Delivery compounds, compositions, and methods of use thereof

Abstract

The present disclosure provides nucleic acid delivery compounds. The present disclosure provides compositions comprising polynucleotide conjugates comprising a nucleic acid delivery compound. The present disclosure also provides compositions comprising polypeptide conjugates comprising a nucleic acid delivery compound. The present disclosure provides methods of modifying a target nucleic acid in a cell. The present disclosure also provides kits and methods for making nucleic acid delivery compounds or compositions. Also provided herein are methods for treating a disease or condition using the nucleic acid delivery compounds, compositions, or the pharmaceutical compositions.

Description

WSGR Docket No. 60555-703.601DELIVERY COMPOUNDS, COMPOSITIONS, AND METHODS OF USE THEREOF CROSS REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 727,081, filed on December 02, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Molecular and cellular therapeutics have changed the field of medicine by offering new ways to treat diseases at the molecular level. One such approach is RNA interference (RNAi), which involves the degradation of specific RNA targets triggered by double-stranded RNAs. By introducing RNA molecules that are complementary to RNA, such as coding or non-coding RNA, RNAi can effectively silence the expression of associated genes. Additionally, RNA aptamers, which are RNA molecules that can bind specifically to proteins, have emerged as potential therapeutics. Similar to small -molecule inhibitors and antibodies, RNA aptamers can block the activity of specific proteins, thereby modulating disease-related pathways. Lastly, clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing has shown promise as a therapeutic tool. CRISPR-Cas systems and associated guide nucleic acids can bind to and modify a targeted nucleic acid. The programmable nature of these CRISPR-Cas effector systems has facilitated their use as a versatile technology for use in, e.g., gene editing. By directly modifying target RNA sequences, CRISPR can correct genetic mutations and treat specific disorders at the molecular level. Overall, these molecular and cellular therapeutic approaches hold potential for developing targeted and personalized treatments for a wide range of diseases.

[0003] Precise delivery of molecular and cellular therapeutic payloads (e.g., gene -manipulating nucleic acid pay loads) unlocks a wide range of therapeutic applications. The growing understanding of payload delivery promotes the application of various molecular and cellular therapeutics to selectively function on hitherto “undruggable” cells, proteins, transcripts, and genes, thus potentially broadening therapeutic targets. For example, several molecular and cellular therapeutics have been approved for clinical use such as the antisense oligonucleotide (ASO) mipomersen for familial hypercholesterolemia, and the splice-switching oligonucleotide (SSO) eteplirsen for Duchenne muscular dystrophy. Molecular and cellular therapeutics also include siRNA delivery, with a recent shift toward mRNA delivery. The shift to mRNA payloads opens a myriad of therapeutic applications. These range from expression of antigens of choice as prophylactic viral and bacterial vaccines as well as therapeutic cancer vaccine applications, supplementation of missing proteins for enzyme replacement therapies, and expression of gene editing machinery, such as CRISPR, to gene edit aberrant natively expressed proteins.

[0004] In the world of delivering molecular and cellular therapeutic payloads (e.g., RNA-based therapeutics) into cells, most, if not all, roads can eventually lead to the endosomal escape abyss. Delivery of molecular and cellular therapeutics often involves internalization via endocytosis followed by trafficking through various membrane -bound vesicular compartments. For example, endocytosed molecular and cellular therapeutics can be transferred to early endosomes, which can mature into late endosomes and eventually into lysosomes. TheWSGR Docket No. 60555-703.601development of delivery modalities, such as LNPs, has addressed some of the challenges related to inefficient delivery. However, despite recent developments in the field, a commonly overlooked aspect regards the very limited release of the payloads into the cytoplasm. For efficient delivery, the payloads must be released into the cytosol before the maturation of late endosomes to lysosomes where the majority of the foreign materials are either degraded enzymatically or recycled outside of the target cells, with only a very limited amount of pay load released into the cytoplasm. The release of the payload prior to lysosomal maturation can be a crucial stage for efficient delivery and is known as endosomal escape. This process can be inefficient and is considered a bottleneck. For example, large, hydrophilic, negatively-charged properties often prevent molecular and cellular therapeutic payloads (e.g., nucleic acid payloads) from passively diffusing across the lipid bilayers. Thus, escaping from the endosome and releasing payloads into the cytoplasm in anon-toxic manner is a critical technical problem, resulting in inefficient access of therapeutic payloads to the sites of action in the nucleus or cytosol of cells. This problem has meant that large payload doses are often administered to attain therapeutic effects, risking drug -related toxicities. One approach to overcome this challenge has been the use of complex delivery systems such as cationic lipid or polymer nanoparticles, however these approaches often suffer from toxicity and biodistribution problems associated with the delivery system itself. Therefore, there remains a need for the development of alternative strategies to enhance the delivery of molecular and cellular therapeutic payloads to their intracellular targets.SUMMARY

[0005] The compositions and methods described herein can overcome the drawbacks of the currently available approaches for payload delivery to sites of action in the nucleus and / or cytosol of cells. Provided herein, are compositions, methods, and kits useful for delivering therapeutic payloads to intracellular targets.

[0006] Provided herein, in some aspects, are compounds of Formula (I), or a pharmaceutically acceptable saltR7thereof, wherein: Formula (I) is is a 3-10 membered heterocycloalkyl comprising 0-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur; each R13is independently selected from halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-C6alkyl, -OC(=O)C3-Ci0cycloalkyl, -OC(=O)C6-Ci0aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -WSGR Docket No. 60555-703.601NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, and -C(=O)N(Ci-C6alkyl)2; or two R13are taken together to form =0 or 3-20 membered heterocycloalkyl; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -OCi-Ce alkyl, -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl; p is 1, 2, 3, 4, or 5; provided thatO-<Ri3>c O- Y JW iW1is not; X is selected from N or CR12; R’-R8and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)C1-C6alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2Ce-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -OCi-C6alkyl, -NH2, -OP(=O)(OH)2, Ci-C6alkyl, Ci-C6heteroalkyl, C6-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.WSGR Docket No. 60555-703.601

[0007] Provided herein, in some aspects, are compounds of Formula (II), or a pharmaceutically acceptable saltthereof, wherein: Formula (II) is R4R5, R9and R10are each independently H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3-C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1-5 R11; X is selected from N or CR12; R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-C6alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-Ce alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCI-C6alkyl, or -C(=O)N(Ci-C6alkyl)2; or two R11are taken together to form =0 or 3-20 membered heterocycloalkyl; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(CI-C6alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-; each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, or -OH; each m is independently 0, 1, 2, or 3; and wherein at least one of R’-R8is -CF3, -NO2, -CN, -O-(C2-C6alkyl), -COOH, -C(=O)H, -COOCi-C6alkyl, -OH, -NH2, -NHCI-C6alkyl wherein Ci-Ce alkyl is optionally substituted with -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, -N(Ci-Ce alkyl)2, C3-C10 cycloalkyl, C2-C6 alkyl optionally substituted with an -OH, or C2-C8 alkynyl.WSGR Docket No. 60555-703.601

[0008] Provided herein, in some aspects, are compounds of Formula (III), or a pharmaceutically acceptablesalt thereof, wherein: Formula (III) is R9and R10are each independently H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3-C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are optionallyI v K / V1VV Q JTJ yv-substituted with 1-5 R11; provided that1is not1or; X is selected from N or CR12; R1- R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; or two R11are taken together to form =0 or 3-20 membered heterocycloalkyl; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-; each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, or -OH; and each m is independently 0, 1, 2, or 3.WSGR Docket No. 60555-703.601

[0009] Provided herein, in some aspects, are compounds of Formula (IV), or a pharmaceutically acceptablesalt thereof, wherein: Formula (IV) is R4R5, R9and R10are each independently H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3-C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1-5 R11; X is selected from N or CR12; R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-C6alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-Ce alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCI-C6alkyl, or -C(=O)N(Ci-C6alkyl)2; or two R11are taken together to form =0 or 3-20 membered heterocycloalkyl; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(CI-C6alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; L1is -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-; each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, or -OH; and each m is independently 0, 1, 2, or 3.WSGR Docket No. 60555-703.601

[0010] Provided herein, in some aspects, are compounds of Formula (V), or a pharmaceutically acceptable saltthereof, wherein: Formula (V) is R4R5, R9and R10are each independently H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3-C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1-5 R11; X is selected from N or CR12; R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-C6alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-Ce alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCI-C6alkyl, or -C(=O)N(Ci-C6alkyl)2; or two R11are taken together to form =0 or 3-20 membered heterocycloalkyl; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(CI-C6alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl; and L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-; each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, or -OH; each m is independently 0, 1, 2, or 3.WSGR Docket No. 60555-703.601

[0011] Provided herein, in some aspects, are compounds of Formula (SML), or a pharmaceutically acceptablesalt thereof, wherein: Formula (SML) is 1— -I, R9and R10are each independently H, Ci-Ce alkyl, C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3-C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl optionally substituted optionally substituted with 1-5 R11; X is selected from N or CR12; R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-C6alkyl, -OC(=O)C3-Ci0cycloalkyl, -OC(=O)C6-Ci0aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; or two R11are taken together to form =0 or 3-20 membered heterocycloalkyl; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-; each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, or -OH; each m is independently 0, 1, 2, or 3; and Lsis a proteolytic group or a pH labile group.WSGR Docket No. 60555-703.601

[0012] Provided herein, in some aspects, are compounds of Formula (SML), or a pharmaceutically acceptablesalt thereof, wherein: Formula (SML) is 1— -I, R9and R10are each independently H, Ci-Ce alkyl, C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3-C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl optionally substituted optionally substituted with 1-5 R11; X is selected from N or CR12; R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-C6alkyl, -OC(=O)C3-Ci0cycloalkyl, -OC(=O)C6-Ci0aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; or two R11are taken together to form =0 or 3-20 membered heterocycloalkyl; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-; each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, or -OH; each m is independently 0, 1, 2, or 3; and Lsis -L-Q, wherein: L is absent or C1-C20 alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with - CR’=CR’-, -O-, -N(R’)-, -C(=O)-, C(=S)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, - N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(OR’)O-, -P(O)(R’)-, -Cy-, or an amino acid sequence comprising 2-25 amino acids; eachWSGR Docket No. 60555-703.601-Cy- is independently a bivalent ring selected from C3-C20 cycloalkylene, C6-C20 arylene, 3-20 membered heteroarylene, or 3-20 membered heterocycloalkylene, wherein each group is optionally and independently 0 0 ir$, irj., substituted with 1-20 Rs; Q is -N=C=O, -NC, -N3, 0, -C(R’)=C(R’)2, or «, wherein 0 is optionally and indpendently subsituted with 1-5 R’; each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, -S(O)2R, or a protecting group; each R is independently hydrogen, halogen, or an optionally substituted group selected from C1-C10 aliphatic, C1-C10 heteroalkyl, Ce-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl, wherein each group is optionally and independently substituted with 1-20 Rs, or two R groups are optionally and independently taken together to form a covalent bond or =0; or two or more R groups on the same atom are optionally and independently taken together with the atom to form a 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the atom, 0-5 heteroatoms; or two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the intervening atoms, 0-5 heteroatoms; and each Rsis independently halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OCi-Ce alkyl, -OC3-C10 cycloalkyl, -OCe-Cioaryl, -0-5-10 membered heteroaryl, -0-3-20 membered heterocycloalkyl, -OC(=O)Ci-C6alkyl, -OC(=O)C3-Ci0cycloalkyl, -OC(=O)C6-Ci0aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2Ce-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, -C(=O)N(Ci-C6alkyl)2; wherein each Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.WSGR Docket No. 60555-703.601

[0013] Provided herein, in some aspects, are compounds of Formula (C), or a pharmaceutically acceptable saltR9and R10are each independently H, Ci-Ce alkyl, C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3-C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl optionally substituted optionally substituted with 1-5 R11; X is selected from N or CR12; R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-C6alkyl, -OC(=O)C3-Ci0cycloalkyl, -OC(=O)C6-Ci0aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; or two R11are taken together to form =0 or 3-20 membered heterocycloalkyl; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-; each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, or -OH; each m is independently 0, 1, 2, or 3; Lcis -L-Q’-, wherein: L is absent or C1-C20 alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with - CR’=CR’-, -O-, -N(R’)-, -C(=O)-, C(=S)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, - N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R’)-, -P(OR’)-WSGR Docket No. 60555-703.601, -P(O)(OR’)-, -P(O)(OR’)O-, -P(O)(R’)-, -Cy-, or an amino acid sequence comprising 2-25 amino acids; each -Cy- is independently a bivalent ring selected from C3-C20 cycloalkylene, C6-C20 arylene, 3-20 membered heteroarylene, or 3-20 membered heterocycloalkylene, wherein each group is optionally and independentlysubstituted with 1-20 Rs; Q’ isO is optionally and indpendently subsituted with 1-5 R’; each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, -S(O)2R, or a protecting group; each R is independently hydrogen, halogen, or an optionally substituted group selected from C1-C10 aliphatic, C1-C10 heteroalkyl, C„-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl, wherein each group is optionally and independently substituted with 1-20 Rs, or two R groups are optionally and independently taken together to form a covalent bond or =0; or two or more R groups on the same atom are optionally and independently taken together with the atom to form a 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the atom, 0-5 heteroatoms; or two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the intervening atoms, 0-5 heteroatoms; and each Rsis independently halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OCi-Ce alkyl, -OC3-C10 cycloalkyl, -OCe-Cio aryl, -0-5-10 membered heteroaryl, -0-3-20 membered heterocycloalkyl, -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2Ce-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, -C(=O)N(Ci-C6alkyl)2; wherein each Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl; and P is a polymer.WSGR Docket No. 60555-703.601

[0014] Provided herein, in some aspects, are compounds of Table 1A or a pharmaceutically acceptable salt thereof.

[0015] Also provided herein, in some aspects, are compounds of Table IB or a pharmaceutically acceptable salt thereof.

[0016] Provided herein, in some aspects, are compositions comprising the compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

[0017] Provided herein, in some aspects, are compositions comprising a polynucleotide conjugate comprising: a synthetic polynucleotide; and a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the polynucleotide conjugate further comprises: a targeting moiety that binds to a target cell, wherein the compound is conjugated to the targeting moiety or the synthetic polynucleotide.

[0019] In some embodiments, the compound is conjugated to the targeting moiety.

[0020] In some embodiments, the targeting moiety binds to an extracellular domain of a receptor expressed by a target cell.

[0021] In some embodiments, the targeting moiety binds to an extracellular domain of transferrin receptor protein 1 (TfRl, CD71), an insulin-like growth factor 1 receptor (IGF1R), an insulin-like growth factor 1 receptor (IGF2R), or Nephrin.

[0022] In some embodiments, the targeting moiety binds to a Nephrin receptor.

[0023] In some embodiments, the targeting moiety comprises polypeptide sequence with less than 150 amino acids.

[0024] In some embodiments, the targeting moiety comprises polypeptide sequence with less than 100 amino acids.

[0025] In some embodiments, the targeting moiety comprises polypeptide sequence with more than 50 amino acids.

[0026] In some embodiments, the targeting moiety comprises polypeptide sequence with more than 60, 70, 80, or more amino acids.

[0027] In some embodiments, the targeting moiety comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs: 31-151.

[0028] In some embodiments, the targeting moiety that binds to a Nephrin receptor comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the sequence of VRVTREGNDLTIETPDRTFHLTYIPGVSPEEAIASAEATLRRLGLDSPEVRAAVRDFVAEQA (SEQ ID NO: 152).

[0029] In some embodiments, the targeting moiety that binds to a Nephrin receptor comprises the sequence of VRVTREGNDLTIETPDRTFHLTYIPGVSPEEAIASAEATLRRLGLDSPEVRAAVRDFVAEQA (SEQ ID NO: 152).WSGR Docket No. 60555-703.601

[0030] In some embodiments, the compound is conjugated to an N-terminus or a C-terminus of the targeting moiety.

[0031] In some embodiments, the compound is conjugated to an N-terminus of the targeting moiety.

[0032] In some embodiments, the compound is conjugated to a C-terminus of the targeting moiety.

[0033] In some embodiments, the compound is conjugated to the synthetic polynucleotide.

[0034] In some embodiments, the compound is conjugated to a 5 ' end or a 3' end of the synthetic polynucleotide.

[0035] In some embodiments, the compound is conjugated to a 3' end of the synthetic polynucleotide.

[0036] In some embodiments, the compound is conjugated to a 5' end of the synthetic polynucleotide.

[0037] In some embodiments, the synthetic polynucleotide comprises a noncoding ribonucleic acid molecule.

[0038] In some embodiments, the synthetic polynucleotide comprises a targeting ribonucleic acid sequence configured to hybridize to a target nucleic acid sequence.

[0039] In some embodiments, the target nucleic acid sequence is a ribonucleic acid (RNA) sequence.

[0040] In some embodiments, the RNA sequence is a messenger RNA (mRNA) sequence.

[0041] In some embodiments, the targeting ribonucleic acid sequence is complementary to an exon, an intron, an exon / intron junction, an intron / exon junction, an untranslated region or a regulatory region of the target nucleic acid sequence.

[0042] In some embodiments, the synthetic polynucleotide comprises a single -stranded synthetic polynucleotide.

[0043] In some embodiments, the single-stranded synthetic polynucleotide is a chemically modified polynucleotide.

[0044] In some embodiments, the single-stranded synthetic polynucleotide comprises about 16 to about 100 contiguous nucleotides.

[0045] Provided herein, in some aspects, are compositions comprising a polypeptide; and a compound disclosed herein, or the pharmaceutically acceptable salt or the solvate thereof.

[0046] Provided herein, in some aspects, are compositions comprising a polypeptide conjugate comprising: a polypeptide; and a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the polypeptide is a CRISPR-Cas effector polypeptide.

[0048] In some embodiments, the CRISPR-Cas effector polypeptide is a Type II CRISPR-Cas effector polypeptide, a Type V CRISPR-Cas effector polypeptide, or a Type VI CRISPR-Cas effector polypeptide.

[0049] In some embodiments, the CRISPR-Cas effector polypeptide is a SpyCas9 or a variant thereof.

[0050] In some embodiments, the CRISPR-Cas effector polypeptide is GeoCas9 or a variant thereof.

[0051] In some embodiments, the CRISPR-Cas effector polypeptide is catalytically active.

[0052] In some embodiments, the CRISPR-Cas effector polypeptide exhibits reduced catalytic activity compared to a wild-type CRISPR-Cas effector polypeptide.

[0053] In some embodiments, the polypeptide conjugate further comprises: an engineered guide ribonucleic acid structure or a nucleic acid encoding the engineered guide ribonucleic acid structure, wherein theWSGR Docket No. 60555-703.601engineered guide ribonucleic acid structure is configured to form a complex with the CRISPR-Cas effector polypeptide, wherein said engineered guide ribonucleic acid structure comprises: a guide ribonucleic acid sequence configured to hybridize to a target nucleic acid sequence; and atracr ribonucleic acid sequence.

[0054] In some embodiments, the engineered guide ribonucleic acid structure comprises: at least two ribonucleic acid polynucleotides; or a single ribonucleic acid polynucleotide comprising the guide ribonucleic acid sequence and the tracr ribonucleic acid sequence.

[0055] In some embodiments, the tracr ribonucleic acid sequence is configured to bind to the CRISPR-Cas effector polypeptide.

[0056] In some embodiments, the guide ribonucleic acid sequence is complementary to a eukaryotic, a fungal, a plant, a mammalian, or a human genomic sequence.

[0057] In some embodiments, the engineered guide ribonucleic acid structure comprises a ribonucleic acid sequence comprising a stem and a loop, wherein said stem comprises at least 12 pairs of ribonucleotides.

[0058] In some embodiments, the engineered guide ribonucleic acid structure further comprises a second stem and a second loop, wherein the second stem comprises at least 5 pairs of ribonucleotides.

[0059] In some embodiments, the engineered guide ribonucleic acid structure further comprises a ribonucleic acid structure comprising at least two hairpins.

[0060] In some embodiments, the engineered guide ribonucleic acid structure comprises a ribonucleic acid sequence comprising at least four hairpins comprising a stem and a loop.

[0061] In some embodiments, the engineered guide ribonucleic acid structure comprises a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to non-degenerate nucleotides of SEQ ID NO: 12.

[0062] In some embodiments, the engineered guide ribonucleic acid structure comprises at least one modification.

[0063] In some embodiments, the least one modification includes 2'-O-methoxyethoxy (2'-0Me), 2'- O-(2-methoxyethyl) (2'-O-moe), 2'-fluoro (2'-F), locked nucleic acid (LNA), pseudouridine (y), phosphorothioate (PS) bond, phosphorodiamidate morpholino oligomer (PMO), and / or 2'-phosphorylation (2'-P).

[0064] In some embodiments, the engineered guide ribonucleic acid structure comprises (i) a 5' end modification, (ii) a 3' end modification, or (iii) a 5' end modification and a 3' end modification.

[0065] In some embodiments, the polypeptide conjugate further comprises: a targeting moiety that binds to a target cell, wherein the compound is conjugated to the polypeptide or the targeting moiety.

[0066] In some embodiments, the compound is conjugated to the targeting moiety.

[0067] In some embodiments, the targeting moiety binds to an extracellular domain of a receptor expressed by a target cell.

[0068] In some embodiments, the targeting moiety binds to an extracellular domain of transferrin receptor protein 1 (TfRl, CD71), an insulin-like growth factor 1 receptor (IGF1R), an insulin-like growth factor 1 receptor (IGF2R), or Nephrin.

[0069] In some embodiments, the targeting moiety binds to a Nephrin receptor.WSGR Docket No. 60555-703.601

[0070] In some embodiments, the targeting moiety comprises polypeptide sequence with less than 150 amino acids.

[0071] In some embodiments, the targeting moiety comprises polypeptide sequence with less than 100 amino acids.

[0072] In some embodiments, the targeting moiety comprises polypeptide sequence with more than 50 amino acids.

[0073] In some embodiments, the targeting moiety comprises polypeptide sequence with more than 60, 70, 80, or more amino acids.

[0074] In some embodiments, the targeting moiety comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs: 31-151.

[0075] In some embodiments, the targeting moiety that binds to a Nephrin receptor comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the sequence of VRVTREGNDLTIETPDRTFHLTYIPGVSPEEAIASAEATLRRLGLDSPEVRAAVRDFVAEQA (SEQ ID NO: 152).

[0076] In some embodiments, the targeting moiety that binds to a Nephrin receptor comprises the sequence of VRVTREGNDLTIETPDRTFHLTYIPGVSPEEAIASAEATLRRLGLDSPEVRAAVRDFVAEQA (SEQ ID NO: 152).

[0077] In some embodiments, the compound is conjugated to an N-terminus or a C-terminus of the targeting moiety.

[0078] In some embodiments, the compound is conjugated to an N-terminus of the targeting moiety.

[0079] In some embodiments, the compound is conjugated to a C-terminus of the targeting moiety.

[0080] In some embodiments, the compound is conjugated to an N-terminus or a C-terminus of the CRISPR-Cas effector polypeptide.

[0081] In some embodiments, the compound is conjugated to an N-terminus or a C-terminus of the CRISPR-Cas effector polypeptide.

[0082] In some embodiments, the compound is conjugated to a C-terminus of the CRISPR-Cas effector polypeptide.

[0083] In some embodiments, the polypeptide conjugate comprises a linker between the targeting moiety and the CRISPR-Cas effector polypeptide.

[0084] In some embodiments, the linker between the targeting moiety and the CRISPR-Cas effector polypeptide is a proteolytically cleavable.

[0085] In some embodiments, the polypeptide conjugate comprises one or more nuclear localization sequences (NLSs).

[0086] In some embodiments, the one or more NLSs comprise the amino acid sequence K(K / R)X(K / R), where X is any amino acid.WSGR Docket No. 60555-703.601

[0087] In some embodiments, the one or more NLSs comprise the amino acid sequence PKKKRKV.

[0088] In some embodiments, the one or more NLSs are located at the N-terminus of the CRISPR-Cas effector polypeptide.

[0089] In some embodiments, the polypeptide conjugate further comprises at least one additional heterologous polypeptide.

[0090] In some embodiments, the at least one additional heterologous polypeptide is a deaminase, a base editor, a reverse transcriptase, a transcription modulator, or an epigenetic modulator.

[0091] Provided herein, in some aspects, are recombinant polynucleotide molecules comprising a nucleotide sequence encoding the polynucleotide disclosed herein, a polypeptide disclosed herein, a NLS disclosed herein, a targeting moiety disclosed herein, or any combination thereof of.

[0092] Provided herein, in some aspects, are recombinant expression vectors comprising a nucleic acid disclosed herein.

[0093] Provided herein, in some aspects, are cells comprising a compound disclosed herein, a composition disclosed herein, a recombinant polynucleotide molecule disclosed herein, a recombinant expression vector disclosed herein, or any combination thereof.

[0094] Provided herein, in some aspects, are pharmaceutical compositions comprising a compound disclosed herein, a composition disclosed herein, a nucleic acid disclosed herein, a recombinant expression vector disclosed herein, a cell disclosed herein, or any combination thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0095] Provided herein, in some aspects, are methods of treating a condition or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, a composition disclosed herein, a nucleic acid disclosed herein, a recombinant expression vector disclosed herein, a cell disclosed herein, a pharmaceutical composition disclosed herein, or any combination thereof, thereby treating the condition or disease in the subject.

[0096] Provided herein, in some aspects, are methods of modifying a target nucleic acid, the method comprising contacting the target nucleic acid with a composition disclosed herein.

[0097] Provided herein, in some aspects, are methods of modifying a target nucleic acid in a cell, the method comprising introducing into the eukaryotic cell a composition disclosed herein.

[0098] Provided herein, in some aspects, are methods of editing a locus within a cell, the method comprising introducing into the cell a composition disclosed herein.INCORPORATION BY REFERENCE

[0099] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGSWSGR Docket No. 60555-703.601

[0100] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0101] FIG. 1 shows a heatmap of the number of Gal9 puncta measured per cell after treatment with additional exemplary compounds of the present disclosure.

[0102] FIG. 2A shows the normalized weight of mice post-treatment with various doses of an exemplary compound of the present disclosure for the determination of the maximum tolerated dose.

[0103] FIG. 2B shows the normalized weight of mice post-treatment with various doses of an additional exemplary compound of the present disclosure for the determination of the maximum tolerated dose.

[0104] FIG. 2C depicts the normalized weight of mice post-treatment with exemplary compounds of the present disclosure for the determination of the maximum tolerated dose.

[0105] FIG. 2D depicts the normalized weight of mice post-treatment with additional exemplary compounds of the present disclosure for the determination of the maximum tolerated dose.

[0106] FIG. 3A depicts the biodistribution of a control endosomal escape compound in a mouse model in various tissue / cell types after treatment with 5 mg / kg of compound or 10 mg / kg for 1 hour.

[0107] FIG. 3B shows a zoomed in view of FIG. 3A.

[0108] FIG. 3C depicts the biodistribution of a control endosomal escape compound in a mouse model in various tissue / cell types after treatment with 5 mg / kg of compound for 15 minutes, 1 hour, or 3 hours.

[0109] FIG. 3D shows a zoomed in view of FIG. 3C.

[0110] FIG. 3E depicts the biodistribution of exemplary compounds of the present disclosure in a mouse model in various tissue / cell types after treatment with 10 mg / kg of compound for 1 hour.

[0111] FIG. 3F depicts the biodistribution of exemplary compounds of the present disclosure in a mouse model in various tissue / cell types, such as blood, brain, GA muscle, and heart.

[0112] FIG. 3G depicts the biodistribution of exemplary compounds of the present disclosure in a mouse model in various tissue / cell types, such as kidney, liver, lung, and spleen.

[0113] FIG. 4A shows the normalized weight of wild-type mice post-treatment with CRISPR-Cas9 RNPs and an exemplary compound of the present disclosure.

[0114] FIG. 4B shows the normalized weight of Ai9 mice post-treatment with CRISPR-Cas9 RNPs and an exemplary compound of the present disclosure.

[0115] FIG. 4C shows the percent editing of a target gene in liver tissue in wild-type mice post-treatment with either a CRISPR-Cas9 RNPs and an exemplary compound of the present disclosure, or an exemplary compound only.

[0116] FIG. 4D shows the percent editing of a target gene in spleen tissue in wild-type mice post-treatment with either a CRISPR-Cas9 RNPs and an exemplary compound of the present disclosure, or an exemplary compound only.WSGR Docket No. 60555-703.601

[0117] FIG. 4E depicts the percent editing of a target gene in kidney tissue in wild-type mice post-treatment with either a CRISPR-Cas9 RNPs and an exemplary compound of the present disclosure, or an exemplary compound only.

[0118] FIG. 4F depicts the percent editing of a target gene in lung tissue in wild-type mice post-treatment with either a CRISPR-Cas9 RNPs and an exemplary compound of the present disclosure, or an exemplary compound only.

[0119] FIG. 4G shows the percent editing of a tdTomato in Ai9 mice post-treatment with either a CRISPR-Cas9 RNPs and an exemplary compound of the present disclosure, or an exemplary compound only.

[0120] FIG. 4H shows the percent editing of tdTomato in Ai9 mice post-treatment with a CRISPR-Cas9 RNPs and an exemplary compound of the present disclosure.

[0121] FIG. 41 depicts shows the percent editing of tdTomato in Ai9 mice post-treatment with either a CRISPR-Cas9 RNPs and an exemplary compound of the present disclosure.DETAILED DESCRIPTION COMPOSITIONS

[0122] The present disclosure provides compositions. Compositions provided herein can comprise a compound (such as a small molecule), a polymer (such as a polynucleotide, a polypeptide, etc.), a polymer-compound conjugate (such as a polynucleotide-small molecule conjugate, a polypeptide -small molecule conjugate, etc.), or any combination thereof.Small molecule

[0123] Provided herein, in some aspects, are compounds for delivering polymers to a location of interest. In some cases, the polymer is a polynucleotide, a polypeptide, or a combination thereof. In some embodiments, the polymer comprises a polymer conjugate, such as a polynucleotide conjugate, a polypeptide conjugate, or a combination thereof. In some cases, the location of interest is a target cell, a target tissue, or a combination thereof. In some cases, the compounds disclosed herein promote endosomal escape (and / or lysosomal escape) of the polymers disclosed herein. For example, the compounds disclosed herein may be useful for delivering polymers to a location of interest by increasing endosome permeability, resulting in release of entrapped polymers (such as a polypeptide conjugate), and enabling payload delivery to sites of action in the nucleus and / or cytosol of target cells. In some embodiments, the compounds disclosed herein disrupt an endosomal membrane (and / or a lysosomal membrane). In some embodiments, the compounds disclosed herein specifically target and disrupt an endosomal membrane (and / or a lysosomal membrane).

[0124] Among other things, the present disclosure provides a compound of Formula (A), or a pharmaceutically acceptable salt thereof, wherein:WSGR Docket No. 60555-703.601Formula (A)R9and R10are each independently H, Ci-Ce alkyl, C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3-C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl optionally substituted optionally substituted with 1-5 R11;X is selected from N or CR12;R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), - O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; ortwo R11are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-;WSGR Docket No. 60555-703.601each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, or -OH; andeach m is independently 0, 1, 2, or 3.

[0125] In some embodiments, the present disclosure provides a compound of Formula (A-l), or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein:Formula (A-l).

