SOS1 protein degrading agent, pharmaceutical composition thereof and therapeutic application thereof

Abstract

Provided herein are SOS1 proteolysers, such as compounds of formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use to treat, prevent, or ameliorate one or more symptoms of an SOS1-mediated disorder, disease, or condition. [Formula 1] TIFF2024522768000139.tif27170

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 211,326, filed June 16, 2021; the disclosure of which is incorporated herein by reference in its entirety.

[0002] (Field) Provided herein are SOS1 protein degraders and pharmaceutical compositions thereof, as well as methods of their use for treating, preventing, or ameliorating one or more symptoms of an SOS1-mediated disorder, disease, or condition. [Background technology]

[0003] (background) The three RAS oncogenes, KRAS, HRAS, and NRAS, are from the oncogene family most frequently mutated in cancer (Milburn et al., Science 1990, 247, 939-45; Cox et al., Nat. Rev. Drug Discov. 2014, 13, 828-51; Papke and Der, Science 2017, 355, 1158-63). RAS mutations have been detected in up to 30% of all human cancers (Cox et al., Nat. Rev. Drug Discov. 2014, 13, 828-51). RAS mutations are found in approximately 95% of pancreatic ductal adenocarcinomas (PDAC), approximately 50% of colorectal adenocarcinomas (CRC), and approximately 30% of lung adenocarcinomas (CAC) (Papke and Der, Science 2017, 355, 1158-63). Of these three, KRAS mutations are the most common, accounting for approximately 1 million deaths per year worldwide (Cox et al., Nat. Rev. Drug Discov. 2014, 13, 828-51; Simanshu et al., Cell 2017, 170, 17-33).

[0004] RAS proteins are small GTPases encoded by the RAS oncogene. Papke and Der, Science 2017, 355, 1158-63. RAS proteins function as molecular switches, cycling between an active guanosine triphosphate (GTP)-bound state and an inactive guanosine diphosphate (GDP)-bound state. Milburn et al., Science 1990, 247, 939-45. GTP-bound active RAS activates downstream effector pathways, including rat fibrosarcoma / mitogen-activated protein kinase kinase / extracellular-regulated kinase (RAF / MEK / ERK) and phosphoinositide 3-kinase / protein kinase B / mechanistic target of rapamycin kinase (PI3K / AKT / mTOR). Rebocho and Marais, Cancer Discov. 2011, 1, 98-9. Oncogenic mutations in RAS proteins impair their ability to hydrolyze GTP, leading to the accumulation of GTP-bound active RAS and hyperactivation of downstream signaling cascades, resulting in uncontrolled cell proliferation and survival. Uras et al., Int. J. Mol. Sci. 2020, 21, 4325.

[0005] RAS signaling is tightly regulated by guanine nucleotide exchange factor (GEF) proteins, which catalyze the exchange of GDP for GTP, and GTPase-activating proteins (GAPs), which increase the rate of GTP hydrolysis to GDP (Simanshu et al., Cell 2017, 170, 17-33). In other words, the RAS GTP / GDP cycle is negatively regulated by GAPs and positively regulated by GEFs (Bos, Cell 2007, 129, 865-77). Son of sevenless homolog 1 (SOS1) is a GEF that binds to RAS and promotes nucleotide exchange and the formation of GTP-bound active RAS (Wang et al., Bioorg. Med. Chem. Lett. 2012, 22, 5766-76). Small-molecule SOS1 inhibitors have been shown to be effective in downregulating active RAS in tumor cells with wild-type KRAS and tumor cells carrying KRAS mutations. Hillig et al., Proc. Nat. Acad. Sci. 2019, 114, 2551-60. By preventing the formation of the KRAS-SOS1 complex, SOS1 inhibitors block the reloading of KRAS with GTP, leading to antiproliferative activity. Ibid.

[0006] Despite advances in cancer treatment, cancer remains a major public health problem worldwide. In 2021, an estimated 1,898,160 new cancer cases will be diagnosed in the United States alone, and 608,570 cancer deaths will occur (Cancer Facts & Figures 2021). Therefore, effective therapies for cancer treatment are needed. Summary of the Invention

[0007] (Disclosure Summary) Provided herein are compounds of formula (I): [ka] (In the formula, L is a linker; one of U, V, X, and Y is -C= or -N-; and the remaining three of U, V, X, and Y are each independently -C(R 4 )= or -N=; R 1 and R 3 are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; R 2 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, Heteroaryl, Heteroaryl-C 1-6 alkylene or heterocyclyl; Each R 4 are independently (i) hydrogen, deuterium, cyano, halo, nitro, or oxo; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(O)SR 1a 、-OC(NR 1a )NR 1b R 1c 、-OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(O)SR 1d 、-NR 1a C(NR 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR 1a C(S)OR 1d 、-NR 1a C(S)NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a 、-S(O)NR 1b R 1c, or -S(O)NR 1b R 1c and; Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; X E is C(R E2 ) or N; Y E is a bond, C 1-6 Alkylene, -O-, -S-, -S(O)-, -S(O2)-, or -N(R E3 )-and; Z E is C 6-14 arylene, heteroarylene, or C 6-14 arylene-heteroarylene; R E1 is hydrogen or C 1-6 is alkyl; R E2 is hydrogen, deuterium, halo, or C 1-6 is alkyl; R E3 is hydrogen or C 1-6 is alkyl; and m is an integer of 0, 1, or 2; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylene, aralkyl, heteroaryl, heteroarylene, and heterocyclyl is optionally substituted with one or more, and in one embodiment one, two, three, or four, substituents Q, wherein each Q is independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) each is one or more, and in one embodiment one, two, three, or four, substituents Q aoptionally further substituted with C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR b ) OR c , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NRa C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c where each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) each one or more, in one embodiment one, two, three, or four, substituents Q a optionally substituted with C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atoms to which they are attached, form one or more, in one embodiment one, two, three or four, substituents Q a forming an optionally substituted heterocyclyl; Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f ) OR g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NRh )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R g where each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclyl) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0008] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.

[0009] Further provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by Son of Sevenless homolog 1 (SOS1) in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0010] Further provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by Ras in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0011] Provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0012] Provided herein is a method of inhibiting proliferation of a cell, comprising contacting the cell with a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0013] Provided herein is a method for inducing degradation of SOS1, comprising contacting the SOS1 with a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. DETAILED DESCRIPTION OF THE INVENTION

[0014] (Detailed explanation) To facilitate understanding of the disclosure set forth herein, several terms are defined below.

[0015] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0016] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.

[0017] The terms "treat," "treating," and "treatment" are intended to include alleviating or arresting a disorder, disease, or condition, or one or more symptoms associated with a disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0018] The terms "prevent," "preventing," and "prevention" are intended to include methods of delaying and / or preventing the onset of a disorder, disease, or condition, and / or its attendant symptoms; methods of barring a subject from acquiring a disorder, disease, or condition; or methods of reducing a subject's risk of acquiring a disorder, disease, or condition.

[0019] The terms "alleviate" and "alleviating" refer to the relief or reduction of one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms may also refer to the reduction of adverse effects associated with an active ingredient. Sometimes, the beneficial effects a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.

[0020] The terms "contacting" or "contacting" refer to bringing together a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue such that a physiological and / or chemical effect occurs as a result of such contact. Contacting can occur in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule. In another embodiment, a therapeutic agent is contacted with cells in cell culture (in vitro) to determine the effect of the therapeutic agent on the cells. In yet another embodiment, contacting a therapeutic agent with a biological molecule, cell, or tissue comprises administering the therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.

[0021] The term "therapeutically effective amount" or "effective amount" is intended to include the amount of a compound that, when administered, is sufficient to prevent the onset of, or alleviate to some extent, one or more symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" or "effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response in a biological molecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0022] The term “IC 50 " or "EC 50 " refers to the amount, concentration, or dosage of a compound required for 50% inhibition of a maximal response in an assay that measures such response.

[0023] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. See, for example, Remington: The Science and Practice of Pharmacy, 23rd ed.; edited by Adejare: Academic Press, 2020; Handbook of Pharmaceutical Excipients, 9th ed.; edited by Sheskey et al.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives, 3rd ed.; edited by Ash and Ash; Synapse Information Resources: 2007; Pharmaceutical Preformulation and Formulation, 1st ed.; edited by Gibson; CRC Press, 2015.

[0024] The term "about" or "approximately" refers to a tolerance for error associated with a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, or 3 standard deviations. In certain embodiments, the term "about" or "approximately" means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0025] The term "alkyl" refers to a straight-chain or branched-chain saturated monovalent hydrocarbon radical, where alkyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In some embodiments, alkyl refers to a group having 1 to 20 carbon atoms (C 1-20 ), 1~15 pieces (C 1-15 ), 1~10 pieces (C 1-10 ), or 1 to 6 (C 1-6 ) or a linear saturated monovalent hydrocarbon radical having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 ) is a branched, saturated, monovalent hydrocarbon radical. 1-6 and branched chain C 3-6 An alkyl group is also referred to as a “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., n-propyl and isopropyl), butyl (including all isomeric forms, e.g., n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl (including all isomeric forms, e.g., n-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl), and hexyl (including all isomeric forms, e.g., n-hexyl, isohexyl, and sec-hexyl).

[0026] The term "heteroalkyl" refers to a straight or branched chain saturated monovalent hydrocarbon radical containing in its backbone one or more heteroatoms independently selected from O, S, and N. Heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6Heteroalkyl refers to a straight-chain saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched-chain saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In some embodiments, heteroalkyl refers to a heteroalkyl group having 1 to 20 carbon atoms (C 1-20 ), 1~15 pieces (C 1-15 ), 1~10 pieces (C 1-10 ), or 1 to 6 (C 1-6 ) or a linear saturated monovalent hydrocarbon radical having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 ) is a branched, saturated, monovalent hydrocarbon radical. As used herein, linear C 1-6 and branched chain C 3-6 Heteroalkyl groups are also referred to as "lower heteroalkyl." Examples of heteroalkyl groups include, but are not limited to, -OCH, -OCHCH, -CHOCH, -NHCH, -ONHCH, -NHOCH, -SCH, -CHNHCHCH, and -NHCHCHCH. Examples of substituted heteroalkyl groups include, but are not limited to, -CHNHC(O)CH and -NHC(O)CHCH.

[0027] The terms "alkylene" and "alkanediyl" are used interchangeably herein, where alkanediyl refers to a straight or branched chain saturated divalent hydrocarbon radical, optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkanediyl refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, alkanediyl refers to a hydrocarbon radical having 1 to 30 carbon atoms (C 1-30 ), 1~20 pieces (C 1-20 ), 1~15 pieces (C 1-15 ), 1~10 pieces (C 1-10 ), or 1 to 6 (C 1-6 ) or a linear saturated divalent hydrocarbon radical having 3 to 30 carbon atoms (C3-30 ), 3~20 pieces (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 ) is a branched, saturated, divalent hydrocarbon radical. As used herein, linear C 1-6 and branched chain C 3-6 Alkanediyl groups are also referred to as “lower alkanediyl.” Examples of alkanediyl groups include methanediyl, ethanediyl (including all isomeric forms, for example, ethane-1,1-diyl and ethane-1,2-diyl), propanediyl (including all isomeric forms, for example, propane-1,1-diyl, propane-1,2-diyl, and propane-1,3-diyl), butanediyl (including all isomeric forms, for example, butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl, and butane-1,4-diyl), pentanediyl (including all isomeric forms, for example, pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl, and pentane-1,5-diyl), and hexanediyl (including all isomeric forms, for example, hexane-1,1-diyl, hexane-1,2-diyl, hexane-1,3-diyl, and hexane-1,6-diyl). Examples of substituted alkanediyl groups include -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, -C(O)(CH2)4-, -C(O)(CH2)5-, -C(O)(CH2)6-, -C(O)(CH2)7-, -C(O)(CH2)8-, -C(O)(CH2)9-, and -C(O)(CH2) 10 Examples include, but are not limited to, -, -C(O)CHC(O)-, -C(O)(CH)C(O)-, -C(O)(CH)C(O)-, -C(O)(CH)C(O)-, or -C(O)(CH)C(O)-.

[0028] The terms "heteroalkylene" and "heteroalkanediyl" are used interchangeably herein to refer to a straight or branched chain saturated divalent hydrocarbon radical containing in its backbone one or more heteroatoms independently selected from O, S, and N. Heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkylene refers to a straight-chain saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched-chain saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In some embodiments, heteroalkylene refers to a hydrocarbon radical having 1 to 20 carbon atoms (C 1-20 ), 1~15 pieces (C 1-15 ), 1~10 pieces (C 1-10 ), or 1 to 6 (C 1-6 ) or a linear saturated divalent hydrocarbon radical having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 ) is a branched, saturated, divalent hydrocarbon radical. As used herein, linear C 1-6 and branched chain C 3-6 Heteroalkylene groups are also referred to as "lower heteroalkylene." Examples of heteroalkylene groups include -CHO-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH) 10These include, but are not limited to, O-, -CH2OCH2-, -CH2CH2O-, -(CH2CH2O)2-, -(CH2CH2O)3-, -(CH2CH2O)4-, -(CH2CH2O)5-, -CH2NH-, -CH2NHCH2-, -CH2CH2NH-, -CH2S-, -CH2SCH2-, and -CH2CH2S-. Examples of substituted heteroalkylene groups include -C(O)CHO-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, 10 Examples include, but are not limited to, O-, -C(O)CHOCHCHO-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)-, -CHNHC(O)CH-, or -CHCHC(O)NH-.

[0029] The term "alkenyl" refers to a straight- or branched-chain monovalent hydrocarbon radical containing one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon double bond(s). The alkenyl is optionally substituted with one or more substituents Q as described herein. The term "alkenyl" encompasses radicals having the "cis" or "trans" configuration or a mixture thereof, or the "Z" or "E" configuration or a mixture thereof, as will be apparent to one of ordinary skill in the art. For example, C 2-6 Alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In some embodiments, alkenyl refers to a hydrocarbon radical of 2 to 20 carbon atoms (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear monovalent hydrocarbon radical of 3 to 20 carbon atoms (C 3-20), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 ) is a branched-chain monovalent hydrocarbon radical. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms, e.g., propen-1-yl, propen-2-yl, and allyl), and butenyl (including all isomeric forms, e.g., buten-1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl).

[0030] The terms "alkenylene" and "alkenediyl" are used interchangeably herein to refer to a straight-chain or branched-chain divalent hydrocarbon radical containing one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon double bond(s). The alkenediyl is optionally substituted with one or more substituents Q as described herein. The term "alkenediyl" encompasses radicals having "cis" or "trans" configurations or mixtures thereof, or "Z" or "E" configurations or mixtures thereof, as recognized by those of skill in the art. For example, C 2-6 Alkenediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, alkenediyl refers to a hydrocarbon radical of 2 to 30 carbon atoms (C 2-30 ), 2~20 pieces (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear divalent hydrocarbon radical having 3 to 30 carbon atoms (C 3-30 ), 3~20 pieces (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6Examples of alkenediyl groups include ethenediyl (including all isomeric forms, for example, ethene-1,1-diyl and ethene-1,2-diyl), propenediyl (including all isomeric forms, for example, 1-propene-1,1-diyl, 1-propene-1,2-diyl, and 1-propene-1,3-diyl), butenediyl (including all isomeric forms, for example, 1-butene-1,1-diyl, 1-butene-1,2-diyl, and 1-butene-1,4-diyl), pentaerythritol, benzophenone, benzophenone, benzophenone-1,1-diyl, benzophenone-1,2-diyl, and benzophenone-1,4-diyl). Examples include, but are not limited to, enediyl (including all isomeric forms, for example, 1-pentene-1,1-diyl, 1-pentene-1,2-diyl, and 1-pentene-1,5-diyl), and hexenediyl (including all isomeric forms, for example, 1-hexene-1,1-diyl, 1-hexene-1,2-diyl, 1-hexene-1,3-diyl, 1-hexene-1,4-diyl, 1-hexene-1,5-diyl, and 1-hexene-1,6-diyl).

[0031] The terms "heteroalkenylene" and "heteroalkenediyl" are used interchangeably herein to refer to a straight-chain or branched-chain divalent hydrocarbon radical containing one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon double bond(s) and containing one or more heteroatoms independently selected from O, S, and N within the hydrocarbon chain. The heteroalkenylene is optionally substituted with one or more substituents Q as described herein. The term "heteroalkenylene" encompasses radicals having a "cis" or "trans" configuration or a mixture thereof, or a "Z" or "E" configuration or a mixture thereof, as recognized by those skilled in the art. For example, C 2-6 Heteroalkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, heteroalkenylene refers to a heteroalkenylene having 2 to 20 carbon atoms (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C2-6 ) or a linear divalent hydrocarbon radical having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 Examples of heteroalkenylene groups include, but are not limited to, -CH=CHO-, -CH=CHOCH2-, -CH=CHCHO-, -CH=CHS-, -CH=CHSCH2-, -CH=CHCH2S-, or -CH=CHCH2NH-.

[0032] The term "alkynyl" refers to a straight- or branched-chain monovalent hydrocarbon radical containing one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon triple bond(s). Alkynyl groups do not contain carbon-carbon double bonds. Alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms. In some embodiments, alkynyl refers to a hydrocarbon radical of 2 to 20 carbon atoms (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear monovalent hydrocarbon radical of 4 to 20 carbon atoms (C 4-20 ), 4~15 pieces (C 4-15 ), 4~10 pieces (C 4-10 ), or 4 to 6 (C 4-6) is a branched-chain monovalent hydrocarbon radical. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (including all isomeric forms, e.g., 1-propynyl (-C≡CCH) and propargyl (-CHC≡CH)), butynyl (including all isomeric forms, e.g., 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl and 2-hexyn-1-yl).

[0033] The terms "alkynylene" and "alkynediyl" are used interchangeably herein to refer to a straight-chain or branched-chain divalent hydrocarbon radical containing one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon triple bond(s). An alkynylene group does not contain a carbon-carbon double bond. If a group containing a carbon-carbon triple bond also contains a carbon-carbon double bond, the group is classified as an alkenediyl group rather than an alkynediyl group. An alkynediyl is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, alkynediyl refers to a hydrocarbon radical of 2 to 30 carbon atoms (C 2-30 ), 2~20 pieces (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear divalent hydrocarbon radical having 4 to 30 carbon atoms (C 4-30 ), 4~20 pieces (C 4-20 ), 4~15 pieces (C 4-15 ), 4~10 pieces (C 4-10 ), or 4 to 6 (C 4-6) is a branched-chain divalent hydrocarbon radical. Examples of alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, for example, 1-propyne-1,3-diyl and 1-propyne-3,3-diyl), butynediyl (including all isomeric forms, for example, 1-butyne-1,3-diyl, 1-butyne-1,4-diyl, and 2-butyne-1,1-diyl), pentynediyl (including all isomeric forms, for example, 1-pentyne-1,3-diyl, 1-pentyne-1,4-diyl, and 2-pentyne-1,1-diyl), and hexynediyl (including all isomeric forms, for example, 1-hexyne-1,3-diyl, 1-hexyne-1,4-diyl, and 2-hexyne-1,1-diyl).

[0034] The terms "heteroalkynylene" and "heteroalkynediyl" are used interchangeably herein to refer to a straight-chain or branched divalent hydrocarbon radical containing one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon triple bond(s) and containing in its backbone one or more heteroatoms independently selected from O, S, and N. A heteroalkynylene group does not contain a carbon-carbon double bond. Heteroalkynylene is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Heteroalkynylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, heteroalkynylene refers to a heteroalkynylene having 2 to 30 carbon atoms (C 2-30 ), 2~20 pieces (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear divalent hydrocarbon radical having 4 to 30 carbon atoms (C 4-30 ), 4~20 pieces (C 4-20 ), 4~15 pieces (C 4-15 ), 4~10 pieces (C 4-10 ), or 4 to 6 (C 4-6Examples of heteroalkynylene groups include, but are not limited to, -C≡CCH2O-, -C≡CCH2S-, or -C≡CCH2NH-.

[0035] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon radical optionally substituted with one or more substituents Q, as described herein. In one embodiment, a cycloalkyl is a saturated or unsaturated but non-aromatic, and / or bridged or unbridged, and / or fused bicyclic group. In certain embodiments, a cycloalkyl is a cyclic group having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 7 (C 3-7 ) In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet another embodiment, the cycloalkyl is tricyclic. In yet another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl.

[0036] The terms "cycloalkylene" and "cycloalkanediyl" are used interchangeably herein to refer to a cyclic divalent hydrocarbon radical, optionally substituted with one or more substituents Q, as described herein. In one embodiment, a cycloalkanediyl group can be a saturated or unsaturated but non-aromatic, and / or bridged and / or unbridged, and / or fused bicyclic group. In certain embodiments, a cycloalkanediyl is a cycloalkanediyl having from 3 to 30 carbon atoms (C 3-30 ), 3~20 pieces (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C3-10 ), or 3 to 7 (C 3-7 Examples of cycloalkanediyl groups include cyclopropanediyl (including all isomeric forms, for example, cyclopropane-1,1-diyl and cyclopropane-1,2-diyl), cyclobutanediyl (including all isomeric forms, for example, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and cyclobutane-1,3-diyl), cyclopentanediyl (including all isomeric forms, for example, cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, and cyclopentane-1,3-diyl), cyclohexanediyl (including all isomeric forms, for example, cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, and cyclohexa-1,4-diyl), cycloheptanediyl (including all isomeric forms, for example, cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cycloheptane-1,3-diyl, and cycloheptane-1,4-diyl), decalindiyl (including all isomeric forms, for example, decalin-1,1-diyl, decalin-1,2-diyl, and decalin-1,8-diyl), and adamantodiyl (including all isomeric forms, for example, adamant-1,2-diyl, adamant-1,3-diyl, and adamant-1,8-diyl).

[0037] The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon radical and / or a monovalent polycyclic aromatic hydrocarbon radical containing at least one aromatic carbocyclic ring. In certain embodiments, an aryl is an aromatic group having from 6 to 20 ring carbon atoms (C 6-20 ), 6~15 pieces (C 6-15 ), or 6 to 10 (C 6-10) Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to a bicyclic or tricyclic carbocycle, where one ring is aromatic and the other ring may be saturated, partially unsaturated, or aromatic, such as dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In one embodiment, an aryl is monocyclic. In another embodiment, an aryl is bicyclic. In yet another embodiment, an aryl is tricyclic. In yet another embodiment, an aryl is polycyclic. In certain embodiments, an aryl is optionally substituted with one or more substituents Q, as described herein.

[0038] The terms "arylene" and "arenediyl" are used interchangeably herein to refer to a divalent monocyclic aromatic hydrocarbon radical or a divalent polycyclic aromatic hydrocarbon radical containing at least one aromatic hydrocarbon ring. In certain embodiments, an arylene is an arylene having 6 to 20 ring atoms (C 6-20 ), 6~15 pieces (C 6-15 ), or 6 to 10 (C 6-10Examples of arylene groups include phenylene (including all isomeric forms, for example, phen-1,2-diyl, phen-1,3-diyl, and phen-1,4-diyl), naphthylene (including all isomeric forms, for example, naphth-1,2-diyl, naphth-1,3-diyl, and naphth-1,8-diyl), fluorenylene (including all isomeric forms, for example, fluorene-1,2-diyl, fluorene-1,4-diyl), and the like. azulenylene (including all isomeric forms, for example, azulen-1,2-diyl, azulen-1,3-diyl, and azulen-1,8-diyl), anthrylene (including all isomeric forms, for example, anthr-1,2-diyl, anthra-1,3-diyl, and anthra-1,8-diyl), , phenanthrylene (including all isomeric forms, for example, phenanthra-1,2-diyl, phenanthra-1,3-diyl, and phenanthra-1,8-diyl), pyrenylene (including all isomeric forms, for example, pyrene-1,2-diyl, pyrene-1,3-diyl, and pyrene-1,8-diyl), biphenylene (including all isomeric forms, for example, biphen-2,3-diyl, biphen-3,4'-diyl, and biphen-4,4'-diyl), and terphenylene (including all isomeric forms, for example, terphen-2,3-diyl, terphen-3,4'-diyl, and terphen-4,4'-diyl).Arylene also refers to a bicyclic or tricyclic carbocyclic ring in which one of the rings is aromatic and the other rings can be saturated, partially unsaturated, or aromatic, for example, dihydronaphthylene (including all isomeric forms, for example, dihydronaphth-1,2-diyl and dihydronaphth-1,8-diyl), indenylene (including all isomeric forms, for example, indene-1,2-diyl, indene-1,5-diyl, and indene-1,7-diyl), indanylene (including all isomeric forms, for example, indan-1,2-diyl, indan-1,5-diyl, and indan-1,7-diyl), or tetrahydronaphthylene (tetralinylene) (including all isomeric forms, for example, tetrahydronaphth-1,2-diyl, tetrahydronaphth-1,5-diyl, and tetrahydronaphth-1,8-diyl). In certain embodiments, the arylene is optionally substituted with one or more substituents Q, as described herein.

