A.3) was dissolved in 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]+.

[0295] To a solution of benzyl 2-(dimethoxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (14.6 g, 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 (400MHz, 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]+.

[0296] Following the similar procedure, other spirocycle amine was prepared. 7-(dimethoxymethyl)-2-azaspiro[3.5]nonane.

[0297] 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

[0298] 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

[0299] 1H NMR (400 MHz, CDCl3) δ1H), 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]undecaneH), .7, H), 0 – as . yl)dihydropyrimidine-2,4(1H,3H)-dione (6)200 mg, 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. The mixture 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: 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. methyl 1-oxa-9-azaspiro[5.5]undecane-3-carboxylate (5)esium 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 chromatography 0-30% 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]+.

[0305] 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]+.

[0306] 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°Cfor 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]+.

[0307] Step 4: 9-(tert-butyl) 3-methyl 1-oxa-9-azaspiro[5.5]undecane-3,9-dicarboxylate (5). A MeOH solution 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]+. Compound A17.3-(2,6-difluoro-4-(4-(((1R,5S,6r)-6-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10- hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6-dione

[0308] Step 1: To a solution of I-6 (45 mg, 0. 14 mmol, 1 equiv.) and 6 (60 mg, 0.28 mmol, 2 equiv.) in MeOH (5 mL) was added NaOAc (35 mg, 0.42 mmol, 3 equiv.) at room temperature. The mixture was stirred for 30 min. Then NaBH3CN (26.6 mg, 1.54 mmol, 3 equiv.) was added. The reaction mixture was stirred for additional 2 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 pure product 7 (46 mg, 68%).

[0309] Step 2: To a solution of 7 (9 mg, 0.018 mmol, 1 equiv.) in DCM (3 mL), was added TFA (1 mL) and the mixture was stirred 60 min. After removing solvent, the crude product 8 was received and can be used in the next step directly.

[0310] Step 3: To a solution of 8 (9 mg, 0.018 mmol, 1.2 equiv.) and 9 (5 mg, 0.015 mmol, 1 equiv.) in MeOH (1 mL) was added NaOAc (3.6 mg, 0.044 mmol, 3 equiv.) at room temperature. The mixture was stirred for 30 min. Then NaBH3CN (2.8 mg, 0.044 mmol, 3 equiv.) was added. The reaction mixture was stirred for additional 5 h. The reaction was purified by pre-HPLC (elution solvents: CH3CN / H2O from 15% to 100%, 0.1%TFA) to get pure product A17 (4.7 mg, 45%).1H NMR (400 MHz, MeOD) δ 11.08 (s, 1H), 8.27 (s, 1H), 7.91 (d, J= 7.0 Hz, 1H), 7.74 (d, J= 8.5 Hz, 1H), 7.38 – 7.07 (m, 5H), 6.85 – 6.82 (m, 2H), 5.07 – 5.06 (m, 1H), 4.23 – 3.82 (m, 4H), 3.61 – 3.58(m, 2H), 3.09 – 3.05 (m, 6H), 2.95 – 2.85 (m, 3H), 2.72 (m, 5H), 2.20 – 2.17 (m, 7H), 1.76 – 1.73 (m, 1H), 1.22 (m, 3H). UPLC-MS m / z: 699.33 [M+H]. UPLC-retention time: 2.12 min. Compound A28.3-(5-fluoro-6-(3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H- pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-1-oxa-9-azaspiro[5.5]undecan-9- yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dionepared following 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 I-6 results in the title compound A28.Compound A30. 3-(2,6-difluoro-4-(3-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro- 8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-1-oxa-9-azaspiro[5.5]undecan- 9-yl)phenyl)piperidine-2,6-dione

[0312] To a solution of 1 (300 mg, 0.62 mmol, 1.0 eq) in dioxane (16 mL) was added 2 (138 mg, 0.75 mmol, 1.2 eq), Pd2(dba)3 (57 mg, 0.062 mmol, 0.1 eq), Xphos (59 mg, 0.12 mmol, 0.2 eq) and Cs2CO3(405 mg, 1.24 mmol, 2.0 eq). The mixture was refluxed for 16 h. After reaction, the mixture was filtered and concentrated, the crude product was purified by silica-gel column chromatography (elution with EA / hexane = 1 / 1) to get product 3 (260 mg, 71%) as a yellow solid. ESI MS m / z: 587.26 [M+H]. Synthesis of compound 4