[0126] In some embodiments, R9is H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3-C10 cycloalkyl are optionally substituted with 1-5 R11as described herein. In some embodiments, R9is H. In some embodiments, R9is Ci-Ce alkyl optionally substituted with 1-5 R11each independently as described herein. In some embodiments, R9is Ci-Ce alkyl optionally substituted with 1-5 halogen or OH. In some embodiments, R9is Ci-Cg alkyl. In some embodiments, R9is C1-C3 alkyl. In some embodiments, R9is methyl. In some embodiments, R9is ethyl. In some embodiments, R9is propyl. In some embodiments, R9is isopropyl. In some embodiments, R9is butyl. In some embodiments, R9is isobutyl. In some embodiments, R9is t-butyl. In some embodiments, R9is C3-C10 cycloalkyl optionally substituted with 1-5 R11each independently as described herein. In some embodiments, R9is C3-C10 cycloalkyl optionally substituted with 1-5 halogen, OH, or methyl. In some embodiments, R9is C3-C6 cycloalkyl optionally substituted with 1-5 Vhalogen, OH, or methyl. In some embodiments, R9is1. In some embodiments, R9isM 9 Q I I. In some embodiments, R9is1. In some embodiments, R9is IIn some embodiments, R9isR10

[0127] In some embodiments, R10is H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3-C10 cycloalkyl are optionally substituted with 1-5 R11as described herein. In some embodiments, R10is H. InWSGR Docket No. 60555-703.601some embodiments, R10is Ci-Ce alkyl optionally substituted with 1-5 R11each independently as described herein. In some embodiments, R10is Ci-Ce alkyl optionally substituted with 1-5 halogen or OH. In some embodiments, R10is Ci-Ce alkyl. In some embodiments, R10is C1-C3 alkyl. In some embodiments, R10is methyl. In some embodiments, R10is ethyl. In some embodiments, R10is propyl. In some embodiments, R10is isopropyl. In some embodiments, R10is butyl. In some embodiments, R10is isobutyl. In some embodiments, R10is t-butyl. In some embodiments, R10is C3-C10 cycloalkyl optionally substituted with 1-5 R11each independently as described herein. In some embodiments, R10is C3-C10 cycloalkyl optionally substituted with 1-5 halogen, OH, or methyl. In some embodiments, R10is C3-C6 cycloalkyl optionally Vsubstituted with 1-5 halogen, OH, or methyl. In some embodiments, R10is1. In some embodiments, R10ri <? Qis1. In some embodiments, R10is1. In some embodiments, R10is I. In some embodiments,x / vw\R10is I

[0128] In some embodiments, whereinR1° NR9\ N / R!° NR9In some embodiments, — ' — is. In some embodiments, — ' — isIn some embodiments,In some embodiments,some embodiments,some embodiments,. In some p10R'N HNembodiments,. In some embodiments,— is

[0129] In some embodiments, R9and R10are taken together to form a 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1-5 R11independently as described herein. In some embodiments, R9and R10are taken together to form a 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is optionally substituted with 1-5 R11independently as described herein. In some embodiments, R9and R10are taken together to form a bridged, bicyclic, or spirocyclic 3-10 membered heterocycloalkyl optionally substituted with 1-5 R11independently as described herein. In some embodiments, R9and R10are takenWSGR Docket No. 60555-703.601together to form a 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is optionally substituted with 1-5 groups selected from halogen, Ci-Ce alkyl, hydroxyl substituted Ci-Ce alkyl, methoxy substituted Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkynyl, =0, -OH, -OMe, -NH2, -NHMe, -NMe2, -NO2, -C(O)Me, or -C(=0)NH2, 3-6 membered heterocycloalkyl, or 3-6 membered heterocycloalkyl substituted with Ci-Ce haloalkyl. In some embodiments, R9and R10are taken together to form a 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted with 1-5 groups selected from halogen, Ci-Ce alkyl, hydroxyl substituted Ci-Ce alkyl, methoxy substituted Ci-Ce alkyl, Ci-C6haloalkyl, C2-C6alkynyl, =0, -OH, -OMe, -NH2, -NHMe, -NMe2, -NO2, -C(0)Me, or -C(=0)NH2, 3-6 membered heterocycloalkyl, or 3-6 membered heterocycloalkyl substituted with Ci-Ce haloalkyl. In some embodiments, R9and R10are taken together to form a 4 membered heterocycloalkyl, wherein the 4 membered heterocycloalkyl is optionally substituted with 1-5 groups selected from halogen, Ci-Ce alkyl, hydroxyl substituted Ci-Ce alkyl, methoxy substituted Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkynyl, =0, -OH, -OMe, -NH2, -NHMe, -NMe2, -NO2, -C(0)Me, or -C(=0)NH2, 3-6 membered heterocycloalkyl, or 3-6 membered heterocycloalkyl substituted with Ci-Ce haloalkyl. In some embodiments, R9and R10are taken together to form a 5 membered heterocycloalkyl, wherein the 5 membered heterocycloalkyl is optionally substituted with 1-5 groups selected from halogen, Ci-Ce alkyl, hydroxyl substituted Ci-Ce alkyl, methoxy substituted Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkynyl, =0, -OH, -OMe, -NH2, -NHMe, -NMe2, -NO2, -C(0)Me, or -C(=0)NH2, 3-6 membered heterocycloalkyl, or 3-6 membered heterocycloalkyl substituted with Ci-Ce haloalkyl. In some embodiments, R9and R10are taken together to form a 6 membered heterocycloalkyl, wherein the 6 membered heterocycloalkyl is optionally substituted with 1-5 groups selected from halogen, Ci-Ce alkyl, hydroxyl substituted Ci-Ce alkyl, methoxy substituted Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkynyl, =0, -OH, -OMe, -NH2, -NHMe, -NMe2, -NO2, -C(0)Me, or -C(=0)NH2, 3-6 membered heterocycloalkyl, or 3-6 membered heterocycloalkyl substituted with Ci-Ce haloalkyl. In some embodiments, R9and R10are taken together to form a 7 membered heterocycloalkyl, wherein the 7 membered heterocycloalkyl is optionally substituted with 1-5 groups selected from halogen, Ci-Ce alkyl, hydroxyl substituted Ci-Ce alkyl, methoxy substituted Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkynyl, =0, -OH, -OMe, -NH2, -NHMe, -NMe2, -NO2, -C(0)Me, or -C(=0)NH2, 3-6 membered heterocycloalkyl, or 3-6 membered heterocycloalkyl substituted with Ci-Ce haloalkyl. In some embodiments, R9and R10are taken together to form a 3-10 membered heterocycloalkyl, wherein the 3-10 membered heterocycloalkyl is optionally substituted with 1-5 groups HO.selected from halogen, methyl,, -CF3, I, -OH, -NH2, -NHMe, =0, -OH, - N=NF3C^COMe, -NH2, -NHMe, -NMe2, -NO2, -C(0)Me, or -C(=0)NH2,, or. In some embodiments, R9and R10are taken together to form a 3-6 membered heterocycloalkyl, wherein the 3-6 membered HO^ HO. heterocycloalkyl is optionally substituted with 1-5 R11selected from halogen, methyl,WSGR Docket No. 60555-703.601-CF3I, -OH, -NH2, -NHMe, =0, -OH, -OMe, -NH2, -NHMe, -NMe2, -N02, -C(O)Me, or - N=NC(=0)NH2, 1 I orIn some embodiments, R9and R10are taken together to form a 3-6 membered heterocycloalkyl.

[0130] In some embodiments, R and R are taken together to form I, optionally substituted with 1-5 R1 1 n vA N / v independently as described herein. In some embodiments, R9and R1are taken together to torn ' optionally substituted with 1-5 R11independently as described herein. In some embodiments, R9and R10aretaken together to form1, optionally substituted with 1-5 R11independently as described herein. In someembodiments, R9and R10are taken together to form1, optionally substituted with 1-5 R11independently as described herein. In some embodiments, R9and R10are taken together to formoptionally substituted with 1-5 R11independently as described herein.v

[0131] In some embodiments, R9and R10are taken together to formI, optionally substituted with 1-5 R11independently as described herein.

[0132] In some embodiments, R9and R10are taken together to form, optionally substituted with 1-5 R11independently as described herein.

[0133] In some embodiments, R9and R10are taken together to form, optionally substituted with 1-5 R11independently as described herein.WSGR Docket No. 60555-703.601

[0134] In some embodiments, R9and R10are taken together to form, optionally substituted with 1-5 R11independently as described herein.L / NWX

[0135] In some embodiments, R9and R10are taken together to form1, optionally substituted with 1-5 R11independently as described herein.HN

[0136] In some embodiments, R9and R10are taken together to form, optionally substituted with 1-5 R11independently as described herein.

[0137] In some embodiments, R9and R10are taken together to form, optionally substituted with 1-5 R11independently as described herein.N.

[0138] In some embodiments, R9and R10are taken together to form, optionally substituted with 1-5 R11independently as described herein..0.•W N'

[0139] In some embodiments, R9and R10are taken together to form1, optionally substituted with 1-5 R11independently as described herein.NCI

[0140] In some embodiments, R9and R10are taken together to form, optionally substituted with 1-5 R11independently as described herein.WSGR Docket No. 60555-703.601

[0141] In some embodiments, R9and R10are taken together to form i. In some embodiments, R9and R10are taken together to form In some embodiments, R9and R10are taken together to form I. In QHsome embodiments, R9and R10are taken together to form1. In some embodiments, R9and R10aretaken together to formIn some embodiments, R9and R10are taken together to formI. Insome embodiments, R9and R10are taken together to form I. In some embodiments, R9and R10areN taken together to form I In some embodiments, R9and R10are taken together to form I. In someembodiments, R9and R10are taken together to form1. In some embodiments, R9and R10are takentogether to formIn some embodiments, R9and R10are taken together to formembodiments, R9and R10are taken together to form1In some embodiments, R9and R10are takenNtogether to form In some embodiments, R9and R10are taken together to form. In someWSGR Docket No. 60555-703.601embodiments, R9and R10are taken together to formIn some embodiments, R9and R10are takentogether to formIn some embodiments, R9and R10are taken together to form. In some OHANembodiments, R9and R10are taken together to form. In some embodiments, R9and R10are takentogether to formIn some embodiments, R9and R10are taken together to form. In someembodiments, R9and R10are taken together to formIn some embodiments, R9and R10are takenOMeN N together to form — ' —. In some embodiments, R9and R10are taken together to form — I —. In someembodiments, R9and R10are taken together to formIn some embodiments, R9and R10are takentogether to formIn some embodiments, R9and R10are taken together to formembodiments, R9and R10are taken together to formIn some embodiments, R9and R10areWSGR Docket No. 60555-703.601taken together to formIn some embodiments, R9and R10are taken together to formIn some embodiments, R9and R10are taken together to formembodiments, R9and R10are taken together to formIn some embodiments, R9and R10aretaken together to formIn some embodiments, R9and R10are taken together to formH0-.. In some embodiments, R9and R10are taken together to form. In some embodiments, R9and R10H2N are taken together to form '9 — I —. In some embodiments, R9and R10are taken together to form. In some embodiments, R9and R10are taken together to formIn some embodiments, R9and R10are taken together to formIn some embodiments, R9and R10are taken together to formIn some embodiments, R9and R10are taken together to form In some embodiments,R9and R10are taken together to form In some embodiments, R9and R10are taken together to formWSGR Docket No. 60555-703.601In some embodiments, R9and R10are taken together to formembodiments, R9and R10are taken together to formIn some embodiments, R9and R10arebNI T taken together to form. In some embodiments, R9and R10are taken together to form1. In NH20JV NW\some embodiments, R9and R10are taken together to form1

[0142] In some embodiments, R9and R10are taken together to form a 5-10 membered heteroaryl, wherein 5-10 membered heteroaryl are optionally substituted with 1-5 R11independently as described herein. In some embodiments, R9and R10are taken together to form a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with 1-5 groups selected from halogen, Ci-Ce alkyl, hydroxyl substituted Ci-Ce alkyl, methoxy substituted Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkynyl, =0, -OH, -OMe, -NH2, -NHMe, -NMe2, -NO2, -C(O)Me, or -C(=O)NH2, 3-6 membered heterocycloalkyl, or 3-6 membered heterocycloalkyl substituted with Ci-Ce haloalkyl. In some embodiments, R9and R10are taken together to form a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with 1-5 groups selected from halogen, Ci-Ce alkyl, hydroxyl substituted Ci-Ce alkyl, methoxy substituted Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6alkynyl, =0, -OH, -OMe, -NH2, -NHMe, -NMe2, -NO2, -C(O)Me, or -C(=O)NH2, 3-6 membered heterocycloalkyl, or 3-6 membered heterocycloalkyl substituted with Ci-Ce haloalkyl. In some embodiments, R9and R10are taken together to form a 5 membered heteroaryl, wherein the 5 membered heteroaryl is optionally substituted with 1-5 groups selected from halogen, Ci-Ce alkyl, hydroxyl substituted Ci-Ce alkyl, methoxy substituted Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkynyl, =0, -OH, -OMe, -NH2, -NHMe, -NMe2, -NO2, -C(O)Me, or -C(=0)NH2, 3-6 membered heterocycloalkyl, or 3-6 membered heterocycloalkylsubstituted with Ci-Ce haloalkyl. In some embodiments, R9and R10are taken together to formoptionally substituted with 1-5 R11independently as described herein.WSGR Docket No. 60555-703.601

[0143] In some embodiments,1is notIn some embodiments,X

[0144] In some embodiments, X is N. In some embodiments, X is CR12, wherein R12is as described herein. In some embodiments, X is CR12, wherein R12is H or Ci-Ce alkyl. In some embodiments, X is CH.R1

[0145] In some embodiments, R1is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)2 -10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)2 -10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2, wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(CI-C6alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R1is H. In some embodiments, R1is halogen. In some embodiments, R1is F. In some embodiments, R1is Cl. In some embodiments, R1is Br. In some embodiments, R1is I. In some embodiments, R1is -NO2. In some embodiments, R1is -CN. In some embodiments, R1is -OH. In some embodiments, R1is optionally substituted Ci-Ce alkyl. In some embodiments, R1is optionally substituted C2-C, alkenyl. In some embodiments, R1is optionally substituted C2-C8 alkynyl. In some embodiments, R1is optionally substituted Ci-Ce heteroalkyl. In some embodiments, R1is optionally substituted Ce-Cio aryl. In some embodiments, R1is optionally substituted C3-C10 cycloalkyl. In some embodiments, R1is optionally substituted 5-10 membered heteroaryl. In some embodiments, R1is optionally substituted 3-20 membered heterocycloalkyl. In some embodiments, R1is optionally substituted -O-(Ci-Ce alkyl). In some embodiments, R1is optionally substituted -0-(C3-Cio cycloalkyl). In some embodiments, R1is optionally substituted -O-(Ce-Cioaryl). In some embodiments, R1is optionally substituted -O-(5-10 membered heteroaryl). In someWSGR Docket No. 60555-703.601embodiments, R1is optionally substituted -O-(3-20 membered heterocycloalkyl). In some embodiments, R1is optionally substituted -OC(=O)Ci-Ce alkyl. In some embodiments, R1is optionally substituted -OC(=O)C3-Cio cycloalkyl. In some embodiments, R1is optionally substituted -OC(=0)Ce-Cio aryl. In some embodiments, R1is optionally substituted -OC(=O)5-10 membered heteroaryl. In some embodiments, R1is optionally substituted -OC(=O)3-20 membered heterocycloalkyl. In some embodiments, R1is optionally substituted -S(=O)Ci-Ce alkyl. In some embodiments, R1is optionally substituted -S(=O)2Ci-Ce alkyl. In some embodiments, R1is -S(=O)2NH2. In some embodiments, R1is optionally substituted -S(=O)2NHCi-Ce alkyl. In some embodiments, R1is optionally substituted -S(=O)2N(Ci-Ce alkyl)2. In some embodiments, R1is -OS(=O)2-halogen. In some embodiments, R1is -NH2. In some embodiments, R1is optionally substituted -NHCi-Ce alkyl. In some embodiments, R1is optionally substituted -N(Ci-Ce alkyl)2. In some embodiments, R1is optionally substituted -NHC(=O)Ci-Ce alkyl. In some embodiments, R1is optionally substituted -N(Ci-C, alkyl)C(=O)Ci-Ce alkyl. In some embodiments, R1is optionally substituted -NHS(=O)2Ci-Ce alkyl. In some embodiments, R1is optionally substituted -NHS(=0)2C3-CIO cycloalkyl. In some embodiments, R1is optionally substituted -NHS(=0)2Ce-Cio aryl. In some embodiments, R1is optionally substituted -NHS(=O)25-10 membered heteroaryl. In some embodiments, R1is optionally substituted -NHS(=O)23-20 membered heterocycloalkyl. In some embodiments, R1is optionally substituted -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl. In some embodiments, R1is optionally substituted -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl. In some embodiments, R1is optionally substituted -N(Ci-C6alkyl)S(=0)2C6-Cio aryl. In some embodiments, R1is optionally substituted -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl. In some embodiments, R1is -C(=O)H. In some embodiments, R1is optionally substituted -C(=O)Ci-Ce alkyl. In some embodiments, R1is -C(=O)OH. In some embodiments, R1is optionally substituted -C(=O)OCi-Ce alkyl. In some embodiments, R1is -C(=0)NH2. In some embodiments, R1is optionally substituted -C(=O)NHCi-Ce alkyl. In some embodiments, R1is optionally substituted -C(=O)N(Ci-C6alkyl)2. As used herein, an optional substituent of R1is defined herein, e.g., a group selected from halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.R2

[0146] In some embodiments, R2is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -WSGR Docket No. 60555-703.601NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=0)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2, wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(CI-C6alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R2is H. In some embodiments, R2is halogen. In some embodiments, R2is F. In some embodiments, R2is Cl. In some embodiments, R2is Br. In some embodiments, R2is I. In some embodiments, R2is -NO2. In some embodiments, R2is -CN. In some embodiments, R2is -OH. In some embodiments, R2is optionally substituted Ci-Ce alkyl. In some embodiments, R2is optionally substituted C2-C, alkenyl. In some embodiments, R2is optionally substituted C2-C8 alkynyl. In some embodiments, R2is optionally substituted Ci-Ce heteroalkyl. In some embodiments, R2is optionally substituted Ce-Cio aryl. In some embodiments, R2is optionally substituted C3-C10 cycloalkyl. In some embodiments, R2is optionally substituted 5-10 membered heteroaryl. In some embodiments, R2is optionally substituted 3-20 membered heterocycloalkyl. In some embodiments, R2is optionally substituted -O-(Ci-Ce alkyl). In some embodiments, R2is optionally substituted -0-(C3-Cio cycloalkyl). In some embodiments, R2is optionally substituted -O-(Ce-Cioaryl). In some embodiments, R2is optionally substituted -O-(5-10 membered heteroaryl). In some embodiments, R2is optionally substituted -O-(3-20 membered heterocycloalkyl). In some embodiments, R2is optionally substituted -OC(=O)Ci-Ce alkyl. In some embodiments, R2is optionally substituted -OC(=O)C3-C10 cycloalkyl. In some embodiments, R2is optionally substituted -OC(=0)Ce-Cio aryl. In some embodiments, R2is optionally substituted -OC(=O)5-10 membered heteroaryl. In some embodiments, R2is optionally substituted -OC(=O)3-20 membered heterocycloalkyl. In some embodiments, R2is optionally substituted -S(=O)Ci-Ce alkyl. In some embodiments, R2is optionally substituted -S(=O)2Ci-Ce alkyl. In some embodiments, R2is -S(=O)2NH2. In some embodiments, R2is optionally substituted -S(=O)2NHCi-Ce alkyl. In some embodiments, R2is optionally substituted -S(=O)2N(Ci-Ce alkyl)2. In some embodiments, R2is -OS(=O)2-halogen. In some embodiments, R2is -OS(=O)2-F. In some embodiments, R2is -NH2. In some embodiments, R2is optionally substituted -NHCi-Ce alkyl. In some embodiments, R2is optionally substituted -N(Ci-Ce alkyl)2. In some embodiments, R2is optionally substituted -NHC(=O)Ci-Ce alkyl. In some embodiments, R2is optionally substituted -N(Ci-Ce alkyl)C(=O)Ci-Ce alkyl. In some embodiments, R2is optionally substituted -NHS(=O)2Ci-Ce alkyl. In some embodiments, R2is optionally substituted -NHS(=0)2C3-CIO cycloalkyl. In some embodiments, R2is optionally substituted -NHS(=0)2Ce-Cio aryl. In some embodiments, R2is optionally substituted -NHS(=O)25-10 membered heteroaryl. In some embodiments, R2is optionally substituted -NHS(=O)23-20 membered heterocycloalkyl. In some embodiments, R2is optionally substituted -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl. In some embodiments, R2isWSGR Docket No. 60555-703.601optionally substituted -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl. In some embodiments, R2is optionally substituted -N(Ci-C6alkyl)S(=0)2C6-Cio aryl. In some embodiments, R2is optionally substituted -N(Ci-Ce alkyl)S(=O)25-10 membered heteroaryl. In some embodiments, R2is -C(=O)H. In some embodiments, R2is optionally substituted -C(=O)Ci-Ce alkyl. In some embodiments, R2is -C(=O)OH. In some embodiments, R2is optionally substituted -C(=O)OCi-Ce alkyl. In some embodiments, R2is -C(=0)NH2. In some embodiments, R2is optionally substituted -C(=O)NHCi-Ce alkyl. In some embodiments, R2is optionally substituted -C(=O)N(Ci-C6alkyl)2. As used herein, an optional substituent of R2is defined herein, e.g., a group selected from halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.R3

[0147] In some embodiments, R3is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2, wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(CI-C6alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R3is H. In some embodiments, R3is halogen. In some embodiments, R3is F. In some embodiments, R3is Cl. In some embodiments, R3is Br. In some embodiments, R3is I. In some embodiments, R3is -NO2. In some embodiments, R3is -CN. In some embodiments, R3is -OH. In some embodiments, R3is optionally substituted Ci-Ce alkyl. In some embodiments, R3is methyl. In some ^0^0^JXAAembodiments, R3is -CF3. In some embodiments, is R3is1. In some embodiments, is R3isWSGR Docket No. 60555-703.601< / VXA1. In some embodiments, is R is 1. In some embodiments, R is optionally substituted C2-C6 alkenyl. In some embodiments, R3is optionally substituted C2-C8 alkynyl. In someembodiments, R3is. In some embodiments, R3is optionally substituted Ci-Ce heteroalkyl. In some embodiments, R3is optionally substituted Ce-Cio aryl. In some embodiments, R3is optionally substituted C3- C10 cycloalkyl. In some embodiments, R3is optionally substituted 5-10 membered heteroaryl. In some embodiments, R3is optionally substituted 3-20 membered heterocycloalkyl. In some embodiments, R3is N=N» / VW « «1. In some embodiments, R is optionally substituted -O-(Ci-Ce alkyl). In some embodiments, R is optionally substituted -0-(C3-Cio cycloalkyl). In some embodiments, R3is optionally substituted -0-(Ce-Cio aryl). In some embodiments, R3is optionally substituted -O-(5-10 membered heteroaryl). In some embodiments, R3is optionally substituted -O-(3-20 membered heterocycloalkyl). In some embodiments, R3is optionally substituted -OC(=O)Ci-Ce alkyl. In some embodiments, R3is optionally substituted -OC(=O)C3- C10 cycloalkyl. In some embodiments, R3is optionally substituted -OC(=0)Ce-Cio aryl. In some embodiments, R3is optionally substituted -OC(=O)5-10 membered heteroaryl. In some embodiments, R3is optionally substituted -OC(=O)3-20 membered heterocycloalkyl. In some embodiments, R3is optionally substituted -S(=O)Ci-Ce alkyl. In some embodiments, R3is optionally substituted -S(=O)2Ci-Ce alkyl. In some embodiments, R3is -S(=O)2NH2. In some embodiments, R3is optionally substituted -S(=O)2NHCi-Ce alkyl. In some embodiments, R3is optionally substituted -S(=O)2N(Ci-Ce alkyl)2. In some embodiments, R3is -OS(=O)2-halogen. In some embodiments, R3is -OS(=O)2-F. In some embodiments, R3is -NH2. In some embodiments, R3is optionally substituted -NHCi-Ce alkyl. In some embodiments, R3is -NHMe. In some embodiments, R3is -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is substituted with -NH(Ci-Ce alkyl) wherein (Ci- OH(I7I-6 0 Ce alkyl) is substituted with -COOH or -OP(=O)(OH)2. In some embodiments,R3is H. In O II HO-P-OH<^2AN^NHsome embodiments, R3isH|nsome embodiments, In some embodiments, R3is optionally substituted -N(Ci-Ce alkyl)2. In some embodiments, R3is optionally substituted -NHC(=O)Ci-Ce alkyl. In some embodiments, R3is -NHC(=O)Ci-Ce alkyl, wherein Ci-Ce alkyl is optionally substituted with -NH2 or -WSGR Docket No. 60555-703.601C(=O)OH. In some embodiments,R3is H In some embodiments,R3is H. In someOHIn some embodiments, R3is H In some embodiments, R3is optionally substituted -N(Ci-Ce alkyl)C(=O)Ci-Ce alkyl. In some embodiments, R3is optionally substituted -NHS(=O)2Ci-Ce alkyl. In some embodiments, R3is optionally substituted -NHS(=0)2C3-CIO cycloalkyl. In some embodiments, R3is optionally substituted -NHS(=0)2Ce-Cio aryl. In some embodiments, R3is optionally substituted -NHS(=O)25-10 membered heteroaryl. In some embodiments, R3is optionally substituted -NHS(=O)23-20 membered heterocycloalkyl. In some embodiments, R3is optionally substituted - N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl. In some embodiments, R3is optionally substituted -N(Ci- C6alkyl)S(=0)2C3-Cio cycloalkyl. In some embodiments, R3is optionally substituted -N(Ci- C6alkyl)S(=0)2C6-Cio aryl. In some embodiments, R3is optionally substituted -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl. In some embodiments, R3is -C(=O)H. In some embodiments, R3is optionally substituted -C(=O)Ci-Ce alkyl. In some embodiments, R3is -C(=O)OH. In some embodiments, R3is optionally substituted -C(=O)OCi-Ce alkyl. In some embodiments, R3is -C(=0)NH2. In some embodiments, R3is optionally substituted -C(=O)NHCi-Ce alkyl. In some embodiments, R3is optionally substituted - C(=O)N(Ci-Cealkyl)2. As used herein, an optional substituent of R3is defined herein, e.g., a group selected from halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.R4

[0148] In some embodiments, R4is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), - O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, - S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)2 -10 membered heteroaryl, - NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-CioWSGR Docket No. 60555-703.601cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=0)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2, wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(CI-C6alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R4is H. In some embodiments, R4is halogen. In some embodiments, R4is F. In some embodiments, R4is Cl. In some embodiments, R4is Br. In some embodiments, R4is I. In some embodiments, R4is -NO2. In some embodiments, R4is -CN. In some embodiments, R4is -OH. In some embodiments, R4is optionally substituted Ci-Ce alkyl. In some embodiments, R4is optionally substituted C2-C, alkenyl. In some embodiments, R4is optionally substituted C2-C8 alkynyl. In some embodiments, R4is optionally substituted Ci-Ce heteroalkyl. In some embodiments, R4is optionally substituted Ce-Cio aryl. In some embodiments, R4is optionally substituted C3-C10 cycloalkyl. In some embodiments, R4is optionally substituted 5-10 membered heteroaryl. In some embodiments, R4is optionally substituted 3-20 membered heterocycloalkyl. In some embodiments, R4is optionally substituted -O-(Ci-Ce alkyl). In some embodiments, R4is optionally substituted -0-(C3-Cio cycloalkyl). In some embodiments, R4is optionally substituted -O-(Ce-Cioaryl). In some embodiments, R4is optionally substituted -O-(5-10 membered heteroaryl). In some embodiments, R4is optionally substituted -O-(3-20 membered heterocycloalkyl). In some embodiments, R4is optionally substituted -OC(=O)Ci-Ce alkyl. In some embodiments, R4is optionally substituted -OC(=O)C3-C10 cycloalkyl. In some embodiments, R4is optionally substituted -OC(=0)Ce-Cio aryl. In some embodiments, R4is optionally substituted -OC(=O)5-10 membered heteroaryl. In some embodiments, R4is optionally substituted -OC(=O)3-20 membered heterocycloalkyl. In some embodiments, R4is optionally substituted -S(=O)Ci-Ce alkyl. In some embodiments, R4is optionally substituted -S(=O)2Ci-Ce alkyl. In some embodiments, R4is -S(=O)2NH2. In some embodiments, R4is optionally substituted -S(=O)2NHCi-Ce alkyl. In some embodiments, R4is optionally substituted -S(=O)2N(Ci-Ce alkyl)2. In some embodiments, R4is -OS(=O)2-halogen. In some embodiments, R4is -NH2. In some embodiments, R4is optionally substituted -NHCi-Ce alkyl. In some embodiments, R4is optionally substituted -N(Ci-Ce alkyl)2. In some embodiments, R4is optionally substituted -NHC(=O)Ci-Ce alkyl. In some embodiments, R4is optionally substituted -N(Ci-C, alkyl)C(=O)Ci-Ce alkyl. In some embodiments, R4is optionally substituted -NHS(=O)2Ci-Ce alkyl. In some embodiments, R4is optionally substituted -NHS(=0)2C3-CIO cycloalkyl. In some embodiments, R4is optionally substituted -NHS(=0)2Ce-Cio aryl. In some embodiments, R4is optionally substituted -NHS(=O)25-10 membered heteroaryl. In some embodiments, R4is optionally substituted -NHS(=O)23-20 membered heterocycloalkyl. In some embodiments, R4is optionally substituted -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl. In some embodiments, R4is optionally substituted -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl. In some embodiments, R4is optionally substituted -N(Ci-C6alkyl)S(=0)2C6-Cio aryl. In some embodiments, R4isWSGR Docket No. 60555-703.601optionally substituted -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl. In some embodiments, R4is -C(=O)H. In some embodiments, R4is optionally substituted -C(=O)Ci-Ce alkyl. In some embodiments, R4is -C(=O)OH. In some embodiments, R4is optionally substituted -C(=O)OCi-Ce alkyl. In some embodiments, R4is -C(=0)NH2. In some embodiments, R4is optionally substituted -C(=O)NHCi-Ce alkyl. In some embodiments, R4is optionally substituted -C(=O)N(Ci-C6alkyl)2. As used herein, an optional substituent of R4is defined herein, e.g., a group selected from halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.R5

[0149] In some embodiments, R5is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCi-Ce alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6 alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2, wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(CI-C6alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R5is H. In some embodiments, R5is halogen. In some embodiments, R5is F. In some embodiments, R5is Cl. In some embodiments, R5is Br. In some embodiments, R5is I. In some embodiments, R5is -NO2. In some embodiments, R5is -CN. In some embodiments, R5is -OH. In some embodiments, R5is optionally substituted Ci-Ce alkyl. In some embodiments, R5is optionally substituted C2-C, alkenyl. In some embodiments, R5is optionally substituted C2-C8 alkynyl. In some embodiments, R5is optionally substituted Ci-Ce heteroalkyl. In some embodiments, R5is optionally substituted Ce-Cio aryl. In some embodiments, R5is optionally substituted C3-C10 cycloalkyl. In some embodiments, R5is optionally substituted 5-10 membered heteroaryl. In some embodiments, R5is optionally substituted 3-20 membered heterocycloalkyl. In some embodiments, R5is optionally substituted -O-(Ci-Ce alkyl). In some embodiments,WSGR Docket No. 60555-703.601R5is optionally substituted -0-(C3-Cio cycloalkyl). In some embodiments, R5is optionally substituted -O-(Ce-Cioaryl). In some embodiments, R5is optionally substituted -O-(5-10 membered heteroaryl). In some embodiments, R5is optionally substituted -O-(3-20 membered heterocycloalkyl). In some embodiments, R5is optionally substituted -OC(=O)Ci-Ce alkyl. In some embodiments, R5is optionally substituted -OC(=O)C3-Cio cycloalkyl. In some embodiments, R5is optionally substituted -OC(=0)Ce-Cio aryl. In some embodiments, R5is optionally substituted -OC(=O)5-10 membered heteroaryl. In some embodiments, R5is optionally substituted -OC(=O)3-20 membered heterocycloalkyl. In some embodiments, R5is optionally substituted -S(=O)Ci-Ce alkyl. In some embodiments, R5is optionally substituted -S(=O)2Ci-Ce alkyl. In some embodiments, R5is -S(=O)2NH2. In some embodiments, R5is optionally substituted -S(=O)2NHCi-Ce alkyl. In some embodiments, R5is optionally substituted -S(=O)2N(Ci-Ce alkyl)2. In some embodiments, R5is -OS(=O)2-halogen. In some embodiments, R5is -NH2. In some embodiments, R5is optionally substituted -NHCi-Ce alkyl. In some embodiments, R5is optionally substituted -N(Ci-Ce alkyl)2. In some embodiments, R5is optionally substituted -NHC(=O)Ci-Ce alkyl. In some embodiments, R5is optionally substituted -N(Ci-C, alkyl)C(=O)Ci-Ce alkyl. In some embodiments, R5is optionally substituted -NHS(=O)2Ci-Ce alkyl. In some embodiments, R5is optionally substituted -NHS(=0)2C3-CIO cycloalkyl. In some embodiments, R5is optionally substituted -NHS(=0)2Ce-Cio aryl. In some embodiments, R5is optionally substituted -NHS(=O)25-10 membered heteroaryl. In some embodiments, R5is optionally substituted -NHS(=O)23-20 membered heterocycloalkyl. In some embodiments, R5is optionally substituted -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl. In some embodiments, R5is optionally substituted -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl. In some embodiments, R5is optionally substituted -N(Ci-C6alkyl)S(=0)2C6-Cio aryl. In some embodiments, R5is optionally substituted -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl. In some embodiments, R5is -C(=O)H. In some embodiments, R5is optionally substituted -C(=O)Ci-Ce alkyl. In some embodiments, R5is -C(=O)OH. In some embodiments, R5is optionally substituted -C(=O)OCi-Ce alkyl. In some embodiments, R5is -C(=0)NH2. In some embodiments, R5is optionally substituted -C(=O)NHCi-Ce alkyl. In some embodiments, R5is optionally substituted -C(=O)N(Ci-C6alkyl)2. As used herein, an optional substituent of R5is defined herein, e.g., a group selected from halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.R6