[0039] The terms "aralkyl" or "arylalkyl" refer to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, an aralkyl is an alkyl group having 7 to 30 carbon atoms (C 7-30 ), 7~20 pieces (C 7-20 ), or 7 to 16 (C 7-16 ) Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomeric forms, e.g., 1-phenylethyl and 2-phenylethyl), and phenylpropyl (including all isomeric forms, e.g., 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In certain embodiments, the aralkyl is optionally substituted with one or more substituents Q, as described herein.

[0040] The terms "aralkylene" or "arylalkylene" refer to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkylene is an alkyl group having 7 to 30 carbon atoms (C 7-30 ), 7~20 pieces (C 7-20 ), or 7 to 16 (C 7-16) Examples of aralkylene groups include, but are not limited to, benzylene (including all isomeric forms, e.g., phenylmethdiyl), phenylethylene (including all isomeric forms, e.g., 2-phenyl-ethane-1,1-diyl and 2-phenyl-ethane-1,2-diyl), and phenylpropylene (including all isomeric forms, e.g., 3-phenyl-propane-1,1-diyl, 3-phenyl-propane-1,2-diyl, and 3-phenyl-propane-1,3-diyl). In certain embodiments, the aralkylene is optionally substituted with one or more substituents Q, as described herein.

[0041] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or a monovalent polycyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N within the ring. For heteroaryl groups containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heteroaryl group is not connected to the rest of the molecule through the non-aromatic heterocyclic ring. Each ring of the heteroaryl group can contain one or two O atoms, one or two S atoms, and / or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, a heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. In one embodiment, a heteroaryl is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl is bicyclic.Examples of bicyclic heteroaryl groups include benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl), imidazolyl, pyridinyl (including all isomeric forms, for example, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, for example, imidazo[2,1-b]thiazolyl and imidazo[4,5-d]thiazolyl), indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzo-thienyl (i.e., benzo[c]thienyl), isoindolyl, isoquinolinyl, naphthyridinyl (including all isomeric forms, for example, 1,5-naphthalene, phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (including all isomeric forms, for example, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl (including all isomeric forms, e.g., [1,2,5]thiadiazolo[3,4-d]pyrimidinyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinyl), and thienopyridyl (including all isomeric forms, e.g., thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[3,2-c]pyridinyl). In yet another embodiment, heteroaryl is tricyclic.Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl is optionally substituted with one or more substituents Q as described herein.

[0042] The terms "heteroarylene" and "heteroarenediyl" are used interchangeably herein to refer to a divalent monocyclic aromatic group or a divalent polycyclic aromatic group comprising at least one aromatic ring, wherein the at least one aromatic ring comprises one or more heteroatoms, each independently selected from O, S, and N, within the ring. For heteroarylene groups comprising a heteroaromatic ring and a non-aromatic heterocyclic ring, the heteroarylene group is not connected to the rest of the molecule through the non-aromatic heterocyclic ring. Each ring of the heteroarylene group can contain one or two O atoms, one or two S atoms, and / or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroarylene has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furandiyl, imidazolediyl, isothiazolediyl, isoxazolediyl, oxadiazolediyl, oxazolediyl, pyrazinediyl, pyrazolediyl, pyridazinediyl, pyridinediyl, pyrimidinediyl, pyrrolediyl, thiadiazolediyl, thiazolediyl, thiendiyl, tetrazolediyl, triazinediyl, and triazolediyl. Examples of bicyclic heteroarylene groups include benzofurandiyl, benzimidazolediyl, benzoisoxazolediyl, benzopyrandiyl, benzothiadiazolediyl, benzothiendiyl, benzotriazolediyl, benzoxazolediyl, furopyridinediyl (all isomeric forms, e.g., furo[2,3-b]pyridinediyl, furo[2,3-c]pyridinediyl, furo[3 ,2-b]pyridinediyl, furo[3,2-c]pyridinediyl, furo[3,4-b]pyridinediyl, and furo[3,4-c]pyridinediyl), imidazopyridinediyl (including all isomeric forms, for example, imidazo[1,2-a]pyridinediyl, imidazo[4,5-b]pyridinediyl, and imidazo[4,5-c]pyridinediyl), imidazothiazolediyl (including all isomeric forms, for example, imidazo[2,1-b]thiazolediyl and imidazo[4,5-d]thiazolediyl), indazolediyl, indolizinediyl, indolediyl, isobenzofurandiyl, isobenzothienediyl (i.e., benzo[c]thienediyl), isoindolediyl, isoquinolinediyl, naphthyridinediyl (including all isomeric forms, for example, 1,5-naphthyridinediyl, 1,6-naphthyridinediyl, 1,7-naphthyridinediyl, and 1,8-naphthyridinediyl), oxazolopyridinediyl (including all isomeric forms, for example, oxazolo[4,5-b]pyridinediyl, oxazolo[4,5-c]pyridinediyl, oxazolo[5,4-b]pyridinediyl, and oxazolo[5,4-c]pyridinediyl), phthalazinediyl, pteridinediyl, purine diyl, pyrrolopyridinediyl (including all isomeric forms, for example, pyrrolo[2,3-b]pyridinediyl, pyrrolo[2,3-c]pyridinediyl, pyrrolo[3,2-b]pyridinediyl, and pyrrolo[3,2-c]pyridinediyl), quinolinediyl, quinoxalinediyl, quinazolinediyl, thiadiazolopyrimidinediyl (including all isomeric forms, for example, [1,2,5]thiadiazo Examples of tricyclic heteroarylene groups include, but are not limited to, thieno[3,4-d]pyrimidinediyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinediyl), and thienopyridinediyl (including all isomeric forms, for example, thieno[2,3-b]pyridinediyl, thieno[2,3-c]pyridinediyl, thieno[3,2-b]pyridinediyl, and thieno[3,2-c]pyridinediyl). Examples of tricyclic heteroarylene groups include acridinediyl, benzindolediyl, carbazolediyl, dibenzofurandiyl, perimidinediyl, phenanthrolinediyl (including all isomeric forms, for example, 1,5-phenanthrolinediyl, 1,6-phenanthrolinediyl, 1,7-phenanthrolinediyl, 1,9-phenanthrolinediyl, and 2,Examples of heteroarylene include, but are not limited to, 10-phenanthrolinediyl, phenanthridinediyl, phenarsazinediyl, phenazinediyl, phenothiazinediyl, phenoxazinediyl, and xanthenediyl. In certain embodiments, heteroarylene is optionally substituted with one or more substituents Q, as described herein.

[0043] The term "heterocyclyl" or "heterocyclic" refers to a monovalent, monocyclic, non-aromatic ring system or a monovalent, polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms is a heteroatom independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. For heterocyclyl groups containing heteroaromatic and non-aromatic heterocyclic rings, the heterocyclyl group is not attached to the rest of the molecule through a heteroaromatic ring. In certain embodiments, the heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In certain embodiments, a heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound.Examples of heterocyclyl and heterocyclic groups include azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4-dihydrobenzo[c][1,2]oxazinyl, and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrobenzothien ...isoindolyl, dihydropyranyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, dihydroisoindolyl, Examples of heterocyclyl include, but are not limited to, hydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, thiochromanyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.

[0044] The term "heterocyclylene" refers to a divalent monocyclic non-aromatic ring system or a divalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms is a heteroatom independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. For heterocyclylene groups containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heterocyclylene group has at least one bond to the rest of the molecule through the non-aromatic heterocyclic ring. In certain embodiments, a heterocyclylene group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In certain embodiments, a heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system that may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated or aromatic. The heterocyclylene may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable compound.Examples of such heterocyclylene groups are azepinediyl, benzodioxanediyl, benzodioxolediyl, benzofuranonediyl, chromandiyl, decahydroisoquinolinediyl, dihydrobenzofurandiyl, dihydrobenzisothiazolediyl, dihydrobenzisoxazinediyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinediyl, 3,4-dihydrobenzo[c][1,2]oxazinediyl, and 3,4-dihydrobenzo[d][1,2]oxazinediyl), dihydrobenzothienediyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thienediyl, dihydrofuldiyl, dihydroisoindolediyl, dihydropyrandiyl, dihydropyrazolediyl, dihydropyrazinediyl, dihydropyridinediyl, dihydropyrimidinediyl, dihydropyrrolediyl, dihydrobenzothienedi ...rrolediyl, dihydrobenzothienediyl, dihydroisoindolediyl, dihydropyrazolediyl, dihydropyrazinediyl, dihydropyrazolediyl, dihydropyrazolediyl, dihydropyrazolediyl, dihydropyrazolediyl, di These include, but are not limited to, oxolanediyl, 1,4-dithianediyl, furanonediyl, imidazolidinediyl, imidazolinediyl, indolinediyl, isochromanediyl, isoindolinediyl, isothiazolidinediyl, isoxazolidinediyl, morpholinediyl, octahydroindolediyl, octahydroisoindolediyl, oxazolidinonediyl, oxazolidinediyl, oxiranediyl, piperazinediyl, piperidinediyl, 4-piperidonediyl, pyrazolidinediyl, pyrazolindiyl, pyrrolidinediyl, pyrrolinediyl, quinuclidinediyl, tetrahydrofuldiyl, tetrahydroisoquinolinediyl, tetrahydropyrandiyl, tetrahydrothienediyl, thiamorpholinediyl, thiazolidinediyl, thiochromanediyl, tetrahydroquinolinediyl, and 1,3,5-trithianediyl. In certain embodiments, the heterocyclylene is optionally substituted with one or more substituents Q, as described herein.

[0045] The terms "halogen," "halide," or "halo" refer to fluoro, chloro, bromo, and / or iodo.

[0046] The term "optionally substituted" refers to a group or substituent, such as an alkyl, heteroalkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene group, that is optionally substituted with, for example, (a) deuterium (-D), cyano (-CN), halo, imino (=NH), nitro (-NO), and oxo (=O); (b) each of one or more, in one embodiment, one, two, three, or four, substituents Q a optionally further substituted with C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR b ) OR c , -OS(O)R a, -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c (where each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) each one or more, in one embodiment one, two, three, or four, substituents Q a optionally substituted with C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atoms to which they are attached, form one or more, in one embodiment one, two, three or four, substituents Q a "Optionally substituted" is intended to mean that the group may be substituted by one or more, and in one embodiment 1, 2, 3, or 4, substituents Q each independently selected from:

[0047] In one embodiment, each Q a are: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e, -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f ) OR g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R g where each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclyl.

[0048] In certain embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules having an enantiomeric excess of about 80% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, or about 99.8% or more. In certain embodiments, an optically active compound contains about 95% or more of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound contains about 98% or more of one enantiomer and about 2% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound contains about 99% or more of one enantiomer and about 1% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question.

[0049] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center(s). The prefixes (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction in which a plane of polarized light is rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the symbols of optical rotation (+) and (-) are independent of the absolute configuration R and S of the compound.

[0050] The term "isotopically enriched" refers to a compound that contains an unnatural proportion of isotopes at one or more atoms that constitute such a compound. In certain embodiments, isotopically enriched compounds include, but are not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-36( 36 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I), and iodine-131( 131 In some embodiments, the isotopically enriched compound is in a stable form, i.e., is non-radioactive. ... 1 H), deuterium (2 H), carbon-12( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), Phosphorus-31( 31 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), and iodine-127( 127 In some embodiments, the isotopically enriched compound is in an unstable form, i.e., radioactive. In some embodiments, the isotopically enriched compound includes, but is not limited to, tritium ( 3 H), carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O), oxygen-15( 15 O), Fluorine-18( 18 F), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-35( 35 S), chlorine-36( 36 Cl), iodine-123( 123 I), iodine-125( 125 I), iodine-129( 129 I), and iodine-131( 131 In the compounds provided herein, any hydrogen atom may be used as an example, if feasible according to the judgment of a person skilled in the art. 2 H or any carbon, e.g. 13 C or any nitrogen, for example15 It can be N or any oxygen, for example 18 It will be understood that the number of

[0051] The term "isotopically enriched" refers to the presence of a more common isotope of an element (e.g., protium or hydrogen-1) at a given position in a molecule. 1 "H" refers to the incorporation of a less common isotope of that element (e.g., D, representing deuterium or hydrogen-2) in place of a less common isotope of that element. As used herein, when an atom at a particular location within a molecule is designated as a particular less common isotope, it is understood that the abundance of that isotope at that location is substantially greater than its natural abundance.

[0052] The term "isotopic enrichment factor" refers to the ratio between the abundance of an isotope in an isotopically enriched compound and the natural abundance of the specified isotope.

[0053] The term "hydrogen" or the symbol "H" refers to protium ( 1 H), deuterium ( 2 H or D), and tritium ( 3 H) at their natural abundance. Protium is the most common hydrogen isotope, with a natural abundance greater than 99.98%. Deuterium is the less common hydrogen isotope, with a natural abundance of approximately 0.0156%.

[0054] The term "deuterium enrichment" refers to the rate at which deuterium is substituted for hydrogen at a given position in a molecule. For example, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at that particular position. Because the natural distribution of deuterium is about 0.0156% on average, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials will be about 0.0156% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially higher than its natural abundance (0.0156%).

[0055] The term "carbon" or the symbol "C" refers to carbon-12 ( 12 C) and carbon-13 ( 13 Carbon-12 refers to the composition of naturally occurring carbon isotopes, including carbon-12, carbon-13, and carbon-14, carbon-15, carbon-16, carbon-17, carbon-18, carbon-19, carbon-20, carbon-21, carbon-22, carbon-23, carbon-24, carbon-25, carbon-26, carbon-27, carbon-28, carbon-29, carbon-30, carbon-31, carbon-32, carbon-33, carbon-34, carbon-35, carbon-36, carbon-37, carbon-38, carbon-39, carbon-40, carbon-41, carbon-42, carbon-43, carbon-44, carbon-45, carbon-46, carbon-47, carbon-48, carbon-49, carbon-50, carbon-51, carbon-52, carbon-53, carbon-54, carbon-55, carbon-56, carbon-57, carbon-58, carbon-

[0056] The term "carbon-13 enriched" or " 13 "C enrichment" refers to the rate of incorporation of carbon-13 in place of carbon at a given position in a molecule. For example, 10% carbon-13 enrichment at a given position means that 10% of the molecules in a given sample contain carbon-13 at that particular position. Because the natural distribution of carbon-13 averages about 1.11%, the carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials will average about 1.11%. As used herein, when a particular position in an isotopically enriched compound is designated as having carbon-13, it is understood that the abundance of carbon-13 at that position in the compound is substantially higher than its natural abundance (1.11%).

[0057] The terms "substantially pure" and "substantially homogeneous," when referring to a substance, mean sufficiently homogeneous to appear free of readily detectable impurities as determined by standard analytical methods used by those of skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure that further purification would not detectably alter the physical, chemical, biological, and / or pharmaceutical properties, such as enzymatic activity and biological activity, of the substance. In certain embodiments, "substantially pure" or "substantially homogeneous" refers to a collection of molecules in which at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single enantiomer, a racemic mixture, or a single compound comprising a mixture of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particular, less common isotope, a molecule containing an isotope other than the designated isotope at that particular position is an impurity with respect to the isotopically enriched compound. Thus, with respect to a deuterated compound having an atom designated as deuterium at a particular position, a compound containing protium at the same position is an impurity.

[0058] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, for example, a compound provided herein, and one or more molecules of a solvent present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in an amorphous form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0059] For divalent groups described herein, no orientation is implied by the direction in which the divalent group is presented. For example, unless a particular orientation is specified, the formula -C(O)NH- represents both -C(O)NH- and -NHC(O)-.

[0060] The phrase "an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof" has the same meaning as the phrase "(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of a compound referred to therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of a compound referred to therein, or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of a compound referred to therein."

[0061] (compound) In one embodiment, provided herein is a compound of formula (I): [ka] (In the formula, L is a linker; one of U, V, X, and Y is -C= or -N-; and the remaining three of U, V, X, and Y are each independently -C(R 4 )= or -N=; R 1 and R 3 are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; R 2 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, Heteroaryl, Heteroaryl-C 1-6 alkylene or heterocyclyl; Each R 4 are independently (i) hydrogen, deuterium, cyano, halo, nitro, or oxo; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and; Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; X E is C(R E2 ) or N; Y E is a bond, C 1-6 Alkylene, -O-, -S-, -S(O)-, -S(O2)-, or -N(R E3 )-and; Z E is C 6-14 arylene, heteroarylene, or C 6-14 arylene-heteroarylene; R E1 is hydrogen or C 1-6 is alkyl; R E2 is hydrogen, deuterium, halo, or C 1-6 is alkyl; R E3 is hydrogen or C 1-6 is alkyl; and m is an integer of 0, 1, or 2; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylene, aralkyl, heteroaryl, heteroarylene, and heterocyclyl is optionally substituted with one or more, and in one embodiment one, two, three, or four, substituents Q, wherein each Q is independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) each is one or more, and in one embodiment one, two, three, or four, substituents Q a optionally further substituted with C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b Rc 、-C(O)SR a 、-C(NR a )NR b R c 、-C(S)R a 、-C(S)OR a 、-C(S)NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(O)SR a 、-OC(NR a )NR b R c 、-OC(S)R a 、-OC(S)OR a 、-OC(S)NR b R c 、-OP(O)(OR b )OR c 、-OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(O)SR d 、-NR a C(NR d )NR b R c 、-NR a C(S)R d 、-NR a C(S)OR d 、-NR a C(S)NR b R c 、-NR a S(O)R d 、-NR a S(O)2R d, -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c where each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) each one or more, in one embodiment one, two, three, or four, substituents Q a optionally substituted with C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atoms to which they are attached, form one or more, in one embodiment one, two, three or four, substituents Q a forming an optionally substituted heterocyclyl; Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SRe 、-C(NR e )NR f R g 、-C(S)R e 、-C(S)OR e 、-C(S)NR f R g 、-OR e 、-OC(O)R e 、-OC(O)OR e 、-OC(O)NR f R g 、-OC(O)SR e 、-OC(NR e )NR f R g 、-OC(S)R e 、-OC(S)OR e 、-OC(S)NR f R g 、-OP(O)(OR f )OR g 、-OS(O)R e 、-OS(O)2R e 、-OS(O)NR f R g 、-OS(O)2NR f R g 、-NR f R g 、-NR e C(O)R h 、-NR e C(O)OR f 、-NR e C(O)NR f R g 、-NR e C(O)SR f 、-NR e C(NR h )NR f R g 、-NR e C(S)R h 、-NR e C(S)OR f 、-NR e C(S)NR f R g 、-NR e S(O)R h 、-NR e S(O)2R h 、-NR eS(O)NR f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R g where each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclyl) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0062] In some embodiments, R 2 is C 1-6 Alkyl, C 7-15 Aralkyl or heteroaryl-C 1-6 and alkyl, and each alkyl, aralkyl, and heteroaryl is optionally substituted with one or more substituents Q. In certain embodiments, R 2 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 2 is a C substituted with heteroaryl 1-6 Alkyl, i.e., heteroaryl-C 1-6and alkylene, wherein heteroaryl and alkylene are each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a monocyclic heteroaryl-C 1-6 and alkylene, wherein heteroaryl and alkylene are each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5- or 6-membered heteroaryl-C 1-6 and alkylene, wherein heteroaryl and alkylene are each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5-membered heteroaryl-C 1-6 and alkylene, wherein heteroaryl and alkylene are each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a bicyclic heteroaryl-C 1-6 and alkylene, wherein heteroaryl and alkylene are each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5,6-fused or 6,6-fused heteroaryl-C 1-6 and alkylene, wherein heteroaryl and alkylene are each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 2 is a monocyclic C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 2 is a bicyclic C optionally substituted with one or more substituents Q 9-15 It is aralkyl.

[0063] In another embodiment, provided herein is a compound of formula (II): [ka] (In the formula, R 2a and R 2b are each independently hydrogen, deuterium, halo, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; R 2c is C 3-10 Cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; and R 1 , R 3 , R E1 , L, U, V, X, Y, X E , Y E , Z E , and m are each as defined herein; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, and in one embodiment, 1, 2, 3, or 4, substituents Q. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0064] In yet another embodiment, provided herein is a compound of formula (III): [ka] (In the formula, R 4a , R 4b , and R 4d are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) each optionally substituted with one or more, and in one embodiment, 1, 2, 3, or 4, substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1aC(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and R 1 , R 3 , R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0065] In yet another embodiment, provided herein is a compound of formula (IV): [ka] (In the formula, R 4c is (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) each optionally substituted with one or more, in one embodiment 1, 2, 3, or 4, substituents Q; 1-6 Alkyl, C1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1aC(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and R 1 , R 3 , R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R 4a , R 4d , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0066] In yet another embodiment, provided herein is a compound of formula (V): [ka] (In the formula, R 1 , R 3 , R2a , R 2b , R 2c , R 4a , R 4b , R 4c , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0067] In yet another embodiment, provided herein is a compound of formula (VI): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 2c , R 4a , R 4d , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0068] In yet another embodiment, provided herein is a compound of formula (VII): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R2c , R 4a , R 4d , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0069] In yet another embodiment, provided herein is a compound of formula (VIII): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 2c , R 4a , R 4c , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0070] In certain embodiments, in any one of Formulas (II) to (VIII), R 2c each optionally substituted with one, two, or three substituents Q; 6-14 In certain embodiments, in any one of Formulas (II) to (VIII), R 2c is C optionally substituted with 1, 2, or 3 substituents Q6-14 In certain embodiments, in any one of Formulas (II) to (VIII), R 2c is phenyl optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of Formulas (II) through (VIII), R 2c each independently represents (i) halo or nitro; (ii) each independently represents one, two, three, or four substituents Q a optionally substituted with C 1-6 alkyl, heteroaryl, or heterocyclyl; or (iii) —NR b R c (In the formula, R b and R c and R is phenyl optionally substituted with 1, 2, or 3 substituents, each of which is as defined herein. In certain embodiments, in any one of Formulas (II) through (VIII), R 2c is phenyl optionally substituted with 1, 2, or 3 substituents, each independently being fluoro, chloro, bromo, iodo, nitro, methyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 2-hydroxy-1,1-difluoroethyl, 3-hydroxyoxetan-3-yl, pyrazol-4-yl, or amino. In certain embodiments, in any one of Formulas (II) through (VIII), R 2cis phenyl, 3-bromophenyl, 3-methylphenyl, 3-difluoromethylphenyl, 3-trifluoromethylphenyl, 3-(2,2,2-trifluoroethyl)phenyl, 3-(1-hydroxyethyl)phenyl, 3-(1-hydroxy-1-methylethyl)phenyl, 3-(2-hydroxy-1,1-difluoroethyl)phenyl, 3-(3-hydroxyoxetan-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-3-difluoromethylphenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-3-(1,1-difluoroethyl)phenyl, 2-methyl-3-difluoromethylphenyl, 2-methyl-3-trifluoromethylphenyl, 3-trifluoromethyl-5-aminophenyl, 2-fluoro-3-trifluoromethyl-5-aminophenyl, or 2-methyl-3-trifluoromethyl-5-aminophenyl. In certain embodiments, in any one of Formulas (II) to (VIII), R 2c is a bicyclic C optionally substituted with 1, 2, or 3 substituents Q 9-14 In certain embodiments, in any one of Formulas (II) to (VIII), R 2c are 5,6-fused or 6,6-fused C groups, each optionally substituted with one, two, or three substituents Q; 9-14 In certain embodiments, in any one of Formulas (II) to (VIII), R 2c is 2,3-dihydro-1H-indenyl or naphthyl, each optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of Formulas (II) through (VIII), R 2c is 2,3-dihydro-1H-inden-5-yl or naphth-1-yl, each optionally substituted with one, two, or three substituents Q.

[0071] In certain embodiments, in any one of Formulas (II) to (VIII), R 2cis heteroaryl optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of Formulas (II) through (VIII), R 2c is a monocyclic heteroaryl optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of Formulas (II) through (VIII), R 2c is a 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of Formulas (II) through (VIII), R 2c is thienyl optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of Formulas (II) through (VIII), R 2c is thien-2-yl or thien-3-yl, each optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of Formulas (II) through (VIII), R 2c is C 6-14 thien-2-yl substituted with aryl or heteroaryl, each of which may be substituted with one, two, or three substituents Q a In certain embodiments, in any one of Formulas (II) to (VIII), R 2c is thien-2-yl, 5-(2-hydroxymethylphenyl)thien-2-yl, 5-(2-aminomethylphenyl)thien-2-yl, 4-(2-methylaminomethylphenyl)thien-2-yl, 5-(2-(2-aminoethyl)phenyl)thien-2-yl, or 5-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)thien-2-yl. In certain embodiments, in any one of Formulas (II) through (VIII), R 2cis 5-(2-hydroxymethylphenyl)thien-2-yl, 5-(2-aminomethylphenyl)thien-2-yl, 4-(2-methylaminomethylphenyl)thien-2-yl, 5-(2-(2-aminoethyl)phenyl)thien-2-yl, or 5-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)thien-2-yl. In certain embodiments, in any one of Formulas (II) to (VIII), R 2c is a bicyclic heteroaryl optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of Formulas (II) through (VIII), R 2c is a 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with 1, 2, or 3 substituents Q.