[0313] To a solution of 3 (250 mg, 0.42 mmol, 1.0 eq) in MeOH (60 mL) was added Pd / C (250 mg, 10% Wt, 50% water contained), The mixture was stirred for 16 h under hydrogen atmosphere. After reaction, the mixture was concentrated to get product 4 (130 mg, 75%). Synthesis of compound 5

[0314] To a solution of 4 (150 mg, 0.37mmol, 1.0 eq) in DCM (15 mL) was added DMP (233 mg, 0.55 mmol, 1.5 eq). The mixture was stirred for 0.5 h. After removing solvent, the mixture was purified by reversal C-18 column chromatography (elution with CH3CN / H2O from 10% to 100%, 0.1% TFA) to get product 5 (45 mg, 30%) as a colorless solid. ESI MS m / z: 407.10 [M+H]. Synthesis of compound A30

[0315] To a solution of 5 (20 mg, 0.05 mmol, 1.0 eq) in DMF / DCE (2 / 2 mL) was added I-6 (14 mg, 0.05 mmol, 1.0 eq), and NaBH(OAc)3 (32 mg, 0.15 mmol, 3.0 eq). the mixture was stirred for 3 h at rt. After reaction, the reaction solution was purified by pre-HPLC (elution with CH3CN / H2O from 10% to 100%, 0.1% TFA) to get product A30 (18 mg, 54%) as a white solid. ESI MS m / z: 674.32 [M+H]. Compound A31. 3-(2,6-difluoro-4-(4-((4-(2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H- pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)cyclohexyl)oxy)piperidin-1- yl)phenyl)piperidine-2,6-dionepreparation of A30.

[0317] Synthesis of A32, A33, and A34 are similar to the procedure of preparation of A30. Compound No. [M+H]+ A31 688.32 A32 846.29 A33 860.30 A34 832.27 Compound A35. 3-(2,6-difluoro-4-(4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H- pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)piperidin-1-yl)phenyl)piperidine- 2,6-dioney

[0318] To a solution of 1 (300 mg, 0.62 mmol, 1.0 eq) in dioxane (16 mL) was added 2 (106 mg, 0.75 mmol, 1.2 eq), Pd2(dba)3(57 mg, 0.062 mmol, 0.1 eq), Xphos (59 mg, 0.12 mmol, 0.2 eq) and Cs2CO3 (405 mg, 1.24 mmol, 2.0 eq). The mixture was refluxed for 16 h. After reaction, the mixture was filtered and concentrated, the crude product was purified by silica-gel column chromatography (elution with EA / hexane = 1 / 1) to get product 3 (260 mg, 77%) as a yellow solid. ESI MS m / z: 545.10 [M+H]. Synthesis of 4

[0319] To a solution of 3 (250 mg, 0.49 mmol, 1.0 eq) in THF (16 mL) was added aqueous NaOH solution (5 mL, 1 N). The mixture was stirred for 3 h. After reaction, the mixture was concentrated and purified by reversal C-18 column chromatography (elution with CH3CN / H2O from 10% to 100%, 0.1% TFA) to get product 4 (225 mg, 93%) as a white solid. ESI MS m / z: 530.17 [M+H]. Synthesis of compound 5

[0320] To a solution of 4 (200 mg, 0.4 mmol, 1.0 eq) in MeOH (50 mL) was added Pd / C (250 mg, 10% Wt, 50% water contained), The mixture was stirred for 16 h under hydrogen atmosphere. After reaction, the mixture was concentrated and purified by reversal C-18 column chromatography (elution with CH3CN / H2O from 10% to 100%, 0.1% TFA) get product 5 (105 mg, 79%). Synthesis of A35

[0321] To a solution of 5 (20 mg, 0.06 mmol, 1.0 eq) in DMF (3 mL) was added 6 (16 mg, 0.06 mmol, 1.0 eq), HATU (43 mg, 0.32 mmol, 2.0 eq) and DIPEA (22 mg, 0.48 mmol, 3 eq). Themixture was stirred for 1 h. After reaction, the mixture was purified by pre-HPLC (elution with CH3CN / H2O from 10% to 100%, 0.1% TFA) to get product A35 (26 mg, 74%) as a white solid. ESI MS m / z: 618.26 [M+H]. Compound A36.3-(2,6-difluoro-4-((S)-3-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro- 5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)pyrrolidin-1- yl)phenyl)piperidine-2,6-dione Compound A37.3-(2,6-difluoro-4-((3S)-3-(3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10- hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidine-1- carbonyl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione Compound A38.3-(2,6-difluoro-4-(4-(3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro- 8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidine-1-carbonyl)piperidin-1- yl)phenyl)piperidine-2,6-dione Compound A39.3-(2,6-difluoro-4-((R)-3-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10- hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidine-1- carbonyl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione Compound A40.3-(2,6-difluoro-4-(4-(4-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro- 8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)piperidine-1-carbonyl)piperidin-1- yl)phenyl)piperidine-2,6-dionepreparation of A35.