[0150] In some embodiments, R6is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -WSGR Docket No. 60555-703.601NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, - NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci- C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2, wherein each Ci-Ce alkyl, C2-Ce alkenyl, C2-Cs alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(CI-C6alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R6is H. In some embodiments, R6is halogen. In some embodiments, R6is F. In some embodiments, R6is Cl. In some embodiments, R6is Br. In some embodiments, R6is I. In some embodiments, R6is -NO2. In some embodiments, R6is -CN. In some embodiments, R6is -OH. In some embodiments, R6is optionally substituted Ci-Ce alkyl. In some embodiments, R6is methyl. In some« / wxembodiments, R is -CF3. In some embodiments, is R is1. In some embodiments, is R isw w w 1 JW3,1. In some embodiments, is R is1. In some embodiments, R is optionally substituted C2-Ce alkenyl. In some embodiments, R6is optionally substituted C2-Cs alkynyl. In some, \AAA / z- embodiments, R is1. In some embodiments, R is optionally substituted Ci-Ce heteroalkyl. In some embodiments, R6is optionally substituted Ce-Cio aryl. In some embodiments, R6is optionally substituted C3-v v v, JVWC10 cycloalkyl. In some embodiments, R is1. In some embodiments, R is1. In some embodiments,R6is. In some embodiments, R6is I. In some embodiments,R6is I. In some embodiments, R6is optionally substituted 5-10 membered heteroaryl. In some embodiments, R6is optionally N=N^CF, « / VW3substituted 3-20 membered heterocycloalkyl. In some embodiments, R is1. In some embodiments, R6is optionally substituted -O-(Ci-Ce alkyl). In some embodiments, R6is -OMe. In some embodiments, R6is optionally substituted -0-(C3-Cio cycloalkyl). In some embodiments, R6is optionally substituted -0-(Ce-CioWSGR Docket No. 60555-703.601aryl). In some embodiments, R6is optionally substituted -O-(5-10 membered heteroaryl). In some embodiments, R6is optionally substituted -O-(3-20 membered heterocycloalkyl). In some embodiments, R6is optionally substituted -OC(=O)Ci-Ce alkyl. In some embodiments, R6is optionally substituted -OC(=O)C3-Cio cycloalkyl. In some embodiments, R6is optionally substituted -OC(=0)Ce-Cio aryl. In some embodiments, R6is optionally substituted -OC(=O)5-10 membered heteroaryl. In some embodiments, R6is optionally substituted -OC(=O)3-20 membered heterocycloalkyl. In some embodiments, R6is optionally substituted -S(=O)Ci-Ce alkyl. In some embodiments, R6is optionally substituted -S(=O)2Ci-Ce alkyl. In some embodiments, R6is -S(=O)2NH2. In some embodiments, R6is optionally substituted -S(=O)2NHCi-Ce alkyl. In some embodiments, R6is optionally substituted -S(=O)2N(Ci-Ce alkyl)2. In some embodiments, R6is -OS(=O)2-halogen. In some embodiments, R6is -OS(=O)2-F. In some embodiments, R6is -NH2. In some embodiments, R6is optionally substituted -NHCi-Ce alkyl. In some embodiments, R6is -NHMe. In some embodiments, R6is optionally substituted -N(Ci-Ce alkyl)2. In some embodiments, R6is optionally substituted -NHC(=O)Ci-Ce alkyl. In some embodiments, R6is optionally substituted -N(Ci-Ce alkyl)C(=O)Ci-Ce alkyl. In some embodiments, R6is optionally substituted -NHS(=O)2Ci-Ce alkyl. In some embodiments, R6is optionally substituted -NHS(=0)2C3-CIO cycloalkyl. In some embodiments, R6is optionally substituted -NHS(=0)2Ce-Cio aryl. In some embodiments, R6is optionally substituted -NHS(=O)25-10 membered heteroaryl. In some embodiments, R6is optionally substituted -NHS(=O)23-20 membered heterocycloalkyl. In some embodiments, R6is optionally substituted -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl. In some embodiments, R6is optionally substituted -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl. In some embodiments, R6is optionally substituted -N(Ci-C6alkyl)S(=0)2C6-Cio aryl. In some embodiments, R6is optionally substituted -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl. In some embodiments, R6is -C(=O)H. In some embodiments, R6is optionally substituted -C(=O)Ci-Ce alkyl. In some embodiments, R6is -C(=O)OH. In some embodiments, R6is optionally substituted -C(=O)OCi-Ce alkyl. In some embodiments, R6is -C(=0)NH2. In some embodiments, R6is optionally substituted -C(=O)NHCi-Ce alkyl. In some embodiments, R6is optionally substituted -C(=O)N(Ci-C6alkyl)2. As used herein, an optional substituent of R6is defined herein, e.g., a group selected from halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.R7

[0151] In some embodiments, R7is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -WSGR Docket No. 60555-703.601NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2, wherein each Ci-Ce alkyl, C2-Ce alkenyl, C2-Cs alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(CI-C6alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R7is H. In some embodiments, R7is halogen. In some embodiments, R7is F. In some embodiments, R7is Cl. In some embodiments, R7is Br. In some embodiments, R7is I. In some embodiments, R7is -NO2. In some embodiments, R7is -CN. In some embodiments, R7is -OH. In some embodiments, R7is optionally substituted Ci-Ce alkyl. In some embodiments, R7is optionally substituted C2-C, alkenyl. In some embodiments, R7is optionally substituted C2-Cs alkynyl. In some embodiments, R7is optionally substituted Ci-Ce heteroalkyl. In some embodiments, R7is optionally substituted Ce-Cio aryl. In some embodiments, R7is optionally substituted C3-C10 cycloalkyl. In some embodiments, R7is optionally substituted 5-10 membered heteroaryl. In some embodiments, R7is optionally substituted 3-20 membered heterocycloalkyl. In some embodiments, R7is optionally substituted -O-(Ci-Ce alkyl). In some embodiments, R7is optionally substituted -0-(C3-Cio cycloalkyl). In some embodiments, R7is optionally substituted -O-(Ce-Cioaryl). In some embodiments, R7is optionally substituted -O-(5-10 membered heteroaryl). In some embodiments, R7is optionally substituted -O-(3-20 membered heterocycloalkyl). In some embodiments, R7is optionally substituted -OC(=O)Ci-Ce alkyl. In some embodiments, R7is optionally substituted -OC(=O)C3-C10 cycloalkyl. In some embodiments, R7is optionally substituted -OC(=0)Ce-Cio aryl. In some embodiments, R7is optionally substituted -OC(=O)5-10 membered heteroaryl. In some embodiments, R7is optionally substituted -OC(=O)3-20 membered heterocycloalkyl. In some embodiments, R7is optionally substituted -S(=O)Ci-Ce alkyl. In some embodiments, R7is optionally substituted -S(=O)2Ci-Ce alkyl. In some embodiments, R7is -S(=O)2NH2. In some embodiments, R7is optionally substituted -S(=O)2NHCi-Ce alkyl. In some embodiments, R7is optionally substituted -S(=O)2N(Ci-Ce alkyl)2. In some embodiments, R7is -OS(=O)2-halogen. In some embodiments, R7is -OS(=O)2-F. In some embodiments, R7is -NH2. In some embodiments, R7is optionally substituted -NHCi-Ce alkyl. In some embodiments, R7is optionally substituted -N(Ci-Ce alkyl)2. In some embodiments, R7is optionally substituted -NHC(=O)Ci-Ce alkyl. In some embodiments, R7is optionally substituted -N(Ci-Ce alkyl)C(=O)Ci-Ce alkyl. In some embodiments, R7is optionally substituted -NHS(=O)2Ci-Ce alkyl. In some embodiments, R7is optionally substituted -NHS(=0)2C3-CIO cycloalkyl. In some embodiments, R7is optionally substituted -NHS(=0)2Ce-Cio aryl. In some embodiments, R7is optionally substituted -NHS(=O)25-10 membered heteroaryl. In someWSGR Docket No. 60555-703.601embodiments, R7is optionally substituted -NHS(=O)23-20 membered heterocycloalkyl. In some embodiments, R7is optionally substituted -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl. In some embodiments, R7is optionally substituted -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl. In some embodiments, R7is optionally substituted -N(Ci-C6alkyl)S(=0)2C6-Cio aryl. In some embodiments, R7is optionally substituted -N(Ci-Ce alkyl)S(=O)25-10 membered heteroaryl. In some embodiments, R7is -C(=O)H. In some embodiments, R7is optionally substituted -C(=O)Ci-Ce alkyl. In some embodiments, R7is -C(=O)OH. In some embodiments, R7is optionally substituted -C(=O)OCi-Ce alkyl. In some embodiments, R7is -C(=O)NH2. In some embodiments, R7is optionally substituted -C(=O)NHCi-Ce alkyl. In some embodiments, R7is optionally substituted -C(=O)N(Ci-C6alkyl)2. As used herein, an optional substituent of R7is defined herein, e.g., a group selected from halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.R8

[0152] In some embodiments, R8is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2, wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(CI-C6alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R8is H. In some embodiments, R8is halogen. In some embodiments, R8is F. In some embodiments, R8is Cl. In some embodiments, R8is Br. In some embodiments, R8is I. In some embodiments, R8is -NO2. In some embodiments, R8is -CN. In some embodiments, R8is -OH. In some embodiments, R8is optionally substituted Ci-Ce alkyl. In some embodiments, R8is optionally substituted C2-C6alkenyl. In some embodiments, R8is optionally substituted C2-C8 alkynyl. In some embodiments, R8isWSGR Docket No. 60555-703.601optionally substituted Ci-Ce heteroalkyl. In some embodiments, R8is optionally substituted Ce-Cio aryl. In some embodiments, R8is optionally substituted C3-C10 cycloalkyl. In some embodiments, R8is optionally substituted 5-10 membered heteroaryl. In some embodiments, R8is optionally substituted 3-20 membered heterocycloalkyl. In some embodiments, R8is optionally substituted -O-(Ci-Ce alkyl). In some embodiments, R8is optionally substituted -0-(C3-Cio cycloalkyl). In some embodiments, R8is optionally substituted -O-(Ce-Cioaryl). In some embodiments, R8is optionally substituted -O-(5-10 membered heteroaryl). In some embodiments, R8is optionally substituted -O-(3-20 membered heterocycloalkyl). In some embodiments, R8is optionally substituted -OC(=O)Ci-Ce alkyl. In some embodiments, R8is optionally substituted -OC(=O)C3-C10 cycloalkyl. In some embodiments, R8is optionally substituted -OC(=0)Ce-Cio aryl. In some embodiments, R8is optionally substituted -OC(=O)5-10 membered heteroaryl. In some embodiments, R8is optionally substituted -OC(=O)3-20 membered heterocycloalkyl. In some embodiments, R8is optionally substituted -S(=O)Ci-Ce alkyl. In some embodiments, R8is optionally substituted -S(=O)2Ci-Ce alkyl. In some embodiments, R8is -S(=O)2NH2. In some embodiments, R8is optionally substituted -S(=O)2NHCi-Ce alkyl. In some embodiments, R8is optionally substituted -S(=O)2N(Ci-Ce alkyl)2. In some embodiments, R8is -OS(=O)2-halogen. In some embodiments, R8is -OS(=O)2-F. In some embodiments, R8is -NH2. In some embodiments, R8is optionally substituted -NHCi-Ce alkyl. In some embodiments, R8is optionally substituted -N(Ci-Ce alkyl)2. In some embodiments, R8is optionally substituted -NHC(=O)Ci-Ce alkyl. In some embodiments, R8is optionally substituted -N(Ci-Ce alkyl)C(=O)Ci-Ce alkyl. In some embodiments, R8is optionally substituted -NHS(=O)2Ci-Ce alkyl. In some embodiments, R8is optionally substituted -NHS(=0)2C3-CIO cycloalkyl. In some embodiments, R8is optionally substituted -NHS(=0)2Ce-Cio aryl. In some embodiments, R8is optionally substituted -NHS(=O)25-10 membered heteroaryl. In some embodiments, R8is optionally substituted -NHS(=O)23-20 membered heterocycloalkyl. In some embodiments, R8is optionally substituted -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl. In some embodiments, R8is optionally substituted -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl. In some embodiments, R8is optionally substituted -N(Ci-C6alkyl)S(=0)2C6-Cio aryl. In some embodiments, R8is optionally substituted -N(Ci-Ce alkyl)S(=O)25-10 membered heteroaryl. In some embodiments, R8is -C(=O)H. In some embodiments, R8is optionally substituted -C(=O)Ci-Ce alkyl. In some embodiments, R8is -C(=O)OH. In some embodiments, R8is optionally substituted -C(=O)OCi-Ce alkyl. In some embodiments, R8is -C(=O)NH2. In some embodiments, R8is optionally substituted -C(=O)NHCi-Ce alkyl. In some embodiments, R8is optionally substituted -C(=O)N(Ci-C6alkyl)2. As used herein, an optional substituent of R8is defined herein, e.g., a group selected from halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, at least one of R'-R8is -CF3, -NO2, -CN, -O-(C2-C6alkyl), -COOH, -C(=O)H, -COOCi-C6alkyl, -OH, -NH2, -NHCI-C6alkyl, wherein Ci-Ce alkyl is optionally substituted with -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, -NHC(=O)Ci-Ce alkyl wherein Ci-Ce alkyl is optionally substitute with -NH2 or -WSGR Docket No. 60555-703.601COOH, -N(Ci-Ce alkyl )2. C3-C10 cycloalkyl, C2-C6 alkyl optionally substituted with an -OH or C2-C8 alkynyl. In some embodiments, at least one of R’-R8is not H.

[0153] In some embodiments, R3is not hydrogen, R6is not hydrogen, and each of R1, R2, R4, R5, R7, and R8is hydrogen. In some embodiments, each of R1, R2, R4, R5, R7, and R8is hydrogen and each of R3and R6is independently halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -O-(C3-C10 cycloalkyl), -O-(Ce-Cioaryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)C1-C6alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; or two R11are taken together to form =O or 3-20 membered heterocycloalkyl; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, each of R1, R2, R4, R5, R7, and R8is hydrogen, R6is halogen, and R3is halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; or two R11are taken together to form =0 or 3-20 membered heterocycloalkyl; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -WSGR Docket No. 60555-703.601C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, each of R1, R2, R4, R5, R7, and R8is hydrogen, R6is Cl, and R3is halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)C6-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)C1-C6alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-Ce alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCI-C6alkyl, or -C(=O)N(Ci-C6alkyl)2; or two R11are taken together to form =0 or 3-20 membered heterocycloalkyl; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(CI-C6alkyl) wherein Ci-C6alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.R11

[0154] In some embodiments, R11is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; or two R11are taken together to form =0 or 3-20 membered heterocycloalkyl; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkylWSGR Docket No. 60555-703.601is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R11is H. In some embodiments, R11is halogen. In some embodiments, R11is F. In some embodiments, R11is Cl. In some embodiments, R11is Br. In some embodiments, R11is I. In some embodiments, R11is -NO2. In some embodiments, R11is -CN. In some embodiments, R11is -OH. In some embodiments, R11is optionally substituted C1-C6alkyl. In some embodiments, R11is methyl. In some embodiments, R11is1. In some HOx^zJVW 'embodiments, R11is [structure]. In some embodiments, R11is [structure]. In some embodiments, R11is -CF3. In some embodiments, R11is optionally substituted C2-C6 alkenyl. In some embodiments, R11is optionallysubstituted C2-C8alkynyl. In some embodiments, R11is [structure]. In some embodiments, R11is optionally substituted C1-C6heteroalkyl. In some embodiments, R11is optionally substituted Ce-Cio aryl. In some embodiments, R11is optionally substituted C3-C10 cycloalkyl. In some embodiments, R11is optionally substituted 5-10 membered heteroaryl. In some embodiments, R11is optionally substituted 3-20 membered N=Nheterocycloalkyl. In some embodiments, R11is [structure]. In some embodiments, R11is. In some embodiments, R11is optionally substituted -O-(Ci-Ce alkyl). In some embodiments, R11is -OMe. In some embodiments, R11is optionally substituted -0-(C3-Cio cycloalkyl). In some embodiments, R11is optionally substituted -O-(Ce-Cioaryl). In some embodiments, R11is optionally substituted -O-(5-10 membered heteroaryl). In some embodiments, R11is optionally substituted -O-(3-20 membered heterocycloalkyl). In some embodiments, R11is optionally substituted -OC(=O)Ci-Ce alkyl. In some embodiments, R11is optionally substituted -OC(=0)C3-Cio cycloalkyl. In some embodiments, R11is optionally substituted -OC(=0)C6-Cio aryl. In some embodiments, R11is optionally substituted -OC(=O)5-10 membered heteroaryl. In some embodiments, R11is optionally substituted -OC(=O)3-20 membered heterocycloalkyl. In some embodiments, R11is optionally substituted -S(=O)Ci-Ce alkyl. In some embodiments, R11is optionally substituted -S(=0)2Ci-Ce alkyl. In some embodiments, R11is -S(=O)2NH2. In some embodiments, R11is optionally substituted -S(=O)2NHCi-Ce alkyl. In some embodiments, R11is optionally substituted -S(=O)2N(C1-C6alkyl)2. In some embodiments, R11is -OS(=O)2-halogen. In some embodiments, R11is -OS(=O)2-F. In some embodiments, R11is -NH2. In some embodiments, R11is optionally substituted -NHC1-C6alkyl. In some embodiments, R11is optionally substituted -N(Ci-Ce alkyl)2. In some embodiments, R11is -NHMe. In some embodiments, R11is -NMe2. In some embodiments, R11is optionally substituted -NHC(=O)Ci-Ce alkyl. In some embodiments, R11is optionally substituted -N(Ci-Ce alkyl)C(=O)Ci-Ce alkyl.WSGR Docket No. 60555-703.601In some embodiments, R11is optionally substituted -NHS(=O)2Ci-Ce alkyl. In some embodiments, R11is optionally substituted -NHS(=0)2C3-CIO cycloalkyl. In some embodiments, R11is optionally substituted -NHS(=0)2C6-CIO aryl. In some embodiments, R11is optionally substituted -NHS(=O)25-10 membered heteroaryl. In some embodiments, R11is optionally substituted -NHS(=O)23-20 membered heterocycloalkyl. In some embodiments, R11is optionally substituted -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl. In some embodiments, R11is optionally substituted -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl. In some embodiments, R11is optionally substituted -N(Ci-C6alkyl)S(=0)2C6-Cio aryl. In some embodiments, R11is optionally substituted -N(Ci-Ce alkyl)S(=O)25-10 membered heteroaryl. In some embodiments, R11is -C(=O)H. In some embodiments, R11is optionally substituted -C(=O)Ci-Ce alkyl. In some embodiments, R11is -C(O)Me. In some embodiments, R11is -C(=O)OH. In some embodiments, R11is optionally substituted -C(=O)OCi-Ce alkyl. In some embodiments, R11is -C(=O)NH2. In some embodiments, R11is optionally substituted -C(=O)NHCi-Ce alkyl. In some embodiments, R11is optionally substituted -C(=O)N(Ci-C6alkyl)2. As used herein, an optional substituent of R11is defined herein, e.g., a group selected from halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, two R11are taken together to form =0 or optionally substituted 3-20 membered heterocycloalkyl. In some embodiments, R11is =0. In some embodiments, two R11are taken together to form optionally substituted 3-20 membered heterocycloalkyl.R12

[0155] In some embodiments, R12is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2, wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(CI-C6alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-CeWSGR Docket No. 60555-703.601heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R12is H. In some embodiments, R12is halogen. In some embodiments, R12is F. In some embodiments, R12is Cl. In some embodiments, R12is Br. In some embodiments, R12is I. In some embodiments, R12is -NO2. In some embodiments, R12is -CN. In some embodiments, R12is -OH. In some embodiments, R12is optionally substituted Ci-Ce alkyl. In some embodiments, R12is optionally substituted C2-C6 alkenyl. In some embodiments, R12is optionally substituted C2-C8 alkynyl. In some embodiments, R12is optionally substituted Ci-Ce heteroalkyl. In some embodiments, R12is optionally substituted Ce-Cio aryl. In some embodiments, R12is optionally substituted C3-C10 cycloalkyl. In some embodiments, R12is optionally substituted 5-10 membered heteroaryl. In some embodiments, R12is optionally substituted 3-20 membered heterocycloalkyl. In some embodiments, R12is optionally substituted -O-(Ci-Ce alkyl). In some embodiments, R12is optionally substituted -0-(C3-Cio cycloalkyl). In some embodiments, R12is optionally substituted -O-(Ce-Cioaryl). In some embodiments, R12is optionally substituted -O-(5-10 membered heteroaryl). In some embodiments, R12is optionally substituted -O-(3-20 membered heterocycloalkyl). In some embodiments, R12is optionally substituted -OC(=O)Ci-Ce alkyl. In some embodiments, R12is optionally substituted -OC(=0)C3-Cio cycloalkyl. In some embodiments, R12is optionally substituted -OC(=0)C6-Cio aryl. In some embodiments, R12is optionally substituted -OC(=O)5-10 membered heteroaryl. In some embodiments, R12is optionally substituted -OC(=O)3-20 membered heterocycloalkyl. In some embodiments, R12is optionally substituted -S(=O)Ci-Ce alkyl. In some embodiments, R12is optionally substituted -S(=O)2Ci-Ce alkyl. In some embodiments, R12is -S(=O)2NH2. In some embodiments, R12is optionally substituted -S(=O)2NHCi-Ce alkyl. In some embodiments, R12is optionally substituted -S(=O)2N(C1-C6alkyl)2. In some embodiments, R12is -OS(=O)2-halogen. In some embodiments, R12is -NH2. In some embodiments, R12is optionally substituted -NHCi-Ce alkyl. In some embodiments, R12is optionally substituted -N(Ci-Ce alkyl)2. In some embodiments, R12is optionally substituted -NHC(=O)Ci-Ce alkyl. In some embodiments, R12is optionally substituted -N(Ci-Ce alkyl)C(=O)Ci-Ce alkyl. In some embodiments, R12is optionally substituted -NHS(=O)2Ci-Ce alkyl. In some embodiments, R12is optionally substituted -NHS(=0)2C3-CIO cycloalkyl. In some embodiments, R12is optionally substituted -NHS(=0)2Ce-Cio aryl. In some embodiments, R12is optionally substituted -NHS(=O)25-10 membered heteroaryl. In some embodiments, R12is optionally substituted -NHS(=O)23-20 membered heterocycloalkyl. In some embodiments, R12is optionally substituted -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl. In some embodiments, R12is optionally substituted -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl. In some embodiments, R12is optionally substituted -N(Ci-C6alkyl)S(=0)2C6-Cio aryl. In some embodiments, R12is optionally substituted -N(Ci-Ce alkyl)S(=O)25-10 membered heteroaryl. In some embodiments, R12is -C(=O)H. In some embodiments, R12is optionally substituted -C(=O)Ci-Ce alkyl. In some embodiments, R12is -C(=O)OH. In some embodiments, R12is optionally substituted -C(=O)OCi-Ce alkyl. In some embodiments, R12is -C(=O)NH2. In some embodiments, R12is optionally substituted -C(=O)NHCi-Ce alkyl. In some embodiments, R12is optionally substituted -C(=O)N(Ci-C6alkyl)2. As used herein, an optional substituent of R12is defined herein, e.g., a group selected from halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -WSGR Docket No. 60555-703.601-OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.n

[0156] In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8.L1

[0157] In some embodiments, L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-, wherein m and RAare each independently as described herein. In some embodiments, L1is -NHC(=O)-. In some embodiments, L1is -NHS(=O)2-. In some embodiments, L1is -NH-[C(RA)2]m-, wherein m and RAare each independently as described herein. In some embodiments, L1is -NH-[C(RA)2]m-, wherein m is 1 or 2 and RAis optionally substituted Ci-Ce alkyl. In some embodiments, L1is -NH-CH2-. In some embodiments, L1is -NH-CH(CF3)-. In some embodiments, L1is -O-[C(RA)2]m-, wherein m and RAare each independently as described herein. In some embodiments, L1is -O-[C(RA)2]m-, wherein m is 1 or 2 and RAis optionally substituted C1-C6alkyl. In some embodiments, L1is -O-CH2. In some embodiments, L1is -O-CH(CF3)-. RA

[0158] In some embodiments, RAis H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, or -OH. In some embodiments, RAis H. In some embodiments, RAis halogen. In some embodiments, RAis -NO2. In some embodiments, RAis -CN. In some embodiments, RAis -OH. In some embodiments, RAis optionally substituted Ci-Ce alkyl. In some embodiments, RAis -CF3. In some embodiments, RAis optionally substituted Ci-Ce heteroalkyl.m

[0159] In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0160] Variable groups in various formulas (e.g., Formula (A), Formula (A-l), Formula (I), Formula (I- 1), Formula (II), Formula (II- 1), Formula (III), Formula (III- 1), Formula (IV), Formula (V), etc.) are described herein as examples. Those skilled in the art reading the present disclosure will be able to select an embodiment for each variable and combine them; such combinations are within the scope of the present disclosure.

[0161] In some embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein:WSGR Docket No. 60555-703.601R4Formula (I)wherein:1is a 3-10 membered heterocycloalkyl comprising 0-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;each R13is independently selected from halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2- C8alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), -O-(5- 10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)2 -10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCi-Ce alkyl, and -C(=O)N(Ci-C6alkyl)2; or two R13are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -OCi-C6alkyl, -NH2, -OP(=O)(OH)2, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl;p is 1, 2, 3, 4, or 5;WSGR Docket No. 60555-703.601provided that1is notX is selected from N or CR12;R’-R8and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), -O-(5- 10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCI-C6alkyl, or -C(=O)N(Ci-C6alkyl)2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -OCi-C6alkyl, -NH2, -OP(=O)(OH)2, Ci-C6alkyl, Ci-C6heteroalkyl, C6-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0162] In some embodiments, the present disclosure provides a compound of Formula (I- 1), or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein:Formula (1-1).RingWSGR Docket No. 60555-703.601I

[0163] In some embodiments,1is a 3-10 membered heterocycloalkyl comprising 0-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein X is as described herein and the 3-10 membered heterocycloalkyl is substituted with 1-5 R13independently as described herein. In someembodiments,I is a 3-6 membered heterocycloalkyl comprising 0-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein X is as described herein and the 3-6 membered heterocycloalkyl isi / ww substituted with 1-5 R13independently as described herein. In some embodiments,1is a 3-6 membered heterocycloalkyl comprising 0-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein X is N and the 3-6 membered heterocycloalkyl is substituted with 1-5 R13independently as described herein. InJW IWsome embodiments,1is a 3 membered heterocycloalkyl comprising 0-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein X is N and the 3 membered heterocycloalkyl is substituted with 1-5O X NI iR13independently as described herein. In some embodiments,1is1substituted with 1-5 R13independently as described herein. In some embodiments,1is a 4 membered heterocycloalkyl comprising 0-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein X is N and the 4 membered heterocycloalkyl is substituted with 1-5 R13independently as described herein. In someembodiments,1is1substituted with 1-5 R13independently as described herein. In some Q Iembodiments,1is a 5 membered heterocycloalkyl comprising 0-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein X is N and the 5 membered heterocycloalkyl is substituted with 1-5 R13WSGR Docket No. 60555-703.601independently as described herein. In some embodiments,substituted with 1-5 R13independently as described herein. In some embodiments,1is a 6 membered heterocycloalkyl comprising 0-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein X is N and the 6 membered heterocycloalkyl is substituted with 1-5 R13independently as described herein. In someembodiments,substituted with 1-5 R13independently as described herein. In someembodiments,1is1, wherein R13independently is as described herein. In someembodiments,1is1, wherein R13independently is as described herein. In someembodiments,, wherein R13independently is as described herein. In someembodiments,is1, wherein R13independently is as described herein. In someIn some embodiments,WSGR Docket No. 60555-703.601embodiments,In some embodiments,. In someIn some embodiments,(R13)P some embodiments,In some embodiments,WSGR Docket No. 60555-703.601(R13)P some embodiments,In some embodiments,In some embodiments,'P some embodiments, In some embodiments,P

[0164] In some embodiments, p is 1, 2, 3, 4, or 5. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.R13

[0165] In some embodiments, R13is halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -0-(Ce-Cio aryl), -O-(5-10 membered heteroaryl), - O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, -OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, - S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, -NHS(=O)2 -10 membered heteroaryl, -WSGR Docket No. 60555-703.601NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=0)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; or two R13are taken together to form =0 or 3-20 membered heterocycloalkyl; wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, R13is halogen. In some embodiments, R13is F. In some embodiments, R13is Cl. In some embodiments, R13is Br. In some embodiments, R13is I. In some embodiments, R13is -NO2. In some embodiments, R13is -CN. In some embodiments, R13is -OH. In some embodiments, R13is optionally substituted Ci-Ce alkyl. In some HO^ HO^| / *A / W. JVW embodiments, R13is methyl. In some embodiments, R13is1. In some embodiments, R13is1In some embodiments, R13is1. In some embodiments, R13is -CF3. In some embodiments, R13is optionally substituted C2-C6 alkenyl. In some embodiments, R13is optionally substituted C2-C8 alkynyl. Insome embodiments, R13is1. In some embodiments, R13is optionally substituted Ci-Ce heteroalkyl. In some embodiments, R13is optionally substituted Ce-Cio aryl. In some embodiments, R13is optionally substituted C3-C10 cycloalkyl. In some embodiments, R13is optionally substituted 5-10 membered heteroaryl. In some embodiments, R13is optionally substituted 3-20 membered heterocycloalkyl. In some embodiments, N=NNYR13is1. In some embodiments, R13is. In some embodiments, R13is optionally substituted -O-(Ci-Ce alkyl). In some embodiments, R13is -OMe. In some embodiments, R13is optionally substituted -0-(C3-Cio cycloalkyl). In some embodiments, R13is optionally substituted -O-(Ce-Cioaryl). In some embodiments, R13is optionally substituted -O-(5-10 membered heteroaryl). In some embodiments, R13is optionally substituted -O-(3-20 membered heterocycloalkyl). In some embodiments, R13is optionally substituted -OC(=O)Ci-Ce alkyl. In some embodiments, R13is optionally substituted -OC(=0)C3-Cio cycloalkyl. In some embodiments, R13is optionally substituted -OC(=0)Ce-Cio aryl. In some embodiments, R13is optionally substituted -OC(=O)5-10 membered heteroaryl. In some embodiments, R13is optionally substituted -OC(=O)3-20 membered heterocycloalkyl. In some embodiments, R13is optionally substituted -S(=O)Ci-Ce alkyl. In some embodiments, R13is optionally substituted -S(=O)2Ci-Ce alkyl. In some embodiments, R13is -S(=O)2NH2. In some embodiments, R13is optionally substituted -S(=O)2NHCi-Ce alkyl.WSGR Docket No. 60555-703.601In some embodiments, R13is optionally substituted -S(=O)2N(Ci-Ce alkyl)2. In some embodiments, R13is -OS(=O)2-halogen. In some embodiments, R13is -OS(=O)2-F. In some embodiments, R13is -NH2. In some embodiments, R13is optionally substituted -NHCi-Ce alkyl. In some embodiments, R13is optionally substituted -N(Ci-Ce alkyl)2. In some embodiments, R13is -NHMe. In some embodiments, R13is -NMe2. In some embodiments, R13is optionally substituted -NHC(=O)Ci-Ce alkyl. In some embodiments, R13is optionally substituted -N(Ci-Ce alkyl)C(=O)Ci-Ce alkyl. In some embodiments, R13is optionally substituted -NHS(=O)2Ci-Ce alkyl. In some embodiments, R13is optionally substituted -NHS(=0)2C3-CIO cycloalkyl. In some embodiments, R13is optionally substituted -NHS(=0)2Ce-Cio aryl. In some embodiments, R13is optionally substituted -NHS(=O)25-10 membered heteroaryl. In some embodiments, R13is optionally substituted -NHS(=O)23-20 membered heterocycloalkyl. In some embodiments, R13is optionally substituted -N(Ci-C6alkyl)S(=O)2Ci-C6 alkyl. In some embodiments, R13is optionally substituted -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl. In some embodiments, R13is optionally substituted -N(Ci-C6alkyl)S(=0)2C6-Cio aryl. In some embodiments, R13is optionally substituted -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl. In some embodiments, R13is -C(=O)H. In some embodiments, R13is optionally substituted -C(=O)Ci-Ce alkyl. In some embodiments, R13is -C(O)Me. In some embodiments, R13is -C(=O)OH. In some embodiments, R13is optionally substituted -C(=O)OCi-Ce alkyl. In some embodiments, R13is -C(=0)NH2. In some embodiments, R13is optionally substituted -C(=O)NHCi-Ce alkyl. In some embodiments, R13is optionally substituted -C(=O)N(Ci-C6alkyl)2. As used herein, an optional substituent of R13is defined herein, e.g., a group selected from halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl. In some embodiments, two R13are taken together to form =0 or optionally substituted 3-20 membered heterocycloalkyl. In some embodiments, R13is =0. In some embodiments, two R13are taken together to form optionally substituted 3-20 membered heterocycloalkyl. In some embodiments, two R13are taken together to form a 4-7 membered heterocycloalkyl.

[0166] In some embodiments, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein:Formula (II)R9and R10are each independently H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3- C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to formWSGR Docket No. 60555-703.601a 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1-5 R11; X is selected from N or CR12;R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), - O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; ortwo R11are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-;each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, or -OH;each m is independently 0, 1, 2, or 3; andwherein at least one of R’-R8is -CF3, -NO2, -CN, -O-(C2-Ce alkyl), -COOH, -C(=O)H, -COOCi- Cealkyl, -OH, -NH2, -NHCi-Ce alkyl, wherein Ci-Ce alkyl is optionally substituted with - NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or - OP(=O)(OH)2, -NHC(=O)Ci-Ce alkyl wherein Ci-Ce alkyl is optionally substitute with -NH2 or -COOH, -N(Ci-Ce alkyl)2, C3-C10 cycloalkyl, C2-C6 alkyl optionally substituted with an - OH, or C2-C8 alkynyl.WSGR Docket No. 60555-703.601

[0167] In some embodiments, the present disclosure provides a compound of Formula (II-l), or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein:Formula (II-l).