[0072] In certain embodiments, in any one of Formulas (II) to (VIII), R 2c is heterocyclyl optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of Formulas (II) through (VIII), R 2c is monocyclic heterocyclyl optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of Formulas (II) through (VIII), R 2c is a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of Formulas (II) through (VIII), R 2c is bicyclic heterocyclyl optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of Formulas (II) through (VIII), R 2c is a 5,5-, 5,6-, or 6,6-fused heterocyclyl, each optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of Formulas (II) through (VIII), R 2c is 2,3-dihydrobenzofuranyl optionally substituted with one, two, or three substituents Q.

[0073] In one embodiment, in any one of Formulas (III) to (VIII), R 1 is hydrogen, methyl, trifluoromethyl, or dimethylamino; R 3 is hydrogen; R 2a and R 2b are each independently hydrogen, deuterium, methyl, or ethyl; R 2c is phenyl, 2,3-dihydroindenyl, naphthyl, thienyl, or 2,3-dihydrobenzofuranyl, each optionally substituted with 1, 2, or 3 substituents, where each substituent is independently fluoro, chloro, bromo, iodo, nitro, methyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 2-hydroxy-1,1-difluoroethyl, 2-hydroxymethylphenyl, 2-aminomethylphenyl, 2-methylaminomethylphenyl, 2-(2-aminoethyl)phenyl, 3-hydroxyoxetan-3-yl, pyrazol-4-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, or amino; R 4a is hydrogen, if present; R 4bis, if present, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, methoxy, tetrahydrofuryloxy, or pyrrolidinyloxy, each optionally substituted with 1, 2, or 3 substituents, where each substituent is independently fluoro, oxo, imino, methyl, difluoromethyl, hydroxycarbonylmethyl, dimethylcarbamoylmethyl, isopropyl, tetrahydrofur-3-yl, acetyl, propionyl, 2-methoxyacetyl, 2-dimethylaminoacetyl, cyclopropylcarbonyl, 3-cyanoazetidin-1-ylcarbonyl, 3-fluoroazetidin-1-ylcarbonyl, 3-methoxyazetidin-1-ylcarbonyl, 3-hydrogen hydroxypyrrolidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-(2-methoxyethyl)piperazin-1-ylcarbonyl, hydroxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, dimethylcarbamoyl, (methyl)(ethyl)carbamoyl, (2-hydroxyethyl)(methyl)carbamoyl, (2-hydroxypropyl)(methyl)carbamoyl, (2-hydroxy-2-methylpropyl)(methyl)carbamoyl, (2,3-dihydroxypropyl)(methyl)carbamoyl, (2-methoxyethyl)(methyl)carbamoyl, (methyl)(oxetan-3-yl)carbamoyl, (methyl)(tetrahydrofur-3-yl)carbamoyl, hydroxyl, or acetoxy; R 4c is, if present, hydrogen or methoxy; and R 4d When present, is hydrogen, fluoro, or methyl.

[0074] In one embodiment, in any one of Formulas (III) to (VIII), R 1 is hydrogen, methyl, trifluoromethyl, or dimthylamino; R 3 is hydrogen; R 2a is hydrogen, methyl, or ethyl; R 2b is hydrogen; R 2c is phenyl, 3-bromophenyl, 3-methylphenyl, 3-difluoromethylphenyl, 3-trifluoromethylphenyl, 3-(2,2,2-trifluoroethyl)phenyl, 3-(1-hydroxyethyl)phenyl, 3-(1-hydroxy-1-methylethyl)phenyl, 3-(2-hydroxy-1,1-difluoroethyl)phenyl, 3-(3-hydroxyoxetan-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-3-difluoromethylphenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-3-(1,1-difluoroethyl)phenyl, 2-methyl-3-difluoromethylphenyl, 2-methyl-3-trifluoromethylphenyl 2-fluoromethylphenyl, 3-trifluoromethyl-5-aminophenyl, 2-fluoro-3-trifluoromethyl-5-aminophenyl, 2-methyl-3-trifluoromethyl-5-aminophenyl, 3,3-difluoro-2,3-dihydro-1H-inden-5-yl, naphth-1-yl, thien-2-yl, 5-(2-hydroxymethylphenyl)thien-2-yl, 5-(2-aminomethylphenyl)thien-2-yl, 4-(2-methylaminomethylphenyl)thien-2-yl, 5-(2-(2-aminoethyl)phenyl)thien-2-yl, 5-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)thien-2-yl, or 3,3-difluoro-2,3-dihydrobenzofuran-5-yl; R 4a is hydrogen, if present; R 4bis, when present, 1-methylcyclopropyl, 1-fluoromethylcyclopropyl, 1-difluoromethylcyclopropyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 4-hydroxycyclohexyl, 4-hydroxycarbonylcyclohexyl, 4-ethoxycarbonylcyclohexyl, 4-(3-cyanoazetidin-1-ylcarbonyl)cyclohexyl, 4-(3-fluoroazetidin-1-ylcarbonyl)cyclohexyl, 4-(3-methoxyazetidin-1-yl carbonyl)cyclohexyl, 4-(3-hydroxypyrrolidin-1-yl)carbonylcyclohexyl, 4-morpholin-4-ylcarbonylcyclohexyl, 4-(4-methylpiperazin-1-yl)carbonylcyclohexyl, 4-(4-(2-methoxyethyl)piperazin-1-yl)carbonylcyclohexyl, 4-dimethylcarbamoylcyclohexyl, 4-(methyl)(ethyl)carbamoylcyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoylcyclohexyl, 4- (2-hydroxypropyl)(methyl)carbamoylcyclohexyl, 4-(2-hydroxy-2-methylpropyl)(methyl)carbamoylcyclohexyl, 4-(2,3-dihydroxypropyl)(methyl)carbamoylcyclohexyl, 4-(2-methoxyethyl)(methyl)carbamoylcyclohexyl, 4-(methyl)(oxetan-3-yl)carbamoylcyclohexyl, 4-(methyl)(tetrahydrofur-3-yl)carbamoylcyclohexyl, 4-acetoxy-1-hydroxycyclohexyl cyclohexyl, 1,4-dihydroxycyclohexyl, 4-hydroxycarbonyl-1-hydroxycyclohexyl, 4-ethoxycarbonyl-1-hydroxycyclohexyl, 4-dimethylcarbamoyl-1-hydroxycyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoyl-1-hydroxycyclohexyl, 4-(2-hydroxypropyl)(methyl)carbamoyl-1-hydroxycyclohexyl, bicyclo[1.1.1]pentan-1-yl, 4-fluorobicyclo[2.2.2]octan-1-yl, 3-methyltetrahydrofuran-3-yl, piperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-(hydroxycarbonylmethyl)piperidin-4-yl, 1-(dimethylcarbamoylmethyl)piperidin-4-yl, 1-tetrahydrofur-3-ylylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-(2-methoxyacetyl)piperidin-4-yl, 1-(2-dimethylaminoacetyl)piperidin-4-yl, 1-t ert-butoxycarbonylpiperidin-4-yl, 4-hydroxypiperidin-4-yl, 1-acetyl-4-hydroxypiperidin-4-yl, 1-(2-methoxyacetyl)-4-hydroxypiperidin-4-yl, 4-hydroxy-1-tert-butoxycarbonylpiperidin-4-yl, 1-dimethylcarbamoyl-4-hydroxypiperidin-4-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, 1-oxotetrahydrothiopyran-4-yl, 1,1-dioxotetrahydrothiopyran-4-yl, 1-oxo-1-iminotetrahydrothiopyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydropyran-4-yl, 3,6-dihydrothiopyran-4-yl, 1-oxo-3,6-dihydrothiopyran-4-yl, 1,1-dioxo-3,6-dihydrothiopyran-4-yl, 1-oxo-1-imino-3,6-dihydrothiopyran-4-yl, 6-hydroxy-2-azaspiro[3.3]hepta benzo[3.5]nonan-6-yl, 2-hydroxy-7-azaspiro[3.5]nonan-2-yl, methoxy, tetrahydrofur-3-yloxy, (R)-tetrahydrofur-3-yloxy, (S)-tetrahydrofur-3-yloxy, pyrrolidin-3-yloxy, 1-acetylpyrrolidin-3-yloxy, 1-propionylpyrrolidin-3-yloxy, 1-cyclopropylcarbonylpyrrolidin-3-yloxy, or 1-tert-butoxycarbonylpyrrolidin-3-yloxy; R 4c is, if present, hydrogen, fluoro, methyl, or methoxy; and R 4d When present, is hydrogen, fluoro, or methyl.

[0075] In one embodiment, in any one of Formulas (III) to (VIII), R 1 is hydrogen, methyl, trifluoromethyl, or dimethylamino; R 3 is hydrogen; R 2a is hydrogen, methyl, or ethyl; R 2b is hydrogen; R 2c are phenyl, 3-bromophenyl, 3-methylphenyl, 3-difluoromethylphenyl, 3-trifluoromethylphenyl, 3-(2,2,2-trifluoroethyl)phenyl, 3-(1-hydroxyethyl)phenyl, 3-(1-hydroxy-1-methylethyl)phenyl, 3-(2-hydroxy-1,1-difluoroethyl)phenyl, 3-(3-hydroxyoxetan-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-3-difluoromethylphenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-3-(1,1-difluoroethyl)phenyl, 2-methyl-3-difluoromethylphenyl, 2-methyl-3-trifluoromethylphenyl, trifluoromethylphenyl, 3-trifluoromethyl-5-aminophenyl, 2-fluoro-3-trifluoromethyl-5-aminophenyl, 2-methyl-3-trifluoromethyl-5-aminophenyl, 3,3-difluoro-2,3-dihydro-1H-inden-5-yl, naphth-1-yl, 5-(2-hydroxymethylphenyl)thien-2-yl, 5-(2-aminomethylphenyl)thien-2-yl, 4-(2-methylaminomethylphenyl)thien-2-yl, 5-(2-(2-aminoethyl)phenyl)thien-2-yl, 5-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)thien-2-yl, or 3,3-difluoro-2,3-dihydrobenzofuran-5-yl; R 4a is hydrogen, if present; R 4bis, when present, 1-methylcyclopropyl, 1-fluoromethylcyclopropyl, 1-difluoromethylcyclopropyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 4-hydroxycyclohexyl, 4-hydroxycarbonylcyclohexyl, 4-ethoxycarbonylcyclohexyl, 4-(3-cyanoazetidin-1-ylcarbonyl)cyclohexyl, 4-(3-fluoroazetidin-1-ylcarbonyl)cyclohexyl, 4-(3-methoxyazetidin-1-yl carbonyl)cyclohexyl, 4-(3-hydroxypyrrolidin-1-yl)carbonylcyclohexyl, 4-morpholin-4-ylcarbonylcyclohexyl, 4-(4-methylpiperazin-1-yl)carbonylcyclohexyl, 4-(4-(2-methoxyethyl)piperazin-1-yl)carbonylcyclohexyl, 4-dimethylcarbamoylcyclohexyl, 4-(methyl)(ethyl)carbamoylcyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoylcyclohexyl, 4- (2-hydroxypropyl)(methyl)carbamoylcyclohexyl, 4-(2-hydroxy-2-methylpropyl)(methyl)carbamoylcyclohexyl, 4-(2,3-dihydroxypropyl)(methyl)carbamoylcyclohexyl, 4-(2-methoxyethyl)(methyl)carbamoylcyclohexyl, 4-(methyl)(oxetan-3-yl)carbamoylcyclohexyl, 4-(methyl)(tetrahydrofur-3-yl)carbamoylcyclohexyl, 4-acetoxy-1-hydroxycyclohexyl cyclohexyl, 1,4-dihydroxycyclohexyl, 4-hydroxycarbonyl-1-hydroxycyclohexyl, 4-ethoxycarbonyl-1-hydroxycyclohexyl, 4-dimethylcarbamoyl-1-hydroxycyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoyl-1-hydroxycyclohexyl, 4-(2-hydroxypropyl)(methyl)carbamoyl-1-hydroxycyclohexyl, bicyclo[1.1.1]pentan-1-yl, 4-fluorobicyclo[2.2.2]octan-1-yl, 3-methyltetrahydrofuran-3-yl, piperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-(hydroxycarbonylmethyl)piperidin-4-yl, 1-(dimethylcarbamoylmethyl)piperidin-4-yl, 1-tetrahydrofur-3-ylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-(2-methoxyacetyl)piperidin-4-yl, 1-(2-dimethylaminoacetyl)piperidin-4-yl, 1-tert-butyl t-Butoxycarbonylpiperidin-4-yl, 4-hydroxypiperidin-4-yl, 1-acetyl-4-hydroxypiperidin-4-yl, 1-(2-methoxyacetyl)-4-hydroxypiperidin-4-yl, 4-hydroxy-1-tert-butoxycarbonylpiperidin-4-yl, 1-dimethylcarbamoyl-4-hydroxypiperidin-4-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, 1-oxotetrahydrothiopyran-4-yl, 1 ,1-dioxotetrahydrothiopyran-4-yl, 1-oxo-1-iminotetrahydrothiopyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydropyran-4-yl, 3,6-dihydrothiopyran-4-yl, 1-oxo-3,6-dihydrothiopyran-4-yl, 1,1-dioxo-3,6-dihydrothiopyran-4-yl, 1-oxo-1-imino-3,6-dihydrothiopyran-4-yl, 6-hydroxy-2-azaspiro[3.3]hepta benzo[3.5]nonan-6-yl, 2-hydroxy-7-azaspiro[3.5]nonan-2-yl, methoxy, tetrahydrofur-3-yloxy, (R)-tetrahydrofur-3-yloxy, (S)-tetrahydrofur-3-yloxy, pyrrolidin-3-yloxy, 1-acetylpyrrolidin-3-yloxy, 1-propionylpyrrolidin-3-yloxy, 1-cyclopropylcarbonylpyrrolidin-3-yloxy, or 1-tert-butoxycarbonylpyrrolidin-3-yloxy; R 4c is, if present, hydrogen, fluoro, methyl, or methoxy; and R 4d When present, is hydrogen, fluoro, or methyl.

[0076] In yet another embodiment, provided herein is a compound of formula (IX): [ka] (In the formula, R 5a , R 5b , R 5c , R 5d , and R 5e are each independently (i) hydrogen, deuterium, cyano, halo, nitro, or oxo; (ii) each optionally substituted with one or more, and in one embodiment, one, two, or three, substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a, -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c or R 5a and R 5b or R 5b and R 5c are each optionally substituted with one or more, in one embodiment one, two or three, substituents Q, together with the carbon atoms to which they are attached. 5-10 Cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; and R 1 , R3 , R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R E1 , L, U, V, X, Y, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0077] In yet another embodiment, provided herein is a compound of formula (X): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0078] In yet another embodiment, provided herein is a compound of formula (XI): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4c , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0079] In yet another embodiment, provided herein is a compound of formula (XII): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0080] In yet another embodiment, provided herein is a compound of formula (XIII): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0081] In yet another embodiment, provided herein is a compound of formula (XIV): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0082] In yet another embodiment, provided herein is a compound of formula (XV): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4c , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0083] In one embodiment, in any one of Formulas (X) to (XV), R 1 is hydrogen, methyl, trifluoromethyl, or dimethylamino; R 3 is hydrogen; R 2a is hydrogen, methyl, or ethyl; R 2b is hydrogen; R 4a is hydrogen, if present; R 4bis, if present, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl, each optionally substituted with 1, 2, or 3 substituents, where each substituent is independently fluoro, methyl, difluoromethyl, 3-cyanoazetidin-1-ylcarbonyl, 3-fluoroazetidin-1-ylcarbonyl, 3-methoxyazetidin-1-ylcarbonyl, 3-hydroxypyrrolidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-(2 -methoxyethyl)piperazin-1-ylcarbonyl, hydroxycarbonyl, ethoxycarbonyl, dimethylcarbamoyl, (methyl)(ethyl)carbamoyl, (2-hydroxyethyl)(methyl)carbamoyl, (2-hydroxypropyl)(methyl)carbamoyl, (2-hydroxy-2-methylpropyl)(methyl)carbamoyl, (2,3-dihydroxypropyl)(methyl)carbamoyl, (2-methoxyethyl)(methyl)carbamoyl, (methyl)(oxetan-3-yl)carbamoyl, (methyl)(tetrahydrofur-3-yl)carbamoyl, hydroxyl, or acetoxy; R 4c is, when present, hydrogen or methoxy; R 4d is, if present, hydrogen, fluoro, or methyl; R 5a is hydrogen, fluoro, or methyl; R 5b is bromo, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, (difluoro)(hydroxy)ethyl, or pyrazolyl; R 5c and R 5e are each hydrogen; and R 5d is hydrogen, nitro, or amino.

[0084] In one embodiment, in any one of Formulas (X) to (XV), R 1is hydrogen, methyl, or trifluoromethyl; R 3 is hydrogen; R 2a is hydrogen, methyl, or ethyl; R 2b is hydrogen; R 4a is hydrogen, if present; R 4bis, when present, 1-methylcyclopropyl, 1-fluoromethylcyclopropyl, 1-difluoromethylcyclopropyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 4-hydroxycyclohexyl, 4-hydroxycarbonylcyclohexyl, 4-ethoxycarbonylcyclohexyl, 4-(3-cyanoazetidin-1-ylcarbonyl)cyclohexyl, 4-(3-fluoroazetidin-1-ylcarbonyl)cyclohexyl, 4-(3-methoxyazetidin-1-ylcarbonyl)cyclohexyl, cyclohexyl, 4-(3-hydroxypyrrolidin-1-yl)carbonylcyclohexyl, 4-morpholin-4-ylcarbonylcyclohexyl, 4-(4-methylpiperazin-1-yl)carbonylcyclohexyl, 4-(4-(2-methoxyethyl)piperazin-1-yl)carbonylcyclohexyl, 4-dimethylcarbamoylcyclohexyl, 4-(methyl)(ethyl)carbamoylcyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoylcyclohexyl, 4-(2-hydroxypropyl) 4-(2-hydroxy-2-methylpropyl)(methyl)carbamoylcyclohexyl, 4-(2,3-dihydroxypropyl)(methyl)carbamoylcyclohexyl, 4-(2-methoxyethyl)(methyl)carbamoylcyclohexyl, 4-(methyl)(oxetan-3-yl)carbamoylcyclohexyl, 4-(methyl)(tetrahydrofur-3-yl)carbamoylcyclohexyl, 4-acetoxy-1-hydroxycyclohexyl, 1,4-dihydroxypropyl hydroxycyclohexyl, 4-hydroxycarbonyl-1-hydroxycyclohexyl, 4-ethoxycarbonyl-1-hydroxycyclohexyl, 4-dimethylcarbamoyl-1-hydroxycyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoyl-1-hydroxycyclohexyl, 4-(2-hydroxypropyl)(methyl)carbamoyl-1-hydroxycyclohexyl, bicyclo[1.1.1]pentan-1-yl, or 4-fluorobicyclo[2.2.2]octan-1-yl; R 4c is, when present, hydrogen or methoxy; R 4dis, if present, hydrogen, fluoro, or methyl; R 5a is hydrogen, fluoro, or methyl; R 5b is bromo, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,1-difluoro-2-hydroxyethyl, or pyrazol-4-yl; R 5c and R 5e are each hydrogen; and R 5d is hydrogen, nitro, or amino.

[0085] In one embodiment, in any one of Formulas (X) to (XV), R 1 is hydrogen, methyl, trifluoromethyl, or dimethylamino; R 3 is hydrogen; R 2a is hydrogen, methyl, or ethyl; R 2b is hydrogen; R 4a is hydrogen, if present; R 4b is, if present, tetrahydrofuryl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridinyl, dihydropyranyl, dihydrothiopyranyl, azaspiro[3.3]heptanyl, or 7-azaspiro[3.5]nonanyl, each optionally substituted with 1, 2, or 3 substituents, where each substituent is independently oxo, imino, isopropyl, hydroxycarbonylmethyl, dimethylcarbamoylmethyl, tetrahydrofur-3-yl, acetyl, 2-methoxyacetyl, 2-dimethylaminoacetyl, tert-butoxycarbonyl, or hydroxyl; R 4c is, when present, hydrogen or methoxy; R 4d is, if present, hydrogen, fluoro, or methyl; R5a is hydrogen, fluoro, or methyl; R 5b is bromo, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, (difluoro)(hydroxy)ethyl, or pyrazolyl; R 5c and R 5e are each hydrogen; and R 5d is hydrogen, nitro, or amino.

[0086] In one embodiment, in any one of Formulas (X) to (XV), R 1 is hydrogen, methyl, trifluoromethyl; R 3 is hydrogen; R 2a is hydrogen, methyl, or ethyl; R 2b is hydrogen; R 4a is hydrogen, if present; R 4bis, when present, 3-methyltetrahydrofuran-3-yl, piperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-(hydroxycarbonylmethyl)piperidin-4-yl, 1-(dimethylcarbamoylmethyl)piperidin-4-yl, 1-tetrahydrofur-3-ylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-(2-methoxyacetyl)piperidin-4-yl, 1-(2-dimethylaminoacetyl)piperidin-4-yl, 1-tert-butoxycarbonylpiperidin-4-yl, 4-hydroxypiperidin-4-yl, 1-acetyl-4-hydroxypiperidin-4-yl, 1-(2-methoxyacetyl)-4-hydroxypiperidin-4-yl, 4-hydroxy-1-tert-butoxycarbonylpiperidin-4-yl, 1-Dimethylcarbamoyl-4-hydroxypiperidin-4-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, 1-oxotetrahydrothiopyran-4-yl, 1,1-dioxotetrahydrothiopyran-4-yl, 1-oxo-1-iminotetrahydrothiopyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydropyran-4- yl, 1-oxo-3,6-dihydrothiopyran-4-yl, 1-oxo-3,6-dihydrothiopyran-4-yl, 1,1-dioxo-3,6-dihydrothiopyran-4-yl, 1-oxo-1-imino-3,6-dihydrothiopyran-4-yl, 6-hydroxy-2-azaspiro[3.3]heptan-6-yl, or 2-hydroxy-7-azaspiro[3.5]nonan-2-yl; R 4c is, when present, hydrogen or methoxy; R 4d is, if present, hydrogen, fluoro, or methyl; R 5a is hydrogen, fluoro, or methyl; R 5b is bromo, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,1-difluoro-2-hydroxyethyl, or pyrazol-4-yl; R 5c and R 5eare each hydrogen; and R 5d is hydrogen, nitro, or amino.

[0087] In one embodiment, in any one of Formulas (X) to (XV), R 1 is hydrogen, methyl, trifluoromethyl, or dimethylamino; R 3 is hydrogen; R 2a is hydrogen, methyl, or ethyl; R 2b is hydrogen; R 4a is hydrogen, if present; R 4b is, if present, tetrahydrofuryloxy or pyrrolidinyloxy, each optionally substituted with acetyl, propionyl, cyclopropylcarbonyl, or tert-butoxycarbonyl; R 4c is, when present, hydrogen or methoxy; R 4d is, if present, hydrogen, fluoro, or methyl; R 5a is hydrogen, fluoro, or methyl; R 5b is bromo, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, (difluoro)(hydroxy)ethyl, or pyrazolyl; R 5c and R 5e are each hydrogen; and R 5d is hydrogen, nitro, or amino.

[0088] In one embodiment, in any one of Formulas (X) to (XV), R 1 is hydrogen, methyl, trifluoromethyl; R 3 is hydrogen; R2a is hydrogen, methyl, or ethyl; R 2b is hydrogen; R 4a is hydrogen, if present; R 4b when present, is tetrahydrofur-3-yloxy, (R)-tetrahydrofur-3-yloxy, (S)-tetrahydrofur-3-yloxy, pyrrolidin-3-yloxy, 1-acetylpyrrolidin-3-yloxy, 1-propionylpyrrolidin-3-yloxy, 1-cyclopropylcarbonylpyrrolidin-3-yloxy, or 1-tert-butoxycarbonylpyrrolidin-3-yloxy; R 4c is, when present, hydrogen or methoxy; R 4d is, if present, hydrogen, fluoro, or methyl; R 5a is hydrogen, fluoro, or methyl; R 5b is bromo, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,1-difluoro-2-hydroxyethyl, or pyrazol-4-yl; R 5c and R 5e are each hydrogen; and R 5d is hydrogen, nitro, or amino.