[0323] Synthesis of A36, A38, A39, A40, and A41 are similar to the procedure of preparation of A35 as well. Compound No. [M+H]+ A36 604.24 A37 673.30 A38 687.31 A39 687.31 A40 701.33 A41 719.52 Table E1. Characterization Data Compound No. LC-MS: [M + H]+A1 644.53 A2 604.39 A3 633.48 A4 673.35 A5 644.98 A6 673.45 A7 687.33 A8 622.11 A9 672.45 A10 700.13 11 632.449 A12 659.98 A13 658.95 A14 686.91 A15 726.88 A16 699.34 A17 699.35Compound No. LC-MS: [M + H]+A18 717.11 A19 685.23 A20 735.45 A21 680.33 A22 680.32 A23 690.20 A24 737.36 A25 752.40 A26 763.38 A27 749.42 A28 A29 662.30 A30 674.32 A31 688.32 A32 846.29 A33 860.30 A34 832.27 A35 618.26 A36 604.24 A37 673.30 A38 687.31 A39 687.31 A40 701.33 A41 719.52 A42 755.26 A43 721.32Compound No. LC-MS: [M + H]+A44 739.31 A45 775.1 A46 779.41 A47 763.30 A48 761.30 II. Biological Activity HiBiT Assays for protein degradation of SMARCA2 and SMARCA4

[0324] Hela cells were genetically modified via CRISPR / Cas9 to fuse HiBiT to the carboxy terminus 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® HiBiT Lytic Detection Assay (Promega N3050). IC50 was obtained using the GraphPad Prism data analysis software. The results of the HiBiT Assay are summarized in Table E2 below. Table E2. Compound SMARCA2 SMARCA4 No. DC50 (nM) Dmax(%) DC50 (nM) Dmax(%) A1 A B B B A2 A B B B A3 B B A B A4 B B B B A5 B B B B A6 A A A ACompound SMARCA2 SMARCA4 No. DC50 (nM) Dmax(%) DC50 (nM) Dmax(%) A7 A A A A A8 A A A A A9 A B D C A10 A B A B A11 A B D C A12 A B D B A13 A A A A A14 A A A B A15 A A A A A16 A B A B A17 A A A B A18 A A A B A19 A A A A A20 A A A A A21 A B D D A22 A B D C A23 A B B C A24 A B B B A25 A B D DCompound SMARCA2 SMARCA4 No. DC50 (nM) Dmax(%) DC50 (nM) Dmax(%) A26 A A A A A27 A A A A A28 A A A B A29 A B D C A30 A B B B A31 A B A B A32 B B B B A33 A A A B A34 A35 B B D C A36 A B B B A37 A A A A A38 A A A A A39 A A A A A40 A A A A A41 A A A A A42 A A A A A43 A A A A A44 A A A ACompound SMARCA2 SMARCA4 No. DC50 (nM) Dmax(%) DC50 (nM) Dmax(%) A45 A46 A47 A48 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

[0325] All publications and patents mentioned herein are hereby incorporated by reference in their entirety 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

[0326] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural 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.

[0327] While specific embodiments of the subject invention have been discussed, the above specification 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 , or a pharmaceutically acceptable thereof,wherein: each RAis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, 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 Ru; a is an integer selected from 0 to 4; B1is CRB1or N; RB1and RB2are 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;RB3is ; wherein * denotes attachment to L; and RB4halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, 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; or RB3and RB4, together with the intervening carbon atoms, form Ring C, wherein Ring C is optionally substituted 7- to 18-membered fused heterocycle attached to L, 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, C6-10arylene, 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, 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-i or I-3-ii-3-ii), wherein: H1is N or CRH1; H2is N or CRH2; H3is N or CRH3; H4is N or CRH4; H5is N or CRH5; RH1, RH2, RH3, RH4, and RH5are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino,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 RH5; ** 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 CRK1or N; 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, C2-6alkenyl, 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; 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, C2-6 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) 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, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl; or two Ru, together with the one or more intervening atoms, form C3-6carbocyclyl, 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, C6-10aryl, 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, C6-10 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, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl.