[0168] Among other things, the present disclosure provides a compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein:Formula (III)R9and R10are each independently H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3- C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1-5 R11;R'X'R99provided that1is not1or1;X is selected from N or CR12;R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), - O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 memberedWSGR Docket No. 60555-703.601heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=0)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; ortwo R11are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-;each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, or -OH; andeach m is independently 0, 1, 2, or 3.

[0169] In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof has a structure of Formula (III- 1 ), or a pharmaceutically acceptable salt thereof, wherein each variable is independently as described herein:Formula (III-l).

[0170] Among other things, the present disclosure provides a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein:Formula (IV)R9and R10are each independently H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3- C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1-5 R11;WSGR Docket No. 60555-703.601X is selected from N or CR12;R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), - O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)2 -10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; ortwo R11are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;L1is -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-;each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, or -OH; andeach m is independently 0, 1, 2, or 3.

[0171] Among other things, the present disclosure provides a compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein:WSGR Docket No. 60555-703.601Formula (V)R9and R10are each independently H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3- C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1-5 R11; X is selected from N or CR12;R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), - O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; ortwo R11are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl; andL1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-;each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, or -OH; andeach m is independently 0, 1, 2, or 3.

[0172] Among other things, the present disclosure provides a compound listed in:Table 1A.Compound CompoundStructureSeries Number NumberWSGR Docket No. 60555-703.601A01 iA02 HO—, 2 o O Ohrr^r\ ^\ O^^l — xx4 H ° °I 1 > N T JLcoA I U- CX o Zz oz O^^A03 \ _OH 3 zxhr) OKO-^x,J JI1 1 NHA04 4 A05 5 / °xr Il^ Jr\NWHJ, JLA06 6WSGR Docket No. 60555-703.601A07 7A08 HN^ 8zv\Il 1T / ^NH JLZZZ<5A / Cj\ y A09 O Z I.I Y 9T[f oo oA10 10 / °K<^N JLIl 1 NH — -^C|All H 11 c N-^ / °vr^r\ 'J’J J JLIl 1 NHX^X~'Z''^CIA12 H2N 12 / °x 0^^.r^VA J JL| 1 NHX-^^s'CIWSGR Docket No. 60555-703.601A13 13^-4 J JL| 1 NHA14 NH214<> / Ox 0^ / ^1 1 4>~ N HH i 1A15 ^° 1 / 15HN"^1 / °v ^° 0 \^^,1 1 Z^NH JLoA16 16A17 ~~NH 17 / °x 0^^,| £ N WH lf 1A18 °x Z~> 18X IozYHr^r-X W j JLIl 1NHWSGR Docket No. 60555-703.601A19 19A20 20or^rX Hl 11 1 / ^NHA21 9z H 21O ^'^z0 J. I1 f I ° °x O^z^X^r-N ^0x 1Il 1 Z>-NHA22 NH222 o0 T oxo-^z^,< J JLIl 1 Z>-NHA23 Z^NH 23 / °K O^Z^s,HA J! JLII 1 / HNH X^X^XCI\^''NA24 24A25 —N J 25r^%-N HA II JLH [, HNH\^-NWSGR Docket No. 60555-703.601A26 26A27 27 oo oIoO OA28 z^ 28 llCO o Z zI I O z / I I YX° \O oA29 29A31 30Amino-A31 31( 1o(r-4 J JWSGR Docket No. 60555-703.601A32 32Hl J11 A / / F3C^X^<'N NHA33 33Oo ooA34 ^x ° 34C ZT CT ZO Z.Y I> oxho^^>AnW,I0JI 1[l Z>-NH ^ xA35 CM k z 35I oA36 36A37 37A38 38 / °x 0^^,Hj 1l| 1 NHfl0WSGR Docket No. 60555-703.601A39 39CIWNJ 1Il J / ^NHA40 40ZEO o T—o| 1 N HH \ zl- J^. OJ^X ° A41 '1°oz-^^ 41 z oz\ xJ^ZEo ozz^T^0Xco—,A42 42A43 43 A44 44WSGR Docket No. 60555-703.601A45 45S 0.Hj YIl I / )— NH\X^NA46 46*0^ / °v O^X^M. Y JLIl J / )-NHX''"'^^'VNH\^N |A47 47< I / °xr^x\ YY Y JLIl J 4>— NHA48 48 / °v o^x^,JL^ ( X'N / ^NHgA49 49*0^ / °xi I^l r 1X / )— N 'MH JJLA50 50 / °v 0-^^,| 1 / >-N ^HAJL JL^X" NN01 51X^r-N Hl 2H2N^ J!^ J^LNHnhWSGR Docket No. 60555-703.601N02 52*0^II 1 NH02N^^'NN03 53 o°2N^^N >- < 1 1T T / ^NHz z zxB01 HO— - / O \ Y1 I - H' ° 54 oz^1l\K'0x / °vi^r-'N H j JLll ± / ^NHoB02 HO-- 55<V^r^rX H l J| 1 z^NHB03 56 B04 57WSGR Docket No. 60555-703.601B05 58B06 — 59NH O O / °xAA J JL| 1 / >-NH1 Ax °I 'AlB07 O ZT60HC / ^\ >N A ° A'0AA A 11 1 / ^NH oB08 61B09 CH362<t> / °xI^T-'N AA J JLII J / ^NH\Z^NBIO 63WSGR Docket No. 60555-703.601Bll 64B12 65YAZZX y^ \ ^ 1°vz7xO ZO Z,,Y 1V" IT1f iB13 Y T 66^° \^"00x xo o oo oB14 H2N 67AYOHl\r / °x O^" YIl J > YNHB15 68 B16 69WSGR Docket No. 60555-703.601B17 0 70JLIl J NH B183,0O 71 H C^> o^x °co^r-A1 O S J Hx?k X=CxzTl 11 / ^ o oN"^HO Z - B19 v i 72'0xoB20 73HN-H\ / °K| 1 NHB21 74B22 75WSGR Docket No. 60555-703.601B23 O-. 76 / °~YISKIl I — NH J JLB24 O 77H3C— ( Jhr / °vV4^' ° j JL| I / ^NH\^"0^^z^Nzzvr O zB25 78HN^Og 2- J ox° \r^< N jf JLIl 1 / ^NHOB26 79B27 80B28 OCH381r^-N j JiII 1 ZZ^NH\e^NWSGR Docket No. 60555-703.601B29 82\ oK0^^ / W 'HNT JLII T NHB30 OH 83co—, / °x 0-^X,'J 4 J JLIl 1 4> — NH B31 J^ / Z Zz<'^z\y 84^T1 / ° 'Hx ^J'0L x JL| 1 NHVB32 o 85 / °x 0-^^r^V-\ Z^N H l1 1 H XV>B33 86P01 F3C^P N'N 87N^ / °x< | v 1 \ / ^N ^HAXXWSGR Docket No. 60555-703.601P02 N 88F3C4^NhrXA X JL11 A / XNHP03 89"10ZX; ox* ■■HX j JLIl 1N H^0xP04 90 o! hr > / °xz^N Hl XN II I NH CF3P05 91O n / 9x Pv> / X J 1F^ o y x HNHP06 92WSGR Docket No. 60555-703.601PA38-1 93< J J]nII J Z^NHXJX\AXo r°PA38-2 94Xx °O z\ / iCl X\ 95\ >N(") R\ Px / SA JI| [ X'-NHv" ^x^C!HQ-X^NC2r-OH 96?N'"5. X XyA v / \\x J5 I Z> NH "’''CiHO"C3 97 t 9h''") q o-~xx1 [, XNH"' JciHO" xX " N1WSGR Docket No. 60555-703.601C4 98\ oH I 1HC0 ] >-NHrP7 990 N"Tf / / \ Q 0........ • >.,...'« O Il [I 2 >--NH - — - O'*CF | / '=\■Q' "' " NlP8 S Zz / < _ 100X\ / _ / )> / % / 2SMI 101r^rNJLH2N-^ JI^ / LN^NHSM2 102) oxJL HNXJ^L / ^JLN^NH1WSGR Docket No. 60555-703.601SM3 103O'+H3N, J / ^-N KA J 1T [| T / ^NHCT 'N / X^'''NH SM4 104J. Il I / ^NHSM5 105I V 'IXI HN^KNJ / < Q^CVNNH^^^CIHn is 1-6SM6 1060(H°-P-°- ) ox0...... / ^,i d° / A J JHHNN^NX 1 ^ JLN-^NHHn is 1-6SM7 107AAX JL-n JJ / L / KNHuy^X^N0WSGR Docket No. 60555-703.601ox108'p-O-XNy JL AN KHA JI JI109X oxnII 1 ANKHAJX JX0 1- o, 110 K'°'0 0^isr|l X AN KHA nr JX, or a pharmaceutically acceptable salt thereof, wherein each variable group, if present, is independently as described herein.

[0173] In some embodiments, a pharmaceutically acceptable salt of a provided compound is a citrate salt. In some embodiments, a pharmaceutically acceptable salt of a provided compound is a lactate salt. In some embodiments, a pharmaceutically acceptable salt of a provided compound is a formate salt.Small Molecule-Linker Compound

[0174] As described herein, a compound as provided herein, e.g., a compound of Formula (A), Formula (A-1), Formula (I), Formula (I- 1), Formula (II), Formula (II- 1), Formula (III), Formula (III- 1), Formula (IV), Formula (V), etc. can be attached to a linker group Lsas described herein, forming a small molecule-linker compound suitable for conjugation to biomolecules.WSGR Docket No. 60555-703.601

[0175] Among other things, the present disclosure provides a compound of Formula (SML), or a pharmaceutically acceptable salt thereof, wherein:Formula (SML)R9and R10are each independently H, Ci-Ce alkyl, C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3-C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl optionally substituted optionally substituted with 1-5 R11;X is selected from N or CR12;R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), - O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; ortwo R11are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl;WSGR Docket No. 60555-703.601n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-;each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, or -OH;each m is independently 0, 1, 2, or 3; andLsis a linker group.Ls

[0176] As is readily understood by those skilled in the art and without altering the definition of various groups (e.g., R’-R10), when Lsis attached to a compound as provided herein, e.g., a compound of Formula (A), Formula (A-l), Formula (I), Formula (I- 1), Formula (II), Formula (II- 1), Formula (III), Formula (III- 1), Formula (IV), Formula (V), etc., Lsis covalently bonded to such compound by e.g., removing a hydrogen from such compound (e.g., if R3is -NH2, by removing a hydrogen of -NH2to form -NH-L8-), forming a salt of such compound (e.g., by forming an ammonium salt of a tertiary amine moiety in such compound), etc.

[0177] In some embodiments, Lsis absent, a proteolytic group, or a pH labile group. In some embodiments, Lsis absent. In some embodiments, Lsis a proteolytic group. A proteolytic group can refer to a moiety that can be cleaved by proteolytic enzymes, such as proteases, peptidases, or proteinases, which cleave the peptide bonds between amino acids. For example, a linking group comprising a proteolytic group can be cleavable linker, wherein the linking group is cleaved by a proteolytic enzyme. In some embodiments, Lsis a pH labile group. A pH labile can refer to a moiety that can release a payload in acidic environments, such as the lysosomal lumen, tumor microenvironment, endosome, etc. For example, a linking group comprising a pH labile group can be a chemically cleavable linker, wherein the linking group is cleaved in an acidic environment (e.g., a pH less than about 7.3-7.5).

[0178] In some embodiments, Lsis -L-Q, wherein:L is absent or Ci-C2o alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -CR’=CR’-,, -O-, -N(R’)-, -C(=O)-, C(=S)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, - N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, - S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(OR’)O-, -P(O)(R’)-, -Cy-, or an amino acid sequence comprising 2-25 amino acids;each -Cy- is independently a bivalent ring selected from C2-C2o cycloalkylene, Ce-C2o arylene, 3-20 membered heteroarylene, or 3-20 membered heterocycloalkylene, wherein each group is optionally and independently substituted with 1-20 Rs;WSGR Docket No. 60555-703.6010 0Q is -N=C=O, -NC, -Ns, 40 ■, -C(R’)=C(R’)2, or *,=.., whereinc0 is optionally and indpendently subsituted with 1-5 R’;each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=0)N(R)2, -S(O)2R, or a protecting group;each R is independently hydrogen, halogen, or an optionally substituted group selected from Ci-Cw aliphatic, Ci-Cio heteroalkyl, Ce-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3- 20 membered heterocycloalkyl, wherein each group is optionally and independently substituted with 1-20 Rs, or two R groups are optionally and independently taken together to form a covalent bond or =0; ortwo or more R groups on the same atom are optionally and independently taken together with the atom to form a 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the atom, 0-5 heteroatoms; ortwo or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the intervening atoms, 0-5 heteroatoms; andeach Rsis independently halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OCi-Ce alkyl, - OC3-C10 cycloalkyl, -OCe-Cioaryl, -0-5-10 membered heteroaryl, -0-3-20 membered heterocycloalkyl, -OC(=O)Ci-C6alkyl, -OC(=O)C3-Ci0cycloalkyl, -OC(=O)C6-Ci0aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, - NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2Ci-Ce alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci- C6alkyl)S(=O)2Ci-C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=O)2C6- C10 aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)Ci-Ce alkyl, -C(=O)OH, -C(=O)OCi-Ce alkyl, - C(=O)NH2, -C(=O)NHCI-C6alkyl, -C(=O)N(Ci-C6alkyl)2; wherein each Ci-C6alkyl, Ci-C6heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.WSGR Docket No. 60555-703.601

[0179] In some embodiments, L is absent. In some embodiments, L is C1-C20 alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -O-, -N(R’)-, -C(=O)-, -C(=O)N(R’)-, -N(R’)C(=O)O-, -P(O)(OR’)O-, -P(O)(R’)-, -Ph- optionally substituted with 1-5 Rs, or an amino acid sequence comprising 2-10 amino acids. In some embodiments, In some embodiments, L is C1-C20 alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -(CH2-CH2-O)n-, wherein n is 1-10. In some embodiments, In some embodiments, L is C1-C20 alkylene optionally substituted with 1-10 -CH3, -COOH, or -CH2-Ph.

[0180] In some embodiments, Q is -N=C=O. In some embodiments, Q is -NC. In some embodiments, Q is - ON3. In some embodiments, Qis - wherein O is optionally and indpendently subsituted with 1- OCjw5 R’ and each R’ is independently as described herein. In some embodiments, Q is O. In some embodiments, Q is -C(R’)=C(R’)2, wherein each R’ is independently as described herein. In some-embodiments, Q is5, wherein each R’ is independently as described herein.

[0181] In some embodiments, -L-Q is not -H. In some embodiments, -L-Q is not -halogen. In someIn some embodiments, -WSGR Docket No. 60555-703.601. In some embodiments, -L-Q is:WSGR Docket No. 60555-703.601

[0182] In some embodiments, Lshas a structure ofindependently as described herein. In some embodiments, Lshas a structure of each other variable is independently as described herein. In some embodiments, Lshas a structure ofWSGR Docket No. 60555-703.601O', wherein each other variable is independently as described herein. In some embodiments,0HO-P-O- I fTn0Lshas a structureof ', wherein each other variable is independently as described herein.O HO-P-O’I fin0In some embodiments, Lshas a structureof, wherein each other variable is independently as described herein.

[0183] Among other things, the present disclosure provides a compound listed in:Table IB:Structure Compound Number 0^NH2SML-1SML-2? H f? j vl jA VLSML-3^WSGR Docket No. 60555-703.601SML-4 NSML-5> A JI. JYH2N—SML-6SML-7 wtT SML-8Pf.yr~XAM S NH2SML-9 ■> — 4 y *H Y H ncy — SV-A^WSGR Docket No. 60555-703.6011 J SML-10 \oh2h9 i 2M, AH£ IH£ i° X)HR1 ° H ° ° SML-11) 9 P'-'if'N';j; ^- NH -" J -C!Xf'Ri = L-Cit, R2= L-Val, n=6R SML-12 O JJC^I / ": Orx ‘lN l< XXR = NH2, N3, OCH3, N(CH3)2,<0 SML-13 S 0 0^.0 O O RHR = H or CH3, n is 3SML-14O L, CH3OH [< Nr' SN\ „XUL xX1 N A P 1 / 1 XNHVI o OX^OHO HSML-15 1 OKO-^X^O^OHOH W\ 1 JIjT P X 11 / ^NF<S-^XA'CIJU °QooHWSGR Docket No. 60555-703.601SML-16 O H?RzHSOo R3R1 = L-Val, R2= L-Ala, R3= H, CH3\0 SML-17 / “I0V"\N-. SML-18 ^X °v i0H "j NHN3SML-190X •X, / ■ SML-20~ a 1MXXO o N / Sf W -f)MHJ0 / '■-- <’: SML-21 X.r \\\ "00 ^^~NHirX-^0WSGR Docket No. 60555-703.601NH2SML-22 z<■ •: S-AAA. J(J- NH X!0=\ 1 SML-23oK>y-NH / H3C / / r0HA "z> n- \ <-■*csX>. 'SML-24 ‘ —f 1—ITz1As °ZAX° °H2N SML-25 A LA JI oho0 / '" ASML-26H fvAzAAX0 0A N 'WSGR Docket No. 60555-703.601SML-27o oSML-28 ok okO z O z^ k?? / ^z A / zzzzz^'X^~''\ oX X SML-29 ZI ZI((( V oU \ A o L:::O o==A) > O O J ftPx> °I / I / )oTZ / °==IZy vSML-300 S\7Z-~ZHCH3OH ° XV / V°Vx^~ z^,\A O= Y 'O'x'N^^NVI o^ Y) O A^OH0 HSML-31 ) <5°YOHOH HJ 1X P JL X JJ0 HuosSML-32 S ° / °’YYi H?hxvyN^XA V^ok'N^k^NclV-k 0 COOH0 10WSGR Docket No. 60555-703.601SML-33 y\O £'=sOyJ Z— A Z— \ O ) OO=O\=\ ZZ ZZ SML-34 \ y 0 o=\=\\ XO O' 0 o 0'' 00 oo73n==--11z ZZ - o^\ °^x O z ° SML-35 0^2 zz / y^'^? Vz / zz^ O^ z^3^z / zz^ O~ z'''1ZI X^^z- / zz^^0\ / 0 0 TO=Z1 yyO.- Q 0a 7 £ T^ 0. 0 SML-36 r^ °O IZ) / \ ZT i o6° '°r P7 / \ —o= / 0 — \=y / ° / 0. / 1\'zr O / z\,o'^ / yo\ orz^== "SML-37WSGR Docket No. 60555-703.601H 0 SML-38V5O5?=k z— / oQ / .NNA0Ht vx°u IZ )ClSML-39 p AoOOT?=-TIZ S 1 / °VVVol N'^^NVL 5 V0 HO °HV^ZZY'O ZTr SML-40 V° \2 H S 0AN'^^^V1NV^NOH if'W KLWLVVi A V i 1 1 VNHX)0'V^O'%A^N oUO H SML-41SML-42 VS 0 O^N,o L. VN 0HrVrVKVVt V\\ ~ ~ H 1 1 / x P 11 / ^^V:iVl S ° H0SML-43 Vvf° 2 S o o^xVN''- / ''^^ OH V^VhAVl VoHL LL k 11 1 / / NH0 HSML-44 O'H [ ° / Q\ z°XVQ-L, NJ rw M2X A1 II J XN HHWSGR Docket No. 60555-703.601SML-45'O^O / H J ) O1 J 1 / ^NHSML-46&Q-irNN NHn is 1-6SML-470(HO-P-O- \ 0,1 ft-0') — 4. ~D J,JiQ-L-N^N^ J!^ JLNz / ^NHHn is 1-6SML-48iXH ) qL 1 n X JXNHHI JLo, or a pharmaceutically acceptable salt thereof, wherein each variable group, if present, is independently as described herein.Polymer

[0184] Disclosed herein in some embodiments are compositions comprising polymers. A “polymer” as disclosed herein can refer to any class of natural or engineered substances composed of large molecules (e.g., macromolecules), which are multiples of monomers (e.g., simpler chemical units). In some embodiments, a polymer can comprise a polynucleotide, a polypeptide, or a combination thereof. In some embodiments, a polymer can be a natural polymer, an engineered polymer, or any combination thereof. In some embodiments, an engineered polymer can comprise an engineered polynucleotide, an engineered polypeptide, or a combination thereof. In some embodiments, an “engineered polymer”, “engineered polynucleotide”, orWSGR Docket No. 60555-703.601“engineered polypeptide” as referred to herein can comprise a composition that is not present in nature. In some embodiments, a composition that is not present in nature can comprise a composition that was produced artificially by humans. In some embodiments an engineered polymer can comprise a sequence that is not present in nature, a combination of components that are not present together in nature, a composition that has been altered from a composition that is otherwise present in nature, or a combination thereof.Polynucleotide

[0185] Disclosed herein in some embodiments are polymers comprising polynucleotides. The terms “polynucleotide” and “nucleic acid,” can be used interchangeably herein, and can refer to a polymeric form of nucleotides of any length. In some embodiments a polymeric form of nucleotides can comprise ribonucleotides, deoxynucleotides, or combinations thereof. In some embodiments, a polynucleotide can comprise single-, double-, or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, a polymer comprising purine and pyrimidine bases or other natural, chemically or biochemically modified, nonnatural, or derivatized nucleotide bases, or any combination thereof. In some embodiments a polynucleotide can comprise single -stranded polynucleotides. In some embodiments a single-stranded polynucleotide can comprise a sense or antisense strand. In some embodiments, a polynucleotide can comprise a double-stranded polynucleotide. Unless specifically limited, a polynucleotide can comprise nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as any sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem.260:2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)).Nucleic acid modifications

[0186] In some embodiments, the polynucleotide can comprise any type of nucleic acid molecule (e.g., ribonucleic acid (RNA) molecule, deoxyribonucleic acid (DNA) molecule, xeno nucleic acid (XNA) molecule, etc.). In some embodiments, the polynucleotide comprises ribonucleic acid (RNA) molecules, deoxyribonucleic acid (DNA) molecules, xeno nucleic acid (XNA) molecules, or any combination thereof. In some embodiments, the polynucleotide is an engineered polynucleotide. An engineered polynucleotide can refer to a synthetically constructed polynucleotide. For example, the polynucleotide can be synthesized by chemical synthesis, enzymatic synthesis, or any combination thereof. In some embodiments, the polynucleotide is a synthetic polynucleotide. In some embodiments, the polynucleotide comprises at least one modification. In some embodiments, the polynucleotides disclosed herein can comprise nucleic acid molecules comprising a modification of a sugar, a phosphate backbone, or a nucleobase. For example, noncoding nucleic acid molecules can be modified through the addition of moieties onto the molecule. A modification can be a chemical modification, a synthetic modification, or a natural modification. For example,WSGR Docket No. 60555-703.601the polynucleotide disclosed herein can comprise a 2'-O-methoxyethoxy (2'-0Me) modification, a 2'- O-(2-methoxyethyl) (2'-O-moe) modification, a 2'-fluoro (2'-F) modification, a locked nucleic acid (LNA) modification, a pseudouridine (y) modification, a phosphorothioate (PS) bond modification, a phosphorodiamidate morpholino oligomer (PMO) modification, a 2'-phosphorylation (2'-P) modification, or any combination thereof. In some embodiments, the polynucleotide comprises (i) a 5' end modification, (ii) a 3' end modification, or (iii) a 5' end modification and a 3' end modification. In some embodiments, the modification is in the middle of the polynucleotide (e.g., between the 3' and the 5' end).

[0187] Nucleic acid molecules of the present disclosure can be modified at the nucleobase. Nucleobase modifications include but are not limited to 2’-O-methylation (2’-O-Me), conversion of uridine to pseudouridine, N(6)-methyladenosine, 5 -methylcytidine, 5 -methyluridine (ribothymidine), 2’-fluoro (2’F), 2’-O-methoxyethyl (2’-M0E), ribose modification with bridged nucleic acids (e.g., locked nucleic acids (LNA), ethylene-bridged nucleic acids (ENA), or constrained ethyl bridged nucleic acid (cEt) modifications), or nucleotides with alternative chemistries (e.g., phosphorodiamidate morpholino oligonucleotides (PMO), peptide nucleic acids (PNA), tricyclo DNA (tcDNA), unlocked nucleic acids (UNA) or glycol nucleic acids (GNA)).

[0188] Nucleic acid molecules of the present disclosure can be modified at the phosphate backbone. A phosphate backbone can be modified to comprise a phosphodiester, phosphorothioate isomers, phosphoryl DMI amidate diester isomers, a phosphorodithioate, a methylphosphontae, a 5 ’-phosphorothioate, a peptide nucleic acid, a 5’-(E)-vinylphosphonate, or a 5 ’-methyl phosphonate.

[0189] Additional moieties can be added or attached onto nucleic acid molecules of the present disclosure. Additional moieties can include, but are not limited to antibodies, lipophilic moieties, small molecules, and RNA aptamers (e.g., ribozymes, docosanoic acid, etc.). Additional moieties can be added to alter the pharmacological features (e.g., structural or chemical parameters) of the nucleic acid molecules of the present disclosure. Nucleic acid molecules of the present disclosure can be modified with at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more moieties. An additional moiety can be added at the 5' end of a nucleic acid molecule. Alternatively, an additional moiety can be added at the 3' end of a nucleic acid molecule. Alternatively, an additional moiety can be added in the middle of a nucleic acid molecule (e.g., neither at the 3' end nor the 5' end).Effector nucleic acid molecules

[0190] In some embodiments, the polynucleotide is an effector nucleic acid molecule. " Effector nucleic acid molecules" can refer to nucleic acid sequences (e.g., microRNAs (miRNAs), small interfering RNAs (siRNAs), etc.) that directly interact with other molecules (e.g., RNA, polypeptides, etc.) to regulate gene expression (e.g., by inhibiting translation, causing degradation of a target mRNA, etc.), essentially acting as "effectors" to influence cellular processes. In some embodiments, the polynucleotide can be configured for polynucleotide-mediated gene expression alteration. Gene expression alteration can include, but is not limited to, changing the level of activity of a gene, such as turning it up (e.g., increasing expression) or down (e.g., decreasing expression) through various mechanisms. Gene expression alterations can also refer to changes inWSGR Docket No. 60555-703.601gene regulation mechanisms, such as translation, transcription, epigenetics, post-transcription, posttranslation, or any combination thereof. For example, in some cases, the polynucleotide can be configured for polynucleotide-mediated gene splicing, such as splice -switching oligonucleotides (SSOs) which can alter pre-mRNA splicing by binding to a target sequence and blocking the access of splicing factors to the pre-mRNA. Gene expression can be altered in a number of ways including, epigenetic alterations, DNA methylation, genome editing, site-directed mutagenesis, or any combination thereof. For example, in some cases, the polynucleotide can be configured for polynucleotide-mediated gene silencing, such as sequence-specific gene silencing. Sequence-specific gene silencing can refer to a decrease in gene expression relative to normal gene expression levels (e.g., in the absence of the polynucleotide disclosed herein). For example, polynucleotide-mediated gene silencing can refer to siRNA-mediated gene silencing (e.g., small interfering RNA, short interfering RNA, silencing RNA, etc.), where gene silencing can be elicited by binding of an siRNA, through complementarity, to a specific mRNA sequence, thereby targeting the specific mRNA sequence for cleavage and degradation.

[0191] In some embodiments, the polynucleotide can be complementary to a target nucleic acid sequence. In some embodiments, the polynucleotide can be complementary to a target ribonucleic acid sequence, such as a messenger ribonucleic acid sequence (mRNA), a pre-mRNA sequence, a coding ribonucleic acid sequence, a noncoding ribonucleic acid sequence, or any combination thereof. In some cases, the polynucleotide can selectively bind to a target amino acid sequence, such as an aptamer configured to bind a target protein. In some embodiments, the polynucleotide can comprise an siRNA, a microRNA (miRNA), an antisense oligonucleotide (ASO), a splice-switching oligonucleotide (SSO), an aptamer, a deoxyribozyme, or any combination thereof. The creation of such polynucleotides is routine to those of skill in the art, including strategies for developing and designing polynucleotides that will be effective for use in the methods disclosed herein (such as inhibition of a target gene). For example, factors such as melting temperature, length, GC percentage, secondary structure, target sequence, splicing enhancer sites, binding affinity, and modifications can be taken into account when designing polynucleotides of the present disclosure.

[0192] In some embodiments, the polynucleotide is an siRNA. Small interfering RNAs (siRNAs) generally comprise a noncoding double-stranded nucleic acid sequence that can be unwound into single stranded RNAs in order to bind to a target nucleic acid sequence, such as another RNA (e.g., mRNA) through Watson-Crick base pairing in a manner mediated by or independent of an argonaute-containing complex (e.g., RISC complex). An siRNA can function to specifically silence the expression of a target gene by binding to a complementary mRNA and causing degradation of the complementary mRNA, thus preventing translation into a protein. siRNAs can be classified into classes I, II, and III based on predicted silencing activities. Class I siRNAs are functional in mammalian cells, while Class III siRNAs are nonfunctional. In some embodiments, the siRNA is a class I siRNA. Strategies for developing and designing siRNAs of the present disclosure that will be effective (such as in silencing the expression of a target gene) can include, but are not limited to, factors such as distance of target region to transcription start site (e.g., avoiding 5' and 3'UTRs), nucleotideWSGR Docket No. 60555-703.601composition (e.g., %GC content, length, etc.), and absence of off-target effects and secondary structures in a target site.

[0193] In some embodiments, the polynucleotide is a short hairpin RNA (shRNA). A short hairpin RNA (shRNA) can refer to a small, artificial RNA molecule that can silence genes by degrading viral or messenger RNA. shRNA is processed in the cytoplasm by the dicer protein, which removes a loop structure to produce siRNA. In some embodiments, the shRNA is configured to produce an siRNA, such as an siRNA disclosed herein.

[0194] In some embodiments, the polynucleotide is an miRNA. In some embodiments, the miRNA is an primary miRNA (pri-miRNA). In some embodiments, the miRNA is a precursor miRNA. In some embodiments, the miRNA is a mature miRNA. MicroRNA (miRNA) can refer to a small, non-coding RNA molecule that regulates gene expression by binding to a target mRNA and preventing or delaying the translation of the target mRNA. Strategies for developing and designing miRNAs of the present disclosure that will be effective (such as in silencing the expression of a target gene) can include, but are not limited to, factors such as seed regions (e.g., including at least one seed match in the 3' UTR), secondary structure (e.g., including a terminal loop, a basal stem, and a flanking sequence on either side), and modifications.

[0195] In some embodiments, the polynucleotide can comprise an antisense oligonucleotide (ASO).Antisense oligonucleotides (ASOs) can refer to synthetic, single -stranded DNA or RNA molecules that bind to target RNA sequences and alter protein expression of the target RNA. For example, ASOs of the present disclosure can induce the degradation of mRNA and / or prevent or inhibit the progression of splicing or the translational machinery. ASOs can be modified to improve stability, uptake, and bioavailability. For example, modifications to the sugar ribose can increase affinity to the target RNA. Strategies for developing and designing ASOs of the present disclosure that will be effective (such as in inducing the degradation of a target gene) can include, but are not limited to, factors such as length, secondary structure, splicing enhancer sites, and modifications.

[0196] In some embodiments, the ASO is a splice-switching oligonucleotide (SSO). In some embodiments, the polynucleotide is an SSO. Splice -switching oligonucleotides (SSOs) are synthetic nucleic acids that can be used to disrupt the normal splicing process by blocking RNA-RNA base-pairing and protein-RNA binding interactions. SSOs of the present disclosure can be designed to target different exons and have different lengths and modification contents. For example, AmNA (Amido-bridged nucleic acids) and GuNA (Guanidine-bridged nucleic acids) modified SSOs have been shown to have higher exon skipping activities than LNA (Locked nucleic acids) modified SSOs.

[0197] In some embodiments, the polynucleotide can comprise an aptamer. An aptamer can refer to a singlestranded nucleic acid molecule that binds to a target by folding into a three-dimensional structure. In some embodiments, the aptamer comprises DNA, RNA, XNA, or any combination thereof. In some embodiments, the aptamer binds to a polypeptide (e.g., protein), nucleic acid sequence, small molecule, or metal ion. In some embodiments, the aptamer is configured to alter gene expression. In some embodiments, the aptamer is an aptamer RNA switch. An RNA switch can refer to an RNA regulatory element that can change its structureWSGR Docket No. 60555-703.601(conformation) in response to the binding of a ligand (e.g., a polypeptide) in order to regulate gene expression of a target gene by either turning the target gene "on" or "off depending on the ligand's presence. Strategies for developing and designing aptamers of the present disclosure that will be effective (such as in altering the expression of a target gene) can include, but are not limited to, factors such as secondary structure, and binding affinity.