[0089] In yet another embodiment, provided herein is a compound of formula (XVI): [ka] (In the formula, R 6a , R 6b , and R 6c are each independently (i) hydrogen, deuterium, cyano, halo, nitro, or oxo; (ii) each optionally substituted with one or more, and in one embodiment, one, two, or three, substituents Q; 1-6 Alkyl, C1-6 Heteroalkyl, alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and R 1 , R 3 , R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R E1 , L, U, V, X, Y, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0090] In yet another embodiment, provided herein is a compound of formula (XVII): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b, R 4a , R 4b , R 4d , R 6a , R 6b , R 6c , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0091] In yet another embodiment, provided herein is a compound of formula (XVIII): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4c , R 4d , R 6a , R 6b , R 6c , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0092] In yet another embodiment, provided herein is a compound of formula (XIX): [ka] (In the formula, R 1, R 3 , R 2a , R 2b , R 4a , R 4b , R 4c , R 6a , R 6b , R 6c , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0093] In yet another embodiment, provided herein is a compound of formula (XX): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4d , R 6a , R 6b , R 6c , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0094] In yet another embodiment, provided herein is a compound of formula (XXI): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4d , R 6a , R 6b , R 6c , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0095] In yet another embodiment, provided herein is a compound of formula (XXII): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4c , R 6a , R 6b , R 6c , R E1 , L, X E , Y E , Z E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0096] In certain embodiments, in any one of Formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b(i) C, each optionally substituted with one or more, in one embodiment one, two or three, substituents Q; 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; or (ii) —OR 1a where R 1a is as defined herein. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is C optionally substituted with 1, 2, or 3 substituents Q 1-6 In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is C optionally substituted with 1, 2, or 3 substituents Q 2-6 In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is C optionally substituted with 1, 2, or 3 substituents Q 6-14 It is aryl.

[0097] In certain embodiments, in any one of Formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is optionally substituted with one or more, in one embodiment one, two or three, substituents Q; 3-10 In certain embodiments, in any one of Formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is a monocyclic C optionally substituted with one, two or three substituents Q 3-10 In certain embodiments, in any one of Formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is a bicyclic C optionally substituted with 1, 2, or 3 substituents Q4-10 In certain embodiments, in any one of Formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl, each optionally substituted with 1, 2, or 3 substituents Q, where each substituent is independently (i) one or more substituents Q a C optionally substituted with 1-6 alkyl; or (ii) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -OR a , or -OC(O)R a where each R a , R b , and R c is as defined herein. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4bis cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl, each of which is optionally substituted with one, two, or three substituents, wherein each substituent is independently fluoro, methyl, difluoromethyl, 3-cyanoazetidin-1-ylcarbonyl, 3-fluoroazetidin-1-ylcarbonyl, 3-methoxyazetidin-1-ylcarbonyl, 3-hydroxypyrrolidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-(2-methoxyphenyl)-2-methyl-1-propanol, 1-methyl ... In certain embodiments, in any one of Formulas (III), (V), (X), (XII), (XVII), and (XIX), R is selected from the group consisting of (methyl)(ethyl)piperazin-1-ylcarbonyl, hydroxycarbonyl, ethoxycarbonyl, dimethylcarbamoyl, (methyl)(ethyl)carbamoyl, (2-hydroxyethyl)(methyl)carbamoyl, (2-hydroxypropyl)(methyl)carbamoyl, (2-hydroxy-2-methylpropyl)(methyl)carbamoyl, (2,3-dihydroxypropyl)(methyl)carbamoyl, (2-methoxyethyl)(methyl)carbamoyl, (methyl)(oxetan-3-yl)carbamoyl, (methyl)(tetrahydrofur-3-yl)carbamoyl, hydroxyl, and acetoxy. 4bare 1-methylcyclopropyl, 1-fluoromethylcyclopropyl, 1-difluoromethylcyclopropyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 4-hydroxycyclohexyl, 4-hydroxycarbonylcyclohexyl, 4-ethoxycarbonylcyclohexyl, 4-(3-cyanoazetidin-1-ylcarbonyl)cyclohexyl, 4-(3-fluoroazetidin-1-ylcarbonyl)cyclohexyl, 4-(3-methoxyazetidin-1-ylcarbonyl)cyclohexyl Sil, 4-(3-hydroxypyrrolidin-1-yl)carbonylcyclohexyl, 4-morpholin-4-ylcarbonylcyclohexyl, 4-(4-methylpiperazin-1-yl)carbonylcyclohexyl, 4-(4-(2-methoxyethyl)piperazin-1-yl)carbonylcyclohexyl, 4-dimethylcarbamoylcyclohexyl, 4-(methyl)(ethyl)carbamoylcyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoylcyclohexyl, 4-(2-hydroxypropyl) (Methyl)carbamoylcyclohexyl, 4-(2-hydroxy-2-methylpropyl)(methyl)carbamoylcyclohexyl, 4-(2,3-dihydroxypropyl)(methyl)carbamoylcyclohexyl, 4-(2-methoxyethyl)(methyl)carbamoylcyclohexyl, 4-(methyl)(oxetan-3-yl)carbamoylcyclohexyl, 4-(methyl)(tetrahydrofur-3-yl)carbamoylcyclohexyl, 4-acetoxy-1-hydroxycyclohexyl, 1,4-dihydro 4-hydroxycyclohexyl, 4-hydroxycarbonyl-1-hydroxycyclohexyl, 4-ethoxycarbonyl-1-hydroxycyclohexyl, 4-dimethylcarbamoyl-1-hydroxycyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoyl-1-hydroxycyclohexyl, 4-(2-hydroxypropyl)(methyl)carbamoyl-1-hydroxycyclohexyl, bicyclo[1.1.1]pentan-1-yl, or 4-fluorobicyclo[2.2.2]octan-1-yl.

[0098] In certain embodiments, in any one of Formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is heteroaryl optionally substituted with one or more, in one embodiment, 1, 2, or 3, substituents Q. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is a monocyclic heteroaryl optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is a 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is pyrazolyl or pyridinyl, each optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, each optionally substituted with 1, 2, or 3 substituents Q.

[0099] In certain embodiments, in any one of Formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is a monocyclic heterocyclyl optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4bis a 5- or 6-membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is a bicyclic heterocyclyl optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is tetrahydrofuryl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridinyl, dihydropyranyl, dihydrothiopyranyl, azaspiro[3.3]heptanyl, or 7-azaspiro[3.5]nonanyl, each of which is optionally substituted with 1, 2, or 3 substituents, where each substituent is independently oxo, imino, isopropyl, hydroxycarbonylmethyl, dimethylcarbamoylmethyl, tetrahydrofur-3-yl, acetyl, 2-methoxyacetyl, 2-dimethylaminoacetyl, tert-butoxycarbonyl, or hydroxyl. In certain embodiments, in any one of Formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4bare 3-methyltetrahydrofuran-3-yl, piperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-(hydroxycarbonylmethyl)piperidin-4-yl, 1-(dimethylcarbamoylmethyl)piperidin-4-yl, 1-tetrahydrofur-3-ylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-(2-methoxyacetyl)piperidin-4-yl, 1-(2-dimethylaminoacetyl)piperidin-4-yl, 1-tert-butoxycarbonylpiperidin-4-yl, 4-hydroxypiperidin-4-yl, 1-acetyl-4-hydroxypiperidin-4-yl, 1-(2-methoxyacetyl)-4-hydroxypiperidin-4-yl, 4-hydroxy-1-tert-butoxycarbonylpiperidin-4-yl, 1- Dimethylcarbamoyl-4-hydroxypiperidin-4-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, 1-oxotetrahydrothiopyran-4-yl, 1,1-dioxotetrahydrothiopyran-4-yl, 1-oxo-1-iminotetrahydrothiopyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydropyran- 4-yl, 3,6-dihydrothiopyran-4-yl, 1-oxo-3,6-dihydrothiopyran-4-yl, 1,1-dioxo-3,6-dihydrothiopyran-4-yl, 1-oxo-1-imino-3,6-dihydrothiopyran-4-yl, 6-hydroxy-2-azaspiro[3.3]heptan-6-yl, or 2-hydroxy-7-azaspiro[3.5]nonan-2-yl.

[0100] In certain embodiments, in any one of Formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b -OR 1a where R 1a is as defined herein. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is —OC optionally substituted with 1, 2, or 3 substituents Q; 1-6In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is —O-heterocyclyl optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is —O-(monocyclic heterocyclyl) optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is —O-(5- or 6-membered heterocyclyl), each optionally substituted with 1, 2, or 3 substituents Q. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is -C(O)R a or -C(O)OR a -O-(5-membered heterocyclyl) optionally substituted with a is as defined herein. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b are -C(O)R a or -C(O)OR a methoxy, tetrahydrofuryloxy, or pyrrolidinyloxy optionally substituted with a is as defined herein. In certain embodiments, in any one of formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4bis methoxy, tetrahydrofuryloxy, or pyrrolidinyloxy, each optionally substituted with acetyl, propionyl, cyclopropylcarbonyl, or tert-butoxycarbonyl. In certain embodiments, in any one of Formulas (III), (V), (X), (XII), (XVII), and (XIX), R 4b is methoxy, tetrahydrofur-3-yloxy, (R)-tetrahydrofur-3-yloxy, (S)-tetrahydrofur-3-yloxy, pyrrolidin-3-yloxy, 1-acetylpyrrolidin-3-yloxy, 1-propionylpyrrolidin-3-yloxy, 1-cyclopropylcarbonylpyrrolidin-3-yloxy, or 1-tert-butoxycarbonylpyrrolidin-3-yloxy.

[0101] In one embodiment, in any one of Formulas (XVII) to (XXII), R 1 is hydrogen, methyl, trifluoromethyl, or dimethylamino; R 3 is hydrogen; R 2a is hydrogen, methyl, or ethyl; R 2b is hydrogen; R 4a is hydrogen, if present; R 4bis, if present, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl, each optionally substituted with 1, 2, or 3 substituents, where each substituent is independently fluoro, methyl, difluoromethyl, 3-cyanoazetidin-1-ylcarbonyl, 3-fluoroazetidin-1-ylcarbonyl, 3-methoxyazetidin-1-ylcarbonyl, 3-hydroxypyrrolidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-(2 -methoxyethyl)piperazin-1-ylcarbonyl, hydroxycarbonyl, ethoxycarbonyl, dimethylcarbamoyl, (methyl)(ethyl)carbamoyl, (2-hydroxyethyl)(methyl)carbamoyl, (2-hydroxypropyl)(methyl)carbamoyl, (2-hydroxy-2-methylpropyl)(methyl)carbamoyl, (2,3-dihydroxypropyl)(methyl)carbamoyl, (2-methoxyethyl)(methyl)carbamoyl, (methyl)(oxetan-3-yl)carbamoyl, (methyl)(tetrahydrofur-3-yl)carbamoyl, hydroxyl, or acetoxy; R 4c is, when present, hydrogen or methoxy; R 4d is, if present, hydrogen, fluoro, or methyl; R 6a and R 6b are each independently hydrogen, hydroxymethylphenyl, aminomethylphenyl, methylaminomethylphenyl, (aminoethyl)phenyl, or 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl; and R 6c is hydrogen.

[0102] In one embodiment, in any one of Formulas (XVII) to (XXII), R 1 is hydrogen, methyl, or trifluoromethyl; R 3 is hydrogen; R 2a is hydrogen, methyl, or ethyl; R 2b is hydrogen; R 4a is hydrogen, if present; R 4bis, when present, 1-methylcyclopropyl, 1-fluoromethylcyclopropyl, 1-difluoromethylcyclopropyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 4-hydroxycyclohexyl, 4-hydroxycarbonylcyclohexyl, 4-ethoxycarbonylcyclohexyl, 4-(3-cyanoazetidin-1-ylcarbonyl)cyclohexyl, 4-(3-fluoroazetidin-1-ylcarbonyl)cyclohexyl, 4-(3-methoxyazetidin-1-ylcarbonyl)cyclohexyl, cyclohexyl, 4-(3-hydroxypyrrolidin-1-yl)carbonylcyclohexyl, 4-morpholin-4-ylcarbonylcyclohexyl, 4-(4-methylpiperazin-1-yl)carbonylcyclohexyl, 4-(4-(2-methoxyethyl)piperazin-1-yl)carbonylcyclohexyl, 4-dimethylcarbamoylcyclohexyl, 4-(methyl)(ethyl)carbamoylcyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoylcyclohexyl, 4-(2-hydroxypropyl) 4-(2-hydroxy-2-methylpropyl)(methyl)carbamoylcyclohexyl, 4-(2,3-dihydroxypropyl)(methyl)carbamoylcyclohexyl, 4-(2-methoxyethyl)(methyl)carbamoylcyclohexyl, 4-(methyl)(oxetan-3-yl)carbamoylcyclohexyl, 4-(methyl)(tetrahydrofur-3-yl)carbamoylcyclohexyl, 4-acetoxy-1-hydroxycyclohexyl, 1,4-dihydroxypropyl hydroxycyclohexyl, 4-hydroxycarbonyl-1-hydroxycyclohexyl, 4-ethoxycarbonyl-1-hydroxycyclohexyl, 4-dimethylcarbamoyl-1-hydroxycyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoyl-1-hydroxycyclohexyl, 4-(2-hydroxypropyl)(methyl)carbamoyl-1-hydroxycyclohexyl, bicyclo[1.1.1]pentan-1-yl, or 4-fluorobicyclo[2.2.2]octan-1-yl; R 4c is, when present, hydrogen or methoxy; R 4dis, if present, hydrogen, fluoro, or methyl; R 6a and R 6b are each independently hydrogen, 2-hydroxymethylphenyl, 2-aminomethylphenyl, 2-methylaminomethylphenyl, 2-(2-aminoethyl)phenyl, or 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl; and R 6c is hydrogen.

[0103] In one embodiment, in any one of Formulas (XVII) to (XXII), R 1 is hydrogen, methyl, trifluoromethyl, or dimethylamino; R 3 is hydrogen; R 2a is hydrogen, methyl, or ethyl; R 2b is hydrogen; R 4a is hydrogen, if present; R 4b when present, is tetrahydrofuryl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridinyl, dihydropyranyl, dihydrothiopyranyl, azaspiro[3.3]heptanyl, or 7-azaspiro[3.5]nonanyl, each optionally substituted with 1, 2, or 3 substituents, where each substituent is independently oxo, imino, isopropyl, hydroxycarbonylmethyl, dimethylcarbamoylmethyl, tetrahydrofur-3-yl, acetyl, 2-methoxyacetyl, 2-dimethylaminoacetyl, tert-butoxycarbonyl, or hydroxyl; R 4c is, when present, hydrogen or methoxy; R 4d is, if present, hydrogen, fluoro, or methyl; R 6a and R 6bare each independently hydrogen, hydroxymethylphenyl, aminomethylphenyl, methylaminomethylphenyl, (aminoethyl)phenyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl; and R 6c is hydrogen.

[0104] In one embodiment, in any one of Formulas (XVII) to (XXII), R 1 is hydrogen, methyl, or trifluoromethyl; R 3 is hydrogen; R 2a is hydrogen, methyl, or ethyl; R 2b is hydrogen; R 4a is hydrogen, if present; R 4bis, when present, 3-methyltetrahydrofuran-3-yl, piperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-(hydroxycarbonylmethyl)piperidin-4-yl, 1-(dimethylcarbamoylmethyl)piperidin-4-yl, 1-tetrahydrofur-3-ylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-(2-methoxyacetyl)piperidin-4-yl, 1-(2-dimethylaminoacetyl)piperidin-4-yl, 1-tert-butoxycarbonylpiperidin-4-yl, 4-hydroxypiperidin-4-yl, 1-acetyl-4-hydroxypiperidin-4-yl, 1-(2-methoxyacetyl)-4-hydroxypiperidin-4-yl, 4-hydroxy-1-tert-butoxycarbonylpiperidin-4-yl yl, 1-dimethylcarbamoyl-4-hydroxypiperidin-4-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, 1-oxotetrahydrothiopyran-4-yl, 1,1-dioxotetrahydrothiopyran-4-yl, 1-oxo-1-iminotetrahydrothiopyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydropyridin-4-yl thiopyran-4-yl, 3,6-dihydrothiopyran-4-yl, 1-oxo-3,6-dihydrothiopyran-4-yl, 1,1-dioxo-3,6-dihydrothiopyran-4-yl, 1-oxo-1-imino-3,6-dihydrothiopyran-4-yl, 6-hydroxy-2-azaspiro[3.3]heptan-6-yl, or 2-hydroxy-7-azaspiro[3.5]nonan-2-yl; R 4c is, when present, hydrogen or methoxy; R 4d is, if present, hydrogen, fluoro, or methyl; R 6a and R 6b are each independently hydrogen, 2-hydroxymethylphenyl, 2-aminomethylphenyl, 2-methylaminomethylphenyl, 2-(2-aminoethyl)phenyl, or 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl; and R 6c is hydrogen.

[0105] In one embodiment, in any one of Formulas (XVII) to (XXII), R 1 is hydrogen, methyl, trifluoromethyl, or dimethylamino; R 3 is hydrogen; R 2a is hydrogen, methyl, or ethyl; R 2b is hydrogen; R 4a is hydrogen, if present; R 4b is, if present, methoxy, tetrahydrofuryloxy, or pyrrolidinyloxy, each optionally substituted with acetyl, propionyl, cyclopropylcarbonyl, or tert-butoxycarbonyl; R 4c is, when present, hydrogen or methoxy; R 4d is, if present, hydrogen, fluoro, or methyl; R 6a and R 6b are each independently hydrogen, hydroxymethylphenyl, aminomethylphenyl, methylaminomethylphenyl, (aminoethyl)phenyl, or 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl; and R 6c is hydrogen.

[0106] In one embodiment, in any one of Formulas (XVII) to (XXII), R 1 is hydrogen, methyl, or trifluoromethyl; R 3 is hydrogen; R 2a is hydrogen, methyl, or ethyl; R 2b is hydrogen; R 4a is hydrogen, if present; R 4b when present, is methoxy, tetrahydrofur-3-yloxy, (R)-tetrahydrofur-3-yloxy, (S)-tetrahydrofur-3-yloxy, pyrrolidin-3-yloxy, 1-acetylpyrrolidin-3-yloxy, 1-propionylpyrrolidin-3-yloxy, 1-cyclopropylcarbonylpyrrolidin-3-yloxy, or 1-tert-butoxycarbonylpyrrolidin-3-yloxy; R 4c is, when present, hydrogen or methoxy; R 4d is, if present, hydrogen, fluoro, or methyl; R 6a and R 6b are each independently hydrogen, 2-hydroxymethylphenyl, 2-aminomethylphenyl, 2-methylaminomethylphenyl, 2-(2-aminoethyl)phenyl, or 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl; and R 6c is hydrogen.

[0107] In certain embodiments, in any one of Formulas (I) to (XXII), Z E is C optionally substituted with one or more substituents Q 6-14 In one embodiment, in any one of Formulas (I) to (XXII), Z E is phendiyl optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is phen-1,3-diyl or phen-1,4-diyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is phen-1,3-diyl optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z Eis phen-1,4-diyl optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is phen-1,3-diyl, phen-1,3-diyl, 2-methylphen-1,3-diyl, 2-methylphen-1,4-diyl, or 2-methylphen-1,5-diyl. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is a bicyclic C optionally substituted with one or more substituents Q 9-14 It is an arylene.

[0108] In certain embodiments, in any one of Formulas (I) to (XXII), Z E is heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is a monocyclic heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is a 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is a 5-membered heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is a 6-membered heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is pyrazolediyl, imidazolediyl, 1,2,3-triazolediyl, or pyridinediyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z Eis pyrazole-1,3-diyl, pyrazole-1,4-diyl, pyrazole-3,5-diyl, imidazole-1,4-diyl, imidazole-2,4-diyl, 1,2,3-triazole-1,4-diyl, 1,2,3-triazole-1,4-diyl, 1,2,3-triazole-2,4-diyl, pyridine-2,4-diyl, pyridine-2,5-diyl, or pyridine-3,5-diyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is pyrazole-1,3-diyl, pyrazole-1,4-diyl, 1-methylpyrazole-3,5-diyl, imidazole-1,4-diyl, 1-methylimidazole-2,4-diyl, 1,2,3-triazole-1,4-diyl, 1,2,3-triazole-2,4-diyl, pyridine-2,4-diyl, pyridine-2,5-diyl, 6-methoxypyridine-2,4-diyl, or 6-methoxypyridine-2,5-diyl.

[0109] In certain embodiments, in any one of Formulas (I) to (XXII), Z E is a bicyclic heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is a 5,6-fused or 6,6-fused heteroarylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is a 5,6-fused heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is a 6,6-fused heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z Eis indolediyl, indazoldiyl, imidazo[1,5-a]pyridinediyl, benzimidazolediyl, benzothiazolediyl, pyrrolo[2,3-b]pyridinediyl, quinolinediyl, or isoquinolinediyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is indole-3,6-diyl, indole-3,7-diyl, indazole-3,6-diyl, indazole-3,7-diyl, imidazo[1,5-a]pyridine-3,7-diyl, imidazo[1,5-a]pyridine-3,8-diyl, benzimidazole-1,4-diyl, benzimidazole-1,5-diyl, benzothiazole-2,4-diyl, benzothiazole-2,5-diyl, benzothiazole-2,6-diyl, benzothiazole-2,7-diyl, pyrrolo[2,3-b]pyridine-3,6-diyl, quinoline-3,7-diyl, quinoline-3,8-diyl, isoquinoline-1,5-diyl, or isoquinoline-1,6-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E are 1-methyl-indole-3,6-diyl, 1-methyl-indole-3,7-diyl, 1-methylindazole-3,6-diyl, 1-methylindazole-3,7-diyl, imidazo[1,5-a]pyridine-3,7-diyl, imidazo[1,5-a]pyridine-3,8-diyl, 1-methylimidazo[1,5-a]pyridine-3,7-diyl, 1-methylimidazo[1,5-a]pyridine-3,8-diyl diyl, 1-methylbenzimidazole-1,4-diyl, 1-methylbenzimidazole-1,5-diyl, benzothiazole-2,4-diyl, 1-methylpyrrolo[2,3-b]pyridine-3,6-diyl, 1-methyl-2-hydroxylquinoline-3,7-diyl, 1-methyl-2-hydroxylquinoline-3,8-diyl, isoquinoline-1,5-diyl, or isoquinoline-1,6-diyl.

[0110] In certain embodiments, in any one of Formulas (I) to (XXII), ZE is C optionally substituted with one or more substituents Q 6-14 arylene-heteroarylene. In some embodiments, in any one of Formulas (I) to (XXII), Z E is phendiyl-monocyclic heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is phendiyl-(5-membered heteroarylene) optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is phendiyl-pyrazolediyl, phendiyl-imidazolediyl, or phendiyl-1,2,3-triazolediyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E are each optionally substituted with one or more substituents Q [ka] In one embodiment, in any one of Formulas (I) to (XXII), Z E teeth, [ka] is.

[0111] In certain embodiments, in any one of Formulas (I) to (XXII), the moiety [ka] are each optionally substituted with one or more substituents Q [ka] In one embodiment, in any one of Formulas (I) to (XXII), the moiety [ka] teeth, [ka] It has the following structure.

[0112] In certain embodiments, in any one of Formulas (I) to (XXII), the moiety [ka] are each optionally substituted with one or more substituents Q [ka] It has the following structure.

[0113] In certain embodiments, in any one of Formulas (I) to (XXII), the moiety [ka] teeth, [ka] It has the following structure.

[0114] In certain embodiments, in any one of Formulas (I) to (XXII), Z E is phendiyl optionally substituted with one or more substituents Q.

[0115] In one embodiment, provided herein is a compound of formula (XXIII): [ka] (In the formula, Each R E4 are independently (i) deuterium, cyano, halo, nitro, or oxo; (ii) each optionally substituted with one or more, and in one embodiment, one, two, or three, substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and; n is an integer of 0, 1, 2, 3, or 4; and R 1 , R 3 , R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 4a , R 4b , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , L, X E , Y E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0116] In another embodiment, provided herein is a compound of formula (XXIV): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , R E4 , L, X E , Y E , m and n are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0117] In another embodiment, provided herein is a compound of formula (XXV): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 6a , R 6b , R 6c , R E1 , R E4 , L, X E , Y E , m and n are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0118] In another embodiment, provided herein is a compound of formula (XXVI): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 6a , R 6b , R 6c , R E1 , R E4 , L, X E , Y E , m and n are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0119] In certain embodiments, in any one of Formulas (I) to (XXVI), X E is C(R E2 ), where R E2 is as defined herein. In certain embodiments, in any one of Formulas (I) to (XXVI), X E is C(R E2 ), where R E2 is hydrogen, deuterium, or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) to (XXVI), X E is C(R E2 ), where R E2 is hydrogen, deuterium, or methyl.

[0120] In one embodiment, provided herein is a compound of formula (XXVII): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , R E2 , R E4 , L., Y. E , m and n are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0121] In another embodiment, provided herein is a compound of formula (XXVIII): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , R E2 , R E4 , L., Y. E , m and n are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0122] In yet another embodiment, provided herein is a compound of formula (XXIX): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 6a , R 6b , R 6c , R E1 , R E2 , R E4 , L., Y. E , m and n are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0123] In yet another embodiment, provided herein is a compound of formula (XXX): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 6a , R 6b , R 6c , R E1 , R E2 , R E4 , L., Y. E , m and n are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0124] In certain embodiments, in any one of Formulas (I) through (XXX), R E2 is hydrogen, deuterium, or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) through (XXX), R E2 is hydrogen. In certain embodiments, in any one of Formulas (I) through (XXX), R E2 is deuterium. In certain embodiments, in any one of Formulas (I) through (XXX), R E2 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (I) through (XXX), R E2 is methyl.

[0125] In certain embodiments, in any one of Formulas (I) to (XXVI), X E is N.