2. The compound of claim 1, wherein Ring C is , wherein:* denotes attachment to L; Ring CIand Ring CIIare independently C4-8carbocycle or 4- to 8-membered heterocycle; wherein at least one of Ring CIand Ring CIIis 4- to 8-membered heterocycle; C3and C4are independently C, CRCx, or N; RCxis hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, 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; each RCis 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, - - -- C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and c is an integer selected from 0 to 8, as valency permits, wherein each RCindependently may be present on either Ring CIor Ring CII.

3. The compound of claim 2, wherein Ring C is, wh RNis hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 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.

4. The compound of claim 3, wherein T is of Formula I-1-i: i).

5. The compound of claim 4, wherein RNis hydrogen, C1-6alkyl, C3-4carbocyclyl, 3- to 4- 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.

6. The compound of any one of claims 2-5, wherein each RCis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; and c is 0.

7. The compound of claim 1, wherein T is of Formula I-1-ii:1-ii).

8. The compound of claim 7, wherein RB4is 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.

9. The compound of any one of claims 1-8, wherein B1is N.

10. The compound of any one of claims 1-9, wherein RB2is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

11. The compound of claim 10, wherein RB2is hydrogen.

12. The compound of any one of claims 1-11, wherein each RAis independently halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; and a is 0 or 1.

13. The compound of any one of claims 1-11, wherein at least one RAis independently halogen.

14. The compound of any one of claims 1-13, wherein L is I-2-i or I-2-ii ii), wherein:L’’ is 3- to 12-membered heterocyclylene optionally substituted with one or more Ru.

15. The compound of claim 14, wherein L’’ is 6- to 12-membered spiro heterocyclylene optionally substituted with one or more Ru.

16. The compound of any one of claims 1-15, wherein each L’ is independently C1-6 alkylene, C1-6heteroalkylene, 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, and l is an integer selected from 0 to 4.

17. The compound of any one of claims 1-13, wherein L is *-C(=O)-(3- to 12-membered heterocyclylene)-, *-(C3-12 carbocyclylene)-O-(3- to 12-membered heterocyclylene), *-(C1-12 alkylene)-(3- to 12-membered heterocyclylene)-C(=O)-(3- to 12-membered heterocyclylene), *- (C1-12 alkylene)-(3- to 12-membered heterocyclylene)-C(=O)-(C1-12 alkylene)-(3- to 12-membered heterocyclylene), *-(3- to 12-membered heterocyclylene)-C(=O)-(3- to 12-membered heterocyclylene), *-(C1-12alkylene)-(3- to 12-membered heterocyclylene)-(C1-12alkylene)-(3- to 12-membered heterocyclylene), *-(3- to 12-membered heterocyclylene)-(C1-12 alkylene)-(3- to 12- membered heterocyclylene), wherein the alkylene, heterocyclylene, or carbocyclylene is optionally substituted with one or more Ru, and *denotes attachment to T.

18. The compound of any one of claims 1-17, wherein C is of Formula I-3-i-1 .

19. The compound of claim 18, wherein RH1, 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.

20. The compound of claim 19, wherein RH1and RH5are independently halogen, and each of RH2and RH4is hydrogen.

21. The compound of claim 20, wherein C is of Formula I-3-i-2 .

22. The compound of any one of Formula I-3-ii-1 3-ii-1).

23. The compound of claim 22, wherein RJ1is C1-6 alkyl or C3-4 carbocyclyl.

24. The compound of claim 22 or 23, 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.

25. The compound of claim 24, wherein RH2, RH4, and RH5are independently hydrogen or halogen.

26. The compound of any one of claims 1-25, wherein K1is CRK1and RK1is hydrogen.

27. The compound of any one of claims 1-25, wherein K1is N.

28. The compound of any one of claims 1-27, wherein q is 1; and k is 0.

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

30. A pharmaceutical composition comprising the compound of any one of claims 1-29, and a pharmaceutically acceptable excipient.

31. A method of treating a disease or disorder comprising administering to a patient in need thereof a compound of any one of claims 1-29.

32. Use of a compound of any one of claims 1-29 in the manufacture of a medicament for treating a disease or disorder.

33. A compound of any one of claims 1-29 for use in treating a disease or disorder.

34. The method, use, or compound for use of any one of claims 31-33, wherein the disease or disorder is a SMARCA2 and / or SMARCA4 protein-mediated disease or disorder.

35. The method, use, or compound for use of any one of claims 31-33, wherein the disease or disorder is cancer.

36. The method, use, or compound for use of claim 35, 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).

37. The method, use, or compound for use of claim 36, 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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