[0198] In some embodiments, the polynucleotide is a deoxyribozyme (such as DNA enzymes, DNAzymes, catalytic DNA, etc.). Deoxyribozymes can refer to DNA sequences that can catalyze chemical reactions, including RNA and / or DNA cleavage, which can be used to control gene expression. In some embodiments, the deoxyribozyme catalyzes DNA cleavage. In some embodiments, the deoxyribozyme catalyzes RNA cleavage. In some embodiments, the deoxyribozyme is a ribonuclease.Nucleic acid molecule structure

[0199] In some embodiments, the polynucleotide can comprise a double -stranded nucleic acid molecule (e.g., a double-stranded polynucleotide). In some embodiments, the double-stranded nucleic acid molecule is any type of nucleic acid (e.g., ribonucleic acid (RNA), deoxyribonucleic acid (DNA), etc.) that contains two strands. In some embodiments, the double-stranded nucleic acid molecules are double-stranded oligonucleotides, which comprise short pieces of a nucleotide sequence (e.g., DNA, RNA). In some embodiments, the double-stranded nucleic acid molecule comprises an antisense strand configured to silence a target single -stranded nucleic acid sequence, such as a messenger RNA (mRNA). In some embodiments, the double -stranded nucleic acid molecule comprises an antisense strand configured to enhance expression of a target nucleic acid sequence (such as a target nucleic acid sequence as described herein). In some embodiments, the double-stranded nucleic acid molecule comprises an antisense strand configured to enhance expression of a single -stranded target nucleic acid sequence. The double -stranded nucleic acid molecule can be synthetic (e.g., engineered). Alternatively, or in addition to, the double-stranded nucleic acid molecule can be a chemically modified nucleic acid molecule, such as the modifications described herein. The doublestranded nucleic acid molecule can comprise two nucleic acid strands, a sense strand, and an antisense strand. The sense strand of the double -stranded nucleic acid molecule will have the same or substantially the same sequence as a target nucleic acid sequence. The antisense strand of the double -stranded nucleic acid molecule can be complementary or substantially complementary to a target nucleic acid sequence.

[0200] Double-stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be at least about 5 nucleotides, at least about 6 nucleotides, at least about 7 nucleotides, at least about 8 nucleotides, at least about 9 nucleotides, at least about 10 nucleotides, at least about 11 nucleotides, at least about 12 nucleotides, at least about 13 nucleotides, at least about 14 nucleotides, at least about 15 nucleotides, at least about 16 nucleotides, at least about 17 nucleotides, at least about 18 nucleotides, at least about 19 nucleotides, at least about 20 nucleotides, at least about 21 nucleotides, at least about 22 nucleotides, at least about 23 nucleotides, at least about 24 nucleotides, at least about 25 nucleotides, at least about 26 nucleotides, at least about 27 nucleotides, at least about 28 nucleotides, at least about 29 nucleotides, at least about 30 nucleotides, at least about 31 nucleotides, at least about 32 nucleotides, at least about 33WSGR Docket No. 60555-703.601nucleotides, at least about 34 nucleotides, at least about 35 nucleotides, at least about 36 nucleotides, at least about 37 nucleotides, at least about 38 nucleotides, at least about 39 nucleotides, at least about 40 nucleotides, at least about 41 nucleotides, at least about 42 nucleotides, at least about 43 nucleotides, at least about 44 nucleotides, at least about 45 nucleotides, at least about 46 nucleotides, at least about 47 nucleotides, at least about 48 nucleotides, at least about 49 nucleotides, at least about 50 nucleotides, at least about 51 nucleotides, at least about 52 nucleotides, at least about 53 nucleotides, at least about 54 nucleotides, at least about 55 nucleotides, at least about 56 nucleotides, at least about 57 nucleotides, at least about 58 nucleotides, at least about 59 nucleotides, at least about 60 nucleotides, or more nucleotides in length.

[0201] Double-stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be at most about 60 nucleotides, at most about 59 nucleotides, at most about 58 nucleotides, at most about 57 nucleotides, at most about 56 nucleotides, at most about 55 nucleotides, at most about 54 nucleotides, at most about 53 nucleotides, at most about 52 nucleotides, at most about 51 nucleotides, at most about 50 nucleotides, at most about 49 nucleotides, at most about 48 nucleotides, at most about 47 nucleotides, at most about 46 nucleotides, at most about 45 nucleotides, at most about 44 nucleotides, at most about 43 nucleotides, at most about 42 nucleotides, at most about 41 nucleotides, at most about 40 nucleotides, at most about 39 nucleotides, at most about 38 nucleotides, at most about 37 nucleotides, at most about 36 nucleotides, at most about 35 nucleotides, at most about 34 nucleotides, at most about 33 nucleotides, at most about 32 nucleotides, at most about 31 nucleotides, at most about 30 nucleotides, at most about 29 nucleotides, at most about 28 nucleotides, at most about 27 nucleotides, at most about 26 nucleotides, at most about 25 nucleotides, at most about 24 nucleotides, at most about 23 nucleotides, at most about 22 nucleotides, at most about 21 nucleotides, at most about 20 nucleotides, at most about 19 nucleotides, at most about 18 nucleotides, at most about 17 nucleotides, at most about 16 nucleotides, at most about 15 nucleotides, at most about 14 nucleotides, at most about 13 nucleotides, at most about 12 nucleotides, at most about 11 nucleotides, at most about 10 nucleotides, at most about 9 nucleotides, at most about 8 nucleotides, at most about 7 nucleotides, at most about 6 nucleotides, at most about 5 nucleotides, or fewer nucleotides in length.

[0202] In some embodiments, the double-stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 5 to about 60 nucleotides in length. In some embodiments, the double -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 5 to about 55 nucleotides in length. In some embodiments, the double -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 5 to about 50 nucleotides in length. In some embodiments, the double-stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 5 to about 45 nucleotides in length. In some embodiments, the double-stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 5 to about 40 nucleotides in length. In some embodiments, the double -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 5 to about 35 nucleotides in length. InWSGR Docket No. 60555-703.601some embodiments, the double -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 5 to about 30 nucleotides in length. In some embodiments, the double-stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 5 to about 25 nucleotides in length. In some embodiments, the double -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 5 to about 20 nucleotides in length. In some embodiments, the double -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 5 to about 15 nucleotides in length. In some embodiments, the double -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 5 to about 10 nucleotides in length. In some embodiments, the double -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 10 to about 60 nucleotides in length. In some embodiments, the double -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 15 to about 60 nucleotides in length. In some embodiments, the double -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 20 to about 60 nucleotides in length. In some embodiments, the double-stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 25 to about 60 nucleotides in length. In some embodiments, the double-stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 30 to about 60 nucleotides in length. In some embodiments, the double -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 35 to about 60 nucleotides in length. In some embodiments, the double -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 40 to about 60 nucleotides in length. In some embodiments, the double -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 45 to about 60 nucleotides in length. In some embodiments, the double -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, etc.) can be between about 50 to about 60 nucleotides in length.

[0203] The antisense strand of a double-stranded noncoding nucleic acid molecule can form complementary binding with an entire sense strand of the double-stranded noncoding nucleic acid molecule. Alternatively, the antisense strand of a double-stranded noncoding nucleic acid molecule can form complementary binding with a part of a sense strand of a double -stranded noncoding nucleic acid molecule. The antisense strand of a double -stranded noncoding nucleic acid molecule can also form complementary binding with an entire target strand. Alternatively, the antisense strand of a double -stranded noncoding nucleic acid molecule can form complementary binding with a part of a target strand. The antisense strand of a double -stranded noncoding nucleic acid molecule can form complementary binding to one or more portions of a target strand (e.g., an mRNA strand) including a 5’ UTR, a 3’UTR, a regulatory region, and / or a coding sequence. A regulatory region of a target strand (e.g., a mRNA) can comprise a promoter region, an enhancer region, an operator region, or a repressor region.WSGR Docket No. 60555-703.601

[0204] The antisense strand of the double-stranded noncoding nucleic acid molecule can form complementary binding to part or all of a portion of an mRNA target strand. The antisense strand of the double -stranded noncoding nucleic acid molecule can be completely complementary (e.g., 100% complementary) to their target strand counterparts. Alternatively, the antisense strand of the double-stranded noncoding nucleic acid molecule and can have imperfect complementarity to their target strand counterparts. An antisense strand of the double-stranded noncoding nucleic acid molecule can have at least about 50% complementarity, at least about 55% complementarity, at least about 60% complementarity, at least about 65% complementarity, at least about 70% complementarity, at least about 75% complementarity, at least about 80% complementarity, at least about 85% complementarity, at least about 90% complementarity, at least about 91% complementarity, at least about 92% complementarity, at least about 93% complementarity, at least about 94% complementarity, at least about 95% complementarity, at least about 96% complementarity, at least about 97% complementarity, at least about 98% complementarity, at least about 99% complementarity, or more to its corresponding target strand. An The antisense strand of the doublestranded noncoding nucleic acid molecule can have at most about 99% complementarity, at most about 98% complementarity, at most about 97% complementarity, at most about 96% complementarity, at most about 95% complementarity, at most about 94% complementarity, at most about 93% complementarity, at most about 92% complementarity, at most about 91% complementarity, at most about 90% complementarity, at most about 85% complementarity, at most about 80% complementarity, at most about 75% complementarity, at most about 70% complementarity, at most about 65% complementarity, at most about 60% complementarity, at most about 55% complementarity, at most about 50% complementarity, or less to its corresponding target strand.

[0205] In some embodiments, the polynucleotide can comprise a single -stranded nucleic acid molecule (e.g., a single -stranded polynucleotide). In some embodiments, the single-stranded nucleic acid molecule is any type of nucleic acid (e.g., ribonucleic acid (RNA), deoxyribonucleic acid (DNA), etc.) that contains one strand. In some embodiments, the single-stranded nucleic acid molecules are single -stranded oligonucleotides, which comprise short pieces of a nucleotide sequence (e.g., DNA, RNA). In some embodiments, the single-stranded nucleic acid molecule is configured to silence a target single-stranded nucleic acid sequence, such as a messenger RNA (mRNA). In some embodiments, the single -stranded nucleic acid molecule is configured to enhance expression of a target nucleic acid sequence (such as a target nucleic acid sequence as described herein). In some embodiments, the single-stranded nucleic acid molecule is configured to enhance expression of a single-stranded target nucleic acid sequence. The single-stranded nucleic acid molecule can be synthetic (e.g., engineered). Alternatively, or in addition to, the single -stranded nucleic acid molecule can be a chemically modified nucleic acid molecule, such as the modifications described herein.

[0206] Single-stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be at least about 5 nucleotides, at least about 6 nucleotides, at least about 7 nucleotides, at least about 8 nucleotides, at least about 9 nucleotides, at least about 10 nucleotides, at least about 11 nucleotides, at least about 12 nucleotides, at least about 13 nucleotides, at least about 14 nucleotides,WSGR Docket No. 60555-703.601at least about 15 nucleotides, at least about 16 nucleotides, at least about 17 nucleotides, at least about 18 nucleotides, at least about 19 nucleotides, at least about 20 nucleotides, at least about 21 nucleotides, at least about 22 nucleotides, at least about 23 nucleotides, at least about 24 nucleotides, at least about 25 nucleotides, at least about 26 nucleotides, at least about 27 nucleotides, at least about 28 nucleotides, at least about 29 nucleotides, at least about 30 nucleotides, at least about 31 nucleotides, at least about 32 nucleotides, at least about 33 nucleotides, at least about 34 nucleotides, at least about 35 nucleotides, at least about 36 nucleotides, at least about 37 nucleotides, at least about 38 nucleotides, at least about 39 nucleotides, at least about 40 nucleotides, at least about 41 nucleotides, at least about 42 nucleotides, at least about 43 nucleotides, at least about 44 nucleotides, at least about 45 nucleotides, at least about 46 nucleotides, at least about 47 nucleotides, at least about 48 nucleotides, at least about 49 nucleotides, at least about 50 nucleotides, at least about 51 nucleotides, at least about 52 nucleotides, at least about 53 nucleotides, at least about 54 nucleotides, at least about 55 nucleotides, at least about 56 nucleotides, at least about 57 nucleotides, at least about 58 nucleotides, at least about 59 nucleotides, at least about 60 nucleotides, or more nucleotides in length.

[0207] Single-stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be at most about 60 nucleotides, at most about 59 nucleotides, at most about 58 nucleotides, at most about 57 nucleotides, at most about 56 nucleotides, at most about 55 nucleotides, at most about 54 nucleotides, at most about 53 nucleotides, at most about 52 nucleotides, at most about 51 nucleotides, at most about 50 nucleotides, at most about 49 nucleotides, at most about 48 nucleotides, at most about 47 nucleotides, at most about 46 nucleotides, at most about 45 nucleotides, at most about 44 nucleotides, at most about 43 nucleotides, at most about 42 nucleotides, at most about 41 nucleotides, at most about 40 nucleotides, at most about 39 nucleotides, at most about 38 nucleotides, at most about 37 nucleotides, at most about 36 nucleotides, at most about 35 nucleotides, at most about 34 nucleotides, at most about 33 nucleotides, at most about 32 nucleotides, at most about 31 nucleotides, at most about 30 nucleotides, at most about 29 nucleotides, at most about 28 nucleotides, at most about 27 nucleotides, at most about 26 nucleotides, at most about 25 nucleotides, at most about 24 nucleotides, at most about 23 nucleotides, at most about 22 nucleotides, at most about 21 nucleotides, at most about 20 nucleotides, at most about 19 nucleotides, at most about 18 nucleotides, at most about 17 nucleotides, at most about 16 nucleotides, at most about 15 nucleotides, at most about 14 nucleotides, at most about 13 nucleotides, at most about 12 nucleotides, at most about 11 nucleotides, at most about 10 nucleotides, at most about 9 nucleotides, at most about 8 nucleotides, at most about 7 nucleotides, at most about 6 nucleotides, at most about 5 nucleotides, or fewer nucleotides in length.

[0208] In some embodiments, the single-stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 5 to about 60 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 5 to about 55 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 5 to about 50 nucleotides inWSGR Docket No. 60555-703.601length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 5 to about 45 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 5 to about 40 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 5 to about 35 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 5 to about 30 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 5 to about 25 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 5 to about 20 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 5 to about 15 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 5 to about 10 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 10 to about 60 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 15 to about 60 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 20 to about 60 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 25 to about 60 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 30 to about 60 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 35 to about 60 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 40 to about 60 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 45 to about 60 nucleotides in length. In some embodiments, the single -stranded nucleic acids of the present disclosure (e.g., siRNAs, miRNAs, ASOs, SSOs, aptamers, deoxyribozymes, etc.) can be between about 50 to about 60 nucleotides in length.Fusion polynucleotidesWSGR Docket No. 60555-703.601

[0209] In some embodiments, the polynucleotide is a fusion polynucleotide. Fusion polynucleotides can refer to polynucleotides that are fused to a protein, such as by fusing a secretable luciferase to a polynucleotide of interest. In some embodiments, the fusion polynucleotide comprises: i) a polynucleotide (e.g., any polynucleotide disclosed herein can be used in a fusion polynucleotide of the present disclosure, such as an siRNA); and ii) one or more heterologous polypeptide, e.g., a targeting moiety that binds to an extracellular domain of a receptor such as a transferrin protein 1 (TfRl, CD71) ); and optionally also includes one or more nuclear localization signals (NLSs), such as an NLS as disclosed herein (see for example NLS sequences in Table 3). The term “heterologous polypeptide” is often used interchangeably herein with “fusion partner.”

[0210] In some cases, nucleic acid modifications (such as nucleic acid modifications disclosed herein), and / or amino acid modifications (such as amino acid modifications disclosed herein) can be used to conjugate a polynucleotide (such as a polynucleotide disclosed herein) to a polypeptide (such as a targeting moiety disclosed herein). For example, the polynucleotide can be chemically modified with a reactive group at either the 5' or 3' end, then a bifunctional crosslinker can be used to attach the polynucleotide to a reactive site on the polypeptide, such as a primary amine group on a lysine residue; common methods can include using click chemistry (e.g., azide-alkyne cycloaddition) or NHS ester coupling, where the polynucleotide is modified with an azide or amine group respectively, and the polypeptide is activated with a complementary reactive group like a DBCO (dibenzocyclooctyne) or NHS ester.Targeting moiety

[0211] A fusion polynucleotide of the present disclosure can include, in addition to the polynucleotide, a targeting moiety. In some embodiments the fusion polypeptide comprises a polynucleotide and one or more heterologous polypeptides, where at least one of the one or more heterologous polypeptides is a targeting moiety. A targeting moiety can be used to direct a polynucleotide to a target cell or tissue. A targeting moiety can be but is not limited to a lipophilic moiety, a small molecule, a peptide (e.g., a polypeptide), an RNA molecule, a nanoparticle, an antibody, a single-domain antibody, a miniprotein, or an antigen binding fragment thereof. A targeting moiety can be specific to an antigen or receptor on the target cell or tissue (e.g., Asialoglycoprotein receptor (ASGPR)). In some embodiments, the targeting moiety specifically binds to a target protein. In some embodiments, the target protein is a receptor expressed by a target cell. In some embodiments, the targeting moiety binds to an extracellular domain of a receptor expressed by a target cell and facilitates cellular uptake.

[0212] A targeting moiety can be a lipophilic moiety, lipophilic moiety can comprise one or more fatty acid groups or salts thereof. A lipophilic be a lipid. Lipids are fatty acids and their derivatives which are insoluble in water but soluble in organic solvents. In some embodiments, a lipophilic moiety can be unsaturated.Alternatively, or in addition to, a lipophilic moiety can be monosaturated. Alternatively, or in addition to, a lipophilic moiety can be poly saturated. In some embodiments, a double bond of an unsaturated lipophilic moiety can be in a cis conformation. Alternatively, or in addition to, a double bond of an unsaturated lipophilic moiety can be in a trans conformation. Non-limiting examples of lipophilic moieties can be aWSGR Docket No. 60555-703.601triglyceride, a phospholipid, a sterol, an oil, a wax, a hormone, a vitamin, cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1 -pyrene butyric acid, dihydrotestosterone, 1,3 -bis- O(hexadecyl)glycerol, geranyloxyhexyanol, hexadecyl glycerol, borneol, menthol, 1,3- propanediol, heptadecyl group, palmitic acid, myristic acid, 03-(oleoyl)lithocholic acid, 03- (oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine.

[0213] A targeting moiety can be a small molecule. A small molecule can be a sugar, an amino acid, a phenolic compound, an alkaloid, a sterol, a lipid, a fatty acid, or other small chemical compound. A chemical compound can be a molecule that has a molecular weight of less than 1000 Daltons. Alternatively, or in addition to, a small molecule is a molecule with a size on the order of 1 nm.

[0214] A targeting moiety can be a sugar or sugar moiety. A sugar can be a monosaccharide. Alternatively, a sugar can be a disaccharide. Alternatively, a sugar can be a polysaccharide. Non-limiting examples of sugars include glucose, dextrose, fructose, galactose, a sugar alcohol, a pentose, xylose, ribose, sucrose, cellulose, starch, lactose, maltose, trehalose, lactulose, cellobiose, chitobiose, glycogen, or chitin. A small molecule can be an amino sugar such as but not limited to N-acetyl Galactosamine (GalNAc), N-acetylglucosamine or sialic acid.

[0215] A targeting moiety can be an RNA molecule. An RNA molecule can comprise an aptamer, a ribozyme, or a hairpin RNA.

[0216] A targeting moiety can be an antibody or an antigen-binding fragment thereof. An antibody, also known as an immunoglobulin, is a blood protein produced to counteract a specific antigen. Antibodies can be Y-shaped proteins which comprise variable binding sites that are specific to particular epitopes. An antibody can be a monoclonal antibody. Alternatively, an antibody can be a polyclonal antibody. An antibody can be a single-domain antibody. An antibody can be an antibody fragment. An antibody can be an agonist.Alternatively, an antibody can be an antagonist. Alternatively, an antibody can be an allosteric modulator (e.g., a positive allosteric modulator or a negative allosteric modulator).

[0217] A targeting moiety can be a polypeptide. Non-limiting examples of polypeptides can be an agonist of IGF1R, IGF2R, TfRl, Nephrin, Nephi, Megalin, cKIT, GLUT4, GLUT1, Neuropilin, FOL1, FOL3, CCR5, CXCR1-4, EGFR, VEGFR1, VEGFR2, PDGFRA, or ADRB3.

[0218] In some embodiments, the targeting moiety binds a cell surface receptor. In certain embodiments, the cell surface receptor is membrane associated. Membrane associated proteins represent about a third of the proteins in living organisms and many membrane proteins are known in the field. Based on their structure, membrane proteins can be largely categorized into three main types: (1) integral membrane protein (IMP), which is permanently anchored or part of the membrane, (2) peripheral membrane protein, which is temporarily attached to the lipid bilayer or to other integral proteins, and (3) lipid-anchored proteins. The most common type of IMP is the transmembrane protein (TM), which spans the entire biological membrane. The cell surface receptor of the present disclosure includes single-pass and multi-pass membrane proteins. Singlepass membrane proteins cross the membrane only once, while multi-pass membrane proteins weave in and out, crossing several times. In some embodiments, the cell surface receptor can be a monomeric receptor. In some embodiments, the cell surface receptor can be a multimeric receptor. In some embodiments, the cellWSGR Docket No. 60555-703.601surface receptor can form a complex with other molecules (e.g., an integrin). The cell surface receptor can be a recycling receptor. For example, a recycling receptor as used herein refers to a cell surface receptor that specifically binds to a ligand (e.g., a targeting moiety) and leads to internalization of the cell surface receptor.

[0219] In some case, the cell surface receptor can be selected by expression levels in one cell type relative to other cell types, where the cell surface receptor is enrichment in the selected cell type and / or tissue type. In some embodiments, the cell surface receptor comprises a tissue-type specific protein. In some embodiments, the cell surface receptor comprises a cell-type specific protein. In some embodiments, the targeting moiety is not an antibody or an antigen binding domain of an antibody. In some embodiments, the targeting moiety is an antibody or an antigen binding domain of an antibody.

[0220] In some embodiments, the targeting moiety binds to an extracellular domain of a receptor protein. In some embodiments, the targeting moiety binds to an extracellular domain of a receptor selected from the group comprising: IGF1R, IGF2R, TfRl, Nephrin, Nephi, Megalin, cKIT, GLUT4, GLUT1, Neuropilin, FOL1, FOL3, CCR5, CXCR1-4, EGFR, VEGFR1, VEGFR2, PDGFRA, and ADRB3. In some embodiments, the targeting moiety binds to an extracellular domain of transferrin receptor protein 1 (TfRl, CD71). In some embodiments, the targeting moiety binds to an extracellular domain of insulin-like growth factor 2 receptor (IGF2R). In some embodiments, the targeting moiety binds to an extracellular domain of insulin-like growth factor 1 receptor (IGF1R). In some embodiments, the targeting moiety comprises polypeptide sequence with less than 150 amino acids. In some embodiments, the targeting moiety comprises polypeptide sequence with less than 100 amino acids.

[0221] In some embodiments, the targeting moiety comprises polypeptide sequence with more than 50 amino acids. In some embodiments, the targeting moiety comprises polypeptide sequence with more than 60 amino acids. In some embodiments, the targeting moiety comprises polypeptide sequence with more than 70 amino acids. In some embodiments, targeting moiety comprises polypeptide sequence with 80 amino acids or more.

[0222] In some embodiments, the targeting moiety comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a polypeptide sequence selected from the sequences in Table 4. In some embodiments, the targeting moiety comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs: 31-151. In some embodiments, the targeting moiety comprises an amino acid sequence having at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to any one of SEQ ID NOs: 31-151. In some embodiments, the targeting moiety comprises an amino acid sequence having at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 91%, at most 92%, at most 93%, at most 94%, at most 95%, at most 96%, at most 97%, at most 98%, or at most 99% sequence identity to any one ofWSGR Docket No. 60555-703.601SEQ ID NOs: 31-151. In some embodiments, the targeting moiety comprises less than 100% sequence identity to any one of SEQ ID NOs: 31-151. In some embodiments, the targeting moiety comprises a sequence to any one of SEQ ID NOs: 31-151. In some embodiments, the targeting moiety comprises a sequence that has at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25 or more amino acid substitutions or mutations relative to any one of SEQ ID NOs: 31-151. In some embodiments, the targeting moiety comprises a sequence that has at most 1, at most 2, at most 3, at most 4, at most 5, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, or at most 25 amino acid substitutions or mutations relative to any one of SEQ ID NOs: 31-151.

[0223] In some embodiments, the targeting moiety binds to a Nephrin receptor.

[0224] In some embodiments, the targeting moiety that binds to a Nephrin receptor comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the sequence of VRVTREGNDLTIETPDRTFHLTYIPGVSPEEAIASAEATLRRLGLDSPEVRAAVRDFVAEQA (SEQ ID NO: 152).

[0225] In some embodiments, the targeting moiety that binds to a Nephrin receptor comprises the sequence of VRVTREGNDLTIETPDRTFHLTYIPGVSPEEAIASAEATLRRLGLDSPEVRAAVRDFVAEQA (SEQ ID NO: 152).

[0226] In some embodiments, the targeting moiety that binds to a Nephrin receptor comprises the sequence of VRVTREGNDLTIETPDRTFHLTYIPGVSPEEAIAS AEATLRRLGLDSPEVRAAVRDFVAEQA, or a sequence with at least 90% sequence identity to VRVTREGNDLTIETPDRTFHLTYIPGVSPEEAIASAEATLRRLGLDSPEVRAAVRDFVAEQA.

[0227] In some embodiments, the targeting moiety binds to an extracellular domain of a Nephrin receptor.

[0228] In some embodiments, the targeting moiety comprises a targeting moiety sequence or mini-protein sequence disclosed in PCT application PCT / US2025 / 011097 (WO2025151729A1), which is incorporated by reference in its entirety.Linkers

[0229] In some cases, a fusion polynucleotide of the present disclosure comprises a linker. In some embodiments, the linker is configured to link a polynucleotide of the present disclosure and a heterologous polypeptide of the present disclosure. In some cases, a fusion polynucleotide of the present disclosure comprises a linker between a heterologous polypeptide (such as a targeting moiety) and the polynucleotide, such as an siRNA, present in the fusion polynucleotide. In some cases, the linker is a proteolytically cleavable linker. In some cases, a polymer conjugate of the present disclosure comprises a linker between a heterologous polypeptide (such as a targeting moiety) and a polynucleotide disclosed herein, such as an siRNA, present in the fusion polynucleotide, and a linking group (as disclosed herein) between the payloadWSGR Docket No. 60555-703.601(e.g., the polypeptide or the polynucleotide) or heterologous polypeptide and the compound disclosed herein. In some cases, the heterologous polypeptide (such as a targeting moiety disclosed herein) is conjugated to a 5' end or a 3' end of the polynucleotide.

[0230] In some cases, the linker is configured to covalently link a polynucleotide of the present disclosure and a polypeptide of the present disclosure. In some cases, the polynucleotide, polypeptide, or a combination thereof comprise at least one reactive moiety. In some cases, the polynucleotide and the polypeptide are covalently linked by an enzymatic reaction. For example, SNAP -tag, a modified form of DNA repair enzyme named human O6alkylguanine-DNA-alkyltransferase, can be used to selectively form a covalent bond with a polynucleotide comprising a benzylguanine (e.g., RNA-TAG can be used to label the polynucleotide with a modified substrate analog, such as benzylguanine), thus allowing the conjugation of a polynucleotide of the present disclosure and a polypeptide of the present disclosure. As an additional example, RNAylation, mediated by the T4 phage ADP-ribosyltransferase (ART) ModB, can be used to covalently link the polynucleotide to the polypeptide through an N-glycosidic bond. In general, ARTs, a class of enzymes ubiquitous across all kingdoms of life, attach an ADP-ribose moiety from the redox cofactor nicotinamide adenine dinucleotide (NAD+, is referred as NAD in the following) to a target protein, nucleic acid, or small molecule in a covalent manner. ARTs generally exhibit high substrate specificity for NAD, such as a NAD-capped-RNA substrate. In some embodiments, a polynucleotide if the present disclosure comprises a NAD-cap (e.g., a NAD at a 5' end of the polynucleotide).

[0231] In some cases, the linker is configured to noncovalently link a polynucleotide of the present disclosure and a polypeptide of the present disclosure. For example, a polypeptide of the present disclosure can comprise a targeting moiety and a nucleic acid (DNA, RNA, etc.) binding domain, wherein the nucleic acid binding domain is configured to bind a polynucleotide of the present disclosure (e.g., an siRNA, ASO, etc.). Thus, forming a noncovalent linkage between the polynucleotide and the polypeptide.

[0232] In some cases, a fusion polynucleotide of the present disclosure comprises a linker. In some embodiments, the linker is conjugated to the polynucleotide and the heterologous polypeptide to produce the fusion polynucleotide. In some embodiments, conjugating comprises chemically conjugating. Many chemical approaches have been developed to crosslink nucleotide and protein, all of which can be used to conjugate a polypeptide described herein, and a polynucleotide described herein. For example, oxime conjugation introduces an aminooxy group on the protein to react with oligosaccharide containing aldehyde or keto group (J. Kubler-Kielb, V. Pozsgay, J Org Chem 2005, 70, 6987-6990). For example, Michael addition often uses thiol group addition to maleimide to form a stable thioester linkage (T. Masuko, A. Minami, N. Iwasaki, T. Majima, S. Nishimura, Y. C. Lee, Biomacromolecules 2005, 6, 880-884). For example, the method of copper (I)-catalyzed cycloaddition of azide to alkyens (click chemistry) provides efficient glycoconjugation (a) H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew Chem Int Ed Engl 2001, 40, 2004-2021; b) S. Hotha, S. Kashyap, J Org Chem 2006, 71, 364-367).

[0233] In some embodiments, chemically conjugating comprises a click chemistry reaction. Click chemistry comprises a group of biocompatible small molecule reactions commonly used in bioconjugation that areWSGR Docket No. 60555-703.601stereospecific, high yielding, wide in scope, and simple to perform. The primary click reaction utilizes copper-catalyzed coupling of a terminal alkyne with a terminal azide to exclusively form the 1,2, 3 -triazole unit. These reactions create only byproducts that can be removed without chromatography, and can be conducted in easily removable or benign solvents. Examples of the click chemistry reaction includes, but are not limited to, Huisgen azide-alkyne 1,3 -dipolar cycloaddition, copper-catalyzed azide-alkyne cycloaddition, ruthenium -catalyzed azide-alkyne cycloaddition, strain-promoted azide-alkyne cycloaddition, strain-promoted alkyne-nitrone cycloaddition, and reactions of strained alkenes such as alkene and azide [3+2] cycloaddition, alkene and tetrazine inverse-demand Diels-Alder, and alkene and tetrazole photoclick reaction. In some embodiments, the click chemistry reaction comprises a copper-catalyzed azide-alkyne cycloaddition. The mechanism of the copper-catalyzed azide-alkyne cycloaddition is described in Himo, et al. J. Am. Chem. Soc.2005. 127: 210-216. In some embodiments, the click chemistry reaction to form a fusion polynucleotide as disclosed herein occurs at ambient temperatures. In some embodiments, the click chemistry reaction to form a fusion polynucleotide as disclosed herein occurs in the presence of a metal catalyst, for example, a copper(I)-catalyzed azide-alkyne cycloaddition. In some embodiments, the click chemistry reaction is performed in the absence of copper.

[0234] In some embodiments, compositions disclosed herein comprise a polynucleotide (such as a polynucleotide as disclosed herein) and a heterologous polypeptide (e.g., to form a fusion polynucleotide). In some cases, a fusion polynucleotide of the present disclosure comprises a linker between a heterologous polypeptide (such as a targeting moiety) and the polynucleotide, such as an siRNA, present in the fusion polynucleotide. In some cases, the heterologous polypeptide (such as a targeting moiety disclosed herein) is conjugated to a 5' end or a 3' end of the polynucleotide. In some cases, the heterologous polypeptide comprises a targeting moiety (such as a targeting moiety as disclosed herein). In some cases, the composition further comprises a pH responsive domain. In some cases, the polynucleotide is conjugated to the targeting moiety or the pH responsive domain. In some cases, the polynucleotide is conjugated to an N-terminus or a C-terminus of the targeting moiety. In some cases, the polynucleotide is conjugated to an N-terminus or a C-terminus of the pH responsive domain.Polypeptide

[0235] Disclosed herein in some embodiments are polymers comprising polypeptides. The terms “peptide,” “polypeptide,” and “protein” can be used interchangeably, and can refer to a polymeric form of amino acids of any length, which can include genetically coded and non-genetically coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified peptide backbones. The term includes fusion proteins, including, but not limited to, fusion proteins with a heterologous amino acid sequence. In some embodiments a protein or polypeptide can refer to a polymeric form of amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein’s or peptide’s sequence. In some embodiments a polypeptide can comprise any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. In some embodiments a polypeptide can comprise shortWSGR Docket No. 60555-703.601chains, such as a peptide, an oligopeptide or an oligomers. In some embodiments a polypeptide can comprise longer chains, such as a protein, of which there are many types. In some embodiments a polypeptide can comprise a biologically active fragment, a substantially homologous polypeptide, an oligopeptide, a homodimer, a heterodimer, a variant of a polypeptide, a modified polypeptide, a derivative, an analog, or a fusion protein, among others. In some embodiments a polypeptide can comprise a natural peptide, a recombinant peptide, or a combination thereof. In some embodiments, a polypeptide can comprise an engineered polypeptide. An engineered polypeptide can refer to a synthetically constructed polypeptide. For example, a polypeptide can be synthesized by chemical synthesis, enzymatic synthesis, or any combination thereof. In some embodiments, the polypeptide is a synthetic polypeptide.