[0126] In one embodiment, provided herein is a compound of formula (XXXI): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , R E4 , L., Y. E, m and n are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0127] In another embodiment, provided herein is a compound of formula (XXXII): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , R E4 , L., Y. E , m and n are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0128] In yet another embodiment, provided herein is a compound of formula (XXXIII): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 6a , R 6b , R 6c, R E1 , R E4 , L., Y. E , m and n are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0129] In yet another embodiment, provided herein is a compound of formula (XXXIV): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 6a , R 6b , R 6c , R E1 , R E4 , L., Y. E , m and n are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0130] In certain embodiments, in any one of Formulas (I) to (XXII), Z E is a bicyclic heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is a 5,6-fused heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z Eis a 5,6-fused heteroarylene containing 1, 2, or 3 N atoms in the ring and optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is a 5,6-fused heteroarylene containing one N atom in the ring and optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is a 5,6-fused heteroarylene containing two N atoms in the ring and optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XXII), Z E is a 5,6-fused heteroarylene containing three N atoms in the ring and optionally substituted with one or more substituents Q.

[0131] In one embodiment, provided herein is a compound of formula (XXXV): [ka] (In the formula, Z 1 is C or N; Z 2 and Z 3 are each independently -C(R E5 )=, -N=, or -N(R E6 )-and; Each R E5 are independently (i) hydrogen, deuterium, cyano, halo, nitro, or oxo; (ii) each optionally substituted with one or more, and in one embodiment, one, two, or three, substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1bR 1c 、-C(O)SR 1a 、-C(NR 1a )NR 1b R 1c 、-C(S)R 1a 、-C(S)OR 1a 、-C(S)NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(O)SR 1a 、-OC(NR 1a )NR 1b R 1c 、-OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(O)SR 1d 、-NR 1a C(NR 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR 1a C(S)OR 1d 、-NR 1a C(S)NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1bR 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and; Each R E6 are independently (i) hydrogen; (ii) C, each optionally substituted with one or more, and in one embodiment one, two, or three, substituents Q. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)NR 1b R 1c and; p is an integer of 0, 1, 2, or 3; and R 1 , R 3 , R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 4a , R 4b , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , RE1 , L, X E , Y E , and m are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0132] In another embodiment, provided herein is a compound of formula (XXXVI): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , R E4 , L, X E , Y E , Z 1 , Z 2 , Z 3 , m, and p are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0133] In yet another embodiment, provided herein is a compound of formula (XXVII): [ka] (In the formula, R 1 , R 3 , R 2a, R 2b , R 4a , R 4b , R 4d , R 6a , R 6b , R 6c , R E1 , R E4 , L, X E , Y E , Z 1 , Z 2 , Z 3 , m, and p are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0134] In yet another embodiment, provided herein is a compound of formula (XXXVIII): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 6a , R 6b , R 6c , R E1 , R E4 , L, X E , Y E , m, and n are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0135] In one embodiment, in any one of Formulas (XXXV) to (XXXVIII), XE is C(R E2 ), where R E2 is as defined herein. In certain embodiments, in any one of Formulas (XXXV) to (XXXVIII), X E is C(R E2 ), where R E2 is hydrogen, deuterium, or C optionally substituted with one or more substituents Q 1-6 In one embodiment, in any one of Formulas (XXXV) to (XXXVIII), X E is C(R E2 ), where R E2 is hydrogen, deuterium, or methyl.

[0136] In one embodiment, in any one of Formulas (XXXV) to (XXXVIII), Z 1 is C;Z 2 -C(R E5 )= and Z 3 -N(R E6 )-, where R E5 and R E6 is as defined herein. In certain embodiments, in any one of Formulas (XXXV) to (XXXVIII), Z 1 is C; Z 2 -C(R E5 )= and Z 3 -N(R E6 )-, where R E5 is hydrogen and R E6 is C optionally substituted with one or more substituents Q 1-6 In one embodiment, in any one of Formulas (XXXV) to (XXXVIII), Z 1 is C;Z 2 is -C(H)= and Z 3 is -N(H)- or -N(CH3)-.

[0137] In one embodiment, in any one of Formulas (XXXV) to (XXXVIII), Z 1is N;Z 2 is -N = and Z 3 -C(R E5 )=, where R E5 is as defined herein. In certain embodiments, in any one of Formulas (XXXV) to (XXXVIII), Z 1 is N;Z 2 is -N = and Z 3 is -C(H)=.

[0138] In one embodiment, provided herein is a compound of formula (XXXIX): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , R E2 , R E4 , R E6 , L., Y. E , m, and p are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0139] In another embodiment, provided herein is a compound of formula (XL): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R4b , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R E1 , R E2 , R E4 , R E5 , L., Y. E , m, and p are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0140] In yet another embodiment, provided herein is a compound of formula (XLI): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 6a , R 6b , R 6c , R E1 , R E2 , R E4 , R E5 , L., Y. E , m, and p are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0141] In yet another embodiment, provided herein is a compound of formula (XLII): [ka] (In the formula, R 1 , R 3 , R 2a , R 2b , R 4a , R 4b , R 4d , R 6a , R 6b , R 6c , R E1 , R E2 , R E4 , R E5 , L., Y. E , m, and p are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0142] In certain embodiments, in any one of Formulas (XXXIX) to (XLII), R E2 is hydrogen, deuterium, or C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (XXXIX) to (XLII), R E2 is hydrogen. In certain embodiments, in any one of Formulas (XXXIX) to (XLII), R E2 is deuterium. In certain embodiments, in any one of Formulas (XXXIX) to (XLII), R E2 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (XXXIX) to (XLII), R E2 is methyl.

[0143] In certain embodiments, L is -Z L -(R L -Z L ) z - (In the formula, Each RL are independently C, each optionally substituted with one or more substituents Q. 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; each Z L are independently a bond, -C(O)-, -C(O)O-, or -C(O)NR 1b -, -C(O)S-, -C(NR 1a )NR 1b -, -C(S)-, -C(S)O-, -C(S)NR 1b -, -O-, -OC(O)O-, -OC(O)NR 1b -, -OC(O)S-, -OC(NR 1a )NR 1b -, -OC(S)O-, -OC(S)NR 1b -, -OS(O)-, -OS(O)2-, -OS(O)NR 1b -,-OS(O)2NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b -, -NR 1a C(O)S-, -NR 1a C(NR 1d )NR 1b -, -NR 1a C(S)NR 1b -, -NR 1a S(O)NR 1b -, -NR 1a S(O)NR 1b -, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b - or -S(O)NR 1b - where each R 1a , R 1b , and R 1d is as defined herein; and z is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. It is a linker having the structure:

[0144] In certain embodiments, each R L are independently C, each optionally substituted with one or more substituents Q; 1-10 Alkylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; each Z L are independently a bond, -C(O)-, or -C(O)NR 1b -, -C(NR 1a )NR 1b -, -O-, -OC(O)NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b -, -NR 1a C(NR 1d )NR 1b -, -NR 1a S(O)NR 1b -, -NR 1a S(O)NR 1b -, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b - or -S(O)NR 1b and z is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each R 1a , R 1b , and R 1d is as defined herein.

[0145] In certain embodiments, each R L are independently C, each optionally substituted with one or more substituents Q; 1-10 Alkylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; each Z L are independently a bond, -C(O)-, or -C(O)NR 1b -, -O-, -OC(O)NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b - or -NR 1a C(NR1d )NR 1b and z is an integer of 1, 2, 3, 4, 5, 6, 7, or 8; each R 1a , R 1b , and R 1d is as defined herein.

[0146] In certain embodiments, each R L is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, undecanediyl, dodecanediyl, tridecanediyl, ethynediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, bicyclo[2.2.2]octanediyl, phendiyl, pyrazolediyl, imidazolediyl, tetrazolediyl, pyrimidinediyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinediyl, 1,3-dioxanediyl, piperazinediyl, piperidinediyl, or 3,9-diazaspiro[5.5]undecanediyl, each optionally substituted with one or more substituents Q; L is independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)NH—, —O—, —NH—, —N(CH)—, or —NHC(O)NH—; and z is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.

[0147] In certain embodiments, each R Lindependently represent methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, ethyne-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,3-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,3-diyl, cycloheptane-1,4-diyl, bis(2-methyl-2-phenyl)-1,2 ...bis(2-methyl-2-phenyl)-1,2-diyl, cyclopentane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,3-diyl, bis(2-methyl-2-phenyl)-1,2-diyl, cyclopentane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,4-diyl, bis(2-methyl-2-phenyl)-1,2-diyl, bis(2-methyl-2-phenyl)-1,2 chloro[2.2.2]octane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, pyrazole-1,3-diyl, pyrazole-1,4-diyl, imidazole-1,4-diyl, 1,2,3-triazole-1,4-diyl, pyrimidine-2,4-diyl, pyrimidine-2,5-diyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazine-1,7-diyl, pyrazolidine-1,3-diyl, pyrazolidine-1,4-diyl, 1,3-dioxane-2,5-diyl, piperazine-1,4-diyl, piperidine-1,3-diyl, piperidine-1,4-diyl, or 3,9-diazaspiro[5.5]undecane-3,9-diyl; each Z L is independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)NH—, —O—, —NH—, —N(CH)—, or —NHC(O)NH—; and z is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.

[0148] In certain embodiments, L is [ka] where each A L are independently a bond, —O—, —NH—, or —N(CH 3 )—.

[0149] In certain embodiments, L is [ka] where each A L are independently a bond, —O—, —NH—, or —N(CH 3 )—.

[0150] In certain embodiments, L is [ka] where each A L are independently a bond, —O—, —NH—, or —N(CH 3 )—.

[0151] In certain embodiments, L is [ka] where each A L is independently a bond, —O—, —NH—, or —N(CH 3 )—; and each amino (NH) group is optionally substituted with methyl.

[0152] In certain embodiments, L is [ka] where each A L is independently a bond, —O—, —NH—, or —N(CH 3 )—; and each amino (NH) group is optionally substituted with methyl.

[0153] In certain embodiments, L is [ka] where each A L is independently a bond, —O—, —NH—, or —N(CH 3 )—; and each amino group (NH) is optionally substituted with methyl.

[0154] In certain embodiments, L is [ka] TIFF2024522768000062.tif220170TIFF2024522768000063.tif78170; where each A L is independently a bond, —O—, —NH—, or —N(CH 3 )—; and each amino (NH) group is optionally substituted with methyl.

[0155] In certain embodiments, L is [ka] where each A L are independently a bond, —O—, —NH—, or —N(CH 3 )—.

[0156] In certain embodiments, L is [ka] where each A L is independently a bond, —O—, —NH—, or —N(CH 3 )—; and each amino group (NH) is optionally substituted with methyl.

[0157] In certain embodiments, L is [ka] where each A L is independently a bond, —O—, —NH—, or —N(CH 3 )—; and each amino group (NH) is optionally substituted with methyl.

[0158] In certain embodiments, L is [ka] where each A L are independently a bond, —O—, —NH—, or —N(CH 3 )—.

[0159] In certain embodiments, L is [ka] where each A L is independently a bond, —O—, —NH—, or —N(CH 3 )—; and each amino group (NH) is optionally substituted with methyl.

[0160] In certain embodiments, L is [ka] where each A L is independently a bond, —O—, —NH—, or —N(CH 3 )—; and each amino group is optionally substituted with methyl.

[0161] In certain embodiments, L is [ka] is.

[0162] In certain embodiments, L is [ka] is.

[0163] The group R in the formulae described herein, including formulae (I) to (XXXVI) 1 , R 2 , R 3 , R 2a , R 2b , R 2c , R 4a , R 4b , R 4c , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R 6a , R 6b , R 6c , R E1 , R E2 , R E3 , R E4 , R L , L, U, V, X, Y, Z 1 , Z2 , Z 3 , X E , Y E , Z E , Z L , m, n, p, and z are further defined in the embodiments described herein. All combinations of embodiments provided herein for groups described in the formulas described herein, including formulas (I) through (XXXVI), are within the scope of the present disclosure.

[0164] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is deuterium. In some embodiments, R 1 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 1 is methyl optionally substituted with one or more substituents Q. In certain embodiments, R 1 is methyl or trifluoromethyl. In certain embodiments, R 1 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 1 is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 1 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 1 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 1 is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 1 is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 1 is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 1is heterocyclyl optionally substituted with one or more substituents Q.

[0165] In some embodiments, R 2 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 2 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 2 is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 2 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 2 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 2 is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 2 is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 2 is benzyl optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a bicyclic C optionally substituted with one or more substituents Q 10-15 In some embodiments, R 2 is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 2 is heteroaryl-C 1-6 and alkylene, wherein the heteroaryl and alkylene are each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a monocyclic heteroaryl-C 1-6 and alkylene, wherein the heteroaryl and alkylene are each optionally substituted with one or more substituents Q. In certain embodiments, R 2is a 5- or 6-membered heteroaryl-C 1-6 and alkylene, wherein the heteroaryl and alkylene are each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is thienylmethylene optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a bicyclic heteroaryl-C 1-6 and alkylene, wherein the heteroaryl and alkylene are each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5,5-, 5,6-, or 6,6-fused heteroaryl-C 1-6 and alkylene, wherein the heteroaryl and alkylene are each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is heterocyclyl optionally substituted with one or more substituents Q.

[0166] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is deuterium. In some embodiments, R 3 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 3 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 3 is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 3 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 3 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 3 is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 3is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 3 is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 3 is heterocyclyl optionally substituted with one or more substituents Q.

[0167] In some embodiments, R 2a is hydrogen. In some embodiments, R 2a is deuterium. In some embodiments, R 2a is halo. In certain embodiments, R 2a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 2a is methyl or ethyl. In certain embodiments, R 2a is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 2a is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 2a is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 2a is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 2a is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 2a is heterocyclyl optionally substituted with one or more substituents Q.

[0168] In some embodiments, R 2b is hydrogen. In some embodiments, R 2b is deuterium. In some embodiments, R 2b is halo. In certain embodiments, R 2b is C optionally substituted with one or more substituents Q 1-6In some embodiments, R 2b is methyl or ethyl. In certain embodiments, R 2b is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 2b is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 2b is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 2b is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 2b is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 2b is heterocyclyl optionally substituted with one or more substituents Q.

[0169] In some embodiments, R 2c is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 2c is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 2c is phenyl optionally substituted with one or more substituents Q. In certain embodiments, R 2c is a bicyclic C optionally substituted with one or more substituents Q 9-14 In some embodiments, R 2c are 5,6- or 6,6-fused C groups, each of which is optionally substituted with one or more substituents Q; 9-14 In some embodiments, R 2c is 2,3-dihydro-1H-indenyl or naphthyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 2c is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 2cis monocyclic heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 2c is a 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R 2c is thienyl optionally substituted with one or more substituents Q. In certain embodiments, R 2c is thien-2-yl or thien-3-yl, each optionally substituted with one or more substituents Q. In certain embodiments, R 2c is a bicyclic heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 2c is 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R 2c is heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 2c is monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 2c is a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 2c is a bicyclic heterocyclyl optionally substituted with one or more substituents Q.

[0170] In some embodiments, R 2cis phenyl, 2,3-dihydroindenyl, naphthyl, thienyl, or 2,3-dihydrobenzofuranyl, each optionally substituted with 1, 2, or 3 substituents, where each substituent is independently fluoro, chloro, bromo, iodo, nitro, methyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 2-hydroxy-1,1-difluoroethyl, 2-hydroxymethylphenyl, 2-aminomethylphenyl, 2-methylaminomethylphenyl, 2-(2-aminoethyl)phenyl, 3-hydroxyoxetan-3-yl, pyrazol-4-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, or amino. In certain embodiments, R 2care phenyl, 3-bromophenyl, 3-methylphenyl, 3-difluoromethylphenyl, 3-trifluoromethylphenyl, 3-(2,2,2-trifluoroethyl)phenyl, 3-(1-hydroxyethyl)phenyl, 3-(1-hydroxy-1-methylethyl)phenyl, 3-(2-hydroxy-1,1-difluoroethyl)phenyl, 3-(3-hydroxyoxetan-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-3-difluoromethylphenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-3-(1,1-difluoroethyl)phenyl, 2-methyl-3-difluoromethylphenyl, 2-methyl-3-trifluoromethylphenyl, trifluoromethylphenyl, 3-trifluoromethyl-5-aminophenyl, 2-fluoro-3-trifluoromethyl-5-aminophenyl, 2-methyl-3-trifluoromethyl-5-aminophenyl, 3,3-difluoro-2,3-dihydro-1H-inden-5-yl, naphth-1-yl, 5-(2-hydroxymethylphenyl)thien-2-yl, 5-(2-aminomethylphenyl)thien-2-yl, 4-(2-methylaminomethylphenyl)thien-2-yl, 5-(2-(2-aminoethyl)phenyl)thien-2-yl, 5-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)thien-2-yl, or 3,3-difluoro-2,3-dihydrobenzofuran-5-yl.

[0171] In some embodiments, R 4a is hydrogen. In some embodiments, R 4a is deuterium. In some embodiments, R 4a is cyano. In some embodiments, R 4a is halo. In certain embodiments, R 4a is fluoro, chloro, or bromo. 4a is nitro. In some embodiments, R 4a is oxo. In some embodiments, R 4a is C optionally substituted with one or more substituents Q 1-6In some embodiments, R 4a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 4a is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 4a is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 4a is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 4a is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 4a is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 4a is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 4a is heterocyclyl optionally substituted with one or more substituents Q.

[0172] In some embodiments, R 4a -C(O)R 1a where R 1a is as defined herein. In certain embodiments, R 4a -C(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 4a is -C(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4a -C(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 4a -C(NR1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4a -C(S)R 1a where R 1a is as defined herein. In certain embodiments, R 4a HA-C(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 4a -C(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4a HA-OR 1a where R 1a is as defined herein. In certain embodiments, R 4a Ha-OC(O)R 1a where R 1a is as defined herein. In certain embodiments, R 4a HA-OC(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 4a -OC(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4a Ha-OC(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 4a -OC(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1cand R are each as defined herein. In certain embodiments, R 4a Ha-OC(S)R 1a where R 1a is as defined herein. In certain embodiments, R 4a HA-OC(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 4a -OC(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4a -OS(O)R 1a where R 1a is as defined herein. In certain embodiments, R 4a -OS(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 4a -OS(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4a -OS(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4a Ha-NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4a Ha-NR 1a C(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4a Ha-NR1a C(O)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4a Ha-NR 1a C(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4a Ha-NR 1a C(O)SR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4a Ha-NR 1a C(NR 1d )NR 1b R 1c where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, R 4a Ha-NR 1a C(S)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4a Ha-NR 1a C(S)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4a Ha-NR 1a C(S)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4a Ha-NR 1a S(O)R 1dwhere R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4a Ha-NR 1a S(O)2R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4a Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4a Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4a Ha-SR 1a where R 1a is as defined herein. In certain embodiments, R 4a -S(O)R 1a where R 1a is as defined herein. In certain embodiments, R 4a -S(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 4a is -S(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4a is -S(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4ais hydrogen, fluoro, methyl, or methoxy.

[0173] In some embodiments, R 4b is hydrogen. In some embodiments, R 4b is deuterium. In some embodiments, R 4b is cyano. In some embodiments, R 4b is halo. In certain embodiments, R 4b is fluoro, chloro, or bromo. 4b is nitro. In some embodiments, R 4b is oxo. In some embodiments, R 4b is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 4b is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 4b is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 4b is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 4b is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 4b is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 4b is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 4b is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 4b is heterocyclyl optionally substituted with one or more substituents Q.

[0174] In some embodiments, R 4b -C(O)R 1awhere R 1a is as defined herein. In certain embodiments, R 4b -C(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 4b is -C(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4b -C(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 4b -C(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4b -C(S)R 1a where R 1a is as defined herein. In certain embodiments, R 4b HA-C(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 4b -C(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4b HA-OR 1a where R 1a is as defined herein. In certain embodiments, R 4b Ha-OC(O)R 1a where R 1a is as defined herein. In certain embodiments, R 4b HA-OC(O)OR 1a where R1a is as defined herein. In certain embodiments, R 4b -OC(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4b Ha-OC(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 4b -OC(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4b Ha-OC(S)R 1a where R 1a is as defined herein. In certain embodiments, R 4b HA-OC(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 4b -OC(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4b -OS(O)R 1a where R 1a is as defined herein. In certain embodiments, R 4b -OS(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 4b -OS(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4b-OS(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4b Ha-NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4b Ha-NR 1a C(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4b Ha-NR 1a C(O)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4b Ha-NR 1a C(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4b Ha-NR 1a C(O)SR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4b Ha-NR 1a C(NR 1d )NR 1b R 1c where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, R 4b Ha-NR 1a C(S)R 1d where R 1a and R1d and R are each as defined herein. In certain embodiments, R 4b Ha-NR 1a C(S)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4b Ha-NR 1a C(S)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4b Ha-NR 1a S(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4b Ha-NR 1a S(O)2R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4b Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4b Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4b Ha-SR 1a where R 1a is as defined herein. In certain embodiments, R 4b -S(O)R 1a where R 1ais as defined herein. In certain embodiments, R 4b -S(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 4b is -S(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4b is -S(O)2NR 1b R 1c where R 1b and R 1c are each as defined herein.

[0175] In some embodiments, R 4b is hydrogen, fluoro, methyl, or methoxy. 4bis cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, methoxy, tetrahydrofuryloxy, or pyrrolidinyloxy, each optionally substituted with one, two, or three substituents, wherein each substituent is independently selected from fluoro, oxo, imino, methyl, difluoromethyl, hydroxycarbonylmethyl, dimethylcarbamoylmethyl, isopropyl, tetrahydrofur-3-yl, acetyl, propionyl, 2-methoxyacetyl, 2-dimethylaminoacetyl, cyclopropylcarbonyl, 3-cyanoazetidin-1-ylcarbonyl, 3-fluoroazetidin-1-ylcarbonyl, 3-methoxyazetidin-1-ylcarbonyl, 3-hydroxypyrrolidinyloxy, lysin-1-ylcarbonyl, morpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-(2-methoxyethyl)piperazin-1-ylcarbonyl, hydroxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, dimethylcarbamoyl, (methyl)(ethyl)carbamoyl, (2-hydroxyethyl)(methyl)carbamoyl, (2-hydroxypropyl)(methyl)carbamoyl, (2-hydroxy-2-methylpropyl)(methyl)carbamoyl, (2,3-dihydroxypropyl)(methyl)carbamoyl, (2-methoxyethyl)(methyl)carbamoyl, (methyl)(oxetan-3-yl)carbamoyl, (methyl)(tetrahydrofur-3-yl)carbamoyl, hydroxyl, or acetoxy. 4bare 1-methylcyclopropyl, 1-fluoromethylcyclopropyl, 1-difluoromethylcyclopropyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 4-hydroxycyclohexyl, 4-hydroxycarbonylcyclohexyl, 4-ethoxycarbonylcyclohexyl, 4-(3-cyanoazetidin-1-ylcarbonyl)cyclohexyl, 4-(3-fluoroazetidin-1-ylcarbonyl)cyclohexyl, 4-(3-methoxyazetidin-1-ylcarbonyl)cyclohexyl cyclohexyl, 4-(3-hydroxypyrrolidin-1-yl)carbonylcyclohexyl, 4-morpholin-4-ylcarbonylcyclohexyl, 4-(4-methylpiperazin-1-yl)carbonylcyclohexyl, 4-(4-(2-methoxyethyl)piperazin-1-yl)carbonylcyclohexyl, 4-dimethylcarbamoylcyclohexyl, 4-(methyl)(ethyl)carbamoylcyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoylcyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoylcyclohexyl, 4-(2-hydroxypropyl)(methyl)carbamoylcyclohexyl, 4-(2-hydroxy-2-methylpropyl)(methyl)carbamoylcyclohexyl, 4-(2,3-dihydroxypropyl)(methyl)carbamoylcyclohexyl, 4-(2-methoxyethyl)(methyl)carbamoylcyclohexyl, 4-(methyl)(oxetan-3-yl)carbamoylcyclohexyl, 4-(methyl)(tetrahydrofur-3-yl)carbamoylcyclohexyl, 4-acetoxy-1-hydroxycyclohexyl xyl, 1,4-dihydroxycyclohexyl, 4-hydroxycarbonyl-1-hydroxycyclohexyl, 4-ethoxycarbonyl-1-hydroxycyclohexyl, 4-dimethylcarbamoyl-1-hydroxycyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoyl-1-hydroxycyclohexyl, 4-(2-hydroxypropyl)(methyl)carbamoyl-1-hydroxycyclohexyl, bicyclo[1.1.1]pentan-1-yl, 4-fluorobicyclo[2.2.2]octan-1-yl, 3-methyltetrahydrofuran-3-yl, piperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-(hydroxycarbonylmethyl)piperidin-4-yl, 1-(dimethylcarbamoylmethyl)piperidin-4-yl, 1-tetrahydrofur-3-ylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-(2-methoxyacetyl)piperidin-4-yl, 1-(2-dimethylaminoacetyl)piperidin-4-yl, 1-tert-butyl t-Butoxycarbonylpiperidin-4-yl, 4-hydroxypiperidin-4-yl, 1-acetyl-4-hydroxypiperidin-4-yl, 1-(2-methoxyacetyl)-4-hydroxypiperidin-4-yl, 4-hydroxy-1-tert-butoxycarbonylpiperidin-4-yl, 1-dimethylcarbamoyl-4-hydroxypiperidin-4-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, 1-oxotetrahydrothiopyran-4-yl, 1 ,1-dioxotetrahydrothiopyran-4-yl, 1-oxo-1-iminotetrahydrothiopyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydropyran-4-yl, 3,6-dihydrothiopyran-4-yl, 1-oxo-3,6-dihydrothiopyran-4-yl, 1,1-dioxo-3,6-dihydrothiopyran-4-yl, 1-oxo-1-imino-3,6-dihydrothiopyran-4-yl, 6-hydroxy-2-azaspiro[3.3]hepta hydroxy-7-azaspiro[3.5]nonan-2-yl, methoxy, tetrahydrofuran-3-yloxy, (R)-tetrahydrofuran-3-yloxy, (S)-tetrahydrofuran-3-yloxy, pyrrolidin-3-yloxy, 1-acetylpyrrolidin-3-yloxy, 1-propionylpyrrolidin-3-yloxy, 1-cyclopropylcarbonylpyrrolidin-3-yloxy, or 1-tert-butoxycarbonylpyrrolidin-3-yloxy.