[0236] Polypeptides (e.g., proteins) can exist in different forms based on the number and arrangement of their subunits. These forms can be a single subunit (monomer), two subunits (dimer), or multiple subunits (multimeric proteins). In some cases, the polypeptide (s) disclosed herein can comprise one or more subunits (e.g., the polypeptide can be monomeric, dimeric, or multimeric). Incorporation of a modifications in the polypeptide can modulate the activity and / or functionality of the polypeptide. For example, incorporation of an amino acid at a particular position of the polypeptide can modulate the folding or the function of the polypeptide. In some cases, incorporation of the modifications can occur within one or more subunits of a multimeric polypeptide. In some cases, incorporation of the modifications at a particular position of the polypeptide can render the polypeptide functional, wherein the particular amino acid and modified amino acid have at least one difference in their chemical structures. Such difference can modulate the folding or the function of the polypeptide when the particular amino acid or the modified amino acid is incorporated at the particular position of the polypeptide. In other cases, incorporation of the modified amino acid at the particular position of the polypeptide can render the polypeptide non-functional. In some cases, incorporation of a particular amino acid in place of the modified amino acid at a particular position of the polypeptide can render the polypeptide non-functional, wherein the particular amino acid and modified amino acid have at least one difference in their chemical structures. Similar considerations apply to any polypeptides described herein (for example, an engineered component). The identity of the modified amino acid have, the particular amino acid, and / or the particular position of the amino acid can depend on the identity of the polypeptide.

[0237] Polypeptides as described herein also include polypeptides having various amino acid additions, deletions, or substitutions relative to the native amino acid sequence of a polypeptide of the present disclosure. In some embodiments, polypeptides that are homologs of a polypeptide of the present disclosure contain nonconservative changes of certain amino acids relative to the native sequence of a polypeptide of the present disclosure. In some embodiments, polypeptides that are homologs of a polypeptide of the present disclosure contain conservative changes of certain amino acids relative to the native sequence of a polypeptide of the present disclosure, and thus may be referred to as conservatively modified variants. A conservatively modified variant may include individual substitutions, deletions or additions to a polypeptide sequence which result in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well-known in the art. Such conservatively modifiedWSGR Docket No. 60555-703.601variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the disclosure. The following eight groups contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (L), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M) (see, e.g., Creighton, Proteins (1984)). A modification of an amino acid to produce a chemically similar amino acid may be referred to as an analogous amino acid.Amino acid modifications

[0238] In some embodiments, the polypeptides disclosed herein can comprise any type of amino acid molecule (e.g., standard amino acids, such as the 20 amino acids commonly found in proteins and used by the genetic code during protein synthesis, nonstandard amino acids, such as chemically modified standard amino acids, amino acids that occur in living organisms but are typically not found in proteins, etc.). In some embodiments, the polypeptide comprises one or more nonstandard amino acid, such as hydroxyproline, hydroxylysine, gamma-carboxyglutamate, desmosine, isodesmosine, citrulline, ornithine, beta-alanine, and selenocysteine. In some embodiments, the polypeptide comprises one or more amino acid modifications. Amino acid modifications can refer to post-translational modifications, such as modifications that can alter the structure and / or function of a polypeptide by changing the properties (e.g., chemical) of an amino acid. Post-translational modifications can occur on the amino acid side chains of a polypeptide, at a C-terminus of the polypeptide, at an N-terminus of the polypeptide, or any combination thereof. Amino acid modifications can include, but are not limited to, acetylation, oxidation, hydroxylation, methylation, phosphorylation, amidation, carboxylation, and dehydroalanine. Amino acid modifications can impact a polypeptide's function, stability, and / or cellular localization.

[0239] In some cases, the polypeptides disclosed herein comprise an amino acid side chain modification. Amino acid side chain modifications can refer to phosphorylation, glycosylation, oxidative modification, proteolytic cleavage, alkene modifications, chemical modifiers, or any combination thereof. Lor example, a carbohydrate molecule can be incorporated into an amino acid side chain to improve stability and promote folding. In some cases, the polypeptides disclosed herein comprise a C-terminus modification. Modifications in the C-terminus of a polypeptide can include, but are not limited to, amidation (e.g., adding an amide group), prenylation (e.g., adding a lipid anchor), glycosylation (e.g., adding a sugar molecule), phosphorylation, methylation, and the addition of a GPI (glycosylphosphatidylinositol) anchor. Lor example, a GPI anchor can be incorporated into a C-terminus of a polypeptide to promote cellular localization of the polypeptide to specific cellular membranes. Modifications in the N-terminus of a polypeptide can include, but are not limited to, removal of the initiator methionine, addition of small chemical groups (e.g., acetylation, propionylation, methylation, myristoylation, palmitoylation, and / or ubiquitylation), and / or attachment of lipid anchors, such as myristoyl or palmitoyl groups. Lor example, an acetyl group can be added to an N-terminal amino group of a polypeptide to impact protein stability and / or protein-protein interactions.Effector polypeptidesWSGR Docket No. 60555-703.601

[0240] In some embodiments, the polypeptide is an effector polypeptide. " Effector polypeptides" can refer to a polypeptide (e.g., zinc -finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), CRISPR / Cas, etc.) that directly interact with other molecules (e.g., RNA, DNA, polypeptides, etc.) to regulate gene expression (e.g., by inhibiting translation, cleaving DNA, causing degradation of a target mRNA, etc.), essentially acting as "effectors" to influence cellular processes. In some embodiments, the polypeptide can be configured for polypeptide-mediated gene expression alteration. Gene expression alteration can include, but is not limited to, changing the level of activity of a gene, such as turning it up (e.g., increasing expression) or down (e.g., decreasing expression) through various mechanisms. Gene expression alterations can also refer to changes in gene regulation mechanisms, such as translation, transcription, epigenetics, post-transcription, post-translation, or any combination thereof. For example, in some cases, the polypeptide can be configured for polypeptide-mediated translation disruption, such as CRISPR-associated (Cas) proteins which can be used to activate or repress translation by binding to the 5' untranslated regions (UTRs) of messenger RNAs (mRNAs). Gene expression can be altered in a number of ways including, epigenetic alterations, DNA methylation, genome editing, site-directed mutagenesis, or any combination thereof. For example, in some cases, the polypeptide can be configured for polypeptide-mediated DNA cleavage, such as ZFNs which can lead to insertions, deletions, inversions, or gene disruption following DNA cleavage. In some embodiments, the effector polypeptide is an enzyme.

[0241] In some embodiments, the effector polypeptide is a nuclease. In some embodiments, the polypeptide comprises dTALEs (e.g., transcription activator-like effectors that are highly target specific and can distinguish 1-2 nucleotide differences in a target sequence), TALENs (e.g., a type of transcription activatorlike effector (TALE) nuclease that can target any desired sequence within a genome, without restrictions on PAM sites), or ZFNs (e.g., a restriction enzyme that cuts DNA at a specific sequence in a genome). In some embodiments, the effector polypeptide is an endonuclease. In some embodiments, the effector polypeptide is a transposon-associated RNA-guided endonucleases. In some embodiments, the polypeptide comprises TnpB (e.g., a transposon-encoded protein that can be programmed to cleave DNA in the presence of a transposon-adjacent motif (TAM)), Fanzor (e.g., an RNA-guided DNA-cutting enzyme that can be reprogrammed to target specific sites in the genome), or Cas (e.g., CRISPR / Cas). In some embodiments, the polypeptide comprises a Cas enzyme.

[0242] Cas enzymes along with their associated Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) guide ribonucleic acids (RNAs) appear to be a pervasive (-45% of bacteria, -84% of archaea) component of prokaryotic immune systems, serving to protect such microorganisms against non-self nucleic acids, such as infectious viruses and plasmids by CRISPR-RNA guided nucleic acid cleavage. While the deoxyribonucleic acid (DNA) elements encoding CRISPR RNA elements may be relatively conserved in structure and length, their CRISPR-associated (Cas) proteins are highly diverse, containing a wide variety of nucleic acid-interacting domains. While CRISPR DNA elements have been observed as early as 1987, the programmable endonuclease cleavage ability of CRISPR / Cas complexes has only been recognized relatively recently, leading to the use of recombinant CRISPR / Cas systems in diverse DNA manipulation and geneWSGR Docket No. 60555-703.601editing applications. Owing to the utility of these enzymes, they are being repurposed for a wide variety of biotechnology, gene editing, and therapeutic applications. In some embodiments, the engineered polypeptide can comprise at least one CRISPR-Cas effector polypeptide. CRISPR-Cas effector polypeptides include, but are not limited to, Type I CRISPR-Cas effector polypeptides, Type II CRISPR-Cas effector polypeptides, Type III CRISPR Cas effector polypeptides, Type IV CRISPR-Cas effector polypeptides, Type V CRISPR Cas effector polypeptides, and Type VI CRISPR-Cas effector polypeptides. In some embodiments, the CRISPR-Cas effector polypeptide is a Type II CRISPR-Cas effector polypeptide, a Type V CRISPR-Cas effector polypeptide, or a Type VI CRISPR-Cas effector polypeptide.

[0243] In some cases, the CRISPR-Cas effector polypeptide is a type II CRISPR-Cas effector polypeptide. Type II CRISPR-Cas systems are considered the simplest in terms of components. In Type II CRISPR-Cas systems, the processing of the CRISPR array into mature crRNAs does not require the presence of a special endonuclease subunit, but rather a small trans-encoded crRNA (tracrRNA) with a region complementary to the array repeat sequence; the tracrRNA interacts with both its corresponding effector nuclease (e.g. Cas9) and the repeat sequence to form a precursor dsRNA structure, which is cleaved by endogenous RNAse III to generate a mature effector enzyme loaded with both tracrRNA and crRNA. Cas II nucleases are DNA nucleases. Type II effectors generally exhibit a structure comprising a RuvC-like endonuclease domain that adopts the RNase H fold with an unrelated HNH nuclease domain inserted within the folds of the RuvC-like nuclease domain. The RuvC-like domain is responsible for the cleavage of the target (e.g., crRNA complementary) DNA strand, while the HNH domain is responsible for cleavage of the displaced DNA strand. In some cases, the type II CRISPR-Cas effector polypeptide is a Cas9 polypeptide, e.g., Staphylococcus aureus Cas9, Streptococcus pyogenes Cas9 (SpCas9), etc. In some cases, the CRISPR-Cas effector polypeptide is a variant of a wild-type SpCas9 and comprises one or more of the following substitutions: A61R, Lil HR, A1322R, D1135L, S1136W, G1218K, E1219Q, N1317R, R1333P, R1335A, and T1337R. In some cases, the CRISPR-Cas effector polypeptide is an SpG polypeptide or a SpRY polypeptide; see, e.g., Walton et al. (2020) Science 368:290, and WO 2019 / 051097. For example, a suitable CRISPR-Cas effector polypeptide is an SpCas9 polypeptide includes DI 135V, R1135Q, and T1137R substitutions, relative to wild-type SpCas9. As another example, a suitable CRISPR-Cas effector polypeptide is an SpCas9 polypeptide includes DI 135V, R1335Q, T1337R, and G1218R substitutions, relative to wildtype SpCas9. As another example, a suitable CRISPR-Cas effector polypeptide is an SpCas9 polypeptide includes D1135L, S1136W, G1218K, E1219Q, R1335A, and T1337R substitutions, relative to wild-type SpCas9. As another example, a suitable CRISPR-Cas effector polypeptide is an SpCas9 polypeptide includes Lil HR, A1322R, D1135L, S1136W, G1218K, E1219Q, R1335A, and T1337R substitutions, relative to wild-type SpCas9. As another example, a suitable CRISPR-Cas effector polypeptide is an SpCas9 polypeptide includes A61R, Lil HR, A1322R, D1135L, S1136W, G1218K, E1219Q, N1317R, R1333P, R1335A, and T1337R substitutions, relative to wild-type SpCas9. In some cases, the CRISPR-Cas effector polypeptide is a SpyCas9 or a variant thereof.WSGR Docket No. 60555-703.601

[0244] In some cases, one or more surface Cys residues of a CRISPR-Cas effector polypeptide are substituted. As one example, in some cases, a Cys at position 80 of the SpCas9 amino acid sequence or a corresponding Cys in another CRISPR-Cas effector polypeptide is substituted with an amino acid other than a Cys. For example, in some cases, a Cys at position 80 of the SpCas9 amino acid sequence, or a corresponding Cys in another CRISPR-Cas effector polypeptide is substituted with a Ser. As another example, in some cases, a Cys at position 574 of the SpCas9 amino acid sequence, or a corresponding Cys in another CRISPR-Cas effector polypeptide is substituted with an amino acid other than a Cys.

[0245] In some cases, the CRISPR-Cas effector polypeptide is a type V CRISPR-Cas effector polypeptide, e.g., a Casl2a, a Casl2b, a Casl2c, a Casl2d, or a Casl2e polypeptide. In some cases, the CRISPR-Cas effector polypeptide is a type VI CRISPR-Cas effector polypeptide, e.g., a Casl3a polypeptide, a Casl3b polypeptide, a Casl3c polypeptide, or a Casl3d polypeptide. In some cases, the CRISPR-Cas effector polypeptide is a Casl4 polypeptide. In some cases, the CRISPR-Cas effector polypeptide is a Casl4a polypeptide, a Casl4b polypeptide, or a Casl4c polypeptide. In some cases, the CRISPR-Cas effector polypeptide is a Cas7-11 polypeptide; see, e.g., Ozcan et al. (2021) Nature 597:720. In some cases, the CRISPR-Cas effector polypeptide is a CRISPRi polypeptide; see, e.g., Qi et al. (2013) Cell 152: 1173; and Jensen et al. (2021) Genome Research doi: 10.1101 / gr.275607.121. In some cases, the CRISPR-Cas effector polypeptide is a CRISPRa polypeptide; see, e.g., Jensen et al. (2021) Genome Researchdoi: 10.1101 / gr.275607.121; and Breinig et al. (2019) Nature Methods 16:51. In some cases, the CRISPR-Cas effector polypeptide is a CRISPRoff polypeptide. See, e.g., Nunez et al. (2021) Cell 184:2503. In some cases, the CRISPR-Cas effector polypeptide is a nickase. In some cases, the CRISPR-Cas effector polypeptide exhibits reduced catalytic activity compared to a wild-type CRISPR-Cas effector polypeptide.

[0246] As noted above, in some cases, a CRISPR-Cas effector polypeptide is a Type VI CRISPR-Cas effector polypeptide, such as a Casl3a polypeptide, a Casl3b polypeptide, a Casl3c polypeptide, a Casl3d polypeptide, a Casl3e polypeptide, a Casl3f polypeptide, a Casl3X polypeptide, or a Casl3Y polypeptide. As noted above, in some cases, a CRISPR-Cas effector polypeptide is a Type III CRISPR-Cas effector polypeptide. A suitable Type III CRISPR-Cas effector polypeptide is a Cas7-11 polypeptide (see, e.g., Ozcan et al. (2021) Nature 597:710). In some cases, a CRISPR-Cas effector polypeptide is an RNA-binding CRISPR-Cas effector polypeptide. For example, in some cases, the CRISPR-Cas effector polypeptide is an RFx Casl3d polypeptide. As another example, in some cases, the CRISPR-Cas effector polypeptide is a dRfxCasl3d polypeptide. As another example, in some cases, the CRISPR-Cas effector polypeptide is a DjCasl3d polypeptide. As another example, in some cases, the CRISPR-Cas effector polypeptide is a PspCasl3b polypeptide, e.g., Prevotella sp. P5-125 Casl3b. As another example, in some cases, the CRISPR-Cas effector polypeptide is a dPspCasl3b polypeptide In some cases, a Casl3 polypeptide (e.g., a Casl3a polypeptide, a Casl3b polypeptide, a Casl3c polypeptide, a Casl3d polypeptide, a Casl3e polypeptide, a Casl3f polypeptide, a Casl3X polypeptide, or a Casl3Y polypeptide) comprises two Higher Eukaryotes and Prokaryotes Nucleotide-binding (HEPN) domains, each comprising a HEPN motif, where each HEPN motif is RXXXXH, RXXXXXH, or RXXXXXXH, where X is any amino acid.WSGR Docket No. 60555-703.601

[0247] In some cases, the CRISPR-Cas effector polypeptide is a variant that exhibits reduced catalytic activity compared to a wild-type CRISPR-Cas effector polypeptide. For example, where the CRISPR-Cas effector polypeptide (e.g., a Casl3 polypeptide) comprises a HEPN domain, the CRISPR-Cas effector polypeptide can comprise a substitution of the Arg and / or the His in the HEPN motif, where such a mutation reduces the catalytic activity of the CRISPR-Cas effector polypeptide. In some cases, the RNA-binding CRISPR-Cas effector polypeptide binds, but does not cleave, a target RNA. In some cases, a CRISPR-Cas effector polypeptide is a variant that, when complexed with a guide nucleic acid, binds but does not cleave a target DNA.

[0248] As another example, in some cases, the CRISPR-Cas effector polypeptide is a Cas7-11 polypeptide (e.g., a DiCas7-l 1 polypeptide). See, e.g., Ozcan et al. (2021) Nature 597:720. In some cases, the Cas7-11 polypeptide is a variant that exhibits reduced catalytic activity compared to a wild-type Cas7-11 effector polypeptide. For example, in some cases, the variant Cas7-11 polypeptide comprises a substitution of one or more of D177, D429, D654, D758, E959, and D998. For example, a variant Cas7-11 can have an Asp at position 177, an Ala at position 429, an Ala at position 654, an Asp at position 758, a Glu at position E959, and an Asp at position 998. In some cases, a variant Cas7-11 comprises a D429A substitution.

[0249] In some embodiments, as an alternative to SpyCas9, other Cas9 enzymes, like GeoCas9 that offer a number of features over SpyCas9 can be employed. Because of the lineage of GeoCas9 from thermophiles, there is no exposure to GeoCas9 in humans and therefore no preexisting antibodies exist in humans to GeoCas9. This expands the possible reach of an RNP therapeutic in terms of patient numbers. In addition, GeoCas9 RNPs have a higher melting temp than SpyCas9 RNPs (72 vs 40°C) leading to a more stable RNP complex that does not release guide RNA after complexation. This can be beneficial for circulation in blood where the guide RNA can disassemble and be degraded by nucleases. GeoCas9 RNPs are not only more stable in mouse and human plasma, but also at lower pH ranges and have an expanded window of endosomal escape, allowing GeoCas9 to escape from early and late endosomes. Unlike GeoCas9, SpyCas9 can have significant loss in activity after exposure to pH 6.0 and below.

[0250] In some embodiments, the CRISPR-Cas effector polypeptide is a GeoCas9 or variant thereof. In some embodiments, the CRISPR-Cas effector polypeptide comprises at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more sequence identity to GeoCas9. In some embodiments, the CRISPR-Cas effector polypeptide comprises at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 91%, at most 92%, at most 93%, at most 94%, at most 95%, at most 96%, at most 97%, at most 98%, or at most 99% sequence identity to a GeoCas9. In some embodiments, the CRISPR-Cas effector polypeptide comprises less than 100% sequence identity to a GeoCas9. In some embodiments, the CRISPR-Cas effector polypeptide comprises a sequence that has at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, atWSGR Docket No. 60555-703.601least 24, at least 25 or more amino acid substitutions or mutations relative to a GeoCas9. In some embodiments, the CRISPR-Cas effector polypeptide comprises a sequence that has at most 1, at most 2, at most 3, at most 4, at most 5, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, or at most 25 amino acid substitutions or mutations relative to a GeoCas9. In some embodiments, the CRISPR-Cas effector polypeptide is a GeoCas9.

[0251] In some embodiments, the CRISPR-Cas effector polypeptide comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs: 1-11. In some embodiments, the polypeptide comprises at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to any one of SEQ ID NOs: 1-11 In some embodiments, the polypeptide comprises an amino acid sequence having at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 91%, at most 92%, at most 93%, at most 94%, at most 95%, at most 96%, at most 97%, at most 98%, or at most 99% sequence identity to any one of SEQ ID NOs: 1-11. In some embodiments, the polypeptide comprises less than 100% sequence identity to any one of SEQ ID NOs: 1-11. In some embodiments, the polypeptide comprises a sequence that has at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25 or more amino acid substitutions or mutations relative to any one of SEQ ID NOs: 1-11. In some embodiments, the polypeptide comprises a sequence that has at most 1, at most 2, at most 3, at most 4, at most 5, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, or at most 25 amino acid substitutions or mutations relative to any one of SEQ ID NOs: 1-11. TABLE 2 below lists the sequences of SEQ ID NOs: 1-11.

[0252] In some embodiments, the polypeptide comprises an amino acid sequence having at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 1. In some embodiments, the polypeptide comprises an amino acid sequence having at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 91%, at most 92%, at most 93%, at most 94%, at most 95%, at most 96%, at most 97%, at most 98%, or at most 99% sequence identity to SEQ ID NO: 1. In some embodiments, the polypeptide comprises less than 100% sequence identity to SEQ ID NO: 1. In some embodiments, the polypeptide comprises a sequence that has at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25 or more amino acid substitutions or mutations relative to SEQ ID NO: 1 In someWSGR Docket No. 60555-703.601embodiments, the polypeptide comprises a sequence that has at most 1, at most 2, at most 3, at most 4, at most 5, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, or at most 25 amino acid substitutions or mutations relative to SEQ ID NO: 1

[0253] In some embodiments, the polypeptide comprises an amino acid sequence having at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 2. In some embodiments, the polypeptide comprises an amino acid sequence having at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 91%, at most 92%, at most 93%, at most 94%, at most 95%, at most 96%, at most 97%, at most 98%, or at most 99% sequence identity to SEQ ID NO: 2. In some embodiments, the polypeptide comprises less than 100% sequence identity to SEQ ID NO: 2. In some embodiments, the polypeptide comprises a sequence that has at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25 or more amino acid substitutions or mutations relative to SEQ ID NO: 2 In some embodiments, the polypeptide comprises a sequence that has at most 1, at most 2, at most 3, at most 4, at most 5, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, or at most 25 amino acid substitutions or mutations relative to SEQ ID NO: 2

[0254] In some embodiments, the polypeptide comprises an amino acid sequence having at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 3. In some embodiments, the polypeptide comprises an amino acid sequence having at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 91%, at most 92%, at most 93%, at most 94%, at most 95%, at most 96%, at most 97%, at most 98%, or at most 99% sequence identity to SEQ ID NO: 3. In some embodiments, the polypeptide comprises less than 100% sequence identity to SEQ ID NO: 3. In some embodiments, the polypeptide comprises a sequence that has at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25 or more amino acid substitutions or mutations relative to SEQ ID NO: 3 In some embodiments, the polypeptide comprises a sequence that has at most 1, at most 2, at most 3, at most 4, at most 5, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, or at most 25 amino acid substitutions or mutations relative to SEQ ID NO: 3WSGR Docket No. 60555-703.601

[0255] In some embodiments, the polypeptide comprises an amino acid sequence having at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 4. In some embodiments, the polypeptide comprises an amino acid sequence having at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 91%, at most 92%, at most 93%, at most 94%, at most 95%, at most 96%, at most 97%, at most 98%, or at most 99% sequence identity to SEQ ID NO: 4. In some embodiments, the polypeptide comprises less than 100% sequence identity to SEQ ID NO: 4. In some embodiments, the polypeptide comprises a sequence that has at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25 or more amino acid substitutions or mutations relative to SEQ ID NO: 4 In some embodiments, the polypeptide comprises a sequence that has at most 1, at most 2, at most 3, at most 4, at most 5, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, or at most 25 amino acid substitutions or mutations relative to SEQ ID NO: 4

[0256] In some embodiments, the polypeptide comprises an amino acid sequence having at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 5. In some embodiments, the polypeptide comprises an amino acid sequence having at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 91%, at most 92%, at most 93%, at most 94%, at most 95%, at most 96%, at most 97%, at most 98%, or at most 99% sequence identity to SEQ ID NO: 5. In some embodiments, the polypeptide comprises less than 100% sequence identity to SEQ ID NO: 5. In some embodiments, the polypeptide comprises a sequence that has at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25 or more amino acid substitutions or mutations relative to SEQ ID NO: 5 In some embodiments, the polypeptide comprises a sequence that has at most 1, at most 2, at most 3, at most 4, at most 5, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, or at most 25 amino acid substitutions or mutations relative to SEQ ID NO: 5

[0257] In some embodiments, the polypeptide comprises an amino acid sequence having at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 6. In some embodiments, the polypeptide comprises an amino acid sequence having at most 40%, at most 45%, at most 50%, at mostWSGR Docket No. 60555-703.60155%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 91%, at most 92%, at most 93%, at most 94%, at most 95%, at most 96%, at most 97%, at most 98%, or at most 99% sequence identity to SEQ ID NO: 6. In some embodiments, the polypeptide comprises less than 100% sequence identity to SEQ ID NO: 6. In some embodiments, the polypeptide comprises a sequence that has at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25 or more amino acid substitutions or mutations relative to SEQ ID NO: 6 In some embodiments, the polypeptide comprises a sequence that has at most 1, at most 2, at most 3, at most 4, at most 5, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, or at most 25 amino acid substitutions or mutations relative to SEQ ID NO: 6

[0258] In some embodiments, the polypeptide comprises an amino acid sequence having at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 7. In some embodiments, the polypeptide comprises an amino acid sequence having at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 91%, at most 92%, at most 93%, at most 94%, at most 95%, at most 96%, at most 97%, at most 98%, or at most 99% sequence identity to SEQ ID NO: 7. In some embodiments, the polypeptide comprises less than 100% sequence identity to SEQ ID NO: 7. In some embodiments, the polypeptide comprises a sequence that has at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25 or more amino acid substitutions or mutations relative to SEQ ID NO: 7. In some embodiments, the polypeptide comprises a sequence that has at most 1, at most 2, at most 3, at most 4, at most 5, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, or at most 25 amino acid substitutions or mutations relative to SEQ ID NO: 7

[0259] In some embodiments, the polypeptide comprises an amino acid sequence having at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 8. In some embodiments, the polypeptide comprises an amino acid sequence having at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 91%, at most 92%, at most 93%, at most 94%, at most 95%, at most 96%, at most 97%, at most 98%, or at most 99% sequence identity to SEQ ID NO: 8. In some embodiments, the polypeptide comprises less than 100% sequence identity to SEQ ID NO: 8. In some embodiments, the polypeptide comprises a sequence that has at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 11, at least 12, at least 13, at leastWSGR Docket No. 60555-703.60114, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25 or more amino acid substitutions or mutations relative to SEQ ID NO: 8 In some embodiments, the polypeptide comprises a sequence that has at most 1, at most 2, at most 3, at most 4, at most 5, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, or at most 25 amino acid substitutions or mutations relative to SEQ ID NO: 8

[0260] In some embodiments, the polypeptide comprises an amino acid sequence having at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 9. In some embodiments, the polypeptide comprises an amino acid sequence having at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 91%, at most 92%, at most 93%, at most 94%, at most 95%, at most 96%, at most 97%, at most 98%, or at most 99% sequence identity to SEQ ID NO: 9. In some embodiments, the polypeptide comprises less than 100% sequence identity to SEQ ID NO: 9. In some embodiments, the polypeptide comprises a sequence that has at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25 or more amino acid substitutions or mutations relative to SEQ ID NO: 9 In some embodiments, the polypeptide comprises a sequence that has at most 1, at most 2, at most 3, at most 4, at most 5, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, or at most 25 amino acid substitutions or mutations relative to SEQ ID NO: 9

[0261] In some embodiments, the polypeptide comprises an amino acid sequence having at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 10. In some embodiments, the polypeptide comprises an amino acid sequence having at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 91%, at most 92%, at most 93%, at most 94%, at most 95%, at most 96%, at most 97%, at most 98%, or at most 99% sequence identity to SEQ ID NO: 10. In some embodiments, the polypeptide comprises less than 100% sequence identity to SEQ ID NO: 10. In some embodiments, the polypeptide comprises a sequence that has at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25 or more amino acid substitutions or mutations relative to SEQ ID NO: 10 In some embodiments, the polypeptide comprises a sequence that has at most 1, at most 2, at most 3, at most 4, at most 5, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, atWSGR Docket No. 60555-703.601most 19, at most 20, at most 21, at most 22, at most 23, at most 24, or at most 25 amino acid substitutions or mutations relative to SEQ ID NO: 10

[0262] In some embodiments, the polypeptide comprises an amino acid sequence having at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 11. In some embodiments, the polypeptide comprises an amino acid sequence having at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 91%, at most 92%, at most 93%, at most 94%, at most 95%, at most 96%, at most 97%, at most 98%, or at most 99% sequence identity to SEQ ID NO: 11. In some embodiments, the polypeptide comprises less than 100% sequence identity to SEQ ID NO: 11. In some embodiments, the polypeptide comprises a sequence that has at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25 or more amino acid substitutions or mutations relative to SEQ ID NO: 11 In some embodiments, the polypeptide comprises a sequence that has at most 1, at most 2, at most 3, at most 4, at most 5, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, or at most 25 amino acid substitutions or mutations relative to SEQ ID NO: 11Table 2. Exemplary polypeptide amino acid sequencesSEQ ID NO. Amino acid sequence Organism 1 MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDR Streptococcus HSIKKNLIGALLFDSGETAEATRLKRTARRRYTRRKNRICY pyogenes LQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIV DEVAYHEI< YPTIYHLRI< I< LVDSTDI< ADLRLIYLALAHMII< FRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENP INASG VDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLG LTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYA DLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDEHH QDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQ EEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIP HQIHLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVGP LARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIER MTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEG MRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIE CFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDI LEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRR YTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQL H4DDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGIL QTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNS RERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTWSGR Docket No. 60555-703.601RSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKF DNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSR MNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREIN NYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDV RKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKR PLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEV QTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVA YSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFL EAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQK GNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQH KHYLDEIIEQISEF SI< R VI LA DA N LDI< VLSAYNI< HRDI< P I RE QAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDAT LIHQSITGLYETRIDLSQLGGD2 MKRNYILGLDIGITSVGYGIIDYETRDVIDAGVRLFKEANVEN NEGRRSKRGARRLKRRRRHRIQRVKKLLFDYNLLTDHSELSGI NPYEARVI< GLSQI< LSEEEFSAALLHLAI< RRGVHNVNEVEEDT GNELSTKEQISRNSKALEEKYVAELQLERLKKDGEVRGSINRF KTSDYVKEAKQLLKVQKAYHQLDQSFIDTYIDLLETRRTYYE GPGEGSPFGWKDIKEWYEMLMGHCTYFPEELRSVKYAYNAD LYNALNDLNNLVITRDENEI< LEYYEI< FQIIENVFI< QI< I< I< PTLI< QIAKEILVNEEDIKGYRVTSTGKPEFTNLKVYHDIKDITARKEII ENAELLDQIAKILTIYQSSEDIQEELTNLNSELTQEEIEQISNLK GYTGTHNLSLI< AINLILDELWHTNDNQIAIFNRL1< LVPI< I< VDL SQQKEIPTTLVDDFILSPWKRSFIQSIKVINAIIKKYGLPNDIIIE LAREI< NSI< DAQI< MINEMQI< RNRQTNERIEEIIRTTGI< ENAI< Y Staphylococcus LIEKIKLHDMQEGKCLYSLEAIPLEDLLNNPFNYEVDHIIPRSVaureus Cas9 SFDNSFNNKVLVKQEENSKKGNRTPFQYLSSSDSKISYETFKK HILNLAKGKGRISKTKKEYLLEERDINRFSVQKDFINRNLVDT RYATRGLMNLLRSYFRVNNLDVKVKSINGGFTSFLRRKWKFI< I< ERNI< GYI< HHAEDALIIANADFIFI< EWI< I< LDI< AI< I< VMENQ MFEEKQAESMPEIETEQEYKEIFITPHQIKHIKDFKDYKYSHRV DI< I< PNREL1NDTLYSTRI< DDI< GNTLIVNNLNGLYDI< DNDI< L1< I< LINI< SPEI< LLMYHHDPQTYQI< LI< LIMEQYGDEI< NPLYI< YYE ETGNYLTKYSKKDNGPVIKKIKYYGNKLNAHLDITDDYPNSR NI< VVI< LSLI< PYRFDVYLDNGVYI< FVTVI< NLDVII< I< ENYYEV NSKCYEEAKKLKKISNQAEFIASFYNNDLIKINGELYRVIGVN NDLLNRIEVNMIDITYREYLENMNDKRPPRIIKTIASKTQSIKK YSTDILGNLYEVKSKKHPQIIKKG3 MSIYQEFVNKYSLSKTLRFELIPQGKTLENIKARGLILDDEKRA KDYKKAKQIIDKYHQFFIEEILSSVCISEDLLQNYSDVYFKLKK SDDDNLQKDFKSAKDTIKKQISEYIKDSEKFKNLFNQNLIDAK KGQESDLILWLKQSKDNGIELFKANSDITDIDEALEIIKSFKGW TTYFI< GFHENRI< NVYSSNDIPTSIIYRIVDDNLPI< FLENI< AI< YE SLKDKAPEAINYEQIKKDLAEELTFDIDYKTSEVNQRVFSLDE VFEIANFNNYLNQSGITI< FNTIIGGI< FVNGENTI< RI< GINEYINL Francisella YSQQINDKTLKKYKMSVLFKQILSDTESKSFVIDKLEDDSDW tularensis Casl2a TTMQSFYEQIAAFKTVEEKSIKETLSLLFDDLKAQKLDLSKIYF KNDKSLTDLSQQVFDDYSVIGTAVLEYITQQIAPKNLDNPSKK EQELIAKKTEKAKYLSLETIKLALEEFNKHRDIDKQCRFEEILA NFAAIPMIFDEIAQNKDNLAQISIKYQNQGKKDLLQASAEDDVI< AII< DLLDQTNNLLHI< LI< IFHISQSEDI< ANILDI< DEHFYLVFEECYFELANIVPLYNKIRNYITQKPYSDEKFKLNFENSTLANGWWSGR Docket No. 60555-703.601DI< NI< EPDNTAILFII< DDI< YYLGVMNI< I< NNI< IFDDI< AII< ENI< G EGYI< I< IVYI< LLPGANI< MLPI< VFFSAI< SII< FYNPSEDILRIRNHS THTKNGSPQKGYEKFEFNIEDCRKFIDFYKQSISKHPEWKDFG FRFSDTQRYNSIDEFYREVENQGYKLTFENISESYIDSWNQGI< LYLFQIYNI< DFSAYSI< GRPNLHTLYWI< ALFDERNLQDVVY I< LNGEAELFYRI< QSIPI< I< ITHPAI< EAIANI< NI< DNPI< I< ESVFEY DLIKDKRFTEDKFFFHCPITINFKSSGANKFNDEINLLLKEKAN DVHILSIDRGERHLAYYTLVDGKGNIIKQDTFNIIGNDRMKTN YHDI< LAAIEI< DRDSARI< DWI< I< INNII< EMI< EGYLSQVVHEIA KLVIEYNAIWFEDLNFGFKRGRFKVEKQVYQKLEKMLIEKL NYLVFKDNEFDKTGGVLRAYQLTAPFETFKKMGKQTGIIYYV PAGFTSKICPVTGFVNQLYPKYESVSKSQEFFSKFDKICYNLD KGYFEFSFDYKNFGDKAAKGKWTIASFGSRLINFRNSDKNHN WDTREVYPTKELEKLLKDYSIEYGHGECIKAAICGESDKKFFA KLTSVLNTILQMRNSKTGTELDYLISPVADVNGNFFDSRQAPK NMPQDADANGAYHIGLI< GLMLLGRIKNNQEGI< I< LNLVII< NE EYFEFVQNRNN4 TQFEGFTNLYQVSKTLRFELIPQGKTLKHIQEQGFIEEDKARN DHYKELKPIIDRIYKTYADQCLQLVQLDWENLSAAIDSYRKE KTEETRNALIEEQATYRNAIHDYFIGRTDNLTDAINKRHAEIY KGLFKAELFNGKVLKQLGTVTTTEHENALLRSFDKFTTYFSGF YENRKNVFSAEDISTAIPHRIVQDNFPKFKENCHIFTRLITAVPS LREHFENVKKAIGIFVSTSIEEVFSFPFYNQLLTQTQIDLYNQLL GGISREAGTEKIKGLNEVLNLAIQKNDETAHIIASLPHRFIPLFK QILSDRNTLSFILEEFKSDEEVIQSFCKYKTLLRNENVLETAEA LFNELNSIDLTHIFISHKKLETISSALCDHWDTLRNALYERRISE LTGKITKSAKEKVQRSLKHEDINLQEIISAAGKELSEAFKQKTS EILSHAHAALDQPLPTTLKKQEEKEILKSQLDSLLGLYHLLDW FAVDESNEVDPEFSARLTGIKLEMEPSLSFYNI< ARNYATI< I< PY SVEKFKLNFQMPTLASGWDVNKEKNNGAILFVKNGLYYLGI MPKQKGRYKALSFEPTEKTSEGFDKMYYDYFPDAAKMIPKCS TQLKAVTAHFQTHTTPILLSNNFIEPLEITKEIYDLNNPEKEPKK Acidaminococcus FQTAYAKKTGDQKGYREALCKWIDFTRDFLSKYTKTTSIDLS sp. BV3L6 SLRPSSQYKDLGEYYAELNPLLYHISFQRIAEKEIMDAVETGK Casl2a LYLFQIYNKDFAKGHHGKPNLHTLYWTGLFSPENLAKTSIKL NGQAELFYRPKSRMKRMAHRLGEKMLNKKLKDQKTPIPDTL YQELYDYVNHRLSHDLSDEARALLPNVITKEVSHEIIKDRRFT SDKFFFHVPITLNYQAANSPSKFNQRVNAYLKEHPETPIIGIDR GERNLIYITVIDSTGKILEQRSLNTIQQFDYQKKLDNREKERVA ARQAWSVVGTIKDLKQGYLSQVIHEIVDLMIHYQAVVVLENL NFGFKSKRTGIAEKAVYQQFEKMLIDKLNCLVLKDYPAEKVG GVLNPYQLTDQFTSFAKMGTQSGFLFYVPAPYTSKIDPLTGFV DPFVWKTIKNHESRKHFLEGFDFLHYDVKTGDFILHFKMNRN LSFQRGLPGFMPAWDIVFEKNETQFDAKGTPFIAGKRFVPVIE NHRFTGRYRDLYPANELIALLEEKGIVFRDGSNILPKLLENDD SHAIDTMVALIRSVLQMRNSNAATGEDYINSPVRDLNGVCFD SRFQNPEWPMDADANGAYHIALKGQLLLNHLKESKDLKLQN GISNQDWLAYIQELRN5 MSKLEKFTNCYSLSKTLRFKAIPVGKTQENIDNKRLLVEDEKR Lachnospiraceae AEDYKGVKKLLDRYYLSFINDVLHSIKLKNLNNYISLFRKKTR bacterium TEKENKELENLEINLRKEIAKAFKGNEGYKSLFKKDIIETILPEF ND2006LDDKDEIALVNSFNGFTTAFTGFFDNRENMFSEEAKSTSIAFR (LbCasl2a)WSGR Docket No. 60555-703.601CINENLTRYISNMDIFEKVDAIFDKHEVQEIKEKILNSDYDVED FFEGEFFNFVLTQEGIDVYNAIIGGFVTESGEKIKGLNEYINLY NQKTKQKLPKFKPLYKQVLSDRESLSFYGEGYTSDEEVLEVF RNTLNKNSEIFS SIKKLEKLFKNFDEYS S AGIFVKNGPAISTISK DIFGEWNVIRDKWNAEYDDIHLKKKAVVTEKYEDDRRKSFK KIGSFSLEQLQEYADADLSWEKLKEIIIQKVDEIYKVYGSSEK LFDADFVLEKSLKKNDAWAIMKDLLDSVKSFENYIKAFFGE GKETNRDESFYGDFVLAYDILLKVDHIYDAIRNYVTQKPYSK DI< FI< LYFQNPQFMGGWDI< DI< ETDYRATILRYGSI< YYLAIMD KKYAKCLQKIDKDDVNGNYEKINYKLLPGPNKMLPKVFFSK I< WMAYYNPSEDIQI< IYI< NGTFI< I< GDMFNLNDCHI< LIDFFI< D SISRYPKWSNAYDFNFSETEKYKDIAGFYREVEEQGYKVSFES ASKKEVDKLVEEGKLYMFQIYNKDFSDKSHGTPNLHTMYFK LLFDENNHGQIRLSGGAELFMRRASLI< I< EELVVHPANSPIANI< NPDNPKKTTTLSYDVYKDKRFSEDQYELHIPIAINKCPKNIFKI NTEVRVLLKHDDNPYVIGIDRGERNLLYIVWDGKGNTVEQY SLNEIINNFNGIRIKTDYHSLLDKKEKERFEARQNWTSIENIKE LKAGYISQVVHKICELVEKYDAVIALEDLNSGFKNSRVKVEK QVYQI< FEI< MLIDI< LNYMVDI< I< SNPCATGGAL1< GYQITNI< FE SFKSMSTQNGFIFYIPAWLTSKIDPSTGFVNLLKTKYTSIADSK KFISSFDRIMYVPEEDLFEFALDYKNFSRTDADYIKKWKLYSY GNRIRIFRNPI< I< NNVFDWEEVCLTSAYI< ELFNI< YGINYQQGDI RALLCEQSDKAFYSSFMALMSLMLQMRNSITGRTDVDFLISP VKNSDGIFYDSRNYEAQENAILPKNADANGAYNIARKVLWAI GQFI< I< AEDEI< LDI< VI< IAISNI< EWLEYAQTSVI< H6 MAVI< SII< VI< LRLDDMPEIRAGLWI< LHI< EVNAGVRYYTEWLS LLRQENLYRRSPNGDGEQECDKTAEECKAELLERLRARQVEN GHRGPAGSDDELLQLARQLYELLVPQAIGAKGDAQQIARKFL SPLADKDAVGGLGIAKAGNKPRWVRMREAGEPGWEEEKEK AETRI< SADRTADVLRALADFGL1< PLMRVYTDSEMSSVEWI< P LRKGQAVRTWDRDMFQQAIERMMSWESWNQRVGQEYAKL VEQKNRFEQKNFVGQEHLVHLVNQLQQDMKEASPGLESKEQ TAHYVTGRALRGSDKVFEKWGKLAPDAPFDLYDAEIKNVQR RNTRRFGSHDLFAKLAEPEYQALWREDASFLTRYAVYNSILR I< LNHAI< MFATFTLPDATAHPIWTRFDI< LGGNLHQYTFLFNEF GERRHAIRFHKLLKVENGVAREVDDVTVPISMSEQLDNLLPR DPNEPIALYFRDYGAEQHFTGEFGGAKIQCRRDQLAHMHRRR GARDVYLNVSVRVQSQSEARGERRPPYAAVFRLVGDNHRAFAacCasl2b VHFDKLSDYLAEHPDDGKLGSEGLLSGLRVMSVDLGLRTSAS ISVFRVARKDELKPNSKGRVPFFFPIKGNDNLVAVHERSQLLK LPGETESKDLRAIREERQRTLRQLRTQLAYLRLLVRCGSEDVG RRERSWAKLIEQPVDAANHMTPDWREAFENELQKLKSLHGIC SDI< EWMDAVYESVRRVWRHMGI< QVRDWRI< DVRSGERPI< I RGYAKDVVGGNSIEQIEYLERQYKFLKSWSFFGKVSGQVIRA EI< GSRFAITLREHIDHAI< EDRLI< I< LADRIIMEALGYVYALDER GKGKWVAKYPPCQLILLEELSEYQFNNDRPPSENNQLMQWS HRGVFQELINQAQVHDLLVGTMYAAFSSRFDARTGAPGIRCR RVPARCTQEHNPEPFPWWLNKFWEHTLDACPLRADDLIPTG EGEIFVSPFSAEEGDFHQIHADLNAAQNLQQRLWSDFDISQIRL RCDWGEVDGELVLIPRLTGKRTADSYSNKVFYTNTGVTYYERERGKKRRKVFAQEKLSEEEAELLVEADEAREKSWLMRDPSGWSGR Docket No. 60555-703.601IINRGNWTRQKEFWSMVNQRIEGYLVKQIRSRVPLQDSACEN TGDI7 MRYKIGLDIGITSVGWAVMNLDIPRIEDLGVRIFDRAENPQTG ESLALPRRLARSARRRLRRRKHRLERIRRLVIREGILTKEELDK LFEEI< HEIDVWQLRVEALDRI< LNNDELARVLLHLAI< RRGFI< S NRKSERSNKENSTMLKEEEENRAILS SYRTVGEMFVKDPKFAL HKRNKGENYTNTIARDDLEREIRLIFSKQREFGNMSCTEEFEN EYITIWASQRPVASKDDIEKKVGFCTFEPKEKRAPKATYTFQS FIAWEHINI< LRLISPSGARGLTDEERRLLYEQAFQI< NI< ITYHDI RTLLHLPDDTYFKGIVYDRGESRKQNENIRFLELDAYHQIRKA VDKVYGKGKSSSFLPIDFDTFGYALTLFKDDADIHSYLRNEYE QNGKRMPNLANKVYDNELIEELLNLSFTKFGHLSLKALRSILP YMEQGEVYSSACERAGYTFTGPKKKQKTMLLPNIPPIANPVV MRALTQARKVVNAIIKKYGSPVSIHLELARDLSQTFDERRKTKI< EQDENRI< I< NETAIRQLMEYGLTLNPTGHDIVI< FI< LWSEQNGGeoCas9 RCAYSLQPIEIERLLEPGYVEVDHVIPYSRSLDDSYTNKVLVLT RENREKGNRIPAEYLGVGTERWQQFETFVLTNKQFSKKKRDR LLRLHYDENEETEFKNRNLNDTRYISRFFANFIREHLKFAESD DKQKVYTVNGRVTAHLRSRWEFNKNREESDLHHAVDAVIVA CTTPSDIAI< VTAFYQRREQNI< ELAI< I< TEPHFPQPWPHFADEL RARLSI< HPI< ESII< ALNLGNYDDQI< LESLQPVFVSRMPI< RSVT GAAHQETLRRYVGIDERSGKIQTVVKTKLSEIKLDASGHFPM YGKESDPRTYEAIRQRLLEHNNDPKKAFQEPLYKPKKNGEPG PVIRTVKIIDTKNQVIPLNDGKTVAYNSNIVRVDVFEKDGKYY CVPVYTMDIMKGILPNKAIEPNKPYSEWKEMTEDYTFRFSLYP NDLIRIELPREKTVKTAAGEEINVKDVFVYYKTIDSANGGLELI SHDHRFSLRGVGSRTLKRFEKYQVDVLGNIYKVRGEKRVGLA SSAHSKPGKTIRPLQSTRD8 MGNLFGHI< RWYEVRDI< I< DFI< II< RI< VI< VI< RNYDGNI< YILNIN ENNNI< EI< IDNNI< FIRI< YINYI< I< NDNIL1< EFTRI< FHAGNILFI< L KGKEGIIRIENNDDFLETEEVVLYIEAYGKSEKLKALGITKKKn DEAIRQGITKDDKKIEIKRQENEEELEIDIRDEYTNKTLNDCSIIL RHENDELETKKSIYEIFKNINMSLYKIIEKIIENETEKVFENRYY EEHLREI< LL1< DDI< IDVILTNFMEIREI< II< SNLEILGFVI< FYLNV GGDKKKSKNKKMLVEKILNINVDLTVEDIADFVIKELEFWNITI< RIEI< VI< I< VNNEFLEI< RRNRTYII< SYVLLDKHEI< FI< IERENI< I< DKIVKFFVENIKNNSIKEKIEKILAEFKIDELIKKLEKELKKGNC DTEIFGIFKKHYKVNFDSKKFSKKSDEEKELYKIIYRYLKGRIE KILVNEQKVRL1< KMEKIEIEKILNESILSEKILI< RVI< QYTLEHI Leptotrichia MYLGKLRHNDIDMTTVNTDDFSRLHAKEELDLELITFFASTN shahii MELNKIFSRENINNDENIDFFGGDREKNYVLDKKILNSKIKIIR (WP_018451595. DLDFIDNKNNITNNFIRKFTKIGTNERNRILHAISKERDLQGTQ 1) Casl3a DDYNKVINnQNLKISDEEVSKALNLDVVFKDKKNIITKINDIKI SEENNNDIKYLPSFSKVLPEILNLYRNNPKNEPFDTIETEKIVLN ALIYVNKELYKKLILEDDLEENESKNIFLQELKKTLGNIDEIDE NIIENYYKNAQISASKGNNKAIKKYQKKVIECYIGYLRKNYEE LFDFSDFKMNIQEIKKQIKDINDNKTYERITVKTSDKTIVINDD FEYIISIFALLNSNAVINKIRNRFFATSVWLNTSEYQNIIDILDEI MQLNTLRNECITENWNLNLEEFIQKMKEIEKDFDDFKIQTKKE IFNNYYEDIKNNILTEFKDDINGCDVLEKKLEKIVIFDDETKFEI DKKSNILQDEQRKLSNINKKDLKKKVDQYIKDKDQEIKSKILCRIIFNSDFLKKYKKEIDNLIEDMESENENKFQEIYYPKERKNELWSGR Docket No. 60555-703.601YIYI< I< NLFLNIGNPNFDI< IYGLISNDII< MADAI< FLFNIDGI< NIR KNKISEIDAILKNLNDKLNGYSKEYKEKYIKKLKENDDFFAKN IQNI< NYI< SFEI< DYNRVSEYI< I< IRDLVEFNYLNI< IESYL1DINW I< LAIQMARFERDMHYIVNGLRELGIII< LSGYNTGISRAYPI< RN GSDGFYTTTAYYKFFDEESYKKFEKICYGFGIDLSENSEINKPE NESIRNYISHFYIVRNPFADYSIAEQIDRVSNLLSYSTRYNNSTY ASVFEVFI< I< DVNLDYDELI< I< I< FI< LIGNNDILERLMI< PI< I< VSV LELESYNSDYIKNLIIELLTKIENTNDTL9 MTTTMKISIEFLEPFRMTKWQESTRRNKNNKEFVRGQAFARW HRNKKDNTKGRPYITGTLLRSAVIRSAENLLTLSDGKISEKTC CPGKFDTEDKDRLLQLRQRSTLRWTDKNPCPDNAETYCPFCE LLGRSGNDGI< I< AEI< I< DWRFRIHFGNLSLPGI< PDFDGPI< AIGS QRVLNRVDFKSGKAHDFFKAYEVDHTRFPRFEGEITIDNKVS AEARKLLCDSLKFTDRLCGALCVIRFDEYTPAADSGKQTENV QAEPNANLAEKTAEQIISILDDNKKTEYTRLLADAIRSLRRSSK LVAGLPKDHDGKDDHYLWDIGKKKKDENSVTIRQILTTSADTI< EL1< NAGI< WREFCEI< LGEALYLI< SI< DMSGGL1< ITRRILGDAE FHGKPDRLEKSRSVSIGSVLKETVVCGELVAKTPFFFGAIDED AKQTDLQVLLTPDNKYRLPRSAVRGILRRDLQTYFDSPCNAE LGGRPCMCKTCRIMRGITVMDARSEYNAPPEIRHRTRINPFTG TVAEGALFNMEVAPEGrVFPFQLRYRGSEDGLPDALKTVLKW WAEGQAFMSGAASTGKGRFRMENAKYETLDLSDENQRNDY LKNWGWRDEKGLEELKKRLNSGLPEPGNYRDPKWHEINVSIE MASPFINGDPIRAAVDKRGTDWTFVKYKAEGEEAKPVCAYK AESFRGVIRSAVARIHMEDGVPLTELTHSDCECLLCQIFGSEYE AGKIRFEDLVFESDPEPVTFDHVAIDRFTGGAADKKKFDDSPL PGSPARPLMLKGSFWIRRDVLEDEEYCKALGKALADVNNGL YPLGGKSAIGYGQVKSLGIKGDDKRISRLMNPAFDETDVAVP DiCas7-ll EI< PI< TDAEVRIEAEI< VYYPHYFVEPHI< I< VEREEI< PCGHQI< FH EGRLTGKIRCKLITKTPLIVPDTSNDDFFRPADKEARKEKDEY HKSYAFFRLHKQIMIPGSELRGMVSSVYETVTNSCFRIFDETK RLSWRMDADHQNVLQDFLPGRVTADGKHIQKFSETARVPFY DKTQKHFDILDEQEIAGEKPVRMWVKRFIKRLSLVDPAKHPQ I< I< QDNI< WI< RRI< EGIATFIEQI< NGSYYFNVVTNNGCTSFHLW HKPDNFDQEKLEGIQNGEKLDCWVRDSRYQKAFQEIPENDPD GWECT< EGYLHVVGPSI< VEFSDI< I< GDVINNFQGTLPSVPNDW KTIRTNDFKNRKRKNEPVFCCEDDKGNYYTMAKYCETFFFDL KENEEYEIPEKARIKYKELLRVYNNNPQAVPESVFQSRVAREN VEI< LI< SGDLVYFI< HNEI< YVEDIVPVRISRTVDDRMIGI< RMSA DLRPCHGDWVEDGDLSALNAYPEKRLLLRHPKGLCPACRLF GTGSYKGRVRFGFASLENDPEWLIPGKNPGDPFHGGPVMLSL LERPRPTWSIPGSDNI< FI< VPGRI< FYVHHHAWI< TII< DGNHPTT GKAIEQSPNNRTVEALAGGNSFSFEIAFENLKEWELGLLIHSLQ LEKGLAHKLGMAKSMGFGSVEIDVESVRLRKDWKQWRNGN SEIPNWLGKGFAKLKEWFRDELDFIENLKKLLWFPEGDQAPR VCYPMLRKKDDPNGNSGYEELKDGEFKKEDRQKKLTTPWTP WA10 IEKKKSFAKGMGVKSTLVSGSKVYMTTFAEGSDARLEKIVEG DSIRSVNEGEAFSAEMADKNAGYKIGNAKFSHPKGYAWAN NPLYTGPVQQDMLGLKETLEKRYFGESADGNDNICIQVIHNIL RfxCasl3d DIEKILAEYITNAAYAVNNISGLDKDIIGFGKFSTVYTYDEFKDPEHHRAAFNNNDKLINAIKAQYDEFDNFLDNPRLGYFGQAFFWSGR Docket No. 60555-703.601SKEGRNYIINYGNECYDILALLSGLRHWWHNNEEESRISRTW LYNLDKNLDNEYISTLNYLYDRITNELTNSFSKNSAANVNYIA ETLGINPAEFAEQYFRFSIMI< EQI< NLGFNITKLREVMLDRI< DM SEIRKNHKVFDSIRTKVYTMMDFVIYRYYIEEDAKVAAANKS LPDNEKSLSEKDIFVINLRGSFNDDQKDALYYDEANRIWRKLE NIMHNIKEFRGNKTREYKKKDAPRLPRILPAGRDVSAFSKLM YALTMFLDGKEINDLLTTLINKFDNIQSFLKVMPLIGVNAKFV EEYAFFKDSAKIADELRLIKSFARMGEPIADARRAMYID AIRIL GTNLSYDELKALADTFSLDENGNKLKKGKHGMRNFIINNVIS NKRFHYLIRYGDPAHLHEIAKNEAWKFVLGRIADIQKKQGQ NGKNQIDRYYETCIGKDKGKSVSEKVDALTKIITGMNYDQFD KKRSVIEDTGRENAEREKFKKIISLYLTVIYHILKNIVNINARY VIGFHCVERDAQLYKEKGYDINLKKLEEKGFSSVTKLCAGIDE TAPDKRKDVEKEMAERAKESIDSLESANPKLYANYIKYSDEK KAEEFTRQINREKAKTALNAYLRNTKWNVIIREDLLRIDNKTC TLFRNKAVHLEVARYVHAYINDIAEVNSYFQLYHYIMQRIIM NERYEKSSGKVSEYFDAVNDEKKYNDRLLKLLCVPFGYCIPR FKNLSIEALFDRNEAAKFDKEI< I< I< VSGNS _ NQKKYFGTYSVMAMLNAQTVLDHIQKVADIEGEQNENNENL WFHPVMSHLYNAKNGYDKQPEKTMFIIERLQSYFPFLKIMAE NQREYSNGKYKQNRVEVNSNDIFEVLKRAFGVLKMYRDLTN HYKTYEEKLNDGCEFLTSTEQPLSGMINNYYTVALRNMNERY GYKTEDLAFIQDKRFKFVKDAYGKKKSQVNTGFFLSLQDYN GDTQKKLHLSGVGIALLICLFLDKQYINIFLSRLPIFSSYNAQSE ERRIIIRSFGINSIKLPKDRIHSEKSNKSVAMDMLNEVKRCPDE LFTTLSAEKQSRFRIISDDHNEVLMKRSSDRFVPLLLQYIDYGK LFDHIRFHVNMGKLRYLLKADKTCIDGQTRVRVIEQPLNGFG RLEEAETMRKQENGTFGNSGIRIRDFENMKRDDANPANYPYI VDTYTHYILENNKVEMFINDKEDSAPLLPVIEDDRYVVKTIPS CRMSTLEIPAMAFHMFLFGSKKTEKLIVDVHNRYKRLFQAMQ KEEVTAENIASFGIAESDLPQKILDLISGNAHGKDVDAFIRLTVPspCasl3b DDMLTDTERRIKRFKDDRKSIRSADNKMGKRGFKQISTGKLA DFLAKDIVLFQPSVNDGENKITGLNYRIMQSAIAVYDSGDDYE AKQQFKLMFEKARLIGKGTTEPHPFLYKVFARSIPANAVEFYE RYLIERKFYLTGLSNEIKKGNRVDVPFIRRDQNKWKTPAMKT LGRIYSEDLPVELPRQMFDNEIKSHLKSLPQMEGIDFNNANVT YLIAEYMKRVLDDDFQTFYQWNRNYRYMDMLKGEYDRKGS LQHCFTSVEEREGLWKERASRTERYRKQASNKIRSNRQMRNA SSEEIETILDKRLSNSRNEYQKSEKVIRRYRVQDALLFLLAKKT LTELADFDGERFKLKEIMPDAEKGILSEIMPMSFTFEKGGKKY TITSEGMKLKNYGDFFVLASDKRIGNLLELVGSDIVSKEDIME EFNKYDQCRPEISSIVFNLEKWAFDTYPELSARVDREEKVDFK SILKILLNNKNINKEQSDILRKIRNAFDHNNYPDKGVVEIKALPEIAMSIKKAFGEYAIMK

[0263] In some embodiments, the CRISPR-Cas effector polypeptide is catalytica...

Claims

WSGR Docket No. 60555-703.601CLAIMSWhat is claimed is:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein:Formula (I)is a 3-10 membered heterocycloalkyl comprising 0-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;each R13is independently selected from halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2- C8alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), -O-(5- 10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)2 -10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCi-Ce alkyl, and -C(=O)N(Ci-C6alkyl)2; or two R13are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -OCi-Ce alkyl, -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl;WSGR Docket No. 60555-703.601p is 1, 2, 3, 4, or 5;provided thatis notX is selected from N or CR12;R’-R8and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), -O-(5- 10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)2 -10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCI-C6alkyl, or -C(=O)N(Ci-C6alkyl)2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -OCi-C6alkyl, -NH2, -OP(=O)(OH)2, Ci-C6alkyl, Ci-C6heteroalkyl, C6-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.2 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has astructure of Formula (I- 1): R, or a pharmaceutically acceptable salt thereof.3 The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is N.4 The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is CR12. 5 The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is CH.WSGR Docket No. 60555-703.6016. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R13is selected from halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, -O-(Ci-C, alkyl), -NH2, -C(=O)Ci-Ce alkyl, and -C(=0)NH2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, - NH2, -OCi-Ce alkyl, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.7 The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R13is selected from halogen, -OH, -NH2, or -C(=O)NH2.8 The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R13is halogen. 9 The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R13is F.10 The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R13is -OH11 The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R13is -NH2 12 The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R13is -C(=O)NH2 13 The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R13is selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, and -O-(Ci-Ce alkyl); wherein each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, - NH2, -OCi-Ce alkyl, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.14 The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R13is selected from Ci-Ce alkyl and Ci-Ce heteroalkyl, whereineach Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally substituted with one or more halogen, -NO2, - CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -NH2, -OCi-C6alkyl, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.15 The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R13is -CH3, -CH2CH3, -CH2OH, -C(CH3)2OH, -CF3, or -CH(OCH3)2.16 The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R13is selected from C2-C8 alkynyl, -O-(Ci-Ce alkyl), and -C(=O)Ci-Ce alkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, - NH2, -OCi-Ce alkyl, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.17 The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R13is -OCH3, -C(=O)CH3, or I HWSGR Docket No. 60555-703.60118. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein two R13are taken together to form =0.

19. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein two R13are taken together to form 3-20 membered heterocycloalkyl.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein two R13are taken together to form a 4-7 membered heterocycloalkyl.

021. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein I is a 4 membered heterocycloalkyl.

22. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein I is23. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein1is a 5 membered heterocycloalkyl.

24. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein I isWSGR Docket No. 60555-703.601QxAAA I A / 25. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein I is a 6 membered heterocycloalkyl.o* / W IW26. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein I is a 7 membered heterocycloalkyl.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein at least one of R’-R8is not H.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein at least one of R’-R8is halogen, -CFs, -NO2, -CN, -O-(Ci-Ce alkyl), -COOH, -C(=O)H, -COOCi-Cealkyl, -OH, -NH2, -NHCi-Ce alkyl wherein Ci-Ce alkyl is optionally substituted with -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -0P(=0)(0H)2, -N(Ci-Ce alkyl)2, C3-C10 cycloalkyl, Ci-Ce alkyl optionally substituted with an -OH, or C2-C8 alkynyl.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R1is halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, -OS(=O)2-halogen, -NH2, -C(=O)H, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)NH2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, - OCi-Ce alkyl, -NH2, -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

30. The compound any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R1is H.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R2is halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, -OS(=O)2-halogen, -NH2, -C(=O)H, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)NH2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, - OCi-Ce alkyl, -NH2, -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein R2is H.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein R3is halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, -OS(=O)2-halogen, -NH2, -C(=O)H, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)NH2; whereinWSGR Docket No. 60555-703.601each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, - OCi-Ce alkyl, -NH2, -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R3is H, -OH, - N...OS(=O)2-halogen, -NH2, or.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein R4is halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, -OS(=O)2-halogen, -NH2, -C(=O)H, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)NH2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, - OCi-Ce alkyl, -NH2, -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein R4is H.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R5is halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, -OS(=O)2-halogen, -NH2, -C(=O)H, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)NH2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, — OCi-Ce alkyl, NH2, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R5is H.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein R6is halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, -OS(=O)2-halogen, -NH2, -C(=O)H, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)NH2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, - OCi-Ce alkyl, -NH2, -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.WSGR Docket No. 60555-703.60140. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein R6is Cl, Br, or41. The compound of any one of claims 1 -40, or a pharmaceutically acceptable salt thereof, wherein R7is halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, -OS(=O)2-halogen, -NH2, -C(=O)H, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)NH2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, - OCi-Ce alkyl, -NH2, -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein R7is H.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein R8is halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, -OS(=O)2-halogen, -NH2, -C(=O)H, -C(=O)C1-C6alkyl, -C(=O)OH, -C(=O)NH2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, - OCi-Ce alkyl, -NH2, -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

44. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein R8is H.

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein n is 0 1, 2, or 3.46 The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 2.47 A compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein:Formula (II)R9and R10are each independently H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3- C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1-5 R11; X is selected from N or CR12;WSGR Docket No. 60555-703.601R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), - O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)2 -10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; ortwo R11are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-;each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, or -OH;each m is independently 0, 1, 2, or 3; andwherein at least one of R’-R8is -CF3, -NO2, -CN, -O-(C2-Ce alkyl), -COOH, -C(=O)H, -COOCi- Cealkyl, -OH, -NH2, -NHCi-Ce alkyl wherein Ci-Ce alkyl is optionally substituted with - NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or - OP(=O)(OH)2, -N(Ci-Ce alkyl)2, C3-C10 cycloalkyl, C2-C6 alkyl optionally substituted with an -OH, or C2-C8 alkynyl.WSGR Docket No. 60555-703.60148. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein the compound has, or a pharmaceutically acceptable salt49. A compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein:R'X'R92 I1I87R3 I'^Y^N J TR4R5Formula (III)R9and R10are each independently H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3- C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1-5 R11;V Qprovided that1is not1or;X is selected from N or CR12;R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-Ce alkenyl, C2-Cs alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), - O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6 alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -WSGR Docket No. 60555-703.601C(=0)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; ortwo R11are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-;each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, or -OH; andeach m is independently 0, 1, 2, or 3.

50. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein the compound hasa structure of Formula (III-l):, or a pharmaceutically acceptable salt thereof.

51. A compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein:Formula (IV)R9and R10are each independently H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3- C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1-5 R11; X is selected from N or CR12;R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl,WSGR Docket No. 60555-703.6013-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), - O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6 alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; ortwo R11are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-Ce alkenyl, C2-Cs alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;L1is -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-;each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, or -OH; andeach m is independently 0, 1, 2, or 3.2 A compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein:R8>2R5Formula (V)R9and R10are each independently H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3- C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to formWSGR Docket No. 60555-703.601a 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl are optionally substituted with 1-5 R11; X is selected from N or CR12;R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), - O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; ortwo R11are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl; andL1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-;each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, or -OH;each m is independently 0, 1, 2, or 3.3 A compound of Formula (SML), or a pharmaceutically acceptable salt thereof, wherein:WSGR Docket No. 60555-703.601Formula (SML)R9and R10are each independently H, Ci-Ce alkyl, C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3-C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl optionally substituted optionally substituted with 1-5 R11;X is selected from N or CR12;R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), - O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; ortwo R11are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-;each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, or -OH;each m is independently 0, 1, 2, or 3; andLsis a proteolytic group or a pH labile group.4 A compound of Formula (SML), or a pharmaceutically acceptable salt thereof, wherein:WSGR Docket No. 60555-703.601Formula (SML)R9and R10are each independently H, Ci-Ce alkyl, C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3-C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl optionally substituted optionally substituted with 1-5 R11;X is selected from N or CR12;R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), - O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci- C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; ortwo R11are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-;WSGR Docket No. 60555-703.601each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, or -OH;each m is independently 0, 1, 2, or 3; andLsis -L-Q, wherein:L is absent or C1-C20 alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -CR’=CR’-,, -O-, -N(R’)-, -C(=O)-, C(=S)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, - N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, - S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(OR’)O-, -P(O)(R’)-, -Cy-, or an amino acid sequence comprising 2-25 amino acids;each -Cy- is independently a bivalent ring selected from Cs- o cycloalkylene, Ce-C2o arylene, 3-20 membered heteroarylene, or 3-20 membered heterocycloalkylene, wherein each group is optionally and independently substituted with 1-20 Rs;O OQis -N=C=O, -NC, -N3, O, -C(R’)=C(R’)2, or *, wherein O is optionally and indpendently subsituted with 1-5 R’;each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, -S(O)2R, or a protecting group;each R is independently hydrogen, halogen, or an optionally substituted group selected from C1-C10 aliphatic, C1-C10 heteroalkyl, Ce-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3- 20 membered heterocycloalkyl, wherein each group is optionally and independently substituted with 1-20 Rs, or two R groups are optionally and independently taken together to form a covalent bond or =0; ortwo or more R groups on the same atom are optionally and independently taken together with the atom to form a 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the atom, 0-5 heteroatoms; ortwo or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the intervening atoms, 0-5 heteroatoms; andeach Rsis independently halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OCi-Ce alkyl, - OC3-C10 cycloalkyl, -OCe-Cioaryl, -0-5-10 membered heteroaryl, -0-3-20 membered heterocycloalkyl, -OC(=O)Ci-C6alkyl, -OC(=O)C3-Ci0cycloalkyl, -OC(=O)C6-Ci0aryl, -WSGR Docket No. 60555-703.601OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, - NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2Ci-Ce alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci- C6alkyl)S(=O)2Ci-C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=O)2C6- Cio aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)Ci-Ce alkyl, -C(=O)OH, -C(=O)OCi-Ce alkyl, - C(=O)NH2, -C(=O)NHCI-C6alkyl, -C(=O)N(Ci-C6alkyl)2; wherein each Ci-C6alkyl, Ci-C6heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl.