[0176] In some embodiments, R 4c is hydrogen. In some embodiments, R 4c is deuterium. In some embodiments, R4c is cyano. In some embodiments, R 4c is halo. In certain embodiments, R 4c is fluoro, chloro, or bromo. 4c is nitro. In some embodiments, R 4c is oxo. In some embodiments, R 4c is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 4c is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 4c is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 4c is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 4c is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 4c is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 4c is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 4c is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 4c is heterocyclyl optionally substituted with one or more substituents Q.

[0177] In some embodiments, R 4c -C(O)R 1a where R 1a is as defined herein. In certain embodiments, R 4c -C(O)OR 1a where R 1a is as defined herein. In certain embodiments, R4c is -C(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4c -C(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 4c -C(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4c -C(S)R 1a where R 1a is as defined herein. In certain embodiments, R 4c HA-C(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 4c -C(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4c HA-OR 1a where R 1a is as defined herein. In certain embodiments, R 4c Ha-OC(O)R 1a where R 1a is as defined herein. In certain embodiments, R 4c HA-OC(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 4c -OC(O)NR 1b R 1c where R 1b and R 1cand R are each as defined herein. In certain embodiments, R 4c Ha-OC(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 4c -OC(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4c Ha-OC(S)R 1a where R 1a is as defined herein. In certain embodiments, R 4c HA-OC(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 4c -OC(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4c -OS(O)R 1a where R 1a is as defined herein. In certain embodiments, R 4c -OS(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 4c -OS(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4c -OS(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4c Ha-NR1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4c Ha-NR 1a C(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4c Ha-NR 1a C(O)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4c Ha-NR 1a C(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4c Ha-NR 1a C(O)SR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4c Ha-NR 1a C(NR 1d )NR 1b R 1c where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, R 4c Ha-NR 1a C(S)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4c Ha-NR 1a C(S)OR 1d where R 1a and R 1dand R are each as defined herein. In certain embodiments, R 4c Ha-NR 1a C(S)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4c Ha-NR 1a S(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4c Ha-NR 1a S(O)2R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4c Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4c Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4c Ha-SR 1a where R 1a is as defined herein. In certain embodiments, R 4c -S(O)R 1a where R 1a is as defined herein. In certain embodiments, R 4c -S(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 4cis -S(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4c is -S(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4c is hydrogen, fluoro, methyl, or methoxy.

[0178] In some embodiments, R 4d is hydrogen. In some embodiments, R 4d is deuterium. In some embodiments, R 4d is cyano. In some embodiments, R 4d is halo. In certain embodiments, R 4d is fluoro, chloro, or bromo. 4d is nitro. In some embodiments, R 4d is oxo. In some embodiments, R 4d is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 4d is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 4d is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 4d is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 4d is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 4d is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 4dis C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 4d is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 4d is heterocyclyl optionally substituted with one or more substituents Q.

[0179] In some embodiments, R 4d -C(O)R 1a where R 1a is as defined herein. In certain embodiments, R 4d -C(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 4d is -C(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4d -C(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 4d -C(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4d -C(S)R 1a where R 1a is as defined herein. In certain embodiments, R 4d HA-C(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 4d -C(S)NR 1b R 1c where R 1b and R 1cand R are each as defined herein. In certain embodiments, R 4d HA-OR 1a where R 1a is as defined herein. In certain embodiments, R 4d Ha-OC(O)R 1a where R 1a is as defined herein. In certain embodiments, R 4d HA-OC(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 4d -OC(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4d Ha-OC(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 4d -OC(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4d Ha-OC(S)R 1a where R 1a is as defined herein. In certain embodiments, R 4d HA-OC(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 4d -OC(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4d -OS(O)R 1a where R 1ais as defined herein. In certain embodiments, R 4d -OS(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 4d -OS(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4d -OS(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4d Ha-NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4d Ha-NR 1a C(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4d Ha-NR 1a C(O)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4d Ha-NR 1a C(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4d Ha-NR 1a C(O)SR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4dHa-NR 1a C(NR 1d )NR 1b R 1c where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, R 4d Ha-NR 1a C(S)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4d Ha-NR 1a C(S)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4d Ha-NR 1a C(S)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4d Ha-NR 1a S(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4d Ha-NR 1a S(O)2R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 4d Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4d Ha-NR 1a S(O)NR 1bR 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 4d Ha-SR 1a where R 1a is as defined herein. In certain embodiments, R 4d -S(O)R 1a where R 1a is as defined herein. In certain embodiments, R 4d -S(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 4d is -S(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4d is -S(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 4d is hydrogen, fluoro, methyl, or methoxy.

[0180] In some embodiments, R 5a is hydrogen. In some embodiments, R 5a is deuterium. In some embodiments, R 5a is cyano. In some embodiments, R 5a is halo. In certain embodiments, R 5a is fluoro, chloro, or bromo. 5a is nitro. In some embodiments, R 5a is oxo. In some embodiments, R 5a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R5a is methyl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is methyl. In some embodiments, R 5a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 5a is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is heterocyclyl optionally substituted with one or more substituents Q.

[0181] In some embodiments, R 5a -C(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5a -C(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 5a is -C(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5a -C(O)SR 1a where R1a is as defined herein. In certain embodiments, R 5a -C(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5a -C(S)R 1a where R 1a is as defined herein. In certain embodiments, R 5a HA-C(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 5a -C(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5a HA-OR 1a where R 1a is as defined herein. In certain embodiments, R 5a Ha-OC(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5a HA-OC(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 5a -OC(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5a Ha-OC(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 5a -OC(NR 1a )NR 1b R1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5a Ha-OC(S)R 1a where R 1a is as defined herein. In certain embodiments, R 5a HA-OC(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 5a -OC(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5a -OS(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5a -OS(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 5a -OS(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5a -OS(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5a Ha-NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5a Ha-NR 1a C(O)R 1d where R 1a and R1d and R are each as defined herein. In certain embodiments, R 5a Ha-NR 1a C(O)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5a Ha-NR 1a C(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5a Ha-NR 1a C(O)SR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5a Ha-NR 1a C(NR 1d )NR 1b R 1c where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, R 5a Ha-NR 1a C(S)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5a Ha-NR 1a C(S)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5a Ha-NR 1a C(S)NR 1b R 1c where R 1a , R 1b , and R 1cand R are each as defined herein. In certain embodiments, R 5a Ha-NR 1a S(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5a Ha-NR 1a S(O)2R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5a Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5a Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5a Ha-SR 1a where R 1a is as defined herein. In certain embodiments, R 5a -S(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5a -S(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 5a is -S(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5a is -S(O)2NR 1b R 1cwhere R 1b and R 1c are each as defined herein.

[0182] In some embodiments, R 5b is hydrogen. In some embodiments, R 5b is deuterium. In some embodiments, R 5b is cyano. In some embodiments, R 5b is halo. In certain embodiments, R 5b is fluoro, chloro, or bromo. 5b is nitro. In some embodiments, R 5b is oxo. In some embodiments, R 5b is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 5b is difluoromethyl, trifluoromethyl, 1,1-difluoromethyl, or 1,1-difluoro-2-hydroxyethyl. 5b is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 5b is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 5b is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 5b is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5bis monocyclic heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is a 5-membered heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is pyrazolyl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is pyrazol-4-yl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is heterocyclyl optionally substituted with one or more substituents Q.

[0183] In some embodiments, R 5b -C(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5b -C(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 5b is -C(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5b -C(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 5b -C(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5b -C(S)R 1a where R 1a is as defined herein. In certain embodiments, R 5b HA-C(S)OR 1a where R 1ais as defined herein. In certain embodiments, R 5b -C(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5b HA-OR 1a where R 1a is as defined herein. In certain embodiments, R 5b Ha-OC(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5b HA-OC(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 5b -OC(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5b Ha-OC(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 5b -OC(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5b Ha-OC(S)R 1a where R 1a is as defined herein. In certain embodiments, R 5b HA-OC(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 5b -OC(S)NR 1b R 1c where R1b and R 1c and R are each as defined herein. In certain embodiments, R 5b -OS(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5b -OS(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 5b -OS(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5b -OS(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5b Ha-NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5b Ha-NR 1a C(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5b Ha-NR 1a C(O)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5b Ha-NR 1a C(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5bHa-NR 1a C(O)SR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5b Ha-NR 1a C(NR 1d )NR 1b R 1c where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, R 5b Ha-NR 1a C(S)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5b Ha-NR 1a C(S)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5b Ha-NR 1a C(S)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5b Ha-NR 1a S(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5b Ha-NR 1a S(O)2R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5b Ha-NR 1a S(O)NR 1b R 1c where R1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5b Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5b Ha-SR 1a where R 1a is as defined herein. In certain embodiments, R 5b -S(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5b -S(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 5b is -S(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5b is -S(O)2NR 1b R 1c where R 1b and R 1c are each as defined herein.

[0184] In some embodiments, R 5c is hydrogen. In some embodiments, R 5c is deuterium. In some embodiments, R 5c is cyano. In some embodiments, R 5c is halo. In certain embodiments, R 5c is fluoro, chloro, or bromo. 5c is nitro. In some embodiments, R 5cis oxo. In some embodiments, R 5c is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 5c is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 5c is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 5c is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 5c is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 5c is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 5c is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 5c is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5c is heterocyclyl optionally substituted with one or more substituents Q.

[0185] In some embodiments, R 5c -C(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5c -C(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 5c is -C(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5c -C(O)SR 1a where R1a is as defined herein. In certain embodiments, R 5c -C(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5c -C(S)R 1a where R 1a is as defined herein. In certain embodiments, R 5c HA-C(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 5c -C(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5c HA-OR 1a where R 1a is as defined herein. In certain embodiments, R 5c Ha-OC(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5c HA-OC(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 5c -OC(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5c Ha-OC(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 5c -OC(NR 1a )NR 1b R1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5c Ha-OC(S)R 1a where R 1a is as defined herein. In certain embodiments, R 5c HA-OC(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 5c -OC(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5c -OS(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5c -OS(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 5c -OS(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5c -OS(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5c Ha-NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5c Ha-NR 1a C(O)R 1d where R 1a and R1d and R are each as defined herein. In certain embodiments, R 5c Ha-NR 1a C(O)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5c Ha-NR 1a C(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5c Ha-NR 1a C(O)SR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5c Ha-NR 1a C(NR 1d )NR 1b R 1c where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, R 5c Ha-NR 1a C(S)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5c Ha-NR 1a C(S)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5c Ha-NR 1a C(S)NR 1b R 1c where R 1a , R 1b , and R 1cand R are each as defined herein. In certain embodiments, R 5c Ha-NR 1a S(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5c Ha-NR 1a S(O)2R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5c Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5c Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5c Ha-SR 1a where R 1a is as defined herein. In certain embodiments, R 5c -S(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5c -S(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 5c is -S(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5c is -S(O)2NR 1b R 1cwhere R 1b and R 1c are each as defined herein.

[0186] In some embodiments, R 5d is hydrogen. In some embodiments, R 5d is deuterium. In some embodiments, R 5d is cyano. In some embodiments, R 5d is halo. In certain embodiments, R 5d is fluoro, chloro, or bromo. 5d is nitro. In some embodiments, R 5d is oxo. In some embodiments, R 5d is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 5d is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 5d is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 5d is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 5d is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 5d is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 5d is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 5d is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5d is heterocyclyl optionally substituted with one or more substituents Q.

[0187] In some embodiments, R5d -C(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5d -C(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 5d is -C(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5d -C(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 5d -C(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5d -C(S)R 1a where R 1a is as defined herein. In certain embodiments, R 5d HA-C(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 5d -C(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5d HA-OR 1a where R 1a is as defined herein. In certain embodiments, R 5d Ha-OC(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5dHA-OC(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 5d -OC(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5d Ha-OC(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 5d -OC(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5d Ha-OC(S)R 1a where R 1a is as defined herein. In certain embodiments, R 5d HA-OC(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 5d -OC(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5d -OS(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5d -OS(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 5d -OS(O)NR 1b R 1c where R 1b and R 1cand R are each as defined herein. In certain embodiments, R 5d -OS(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5d Ha-NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5d is —NH. In some embodiments, R 5d Ha-NR 1a C(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5d Ha-NR 1a C(O)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5d Ha-NR 1a C(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5d Ha-NR 1a C(O)SR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5d Ha-NR 1a C(NR 1d )NR 1b R 1c where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, R5d Ha-NR 1a C(S)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5d Ha-NR 1a C(S)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5d Ha-NR 1a C(S)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5d Ha-NR 1a S(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5d Ha-NR 1a S(O)2R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5d Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5d Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5d Ha-SR 1a where R 1ais as defined herein. In certain embodiments, R 5d -S(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5d -S(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 5d is -S(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5d is -S(O)2NR 1b R 1c where R 1b and R 1c are each as defined herein.

[0188] In some embodiments, R 5e is hydrogen. In some embodiments, R 5e is deuterium. In some embodiments, R 5e is cyano. In some embodiments, R 5e is halo. In certain embodiments, R 5e is fluoro, chloro, or bromo. 5e is nitro. In some embodiments, R 5e is oxo. In some embodiments, R 5e is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 5e is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 5e is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 5e is C optionally substituted with one or more substituents Q 2-6In certain embodiments, R 5e is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 5e is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 5e is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 5e is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5e is heterocyclyl optionally substituted with one or more substituents Q.

[0189] In some embodiments, R 5e -C(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5e -C(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 5e is -C(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5e -C(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 5e -C(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5e -C(S)R 1a where R 1a is as defined herein. In certain embodiments, R5e HA-C(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 5e -C(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5e HA-OR 1a where R 1a is as defined herein. In certain embodiments, R 5e Ha-OC(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5e HA-OC(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 5e -OC(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5e Ha-OC(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 5e -OC(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5e Ha-OC(S)R 1a where R 1a is as defined herein. In certain embodiments, R 5e HA-OC(S)OR 1a where R 1a is as defined herein. In certain embodiments, R5e -OC(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5e -OS(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5e -OS(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 5e -OS(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5e -OS(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5e Ha-NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5e Ha-NR 1a C(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5e Ha-NR 1a C(O)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5e Ha-NR 1a C(O)NR 1b R 1c where R 1a , R 1b , and R1c and R are each as defined herein. In certain embodiments, R 5e Ha-NR 1a C(O)SR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5e Ha-NR 1a C(NR 1d )NR 1b R 1c where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, R 5e Ha-NR 1a C(S)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5e Ha-NR 1a C(S)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5e Ha-NR 1a C(S)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5e Ha-NR 1a S(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5e Ha-NR 1a S(O)2R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 5e Ha-NR1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5e Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 5e Ha-SR 1a where R 1a is as defined herein. In certain embodiments, R 5e -S(O)R 1a where R 1a is as defined herein. In certain embodiments, R 5e -S(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 5e is -S(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 5e is -S(O)2NR 1b R 1c where R 1b and R 1c are each as defined herein.

[0190] In some embodiments, R 6a is hydrogen. In some embodiments, R 6a is deuterium. In some embodiments, R 6a is cyano. In some embodiments, R 6a is halo. In certain embodiments, R 6a is fluoro, chloro, or bromo.6a is nitro. In some embodiments, R 6a is oxo. In some embodiments, R 6a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 6a is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 6a is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 6a is phenyl optionally substituted with one or more substituents Q. In certain embodiments, R 6a is 2-hydroxymethylphenyl, 2-aminomethylphenyl, 2-methylaminomethylphenyl, or 2-(2-aminoethyl)phenyl. 6a is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 6a is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 6a is 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl optionally substituted with one or more substituents Q. In certain embodiments, R 6a is heterocyclyl optionally substituted with one or more substituents Q.

[0191] In some embodiments, R 6a -C(O)R 1a where R 1ais as defined herein. In certain embodiments, R 6a -C(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 6a is -C(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6a -C(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 6a -C(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6a -C(S)R 1a where R 1a is as defined herein. In certain embodiments, R 6a HA-C(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 6a -C(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6a HA-OR 1a where R 1a is as defined herein. In certain embodiments, R 6a Ha-OC(O)R 1a where R 1a is as defined herein. In certain embodiments, R 6a HA-OC(O)OR 1a where R 1ais as defined herein. In certain embodiments, R 6a -OC(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6a Ha-OC(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 6a -OC(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6a Ha-OC(S)R 1a where R 1a is as defined herein. In certain embodiments, R 6a HA-OC(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 6a -OC(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6a -OS(O)R 1a where R 1a is as defined herein. In certain embodiments, R 6a -OS(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 6a -OS(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6a -OS(O)2NR1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6a Ha-NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6a Ha-NR 1a C(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6a Ha-NR 1a C(O)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6a Ha-NR 1a C(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6a Ha-NR 1a C(O)SR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6a Ha-NR 1a C(NR 1d )NR 1b R 1c where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, R 6a Ha-NR 1a C(S)R 1d where R 1a and R 1dand R are each as defined herein. In certain embodiments, R 6a Ha-NR 1a C(S)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6a Ha-NR 1a C(S)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6a Ha-NR 1a S(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6a Ha-NR 1a S(O)2R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6a Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6a Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6a Ha-SR 1a where R 1a is as defined herein. In certain embodiments, R 6a -S(O)R 1a where R 1ais as defined herein. In certain embodiments, R 6a -S(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 6a is -S(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6a is -S(O)2NR 1b R 1c where R 1b and R 1c are each as defined herein.

[0192] In some embodiments, R 6b is hydrogen. In some embodiments, R 6b is deuterium. In some embodiments, R 6b is cyano. In some embodiments, R 6b is halo. In certain embodiments, R 6b is fluoro, chloro, or bromo. 6b is nitro. In some embodiments, R 6b is oxo. In some embodiments, R 6b is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 6b is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 6b is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 6b is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 6b is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 6bis C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 6b is phenyl optionally substituted with one or more substituents Q. In certain embodiments, R 6b is 2-hydroxymethylphenyl, 2-aminomethylphenyl, 2-methylaminomethylphenyl, or 2-(2-aminoethyl)phenyl. 6b is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 6b is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 6b is 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl optionally substituted with one or more substituents Q. In certain embodiments, R 6b is heterocyclyl optionally substituted with one or more substituents Q.

[0193] In some embodiments, R 6b -C(O)R 1a where R 1a is as defined herein. In certain embodiments, R 6b -C(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 6b is -C(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6b -C(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 6b -C(NR 1a )NR 1b R 1c where R 1a , R 1b , and R1c and R are each as defined herein. In certain embodiments, R 6b -C(S)R 1a where R 1a is as defined herein. In certain embodiments, R 6b HA-C(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 6b -C(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6b HA-OR 1a where R 1a is as defined herein. In certain embodiments, R 6b Ha-OC(O)R 1a where R 1a is as defined herein. In certain embodiments, R 6b HA-OC(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 6b -OC(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6b Ha-OC(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 6b -OC(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6b Ha-OC(S)R 1a where R1a is as defined herein. In certain embodiments, R 6b HA-OC(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 6b -OC(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6b -OS(O)R 1a where R 1a is as defined herein. In certain embodiments, R 6b -OS(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 6b -OS(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6b -OS(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6b Ha-NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6b Ha-NR 1a C(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6b Ha-NR 1a C(O)OR 1d where R 1a and R 1dand R are each as defined herein. In certain embodiments, R 6b Ha-NR 1a C(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6b Ha-NR 1a C(O)SR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6b Ha-NR 1a C(NR 1d )NR 1b R 1c where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, R 6b Ha-NR 1a C(S)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6b Ha-NR 1a C(S)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6b Ha-NR 1a C(S)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6b Ha-NR 1a S(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R6b Ha-NR 1a S(O)2R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6b Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6b Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6b Ha-SR 1a where R 1a is as defined herein. In certain embodiments, R 6b -S(O)R 1a where R 1a is as defined herein. In certain embodiments, R 6b -S(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 6b is -S(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6b is -S(O)2NR 1b R 1c where R 1b and R 1c are each as defined herein.

[0194] In some embodiments, R 6c is hydrogen. In some embodiments, R 6cis deuterium. In some embodiments, R 6c is cyano. In some embodiments, R 6c is halo. In certain embodiments, R 6c is fluoro, chloro, or bromo. 6c is nitro. In some embodiments, R 6c is oxo. In some embodiments, R 6c is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 6c is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 6c is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 6c is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 6c is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 6c is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 6c is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 6c is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 6c is heterocyclyl optionally substituted with one or more substituents Q.

[0195] In some embodiments, R 6c -C(O)R 1a where R 1a is as defined herein. In certain embodiments, R 6c -C(O)OR 1a where R 1ais as defined herein. In certain embodiments, R 6c is -C(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6c -C(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 6c -C(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6c -C(S)R 1a where R 1a is as defined herein. In certain embodiments, R 6c HA-C(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 6c -C(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6c HA-OR 1a where R 1a is as defined herein. In certain embodiments, R 6c Ha-OC(O)R 1a where R 1a is as defined herein. In certain embodiments, R 6c HA-OC(O)OR 1a where R 1a is as defined herein. In certain embodiments, R 6c -OC(O)NR 1b R 1c where R 1band R 1c and R are each as defined herein. In certain embodiments, R 6c Ha-OC(O)SR 1a where R 1a is as defined herein. In certain embodiments, R 6c -OC(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6c Ha-OC(S)R 1a where R 1a is as defined herein. In certain embodiments, R 6c HA-OC(S)OR 1a where R 1a is as defined herein. In certain embodiments, R 6c -OC(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6c -OS(O)R 1a where R 1a is as defined herein. In certain embodiments, R 6c -OS(O)2R 1a where R 1a is as defined herein. In certain embodiments, R 6c -OS(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6c -OS(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R6c Ha-NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6c Ha-NR 1a C(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6c Ha-NR 1a C(O)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6c Ha-NR 1a C(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6c Ha-NR 1a C(O)SR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6c Ha-NR 1a C(NR 1d )NR 1b R 1c where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, R 6c Ha-NR 1a C(S)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6c Ha-NR 1a C(S)OR 1d where R 1a and R1d and R are each as defined herein. In certain embodiments, R 6c Ha-NR 1a C(S)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6c Ha-NR 1a S(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6c Ha-NR 1a S(O)2R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R 6c Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6c Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R 6c Ha-SR 1a where R 1a is as defined herein. In certain embodiments, R 6c -S(O)R 1a where R 1a is as defined herein. In certain embodiments, R 6c -S(O)2R 1a where R 1a is as defined herein. In certain embodiments, R6c is -S(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R 6c is -S(O)2NR 1b R 1c where R 1b and R 1c are each as defined herein.

[0196] In some embodiments, R E1 is hydrogen. In some embodiments, R E1 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R E1 is -OC(O)R a C is replaced by 1-6 alkyl, where R a is as defined herein. In certain embodiments, R E1 is -OC(O)R a C is replaced by 1-6 alkyl, where R a is -NR f R g C is replaced by 1-6 alkyl; and R f and R g and R are each as defined herein. In certain embodiments, R E1 is valyloxymethyl, D-valyloxymethyl, or L-valyloxymethyl. In certain embodiments, R E1 is -OP(O)(OR b ) OR c C is replaced by 1-6 alkyl, where R b and R c and R are each as defined herein. In certain embodiments, R E1 is (di-tert-butoxyphosphoryloxy)methyl.

[0197] In some embodiments, R E2 is hydrogen. In some embodiments, R E2 is deuterium. In some embodiments, R E2 is halo. In certain embodiments, R E2 is fluoro. In some embodiments, R E2 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R E2 is methyl optionally substituted with one or more substituents Q. In certain embodiments, R E2 is methyl.

[0198] In some embodiments, R E3 is hydrogen. In some embodiments, R E3 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R E3 is methyl optionally substituted with one or more substituents Q. In certain embodiments, R E3 is methyl.

[0199] In some embodiments, R E4 is deuterium. In some embodiments, R E4 is cyano. In some embodiments, R E4 is halo. In certain embodiments, R E4 is fluoro, chloro, or bromo. E4 is nitro. In some embodiments, R E4 is oxo. In some embodiments, R E4 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R E4 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R E4 is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R E4is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R E4 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R E4 is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R E4 is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R E4 is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R E4 is heterocyclyl optionally substituted with one or more substituents Q.

[0200] In some embodiments, R E4 -C(O)R 1a where R 1a is as defined herein. In certain embodiments, R E4 -C(O)OR 1a where R 1a is as defined herein. In certain embodiments, R E4 is -C(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R E4 -C(O)SR 1a where R 1a is as defined herein. In certain embodiments, R E4 -C(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R E4 -C(S)R 1a where R 1ais as defined herein. In certain embodiments, R E4 HA-C(S)OR 1a where R 1a is as defined herein. In certain embodiments, R E4 -C(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R E4 HA-OR 1a where R 1a is as defined herein. In certain embodiments, R E4 Ha-OC(O)R 1a where R 1a is as defined herein. In certain embodiments, R E4 HA-OC(O)OR 1a where R 1a is as defined herein. In certain embodiments, R E4 -OC(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R E4 Ha-OC(O)SR 1a where R 1a is as defined herein. In certain embodiments, R E4 -OC(NR 1a )NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R E4 Ha-OC(S)R 1a where R 1a is as defined herein. In certain embodiments, R E4 HA-OC(S)OR 1a where R 1ais as defined herein. In certain embodiments, R E4 -OC(S)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R E4 -OS(O)R 1a where R 1a is as defined herein. In certain embodiments, R E4 -OS(O)2R 1a where R 1a is as defined herein. In certain embodiments, R E4 -OS(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R E4 -OS(O)2NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R E4 Ha-NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R E4 Ha-NR 1a C(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R E4 Ha-NR 1a C(O)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R E4 Ha-NR 1a C(O)NR 1b R 1c where R1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R E4 Ha-NR 1a C(O)SR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R E4 Ha-NR 1a C(NR 1d )NR 1b R 1c where R 1a , R 1b , R 1c , and R 1d and R are each as defined herein. In certain embodiments, R E4 Ha-NR 1a C(S)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R E4 Ha-NR 1a C(S)OR 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R E4 Ha-NR 1a C(S)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R E4 Ha-NR 1a S(O)R 1d where R 1a and R 1d and R are each as defined herein. In certain embodiments, R E4 Ha-NR 1a S(O)2R 1d where R 1a and R 1dand R are each as defined herein. In certain embodiments, R E4 Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R E4 Ha-NR 1a S(O)NR 1b R 1c where R 1a , R 1b , and R 1c and R are each as defined herein. In certain embodiments, R E4 Ha-SR 1a where R 1a is as defined herein. In certain embodiments, R E4 -S(O)R 1a where R 1a is as defined herein. In certain embodiments, R E4 -S(O)2R 1a where R 1a is as defined herein. In certain embodiments, R E4 is -S(O)NR 1b R 1c where R 1b and R 1c and R are each as defined herein. In certain embodiments, R E4 is -S(O)2NR 1b R 1c where R 1b and R 1c are each as defined herein.

[0201] In certain embodiments, L is -Z L -R L -Z L -, and each R L and Z L is as defined herein. In certain embodiments, L is -ZL -(R L -Z L )2-, and each R L and Z L is as defined herein. In certain embodiments, L is -Z L -(R L -Z L )3-, and each R L and Z L is as defined herein. In certain embodiments, L is -Z L -(R L -Z L )4-, and each R L and Z L is as defined herein. In certain embodiments, L is -Z L -(R L -Z L )5-, and each R L and Z L is as defined herein. In certain embodiments, L is -Z L -(R L -Z L )6-, and each R L and Z L is as defined herein. In certain embodiments, L is -Z L -(R L -Z L )7-, and each R L and Z L is as defined herein. In certain embodiments, L is -Z L -(R L -Z L )8-, and each R L and Z L is as defined herein. In certain embodiments, L is -Z L -(R L -Z L )9-, and each R L and Z Lis as defined herein. In certain embodiments, L is -Z L -(R L -Z L ) 10 -, and each R L and Z L is as defined herein.

[0202] In some embodiments, R L The group is a C optionally substituted with one or more substituents Q independently. 1-10 In some embodiments, R L The groups are independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, undecanediyl, dodecanediyl, or tridecanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, R L The groups are independently methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, or tridecane-1,13-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, R L The groups are independently methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, or octane-1,8-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, R L The group is independently a C optionally substituted with one or more substituents Q 2-10 In some embodiments, R L The group is independently a C optionally substituted with one or more substituents Q 2-10 In some embodiments, R LThe groups are independently ethyne-1,2-diyl. In certain embodiments, R L The group is independently a C optionally substituted with one or more substituents Q 3-10 In some embodiments, R L The group is independently a monocyclic C optionally substituted with one or more substituents Q. 3-10 In some embodiments, R L The group is independently a bicyclic C optionally substituted with one or more substituents Q. 4-10 In some embodiments, R L The groups are independently cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cyclohexanediyl, or bicyclo[2.2.2]octanediyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, R L The groups are independently cyclobutene-1,3-diyl, cyclopentane-1,3-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, or bicyclo[2.2.2]octane-1,4-diyl, each optionally substituted with one or more substituents Q.

[0203] In some embodiments, R L The group is a C optionally substituted with one or more substituents Q independently. 6-14 In some embodiments, R L The group is phendiyl, optionally substituted independently with one or more substituents Q. In certain embodiments, R L The groups are independently phen-1,3-diyl or phen-1,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, R L The group is heteroarylene, optionally substituted independently with one or more substituents Q. In certain embodiments, R L The group is a monocyclic heteroarylene optionally substituted independently with one or more substituents Q. In certain embodiments, R LThe groups are independently 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, R L The groups are independently pyrazolediyl, pyrazolediyl, imidazolediyl, 1,2,3-triazolediyl, pyrimidinediyl, pyrimidinediyl, or 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinediyl, each optionally substituted with one or more substituents Q. In certain embodiments, R L The groups are independently pyrazole-1,3-diyl, pyrazole-1,4-diyl, imidazole-1,4-diyl, 1,2,3-triazole-1,4-diyl, pyrimidine-2,4-diyl, pyrimidine-2,5-diyl, or 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazine-1,7-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, R L The group is heterocyclylene, optionally substituted independently with one or more substituents Q. In certain embodiments, R L The group is a monocyclic heterocyclylene optionally substituted independently with one or more substituents Q. In certain embodiments, R L The groups are independently 5- or 6-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, R L The group is a bicyclic heterocyclylene optionally substituted with one or more substituents Q. In certain embodiments, R L The groups are independently pyrazolidinediyl, pyrazolidinediyl, 1,3-dioxanediyl, piperazinediyl, piperidinediyl, piperidinediyl, or 3,9-diazaspiro[5.5]-undecanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, R LThe groups are independently pyrazolidine-1,3-diyl, pyrazolidine-1,4-diyl, 1,3-dioxane-2,5-diyl, piperazine-1,4-diyl, piperidine-1,3-diyl, piperidine-1,4-diyl, or 3,9-diazaspiro[5.5]undecane-3,9-diyl, each optionally substituted with one or more substituents Q.

[0204] In some embodiments, Z L The groups are independently a bond. L The groups are independently —C(O)—. In some embodiments, Z L The groups are independently —C(O)O—. In some embodiments, Z L The groups are independently —C(O)NR 1b -, where R 1b is as defined herein. In certain embodiments, Z L The groups are independently —C(O)NH—. In some embodiments, Z L The groups are independently —C(O)NCH—. In some embodiments, Z L The groups are independently —C(O)S—. In some embodiments, Z L The groups are independently —C(NR 1a )NR 1b -, where R 1a and R 1b and Z are each as defined herein. In certain embodiments, Z L The groups are independently -C(S)-. In some embodiments, Z L The groups are independently —C(S)O—. In some embodiments, Z L The groups are independently —C(S)NR 1b -, where R 1b is as defined herein. In certain embodiments, Z L The groups are independently -O-. L The groups are independently -OC(O)O-. In some embodiments, Z L The groups are independently —OC(O)NR 1b -, where R 1bis as defined herein. In certain embodiments, Z L The groups are independently -OC(O)NH-. In some embodiments, Z L The groups are independently -OC(O)NCH3-. In some embodiments, Z L The groups are independently -OC(O)S-. In some embodiments, Z L The groups are independently -OC(NR 1a )NR 1b -, where R 1a and R 1b and Z are each as defined herein. In certain embodiments, Z L The groups are independently -OC(S)O-. In some embodiments, Z L The groups are independently -OC(S)NR 1b -, where R 1b and Z are each as defined herein. In certain embodiments, Z L The groups are independently -OS(O)-. In some embodiments, Z L The groups are independently -OS(O)-. In some embodiments, Z L The groups are independently -OS(O)NR 1b -, where R 1b is as defined herein. In certain embodiments, Z L The groups are independently -OS(O)NR 1b -, where R 1b is as defined herein. In certain embodiments, Z L The groups are independently -NR 1b -, where R 1b is as defined herein. In certain embodiments, Z L The groups are independently -NH-. In some embodiments, Z L The groups are independently -NCH3-. In some embodiments, Z L The groups are independently -NR 1a C(O)NR 1b In some embodiments, Z L The groups are independently -NHC(O)NH-. In some embodiments, Z LThe groups are independently -NHC(O)NCH3-. In some embodiments, Z L The groups are independently —NCH3C(O)NCH3—. In some embodiments, Z L The groups are independently -NR 1a C(O)S-, where R 1a is as defined herein. In certain embodiments, Z L The groups are independently -NR 1a C(NR 1d )NR 1b -, where R 1a , R 1b , and R 1d and Z are each as defined herein. In certain embodiments, Z L The groups are independently -NR 1a C(S)NR 1b -, where R 1a and R 1b and Z are each as defined herein. In certain embodiments, Z L The groups are independently -NR 1a S(O)NR 1b -, where R 1a and R 1b and Z are each as defined herein. In certain embodiments, Z L The groups are independently -NR 1a S(O)NR 1b -, where R 1a and R 1b and Z are each as defined herein. In certain embodiments, Z L The groups are independently -S-. In some embodiments, Z L The groups are independently -S(O)-. In some embodiments, Z L The groups are independently -S(O)-. In some embodiments, Z L The groups are independently —S(O)NR 1b In some embodiments, Z L The groups are independently -S(O)NR 1b -, where R 1b is as defined herein.

[0205] In some embodiments, U is -C=. In some embodiments, U is -N-. In some embodiments, U is -C(R 4 )=, where R 4 is as defined herein. In certain embodiments, U is -N=.

[0206] In some embodiments, V is -C=. In some embodiments, V is -N-. In some embodiments, V is -C(R 4 )=, where R 4 is as defined herein. In certain embodiments, V is -N=.

[0207] In some embodiments, X is -C=. In some embodiments, X is -N-. In some embodiments, X is -C(R 4 )=, where R 4 is as defined herein. In certain embodiments, X is -N=.

[0208] In some embodiments, Y is -C=. In some embodiments, Y is -N-. In some embodiments, Y is -C(R 4 )=, where R 4 is as defined herein. In certain embodiments, Y is -N=.

[0209] In some embodiments, Z 1 is C. In some embodiments, Z 1 is N.

[0210] In some embodiments, Z 2 -C(R E5 )=, where R E5 is as defined herein. In certain embodiments, Z 2 is -C(H)=. In some embodiments, Z 2 is -N=. In some embodiments, Z 2 -N(R E6)-, where R E6 is as defined herein. In certain embodiments, Z 2 -N(R E6 )-, where R E6 is hydrogen or C optionally substituted with one or more substituents Q 1-6 In some embodiments, Z is alkyl. 2 is —N(H)— or —N(CH3)—.

[0211] In some embodiments, Z 3 -C(R E5 )=, where R E5 is as defined herein. In certain embodiments, Z 3 is -C(H)=. In some embodiments, Z 3 is -N=. In some embodiments, Z 3 -N(R E6 )-, where R E6 is as defined herein. In certain embodiments, Z 3 -N(R E6 )-, where R E6 is hydrogen or C optionally substituted with one or more substituents Q 1-6 In some embodiments, Z is alkyl. 3 is —N(H)— or —N(CH3)—.

[0212] In some embodiments, X E is C(R E2 ), where R E2 is as defined herein. In certain embodiments, X E is C(H), C(D), or C(CH). In some embodiments, X E is C(H). In some embodiments, X E is C(CH). In some embodiments, X E is N.

[0213] In one embodiment, Y E is a bond. In some embodiments, YE is C optionally substituted with one or more substituents Q 1-6 In some embodiments, Y is alkylene. E is methanediyl optionally substituted with one or more substituents Q. In certain embodiments, Y E is methanediyl. In some embodiments, Y E is —O—. In some embodiments, Y E is -S-. In some embodiments, Y E is -S(O)-. In some embodiments, Y E is —S(O)—. In some embodiments, Y E -N(R E3 )-, where R E2 is as defined herein. In some embodiments, Y E is —N(H)— or —N(CH)—. In certain embodiments, Y E is -N(H)-.

[0214] In some embodiments, Z E is C optionally substituted with one or more substituents Q 6-14 In some embodiments, Z is arylene. E is phendiyl optionally substituted with one or more substituents Q. In certain embodiments, Z E is phen-1,3-diyl or phen-1,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, Z E is phen-1,3-diyl optionally substituted with one or more substituents Q. In certain embodiments, Z E is phen-1,4-diyl optionally substituted with one or more substituents Q. In certain embodiments, Z E is phen-1,3-diyl, phen-1,3-diyl, 2-methylphen-1,3-diyl, or 2-methylphen-1,4-diyl. E is a bicyclic C optionally substituted with one or more substituents Q 9-14 It is an arylene.

[0215] In some embodiments, Z E is heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, Z E is a monocyclic heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, Z E is a 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, Z E is a 5-membered heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, Z E is a 6-membered heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, Z E is pyrazolediyl, imidazolediyl, 1,2,3-triazolediyl, or pyridinediyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, Z E is pyrazole-1,3-diyl, pyrazole-1,4-diyl, pyrazole-3,5-diyl, imidazole-1,4-diyl, imidazole-2,4-diyl, 1,2,3-triazole-1,4-diyl, pyridine-2,4-diyl, pyridine-2,5-diyl, or pyridine-3,5-diyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, Z E is pyrazole-1,3-diyl, pyrazole-1,4-diyl, 1-methylpyrazole-3,5-diyl, imidazole-1,4-diyl, 1-methylimidazole-2,4-diyl, 1,2,3-triazole-1,4-diyl, pyridine-2,4-diyl, pyridine-2,5-diyl, 6-methoxypyridine-2,4-diyl, or 6-methoxypyridine-2,5-diyl.

[0216] In some embodiments, Z E is a bicyclic heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, Z Eis a 5,6-fused or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, Z E is a 5,6-fused heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, Z E is a 6,6-fused heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, Z E is indolediyl, indazoldiyl, imidazo[1,5-a]pyridinediyl, benzimidazolediyl, benzothiazolediyl, pyrrolo[2,3-b]pyridinediyl, quinolinediyl, or isoquinolinediyl, each optionally substituted with one or more substituents Q. In certain embodiments, Z E is indole-3,6-diyl, indole-3,7-diyl, indazole-3,6-diyl, indazole-3,7-diyl, imidazo[1,5-a]pyridine-3,7-diyl, imidazo[1,5-a]pyridine-3,8-diyl, benzimidazole-1,4-diyl, benzimidazole-1,5-diyl, benzothiazole-2,4-diyl, benzothiazole-2,5-diyl, pyrrolo[2,3-b]pyridine-3,6-diyl, quinoline-3,7-diyl, quinoline-3,8-diyl, isoquinoline-1,5-diyl, or isoquinoline-1,6-diyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, Z Eare 1-methyl-indole-3,6-diyl, 1-methyl-indole-3,7-diyl, 1-methylindazole-3,6-diyl, 1-methylindazole-3,7-diyl, imidazo[1,5-a]pyridine-3,7-diyl, imidazo[1,5-a]pyridine-3,8-diyl, imidazo[1,5-a]pyridine-3,7-diyl, imidazo[1,5-a] pyridine-3,8-diyl, benzimidazole-1,4-diyl, benzimidazole-1,5-diyl, 1-methylpyrrolo[2,3-b]pyridine-3,6-diyl, 1-methyl-2-hydroxylquinoline-3,7-diyl, 1-methyl-2-hydroxylquinoline-3,8-diyl, isoquinoline-1,5-diyl, or isoquinoline-1,6-diyl.

[0217] In some embodiments, Z E is C optionally substituted with one or more substituents Q 6-14 arylene-heteroarylene. In certain embodiments, Z E is phendiyl-monocyclic heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, Z E is phendiyl-5-membered heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, Z E is phendiyl-pyrazolediyl, phendiyl-imidazolediyl, or phendiyl-1,2,3-triazolediyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, Z E each optionally substituted with one or more substituents Q; [ka] In some embodiments, Z E teeth, [ka] is.

[0218] In some embodiments, m is an integer of 0. In some embodiments, m is an integer of 1. In some embodiments, m is an integer of 2.

[0219] In some embodiments, n is an integer of 0. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4.

[0220] In some embodiments, p is an integer of 0. In some embodiments, p is an integer of 1. In some embodiments, p is an integer of 2. In some embodiments, p is an integer of 3.

[0221] In some embodiments, z is an integer equal to 1. In some embodiments, z is an integer equal to 2. In some embodiments, z is an integer equal to 3. In some embodiments, z is an integer equal to 4. In some embodiments, z is an integer equal to 5. In some embodiments, z is an integer equal to 6. In some embodiments, z is an integer equal to 7. In some embodiments, z is an integer equal to 8. In some embodiments, z is an integer equal to 9. In some embodiments, z is an integer equal to 10.

[0222] In certain embodiments, provided herein is 3-((3-((7-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)amino)phenyl)amino)piperidine-2,6-dione A1, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0223] In another embodiment, provided herein is a method for treating a psoriasis comprising administering to a subject a therapeutically effective amount of a psoriasis-causing agent comprising: 3-(3-((2-(4-(7-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methyl-quinazolin-7-yl)oxy)heptyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B1; 3-(3-((2-(4-(9-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B2; 3-(3-((2-(4-(11-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B3; 3-(4-((2-(4-(7-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B4; 3-(4-((2-(4-(9-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B5; 3-(4-((2-(4-(11-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B6; 3-(3-(2-(4-(9-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethoxy)phenyl)piperidine-2,6-dione B7; 3-(4-((2-(4-(5-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)pentyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B8; or 3-(3-((2-(4-(5-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)pentyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B9; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0224] In yet another embodiment, provided herein is a method for treating a psoriasis comprising administering to a subject a therapeutically effective amount of a psoriasis-causing agent comprising: (R)-1-(4-(2-(4-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)piperazin-1-yl)-2-oxoethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione C1; (R)-1-(4-(2-(4-(9-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione C2; (R)-1-(4-(2-(4-(11-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione C3; (R)-1-(3-(2-(4-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)piperazin-1-yl)-2-oxoethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione C4; (R)-1-(3-(2-(4-(9-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione C5; or (R)-1-(3-(2-(4-(11-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione C6; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0225] In yet another embodiment, provided herein is a method for treating a psoriasis comprising administering to a subject a therapeutically effective amount of a psoriasis-causing agent comprising: 3-(6-((2-(4-(7-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)-piperidine-2,6-dione D1; 3-(6-((2-(4-(9-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)-piperidine-2,6-dione D2; 3-(6-((2-(4-(11-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)-piperidine-2,6-dione D3; 3-(7-((2-(4-(7-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)-piperidine-2,6-dione D4; 3-(7-((2-(4-(9-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)-piperidine-2,6-dione D5; 3-(7-((2-(4-(11-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione D6; (R)-1-(6-((2-(4-(11-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione D7; (R)-1-(6-((2-(4-(9-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione D8; (S)-1-(7-((2-(4-(9-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione D9; (R)-1-(7-((2-(4-(11-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione D10; or (R)-1-(7-((2-(4-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione D11; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0226] In some embodiments, the compounds provided herein are deuterium enriched. In some embodiments, the compounds provided herein are carbon-13 enriched. In some embodiments, the compounds provided herein are carbon-14 enriched. In some embodiments, the compounds provided herein are nitrogen enriched. 15 N; for oxygen 17 O or 18 O and sulfur 34 S, 35 S, or 36 It includes one or more less common isotopes of other elements, including but not limited to S.

[0227] In some embodiments, the compounds provided herein have an isotopic enrichment factor of about 5 or more, about 10 or more, about 20 or more, about 50 or more, about 100 or more, about 200 or more, about 500 or more, about 1,000 or more, about 2,000 or more, about 5,000 or more, or about 10,000 or more. However, in any case, the isotopic enrichment factor of a specified isotope does not exceed the maximum isotopic enrichment factor of the specified isotope, which is the isotopic enrichment factor when the compound is 100% enriched with that specified isotope at a given position. Therefore, the maximum isotopic enrichment factor for different isotopes is different. The maximum isotopic enrichment factor is 6,410 for deuterium and 90 for carbon-13.

[0228] In certain embodiments, the compounds provided herein have an RI of about 64 (about 1% deuterium enriched) or greater, about 130 (about 2% deuterium enriched) or greater, about 320 (about 5% deuterium enriched) or greater, about 640 (about 10% deuterium enriched) or greater, about 1,300 (about 20% deuterium enriched) or greater, about 3,200 (about 50% deuterium enriched) or greater, about 4,800 (about 75% deuterium enriched) or greater, about 5,130 (about 80% deuterium enriched) or greater. The compound has a deuterium enrichment factor of about 5,450 (about 85% deuterium enriched) or greater, about 5,770 (about 90% deuterium enriched) or greater, about 6,090 (about 95% deuterium enriched) or greater, about 6,220 (about 97% deuterium enriched) or greater, about 6,280 (about 98% deuterium enriched) or greater, about 6,350 (about 99% deuterium enriched) or greater, or about 6,380 (about 99.5% deuterium enriched) or greater. Deuterium enrichment can be determined using routine analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy. In certain embodiments, at least one atom of a compound provided herein that is specified as being deuterium enriched has a deuterium enrichment of about 50% or greater, about 70% or greater, about 80% or greater, about 90% or greater, or about 98% or greater.

[0229] In certain embodiments, the compounds provided herein are isolated or purified, ie, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% pure by weight.

[0230] The compounds provided herein are intended to encompass all possible stereoisomers unless a specific stereochemistry is specified. When a compound provided herein contains an alkenyl group, the compound can exist as one or a mixture of cis / trans (or Z / E) geometric isomers. Where structural isomers are interchangeable, the compound can exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in compounds containing imino, keto, or oxime groups; or so-called valence tautomerism in compounds containing aromatic moieties. A single compound may exhibit more than one type of isomerism.

[0231] The compounds provided herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer; or can be a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a stereoisomeric mixture, such as a mixture of two or more diastereomers. Thus, those skilled in the art will recognize that, for compounds that undergo epimerization in vivo, administration of a compound in its (R) form is equivalent to administration of the compound in its (S) form. Conventional techniques for the preparation / isolation of individual enantiomers include synthesis from appropriate optically pure precursors, asymmetric synthesis from achiral starting materials, or resolution of enantiomeric mixtures, e.g., chiral chromatography, recrystallization, resolution, formation of diastereomeric salts, or derivatization to diastereomeric adducts followed by separation.

[0232] When the compound provided herein contains an acidic or basic moiety, it can also be provided as a pharmaceutically acceptable salt.See Berge et al., J.Pharm.Sci.1977,66,1-19; "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2nd Edition; Stahl and Wermuth, eds.; John Wiley & Sons, 2011.In some embodiments, the pharmaceutically acceptable salt of the compound provided herein is a solvate.In some embodiments, the pharmaceutically acceptable salt of the compound provided herein is a hydrate.

[0233] Suitable acids for use in preparing the pharmaceutically acceptable salts of the compounds provided herein include acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α- These include, but are not limited to, oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0234] Bases suitable for use in preparing the pharmaceutically acceptable salts of the compounds provided herein include inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; as well as L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methylglucamine, hydrabamine, 1H-imidazole, L-lysine, methylaminopropanol ... The bases include, but are not limited to, organic bases such as primary, secondary, tertiary, and quaternary aliphatic and aromatic amines, including, but not limited to, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

[0235] The compounds provided herein may also be provided as prodrugs, which are functional derivatives of the compounds and can be easily converted into the parent compounds in vivo. In some situations, prodrugs are often useful because they can be administered more easily than the parent compounds. For example, prodrugs may be bioavailable by oral administration, whereas the parent compounds may not. Prodrugs may also have increased solubility in pharmaceutical compositions compared to the parent compounds. Prodrugs can be converted into the parent drugs by various mechanisms, including enzymatic processing and metabolic hydrolysis.

[0236] (Pharmaceutical composition) In one embodiment, provided herein is a pharmaceutical composition comprising a compound provided herein, e.g., a compound of Formula (I), or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.