055. The compound of claim 54, or a pharmaceutically acceptable salt thereof, wherein Q is 0 56. The compound of claim 54, or a pharmaceutically acceptable salt thereof, wherein -L-Q is:WSGR Docket No. 60555-703.601WSGR Docket No. 60555-703.60157. The compound of any one of claims 53-56, or a pharmaceutically acceptable salt thereof, wherein Lsis a proteolytic group or a pH labile group.

58. A compound of Formula (C), or a pharmaceutically acceptable salt thereof, wherein:Formula (C)R9and R10are each independently H, Ci-Ce alkyl, C3-C10 cycloalkyl, wherein Ci-Ce alkyl and C3-C10 cycloalkyl are optionally substituted with 1-5 R11; or R9and R10are taken together to form a 3-10 membered heterocycloalkyl and 5-10 membered heteroaryl, wherein 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl optionally substituted optionally substituted with 1-5 R11;X is selected from N or CR12;R’-R8, R11, and R12are each independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -0-(C3-Cio cycloalkyl), -O-(Ce-Cioaryl), - O-(5-10 membered heteroaryl), -O-(3-20 membered heterocycloalkyl), -OC(=O)Ci-Ce alkyl, - OC(=0)C3-Cio cycloalkyl, -OC(=0)Ce-Cio aryl, -OC(=O)5-10 membered heteroaryl, - OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-Ce alkyl, - S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, -OS(=O)2-halogen, -NH2, - NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, - NHS(=O)2CI-C6alkyl, -NHS(=0)2C3-Cio cycloalkyl, -NHS(=0)2C6-Cio aryl, -NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci-C6alkyl)S(=O)2Ci-WSGR Docket No. 60555-703.601C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=0)2C6-Cio aryl, -N(CI-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, - C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; ortwo R11are taken together to form =0 or 3-20 membered heterocycloalkyl; whereineach Ci-Ce alkyl, C2-Ce alkenyl, C2-Cs alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5- 10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, - C(=O)H, -OH, -O-(Ci-Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;L1is -NHC(=O)-, -NHS(=O)2-, -NH-[C(RA)2]m-, or -O-[C(RA)2]m-;each RAis independently H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, or Ci-Ce heteroalkyl, wherein each Ci-Ce alkyl and Ci-Ce heteroalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, or -OH;each m is independently 0, 1, 2, or 3;Lcis -L-Q’-, wherein:L is absent or Ci-C2o alkylene optionally substituted with 1-30 Rs, wherein one or more methylene units of the group are optionally and independently replaced with -CR’=CR’-,, -O-, -N(R’)-, -C(=O)-, C(=S)-, -C(=O)O-, -C(=O)N(R’)-, -N(R’)C(=O)O-, - N(R’)C(=O)N(R’)S(O)2-, -OC(=O)N(R’)-, -OC(=O)N(R’)S(O)2-, -S-, -S(O)-, -S(O)2-, - S(O)2N(R’)-, -P(OR’)-, -P(O)(OR’)-, -P(O)(OR’)O-, -P(O)(R’)-, -Cy-, or an amino acid sequence comprising 2-25 amino acids;each -Cy- is independently a bivalent ring selected from C3-C2o cycloalkylene, Ce-C2o arylene, 3-20 membered heteroarylene, or 3-20 membered heterocycloalkylene, wherein each group is optionally and independently substituted with 1-20 Rs;0 ooptionally and indpendently subsituted with 1-5 R’;each R’ is independently R, -OR, -OC(=O)R, -C(=O)R, -C(=O)OR, -C(=O)N(R)2, -S(O)2R, or a protecting group;WSGR Docket No. 60555-703.601each R is independently hydrogen, halogen, or an optionally substituted group selected from C1-C10 aliphatic, C1-C10 heteroalkyl, Ce-Cioaryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3- 20 membered heterocycloalkyl, wherein each group is optionally and independently substituted with 1-20 Rs, or two R groups are optionally and independently taken together to form a covalent bond or =0; ortwo or more R groups on the same atom are optionally and independently taken together with the atom to form a 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the atom, 0-5 heteroatoms; ortwo or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-20 membered ring optionally substituted with 1-20 Rs, wherein the ring has, in addition to the intervening atoms, 0-5 heteroatoms; andeach Rsis independently halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -OCi-Ce alkyl, - OC3-C10 cycloalkyl, -OCe-Cioaryl, -0-5-10 membered heteroaryl, -0-3-20 membered heterocycloalkyl, -OC(=O)Ci-C6alkyl, -OC(=O)C3-Ci0cycloalkyl, -OC(=O)C6-Ci0aryl, - OC(=O)5-10 membered heteroaryl, -OC(=O)3-20 membered heterocycloalkyl, -S(=O)Ci-Ce alkyl, -S(=O)2Ci-C6alkyl, -S(=O)2NH2, -S(=O)2NHCI-C6alkyl, -S(=O)2N(CI-C6alkyl)2, - NH2, -NHCI-C6alkyl, -N(CI-C6alkyl)2, -NHC(=O)CI-C6alkyl, -N(CI-C6alkyl)C(=O)Ci-C6alkyl, -NHS(=O)2Ci-Ce alkyl, -NHS(=0)2C3-CIO cycloalkyl, -NHS(=0)2Ce-Cio aryl, - NHS(=O)25-10 membered heteroaryl, -NHS(=O)23-20 membered heterocycloalkyl, -N(Ci- C6alkyl)S(=O)2Ci-C6alkyl, -N(Ci-C6alkyl)S(=0)2C3-Cio cycloalkyl, -N(Ci-C6alkyl)S(=O)2C6- C10 aryl, -N(Ci-C6alkyl)S(=O)25-10 membered heteroaryl, -N(Ci-C6alkyl)S(=O)23-20 membered heterocycloalkyl, -C(=O)Ci-Ce alkyl, -C(=O)OH, -C(=O)OCi-Ce alkyl, - C(=O)NH2, -C(=O)NHCI-C6alkyl, -C(=O)N(Ci-C6alkyl)2; wherein each Ci-C6alkyl, Ci-C6heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -OH, Ci-Ce alkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl; andP is a polymer.9 The compound of claim 58, or a pharmaceutically acceptable salt thereof, wherein Q’ isWSGR Docket No. 60555-703.60160. The compound of claim 58, or a pharmaceutically acceptable salt thereof, wherein -L-Q’- is:WSGR Docket No. 60555-703.601WSGR Docket No. 60555-703.60161. The compound of any one of claims 57-60, or a pharmaceutically acceptable salt thereof, wherein Lsis a proteolytic group or a pH labile group.

62. The compound of any one of claims 57-60, or a pharmaceutically acceptable salt thereof, wherein the polymer is synthetic polynucleotide or a polypeptide.

63. The compound of any one of claims 46-61, or a pharmaceutically acceptable salt thereof, wherein X is N.

64. The compound of any one of claims 46-61, or a pharmaceutically acceptable salt thereof, wherein X is CR12.

65. The compound any one of claims 46-61, or a pharmaceutically acceptable salt thereof, wherein X is CH.

66. The compound of any one of claims 46-65, or a pharmaceutically acceptable salt thereof, wherein R11is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, C3-C10 cycloalkyl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -OS(=O)2-halogen, -NH2, -NHCi-Ce alkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)NH2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, C3-C10 cycloalkyl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -NH2, -O-(Ci-C6alkyl), Ci-C6alkyl, Ci-C6haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

67. The compound of any one of claims 46-65, or a pharmaceutically acceptable salt thereof, wherein R11are each independently H, halogen, -NO2, -CN, -OH, -OS(=O)2-halogen, -NH2, -C(=O)H, -C(=O)OH, or -C(=O)NH2.

68. The compound of any one of claims 46-65, or a pharmaceutically acceptable salt thereof, wherein R11is halogen, -OH, -OS(=O)2-halogen, -NH2, -C(=O)H, or -C(=O)NH2.WSGR Docket No. 60555-703.60169. The compound of any one of claims 46-65, or a pharmaceutically acceptable salt thereof, wherein R11is F.

70. The compound of any one of claims 46-65, or a pharmaceutically acceptable salt thereof, wherein R11is -OS(=O)2F.

71. The compound of any one of claims 46-65, or a pharmaceutically acceptable salt thereof, wherein R11are each independently Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, C3-C10 cycloalkyl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -NHCi-Ce alkyl, -C(=O)Ci-Ce alkyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, C3-C10 cycloalkyl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -NH2, -O-(Ci-C6alkyl), Ci-C6alkyl, Ci-C6haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

72. The compound of any one of claims 46-65, or a pharmaceutically acceptable salt thereof, wherein R11are each independently Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, C3-C10 cycloalkyl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -NH2, -O-(Ci-C6alkyl), Ci-C6alkyl, Ci-C6haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

73. The compound of any one of claims 46-65, or a pharmaceutically acceptable salt thereof, wherein R11is -CH3, -CH2CH3, -CH2OH, -C(CH3)2OH, -CF3, or?74. The compound of any one of claims 46-65, or a pharmaceutically acceptable salt thereof, wherein R11are each independently Ci-Ce heteroalkyl, C3-C10 cycloalkyl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -NHCi-Ce alkyl, -C(=O)Ci-Ce alkyl; whereineach Ci-Ce alkyl, Ci-Ce heteroalkyl, C3-C10 cycloalkyl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, - COOCi-C6alkyl, -C(=O)H, -OH, -NH2, -O-(Ci-C6alkyl), Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

75. The compound of any one of claims 46-65, or a pharmaceutically acceptable salt thereof, wherein R11is -NHCH3, -C(=O)CH3, -CH(OCH3)2, or -OCH376. The compound of any one of claims 46-65, or a pharmaceutically acceptable salt thereof, wherein R11is 3-20 membered heterocycloalkyl optionally substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-C6alkyl, -C(=O)H, -OH, -O-(Ci-C6alkyl), -OP(=O)(OH)2, -NH2, -NH(CI-C6alkyl) wherein Ci-C6alkyl is optionally substituted with -COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.WSGR Docket No. 60555-703.60177. The compound of claim 76, or a pharmaceutically acceptable salt thereof, wherein R11is78. The compound of any one of claims 46-62, or a pharmaceutically acceptable salt thereof, wherein two R11are taken together to form =0.

79. The compound of any one of claims 46-78, or a pharmaceutically acceptable salt thereof, wherein R9and R10are each independently H, Ci-Ce alkyl, or C3-C10 cycloalkyl, wherein Ci-Ce alkyl, C3-C10 cycloalkyl, or 5-10 membered heteroaryl are optionally substituted with 1-5 R11.

80. The compound of claim 79, or a pharmaceutically acceptable salt thereof, wherein R9is H is Ci-Ce alkyl optionally substituted with 1-5 R11.

81. The compound of claim 79, or a pharmaceutically acceptable salt thereof, wherein R9is C3-C10 cycloalkyl optionally substituted with 1-5 R11.

82. The compound of claim 79, or a pharmaceutically acceptable salt thereof, wherein R10is H is Ci-Ce alkyl optionally substituted with 1-5 R11.

83. The compound of claim 79, or a pharmaceutically acceptable salt thereof, wherein R10is C3-C10 cycloalkyl optionally substituted with 1-5 R11.

84. The compound of claim 79, or a pharmaceutically acceptable salt thereof, wherein85. The compound of any one of claims 46-78, or a pharmaceutically acceptable salt thereof, wherein R9and R10are taken together to form a 3-10 membered heterocycloalkyl optionally substituted with 1-5 R11.

86. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein R9and R10are taken together to form a 4-7 membered heterocycloalkyl optionally substituted with 1-5 R11.

87. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein R9and R10are taken together to form a 4 membered heterocycloalkyl optionally substituted with 1-5 R11.WSGR Docket No. 60555-703.60188. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein R9and R10aretaken together to form89. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein R9and R10aretaken together to form90. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein R9and R10are taken together to form a 5 membered heterocycloalkyl optionally substituted with 1-5 R11.

91. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein R9and R10are92. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein R9and R10areWSGR Docket No. 60555-703.60193. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein R9and R10are taken together to form a 6 membered heterocycloalkyl optionally substituted with 1-5 R11.

94. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein R9and R10are95. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein R9and R10are taken together to form a 7 membered heterocycloalkyl optionally substituted with 1-5 R11.

96. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein R9and R10are 0N Ntaken together to form—L~,, or97. The compound of any one of claims 46-78, or a pharmaceutically acceptable salt thereof, wherein R9and R10are taken together to form a 5-10 membered heteroaryl optionally substituted with 1-5 R11.

98. The compound of claim 97, or a pharmaceutically acceptable salt thereof, wherein R9and R10are taken together to form a 5 membered heteroaryl optionally substituted with 1-5 R11.

99. The compound of claim 97, or a pharmaceutically acceptable salt thereof, wherein R9and R10aretaken together to form100. The compound of any one of claims 46-99, or a pharmaceutically acceptable salt thereof, wherein R1is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3- C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -OS(=O)2- halogen, -NH2, -NHCI-C6alkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -NH2, - O-(Ci-Ce alkyl), Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

101. The compound of claim 99, or a pharmaceutically acceptable salt thereof, wherein R1is H.

102. The compound of any one of claims 46-101, or a pharmaceutically acceptable salt thereof, wherein R2is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3- C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -OS(=O)2-WSGR Docket No. 60555-703.601halogen, -NH2, -NHCI-C6alkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-Cealkyl)2; whereineach Ci-Ce alkyl, C2-Ce alkenyl, C2-Cs alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -NH2, - O-(Ci-Ce alkyl), Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

103. The compound of claim 102, or a pharmaceutically acceptable salt thereof, wherein R2is H, -OH, -NH2, Cl, -NO2, or -OS(=O)2F.

104. The compound of any one of claims 46-103, or a pharmaceutically acceptable salt thereof, wherein R3is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-Ce alkenyl, C2-Cs alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-Cealkyl)2; whereineach Ci-Ce alkyl, C2-Ce alkenyl, C2-Cs alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -NH2, - O-(Ci-Ce alkyl), Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

105. The compound of claim 104, or a pharmaceutically acceptable salt thereof, wherein R3is H, halogen, -NO2, -CN, -OH, -OS(=O)2-halogen, -NH2, -C(=O)H,-C(=O)OH, -C(=O)OCi-C6alkyl, or -C(=O)NH2.

106. The compound of claim 104, or a pharmaceutically acceptable salt thereof, wherein R3is H, F, Cl, Br, -NO2, -OH, -NH2, -OS(=O)2F, or -C(=O)H.

107. The compound of claim 104, or a pharmaceutically acceptable salt thereof, wherein R3is Ci-Ce alkyl, C2-Ce alkenyl, C2-Cs alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -NHCi-Ce alkyl, -C(=O)Ci-Ce alkyl, -C(=O)OCi-Ce alkyl, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-Cealkyl)2; whereineach Ci-Ce alkyl, C2-Ce alkenyl, C2-Cs alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci- Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with - COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.WSGR Docket No. 60555-703.601108. The compound of claim 104, or a pharmaceutically acceptable salt thereof, wherein R3is -CH3, -CF3,-CH(OCH2CH3)2;109. The compound of any one of claims 46-108, or a pharmaceutically acceptable salt thereof, wherein R4is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-Cealkyl)2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci- Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with - COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

110. The compound of claim 109, or a pharmaceutically acceptable salt thereof, wherein R4is H.

111. The compound of any one of claims 46-110, or a pharmaceutically acceptable salt thereof, wherein R5is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-Cealkyl)2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci- Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with - COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

112. The compound of claim 111, or a pharmaceutically acceptable salt thereof, wherein R5is H or Cl.

113. The compound of any one of claims 46-112, or a pharmaceutically acceptable salt thereof, wherein R6is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-Cealkyl)2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci-WSGR Docket No. 60555-703.601Ce alkyl), -0P(=0)(0H)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with - COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

114. The compound of claim 113, or a pharmaceutically acceptable salt thereof, wherein R6is H, halogen, -NO2, -CN, -OH, -OS(=O)2-halogen, -NH2, -C(=O)H,-C(=O)OH, -C(=O)OCi-C6alkyl, or -C(=O)NH2.

115. The compound of claim 113, or a pharmaceutically acceptable salt thereof, wherein R6is H, Cl, Br, -OH, or -C(=O)H.

116. The compound of claim 113, or a pharmaceutically acceptable salt thereof, wherein R6is Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -NHCi-Ce alkyl, -C(=O)Ci-Ce alkyl, -C(=O)OCi-Ce alkyl, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-C6alkyl)2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci- Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with - COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

117. The compound of claim 113, or a pharmaceutically acceptable salt thereof, wherein R6is -OCH3, -NHCH3, -CH3, cyclopropyl, cyclobutyl, or’118. The compound of any one of claims 46-117, or a pharmaceutically acceptable salt thereof, wherein R7is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-Cealkyl)2; whereineach Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci- Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with - COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

119. The compound of claim 118, or a pharmaceutically acceptable salt thereof, wherein R7is H or Cl.

120. The compound of any one of claims 46-119, or a pharmaceutically acceptable salt thereof, wherein R8is H, halogen, -NO2, -CN, -OH, Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, 3-20 membered heterocycloalkyl, -O-(Ci-Ce alkyl), -OS(=O)2-halogen, -NH2, -NHCI-C6alkyl, -C(=O)H, -C(=O)Ci-C6alkyl, -C(=O)OH, -C(=O)OCi-C6alkyl, -C(=O)NH2, -C(=O)NHCi-Ce alkyl, or -C(=O)N(Ci-Cealkyl)2; whereinWSGR Docket No. 60555-703.601each Ci-Ce alkyl, C2-C6 alkenyl, C2-C8 alkynyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, and 3-20 membered heterocycloalkyl is optionally and independently substituted with one or more halogen, -NO2, -CN, -COOH, -COOCi-Cealkyl, -C(=O)H, -OH, -O-(Ci- Ce alkyl), -OP(=O)(OH)2, -NH2, -NH(Ci-Ce alkyl) wherein Ci-Ce alkyl is optionally substituted with - COOH or -OP(=O)(OH)2, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce heteroalkyl, Ce-Cio aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 3-20 membered heterocycloalkyl.

121. The compound of claim 120, or a pharmaceutically acceptable salt thereof, wherein R8is H or F.

122. The compound of any one of claims 47-51 and 54-121, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

123. The compound of claim 122, or a pharmaceutically acceptable salt thereof, wherein n is 2.

124. The compound of any one of claims 47-50 and 52-123, or a pharmaceutically acceptable salt thereof, wherein L1is -NHC(=O)-.

125. The compound of any one of claims 46-121, or a pharmaceutically acceptable salt thereof, wherein L1is -NHS(=O)2-.

126. The compound of any one of claims 46-121, or a pharmaceutically acceptable salt thereof, wherein L1is -NH-CH2-.

127. The compound of any one of claims 46-121, or a pharmaceutically acceptable salt thereof, wherein L1is -O-CH2-.

128. A compound of Table 1A or a pharmaceutically acceptable salt thereof.

129. A compound of Table IB or a pharmaceutically acceptable salt thereof.

130. A composition comprising the compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

131. A composition comprising a polynucleotide conjugate comprising:(i) a synthetic polynucleotide; and(ii) a compound of any one of claims 1-129, or a pharmaceutically acceptable salt thereof.

132. The composition of claim 131, wherein the polynucleotide conjugate further comprises:a targeting moiety that binds to a target cell,wherein the compound is conjugated to the targeting moiety or the synthetic polynucleotide.

133. The composition of claim 129, wherein the compound is conjugated to the targeting moiety.

134. The composition of claim 130 or 133, wherein the targeting moiety binds to an extracellular domain of a receptor expressed by a target cell.

135. The composition of any one of claims 132-134, wherein the targeting moiety binds to an extracellular domain of transferrin receptor protein 1 (TfRl, CD71), an insulin-like growth factor 1 receptor (IGF1R), an insulin-like growth factor 1 receptor (IGF2R), or Nephrin.

136. The composition of any one of claims 132-134, wherein the targeting moiety binds to a Nephrin receptor.WSGR Docket No. 60555-703.601137. The composition of any one of claims 132-136, wherein the targeting moiety comprises polypeptide sequence with less than 150 amino acids.

138. The composition of any one of claims 132-137, wherein the targeting moiety comprises polypeptide sequence with less than 100 amino acids.

139. The composition of claim 137 or 138, wherein the targeting moiety comprises polypeptide sequence with more than 50 amino acids.

140. The composition of claim 139, wherein the targeting moiety comprises polypeptide sequence with more than 60, 70, 80, or more amino acids.

141. The composition of any one of claims 132-140, wherein the targeting moiety comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs: 31-151.

142. The composition of any one of claims 136-140, wherein the targeting moiety that binds to a Nephrin receptor comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the sequence of VRVTREGNDLTIETPDRTFHLTYIPGVSPEEAIASAEATLRRLGLDSPEVRAAVRDFVAEQA (SEQ ID NO: 152).

143. The composition of any one of claims 136-140 and 142, wherein the targeting moiety that binds to a Nephrin receptor comprises the sequence of VRVTREGNDLTIETPDRTFHLTYIPGVSPEEAIASAEATLRRLGLDSPEVRAAVRDFVAEQA (SEQ ID NO: 152).

144. The composition of any one of claims 137-143, wherein the compound is conjugated to an N-terminus or a C-terminus of the targeting moiety.

145. The composition of claim 144, wherein the compound is conjugated to an N-terminus of the targeting moiety.

146. The composition of claim 144, wherein the compound is conjugated to a C-terminus of the targeting moiety.

147. The composition of claim 132, wherein the compound is conjugated to the synthetic polynucleotide.

148. The composition of claim 147, wherein the compound is conjugated to a 5 ' end or a 3' end of the synthetic polynucleotide.

149. The composition of claim 148, wherein the compound is conjugated to a 3' end of the synthetic polynucleotide.

150. The composition of claim 148, wherein the compound is conjugated to a 5' end of the synthetic polynucleotide.

151. The composition of any one of claims 132-150, wherein the synthetic polynucleotide comprises a noncoding ribonucleic acid molecule.WSGR Docket No. 60555-703.601152. The composition of any one of claims 132-151, wherein the synthetic polynucleotide comprises a targeting ribonucleic acid sequence configured to hybridize to a target nucleic acid sequence.

153. The composition of claim 152, wherein the target nucleic acid sequence is a ribonucleic acid (RNA) sequence.

154. The composition of claim 153, wherein the RNA sequence is a messenger RNA (mRNA) sequence.

155. The composition of any one of claims 152-154, wherein the targeting ribonucleic acid sequence is complementary to an exon, an intron, an exon / intron junction, an intron / exon junction, an untranslated region or a regulatory region of the target nucleic acid sequence.

156. The composition of any one of claims 132-155, wherein the synthetic polynucleotide comprises a single-stranded synthetic polynucleotide.

157. The composition of claim 156, wherein the single-stranded synthetic polynucleotide is a chemically modified polynucleotide.

158. The composition of claim 156 or 157, wherein the single-stranded synthetic polynucleotide comprises about 16 to about 100 contiguous nucleotides.

159. A composition comprising a polypeptide; and the compound of any one of claims 1-82, or the pharmaceutically acceptable salt or the solvate thereof.

160. A composition comprising a polypeptide conjugate comprising:(i) a polypeptide; and(ii) a compound of any one of claims 1-129, or a pharmaceutically acceptable salt thereof.

161. The composition of claim 160, wherein the polypeptide is a CRISPR-Cas effector polypeptide.

162. The composition of claim 160 or 161, wherein the CRISPR-Cas effector polypeptide is a Type II CRISPR-Cas effector polypeptide, a Type V CRISPR-Cas effector polypeptide, or a Type VI CRISPR-Cas effector polypeptide.

163. The composition of claim 160 or 161, wherein the CRISPR-Cas effector polypeptide is a SpyCas9 or a variant thereof.

164. The composition of claim 160 or 161, wherein the CRISPR-Cas effector polypeptide is GeoCas9 or a variant thereof.

165. The composition of any one of claims 160-164, wherein the CRISPR-Cas effector polypeptide is catalytically active.

166. The composition of any one of claims 160-165, wherein the CRISPR-Cas effector polypeptide exhibits reduced catalytic activity compared to a wild-type CRISPR-Cas effector polypeptide.

167. The composition of any one of claims 160-166, wherein the polypeptide conjugate further comprises: an engineered guide ribonucleic acid structure or a nucleic acid encoding the engineered guide ribonucleic acid structure, wherein the engineered guide ribonucleic acid structure is configured to form a complex with the CRISPR-Cas effector polypeptide,wherein said engineered guide ribonucleic acid structure comprises:WSGR Docket No. 60555-703.601(i) a guide ribonucleic acid sequence configured to hybridize to a target nucleic acid sequence;and(ii) a tracr ribonucleic acid sequence.

168. The composition of claim 167, wherein the engineered guide ribonucleic acid structure comprises:(i) at least two ribonucleic acid polynucleotides; or(ii) a single ribonucleic acid polynucleotide comprising the guide ribonucleic acid sequence and the tracr ribonucleic acid sequence.

169. The composition of claim 152 or 168, wherein the tracr ribonucleic acid sequence is configured to bind to the CRISPR-Cas effector polypeptide.

170. The composition of any one of claims 167-169, wherein the guide ribonucleic acid sequence is complementary to a eukaryotic, a fungal, a plant, a mammalian, or a human genomic sequence.

171. The composition of any one of claims 167-170, wherein the engineered guide ribonucleic acid structure comprises a ribonucleic acid sequence comprising a stem and a loop, wherein said stem comprises at least 12 pairs of ribonucleotides.

172. The composition of claim 171, wherein the engineered guide ribonucleic acid structure further comprises a second stem and a second loop, wherein the second stem comprises at least 5 pairs of ribonucleotides.

173. The composition of claim 171, wherein the engineered guide ribonucleic acid structure further comprises a ribonucleic acid structure comprising at least two hairpins.

174. The composition of any one of claims 167-173, wherein the engineered guide ribonucleic acid structure comprises a ribonucleic acid sequence comprising at least four hairpins comprising a stem and a loop.

175. The composition of any one of claims 167-174, wherein the engineered guide ribonucleic acid structure comprises a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to non-degenerate nucleotides of SEQ ID NO: 12.

176. The composition of any one of claims 167-175, wherein the engineered guide ribonucleic acid structure comprises at least one modification.

177. The composition of claim 176, wherein the least one modification includes 2'-O-methoxyethoxy (2'-OMe), 2'- O-(2 -methoxyethyl) (2'-O-moe), 2'-fluoro (2'-F), locked nucleic acid (LNA), pseudouridine (y), phosphorothioate (PS) bond, phosphorodiamidate morpholino oligomer (PMO), and / or 2'-phosphorylation (2'-P178 The composition of any one of claims 175-177, wherein the engineered guide ribonucleic acid structure comprises (i) a 5' end modification, (ii) a 3' end modification, or (iii) a 5' end modification and a 3' end modification.179 The composition of any one of claims 160-178, wherein the polypeptide conjugate further comprises: a targeting moiety that binds to a target cell,WSGR Docket No. 60555-703.601wherein the compound is conjugated to the polypeptide or the targeting moiety.

180. The composition of claim 179, wherein the compound is conjugated to the targeting moiety.

181. The composition of claim 179 or 180, wherein the targeting moiety binds to an extracellular domain of a receptor expressed by a target cell.

182. The composition of any one of claims 179-181, wherein the targeting moiety binds to an extracellular domain of transferrin receptor protein 1 (TfRl, CD71), an insulin-like growth factor 1 receptor (IGF1R), an insulin-like growth factor 1 receptor (IGF2R), or Nephrin.

183. The composition of any one of claims 179-181, wherein the targeting moiety binds to aNephrin receptor.

184. The composition of any one of claims 179-183, wherein the targeting moiety comprises polypeptide sequence with less than 150 amino acids.

185. The composition of any one of claims 179-184, wherein the targeting moiety comprises polypeptide sequence with less than 100 amino acids.

186. The composition of claim 184 or 185, wherein the targeting moiety comprises polypeptide sequence with more than 50 amino acids.

187. The composition of claim 186, wherein the targeting moiety comprises polypeptide sequence with more than 60, 70, 80, or more amino acids.

188. The composition of any one of claims 179-187, wherein the targeting moiety comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs: 31-151.

189. The composition of any one of claims 183-187, wherein the targeting moiety that binds to aNephrin receptor comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the sequence of VRVTREGNDLTIETPDRTFHLTYIPGVSPEEAIASAEATLRRLGLDSPEVRAAVRDFVAEQA (SEQ ID NO: 152).

190. The composition of any one of claims 183-187 and 189, wherein the targeting moiety that binds to a Nephrin receptor comprises the sequence of VRVTREGNDLTIETPDRTFHLTYIPGVSPEEAIASAEATLRRLGLDSPEVRAAVRDFVAEQA (SEQ ID NO: 152).

191. The composition of any one of claims 179-190, wherein the compound is conjugated to an N-terminus or a C-terminus of the targeting moiety.

192. The composition of claim 191, wherein the compound is conjugated to an N-terminus of the targeting moiety.

193. The composition of claim 191, wherein the compound is conjugated to a C-terminus of the targeting moiety.WSGR Docket No. 60555-703.601194. The composition of any one of claims 160-190, wherein the compound is conjugated to an N-terminus or a C-terminus of the CRISPR-Cas effector polypeptide.

195. The composition of claim 194, wherein the compound is conjugated to an N-terminus or a C-terminus of the CRISPR-Cas effector polypeptide.

196. The composition of claim 194, wherein the compound is conjugated to a C-terminus of the CRISPR-Cas effector polypeptide.

197. The composition of any one of claims 167-196, wherein the polypeptide conjugate comprises a linker between the targeting moiety and the CRISPR-Cas effector polypeptide.

198. The composition of claim 197, wherein the linker between the targeting moiety and the CRISPR-Cas effector polypeptide is a proteolytically cleavable.

199. The composition of any one of claims 160-198, wherein the polypeptide conjugate comprises one or more nuclear localization sequences (NLSs).

200. The composition of claim 199, wherein the one or more NLSs comprise the amino acid sequence K(K / R)X(K / R), where X is any amino acid.

201. The composition of claim 199, wherein the one or more NLSs comprise the amino acid sequence PKKKRKV.

202. The composition of any one of claims 199-201, wherein the one or more NLSs are located at the N-terminus of the CRISPR-Cas effector polypeptide.

203. The composition of any one of claims 160-202, wherein the polypeptide conjugate further comprises at least one additional heterologous polypeptide.

204. The composition of claim 203, wherein the at least one additional heterologous polypeptide is a deaminase, a base editor, a reverse transcriptase, a transcription modulator, or an epigenetic modulator.

205. A recombinant polynucleotide molecule comprising a nucleotide sequence encoding the polynucleotide, the polypeptide, the NLS, the targeting moiety, or any combination thereof of any one of claims 160-204.

206. A recombinant expression vector comprising the nucleic acid of claim 205.

207. A cell comprising the compound of any one of claims 1-129, the composition of any one of claims 130-204, the recombinant polynucleotide molecule of claim 205, the recombinant expression vector of claim 206, or any combination thereof.

208. A pharmaceutical composition comprising the compound of any one of claims 1-129, the composition of any one of claims 130-204, the nucleic acid of claim 205, the recombinant expression vector of claim 206, or the cell of claim 207, and a pharmaceutically acceptable carrier, excipient, or diluent.

209. A method of treating a condition or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-129, the composition of any one of claims 130-204, the nucleic acid of claim 205, the recombinant expression vector of claim 206, or the cell of claim 207, the pharmaceutical composition of claim 208, or any combination thereof, thereby treating the condition or disease in the subject.WSGR Docket No. 60555-703.601210. A method of modifying a target nucleic acid, the method comprising contacting the target nucleic acid with the composition of any one of claims 130-204.

211. A method of modifying a target nucleic acid in a cell, the method comprising introducing into the eukaryotic cell the composition of any one of claims 130-204.

212. A method of editing a locus within a cell, the method comprising introducing into the cell the composition of any one of claims 130-204.

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