[0237] The pharmaceutical compositions provided herein can be formulated in a variety of dosage forms, including, but not limited to, dosage forms for oral, parenteral, and topical administration. The pharmaceutical compositions can also be formulated as modified-release dosage forms, including delayed-release, extended-release, prolonged-release, sustained-release, pulsed-release, controlled-release, accelerated-release, fast-release, targeted-release, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al. (eds.); Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.

[0238] In one embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for oral administration.In another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for parenteral administration.In yet another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for intravenous administration.In yet another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for intramuscular administration.In yet another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for subcutaneous administration.In yet another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for topical administration.

[0239] The pharmaceutical compositions provided herein can be provided in unit-dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to a physically discrete unit suitable for administration to a subject and packaged individually as known in the art. Each unit dose contains a predetermined amount of active ingredient(s) (e.g., a compound provided herein) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical excipient(s). Examples of unit-dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. Unit-dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of multiple-dosage forms include, but are not limited to, vials, bottles of tablets or capsules, or bottles of pints or gallons.

[0240] The pharmaceutical compositions provided herein can be administered once or multiple times at intervals.It is understood that the exact dosage and duration of treatment can vary according to the age, weight and condition of the subject being treated, and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro testing or diagnostic data.It is further understood that for any particular individual, specific dosage regimen must be adjusted over time according to the needs of the subject and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition.

[0241] (A. Oral Administration) The pharmaceutical compositions for oral administration provided herein can be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, lozenges, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. The pharmaceutical compositions may contain, in addition to the active ingredient(s), one or more pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, color transfer inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and a carbon dioxide source.

[0242] Binders or granulating agents impart cohesive properties to the tablet and ensure that the tablet remains intact after compression. Suitable binders or granulating agents include starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500®); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as gum arabic, alginic acid, alginates, Chorizoides extract, panwar gum, ghatti gum, isagol husk mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum®, larch arabinogalactan, powdered tragacanth, and guar gum; celluloses such as ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); and AVICEL® PH-101, AVICEL® PH-103, AVICEL® Suitable fillers include, but are not limited to, microcrystalline cellulose, such as PH-105 and AVICEL® RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, and pregelatinized starch. The amount of binder or filler in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to one of ordinary skill in the art. The binder or filler may be present in the pharmaceutical compositions provided herein at about 50 to about 99% by weight.

[0243] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Some diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient amounts, can impart properties to some compressed tablets that allow them to disintegrate in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of diluent in the pharmaceutical compositions provided herein varies depending on the type of formulation and can be easily determined by those skilled in the art.

[0244] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation exchange resins; alginic acid; gums such as guar gum and Veegum® HV; citrus pulp; cross-linked celluloses such as croscarmellose; cross-linked polymers such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline celluloses such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; and algin. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to those skilled in the art. The pharmaceutical compositions provided herein may contain about 0.5 to about 15% or about 1 to about 5% by weight of disintegrant.

[0245] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; and silica or silica gels such as AEROSIL® 200 and CAB-O-SIL®. The amount of lubricant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to one of skill in the art. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of lubricant.

[0246] Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL®, and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water-soluble FD&C dyes, water-insoluble FD&C dyes suspended on alumina hydrate, and color lakes. Color lakes are the combination of a water-soluble dye by adsorption to a hydrous oxide of a heavy metal, rendering the dye insoluble. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce a pleasant taste, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, gum arabic, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum®, gum arabic, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, and sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid.Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

[0247] It should be understood that many carriers and excipients may serve several functions, even within the same formulation.

[0248] The pharmaceutical compositions for oral administration provided herein can be provided as compressed tablets, molded tablets, chewable lozenges, quick-dissolving tablets, multi-layer compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, protecting the active ingredient(s) from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in masking objectionable tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets coated with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings exhibit the same general characteristics as sugar coatings. Multilayer compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets and press-coated or dry-coated tablets.

[0249] Tablet dosage forms can be prepared from the active ingredient(s) in powdered, crystalline, or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, release-controlling polymers, lubricants, diluents, and / or coloring agents. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0250] The pharmaceutical compositions for oral administration provided herein can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-fill capsules (DFCs), consist of two sections, one sliding over the other, completely enclosing the active ingredient(s). Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives include those described herein, including methylparaben and propylparaben, and sorbic acid. Liquid, semisolid, and solid dosage forms provided herein may be encapsulated. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. Capsules may also be coated as known to those skilled in the art to modify or maintain dissolution of the active ingredient(s).

[0251] The pharmaceutical compositions for oral administration provided herein can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid and can be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and a preservative. Hydroalcoholic solutions may contain a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, e.g., sucrose, and may also contain a preservative. For a liquid dosage form, for example, the solution in a polyethylene glycol solvent may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be conveniently measured for administration.

[0252] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) and dialkylated mono- or poly-alkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (where 350, 550, and 750 refer to the approximate average molecular weights of the polyethylene glycol). These dosage forms may further contain one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0253] The pharmaceutical compositions for oral administration provided herein can also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micelle dosage forms can be prepared as described in U.S. Patent No. 6,350,458.

[0254] The pharmaceutical compositions for oral administration provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and a carbon dioxide source.

[0255] Coloring and flavoring agents can be used in all of the dosage forms described herein.

[0256] The pharmaceutical compositions for oral administration provided herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0257] (B. Parenteral Administration) The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraureteral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.

[0258] The pharmaceutical compositions for parenteral administration provided herein can be formulated in any dosage form suitable for parenteral administration, including, but not limited to, solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solution or suspension in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical sciences. See, e.g., Remington: The Science and Practice of Pharmacy, supra.

[0259] Pharmaceutical compositions for parenteral administration provided herein can comprise one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to prevent the growth of microorganisms, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.

[0260] Suitable aqueous vehicles include, but are not limited to, water, saline, normal saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and coconut oil, medium-chain triglycerides, and palm kernel oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0261] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-paraben, and sorbic acid. Suitable tonicity adjusting agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphates and citrates. Suitable antioxidants include those described herein, such as bisulfites and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, such as sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-β-cyclodextrin (CAPTISOL®).

[0262] When the pharmaceutical compositions provided herein are formulated for multiple-dose administration, the multiple-dose parenteral formulation must contain the antibacterial agent in a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as known and practiced in the art.

[0263] In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution.In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, including lyophilized powder and hypodermic tablet, which must be reconstituted with a vehicle before use.In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension.In yet another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product, which must be reconstituted with a vehicle before use.In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

[0264] The pharmaceutical compositions provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0265] The pharmaceutical compositions provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient(s) in the pharmaceutical composition to diffuse through.

[0266] Suitable inner matrices include, but are not limited to, polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers (such as hydrogels of esters of acrylic and methacrylic acid), collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0267] Suitable polymeric outer membranes include, but are not limited to, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, vinyl chloride copolymers with ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers.

[0268] (C. Topical Administration) The pharmaceutical compositions provided herein can be administered topically to the skin, orifices, or mucosa. As used herein, topical administration includes (intracutaneous), conjunctival, intracorneal, intraocular, intraocular, otic, transdermal, nasal, vaginal, urethral, ​​respiratory, and rectal administration.

[0269] The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for topical administration for local or systemic effect, including, but not limited to, emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, bandages, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, douches, sprays, suppositories, bandages, and skin patches. Topical formulations of the pharmaceutical compositions provided herein can also include liposomes, micelles, microspheres, and nanosystems.

[0270] Pharmaceutically acceptable carriers and excipients suitable for use in topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to prevent the growth of microorganisms, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

[0271] The pharmaceutical compositions may also be administered locally by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection such as POWDERJECT™ and BIOJECT™.

[0272] The pharmaceutical compositions provided herein can be provided in the form of ointments, creams, and gels. Suitable ointment vehicles include oily or hydrocarbon vehicles, including lard, benzoic lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifying or absorbing vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; moisture-removing vehicles, such as hydrophilic ointments; water-soluble ointment vehicles, including polyethylene glycols of various molecular weights; and emulsion vehicles, either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. See, for example, Remington: The Science and Practice of Pharmacy, supra. These vehicles are emollients, but generally require the addition of antioxidants and preservatives.

[0273] Suitable cream bases can be oil-in-water or water-in-oil. Suitable cream vehicles can be water-washable and include an oil phase, an emulsifier, and an aqueous phase. The oil phase, also referred to as the "internal" phase, is generally composed of petrolatum and a fatty alcohol such as cetyl alcohol or stearyl alcohol. Although not required, the aqueous phase is usually larger in volume than the oil phase and generally conta...

Claims

1. Formula (I): 【Chemical 1】 (In the formula, L is a linker; one of U, V, X, and Y is -C= or -N-; and the remaining three of U, V, X, and Y are each independently -C(R 4 )= or -N=; R 1 and R 3 are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; R 2 is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, Heteroaryl, Heteroaryl-C 1-6 alkylene, or heterocyclyl; Each R 4 are independently (i) hydrogen, deuterium, cyano, halo, nitro, or oxo; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and; Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; X E is C(R E2 ) or N; Y E is a bond, C 1-6 Alkylene, -O-, -S-, -S(O)-, -S(O 2 )- or -N(R E3 )-and; Z E is C 6-14 arylene, heteroarylene, or C 6-14 arylene-heteroarylene; R E1 is hydrogen or C 1-6 is alkyl; R E2 is hydrogen, deuterium, halo, or C 1-6 is alkyl; R E3 is hydrogen or C 1-6 is alkyl; and m is an integer of 0, 1, or 2; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylene, aralkyl, heteroaryl, heteroarylene, and heterocyclyl is optionally substituted with one or more, and in one embodiment 1, 2, 3, or 4, substituents Q, wherein each Q is independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) each is one or more substituents Q a optionally further substituted with C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR b ) OR c , -OS(O)R a , -OS(O) 2 R a , -OS(O)NR b R c , -OS(O) 2 NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O) 2 R d , -NR a S(O)NR b R c , -NR a S(O) 2 NR b R c , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR b R c , and -S(O) 2 NR b R c where each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) each is one or more substituents Q a optionally substituted with C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atoms to which they are attached, one or more substituents Q a forming an optionally substituted heterocyclyl; Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f ) OR g , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR f R g , -OS(O) 2 NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O) 2 R h , -NR e S(O)NR f R g , -NR e S(O) 2 NR f R g , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR f R g , and -S(O) 2 NR f R g where each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclyl) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

2. Formula (III): 【Chemistry 2】 or formula (IV): 【Chemistry 3】 or formula (V): 【Chemistry 4】 (In the formula, R 2a and R 2b are each independently (i) hydrogen, deuterium, or halo; or (ii) each optionally substituted with one or more substituents Q, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; and R 2c each independently represents C, each of which is optionally substituted with one or more substituents Q; 6-14 is aryl or heteroaryl; and R 4a , R 4b , R 4c , and R 4d are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c is) or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

3. R 2c each optionally substituted with 1, 2, or 3 substituents Q; 6-14 is aryl or heteroaryl; or R 2c C optionally substituted with 1, 2 or 3 substituents Q 6-14 is aryl; or R 2c is phenyl optionally substituted by 1, 2, or 3 substituents, each of which is independently fluoro, chloro, bromo, iodo, nitro, methyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 2-hydroxy-1,1-difluoroethyl, 3-hydroxyoxetan-3-yl, pyrazol-4-yl, or amino; or R 2c is optionally substituted with one, two, or three substituents Q; 9-14 is aryl; or R 2c is heteroaryl optionally substituted with 1, 2, or 3 substituents Q; or R 2c is a monocyclic heteroaryl optionally substituted with 1, 2, or 3 substituents Q; or R 2c is a 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents Q; or R 2c is thienyl optionally substituted with 1, 2, or 3 substituents Q; or R 2c is thien-2-yl or thien-3-yl, each optionally substituted with 1, 2, or 3 substituents Q; or R 2c phenyl, 3-bromophenyl, 3-methylphenyl, 3-difluoromethylphenyl, 3-trifluoromethylphenyl, 3-(2,2,2-trifluoroethyl)phenyl, 3-(1-hydroxyethyl)phenyl, 3-(1-hydroxy-1-methylethyl)phenyl, 3-(2-hydroxy-1,1-difluoroethyl)phenyl, 3-(3-hydroxyoxetan-3-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-3-difluoromethylphenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-3-(1,1-difluoroethyl)phenyl, 2-methyl-3-difluoromethylphenyl, 2-methyl-3-trifluoromethylphenyl 3. The compound of claim 2, wherein the compound is selected from the group consisting of 3-trifluoromethyl-5-aminophenyl, 2-fluoro-3-trifluoromethyl-5-aminophenyl, 2-methyl-3-trifluoromethyl-5-aminophenyl, 3,3-difluoro-2,3-dihydro-1H-inden-5-yl, naphth-1-yl, thien-2-yl, 5-(2-hydroxymethylphenyl)thien-2-yl, 5-(2-aminomethylphenyl)thien-2-yl, 4-(2-methylaminomethylphenyl)thien-2-yl, 5-(2-(2-aminoethyl)phenyl)thien-2-yl, 5-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)thien-2-yl, and 3,3-difluoro-2,3-dihydrobenzofuran-5-yl.

4. Formula (X): 【Chemistry 5】 (In the formula, R 5a , R 5b , R 5c , R 5d , and R 5e are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c or R 5a and R 5b or R 5b and R 5c each, together with the carbon atom to which they are attached, optionally substituted with one or more substituents Q; 5-10 Cycloalkyl, C 6-14 Aryl, C 7-15 forming an aralkyl, heteroaryl, or heterocyclyl); or Formula (XVII): 【Chemistry 6】 (In the formula, R 6a , R 6b , and R 6c are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c is) 3. The compound of claim 2 having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

5. Z E C optionally substituted with one or more substituents Q 6-14 is arylene; or Z E is phendiyl optionally substituted by one or more substituents Q; or Z E is heteroarylene optionally substituted with one or more substituents Q; or Z E is a monocyclic heteroarylene optionally substituted with one or more substituents Q; or Z E is a 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q; or Z E is pyrazolediyl, imidazolediyl, 1,2,3-triazolediyl, or pyridinediyl, each optionally substituted with one or more substituents Q; or Z E is pyrazole-1,3-diyl, pyrazole-1,4-diyl, pyrazole-3,5-diyl, imidazole-1,4-diyl, imidazole-2,4-diyl, 1,2,3-triazole-1,4-diyl, pyridine-2,4-diyl, pyridine-2,5-diyl, or pyridine-3,5-diyl, each of which is optionally substituted with one or more substituents Q; or Z E is a bicyclic heteroarylene optionally substituted with one or more substituents Q; or Z E is a 5,6-fused or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q; or Z E is indolediyl, indazoldiyl, imidazo[1,5-a]pyridinediyl, benzimidazoldiyl, benzothiazolediyl, pyrrolo[2,3-b]pyridinediyl, quinolinediyl, or isoquinolinediyl, each optionally substituted with one or more substituents Q; or Z E is indole-3,6-diyl, indole-3,7-diyl, indazole-3,6-diyl, indazole-3,7-diyl, imidazo[1,5-a]pyridine-3,7-diyl, imidazo[1,5-a]pyridine-3,8-diyl, benzimidazole-1,4-diyl, benzimidazole-1,5-diyl, benzothiazole-2,4-diyl, benzothiazole-2,5-diyl, pyrrolo[2,3-b]pyridine-3,6-diyl, quinoline-3,7-diyl, quinoline-3,8-diyl, isoquinoline-1,5-diyl, or isoquinoline-1,6-diyl, each optionally substituted with one or more substituents Q; or Z E C optionally substituted with one or more substituents Q 6-14 arylene-heteroarylene; or Z E is phendiyl-monocyclic heteroarylene optionally substituted with one or more substituents Q; or Z E is phendiyl-5-membered heteroarylene optionally substituted with one or more substituents Q; or Z E is phendiyl-pyrazolediyl, phendiyl-imidazolediyl, or phendiyl-1,2,3-triazolediyl, each optionally substituted with one or more substituents Q; or Z E each optionally substituted with one or more substituents Q 【Chemistry 7】 2. The compound of claim 1, wherein:

6. Formula (XXIII): 【Chemistry 8】 or formula (XXIV): 【Chemistry 9】 or formula (XXV): 【Chemistry 10】 or formula (XXVI): 【Chemistry 11】 (In the formula, Each R E4 are independently (i) deuterium, cyano, halo, or nitro; (ii) each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and each n is independently an integer of 0, 1, 2, 3, or 4; and each n is optionally an integer of 0.

5. The compound of claim 4 having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

7. Formula (XXXV): 【Chemistry 12】 or formula (XXXVI): 【Chemistry 13】 or formula (XXXVII): 【Chemistry 14】 or formula (XXXVIII): 【Chemistry 15】 (In the formula, Z 1 are each independently C or N; Z 2 and Z 3 are independently -C(R E5 )=, -N=, or -N(R E6 )-and; Each R E4 are independently (i) deuterium, cyano, halo, or nitro; (ii) each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and; Each R E5 are independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and; Each R E6 are independently (i) hydrogen; (ii) each optionally substituted with one or more substituents Q; C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and Each p is independently an integer of 0, 1, 2, or 3; and each p is optionally an integer of 0.

5. The compound of claim 4 having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

8. Z 1 is C; or Z 1 is N; and / or Z 2 -C(R E5 )=, and optionally R E5 is hydrogen; or Z 2 is -N=; or Z 2 -N(R E6 )-; and / or Z 3 -C(R E5 ) = , optionally R E5 is hydrogen; or Z 3 is -N=; or Z 3 -N(R E6 8. The compound of claim 7, wherein:

9. Formula(XXXIX): 【Chemistry 16】 or formula (XL): 【Chemistry 17】 or formula (XLI): 【Chemistry 18】 or formula (XLII): 【Chemistry 19】 8. The compound of claim 7 having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

10. R E2 is hydrogen; or R E2 C optionally substituted with one or more substituents Q 1-6 alkyl; or R E2 10. The compound of claim 9, wherein is methyl.

11. R 1 is hydrogen or C optionally substituted with 1, 2 or 3 substituents Q 1-6 alkyl; or R 1 is hydrogen, methyl, trifluoromethyl, or dimethylamino; or R 1 is methyl; and / or R 3 is hydrogen; and / or R 2a is hydrogen or C optionally substituted with 1, 2 or 3 substituents Q 1-6 alkyl; or R 2a is hydrogen, methyl, or ethyl; and / or R 2b is hydrogen or C optionally substituted with 1, 2 or 3 substituents Q 1-6 alkyl; or R 2b is hydrogen, methyl, or ethyl; and / or R 4a is hydrogen; and / or R 4b (i) each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; or (ii) —OR 1a or R 4b C optionally substituted with one, two or three substituents Q 3-10 is cycloalkyl; or R 4b is optionally substituted with one, two or three substituents Q; 3-10 is cycloalkyl; or R 4b is optionally substituted with one, two, or three substituents Q; 4-10 is cycloalkyl; or R 4b is cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl, each optionally substituted with 1, 2, or 3 substituents, wherein each substituent is independently fluoro, methyl, difluoromethyl, 3-cyanoazetidin-1-ylcarbonyl, 3-fluoroazetidin-1-ylcarbonyl, 3-methoxyazetidin-1-ylcarbonyl, 3-hydroxypyrrolidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-(2-methoxyethyl)-2-pyrrolidin ... or R is (methyl)(ethyl)piperazin-1-ylcarbonyl, hydroxycarbonyl, ethoxycarbonyl, dimethylcarbamoyl, (methyl)(ethyl)carbamoyl, (2-hydroxyethyl)(methyl)carbamoyl, (2-hydroxypropyl)(methyl)carbamoyl, (2-hydroxy-2-methylpropyl)(methyl)carbamoyl, (2,3-dihydroxypropyl)(methyl)carbamoyl, (2-methoxyethyl)(methyl)carbamoyl, (methyl)(oxetan-3-yl)carbamoyl, (methyl)(tetrahydrofur-3-yl)carbamoyl, hydroxyl, or acetoxy; or R is 4b 1-methylcyclopropyl, 1-fluoromethylcyclopropyl, 1-difluoromethylcyclopropyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 4-hydroxycyclohexyl, 4-hydroxycarbonylcyclohexyl, 4-ethoxycarbonylcyclohexyl, 4-(3-cyanoazetidin-1-ylcarbonyl)cyclohexyl, 4-(3-fluoroazetidin-1-ylcarbonyl)cyclohexyl, 4-(3-methoxyazetidin-1-ylcarbonyl)cyclohexyl cyclohexyl, 4-(3-hydroxypyrrolidin-1-yl)carbonylcyclohexyl, 4-morpholin-4-ylcarbonylcyclohexyl, 4-(4-methylpiperazin-1-yl)carbonylcyclohexyl, 4-(4-(2-methoxyethyl)piperazin-1-yl)carbonylcyclohexyl, 4-dimethylcarbamoylcyclohexyl, 4-(methyl)(ethyl)carbamoylcyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoylcyclohexyl, 4-(2-hydroxypropyl)( 4-(methyl)carbamoylcyclohexyl, 4-(2-hydroxy-2-methylpropyl)(methyl)carbamoylcyclohexyl, 4-(2,3-dihydroxypropyl)(methyl)carbamoylcyclohexyl, 4-(2-methoxyethyl)(methyl)carbamoylcyclohexyl, 4-(methyl)(oxetan-3-yl)carbamoylcyclohexyl, 4-(methyl)(tetrahydrofur-3-yl)carbamoylcyclohexyl, 4-acetoxy-1-hydroxycyclohexyl, 1,4-dihydroxy cyclohexyl, 4-hydroxycarbonyl-1-hydroxycyclohexyl, 4-ethoxycarbonyl-1-hydroxycyclohexyl, 4-dimethylcarbamoyl-1-hydroxycyclohexyl, 4-(2-hydroxyethyl)(methyl)carbamoyl-1-hydroxycyclohexyl, 4-(2-hydroxypropyl)(methyl)carbamoyl-1-hydroxycyclohexyl, bicyclo[1.1.1]pentan-1-yl, or 4-fluorobicyclo[2.2.2]octan-1-yl; or R 4b is heterocyclyl optionally substituted with 1, 2, or 3 substituents Q; or R 4b is monocyclic heterocyclyl optionally substituted with 1, 2, or 3 substituents Q; or R 4b is a bicyclic heterocyclyl optionally substituted with 1, 2, or 3 substituents Q; or R 4b is tetrahydrofuryl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridinyl, dihydropyranyl, dihydrothiopyranyl, azaspiro[3.3]heptanyl, or 7-azaspiro[3.5]nonanyl, each of which is optionally substituted with one, two, or three substituents, where each substituent is independently oxo, imino, isopropyl, hydroxycarbonylmethyl, dimethylcarbamoylmethyl, tetrahydrofur-3-yl, acetyl, 2-methoxyacetyl, 2-dimethylaminoacetyl, tert-butoxycarbonyl, or hydroxyl; or R 4b However, 3-methyltetrahydrofuran-3-yl, piperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-(hydroxycarbonylmethyl)piperidin-4-yl, 1-(dimethylcarbamoylmethyl)piperidin-4-yl, 1-tetrahydrofur-3-yl-piperidin-4-yl, 1-acetylpiperidin-4-yl, 1-(2-methoxyacetyl)piperidin-4-yl, 1-(2-dimethylaminoacetyl)piperidin-4-yl, 1-tert-butoxycarbonylpiperidin-4-yl, 4-hydroxypiperidin-4-yl, 1-acetyl-4-hydroxypiperidin-4-yl, 1-(2-methoxyacetyl)-4-hydroxypiperidin-4-yl, 4-hydroxy-1-tert-butoxycarbonylpiperidin-4-yl, 1- Dimethylcarbamoyl-4-hydroxypiperidin-4-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, 1-oxotetrahydrothiopyran-4-yl, 1,1-dioxotetrahydrothiopyran-4-yl, 1-oxo-1-iminotetrahydrothiopyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydropyran-4 -yl, 3,6-dihydrothiopyran-4-yl, 1-oxo-3,6-dihydrothiopyran-4-yl, 1,1-dioxo-3,6-dihydrothiopyran-4-yl, 1-oxo-1-imino-3,6-dihydrothiopyran-4-yl, 6-hydroxy-2-azaspiro[3.3]heptan-6-yl, or 2-hydroxy-7-azaspiro[3.5]nonan-2-yl; or R 4b -OR 1a or R 4b is optionally substituted with one, two, or three substituents Q; 1-6 alkyl; or R 4b is —O-heterocyclyl optionally substituted with 1, 2, or 3 substituents Q; or R 4b is —O-(monocyclic heterocyclyl) optionally substituted with 1, 2, or 3 substituents Q; or R 4b is methoxy, tetrahydrofuryloxy, or pyrrolidinyloxy, each optionally substituted with acetyl, propionyl, cyclopropylcarbonyl, or tert-butoxycarbonyl; or R 4b is methoxy, tetrahydrofur-3-yloxy, (R)-tetrahydrofur-3-yloxy, (S)-tetrahydrofur-3-yloxy, pyrrolidin-3-yloxy, 1-acetylpyrrolidin-3-yloxy, 1-propionylpyrrolidin-3-yloxy, 1-cyclopropylcarbonylpyrrolidin-3-yloxy, or 1-tert-butoxycarbonylpyrrolidin-3-yloxy; or R 4b is methoxy; or R 4b is (R)-tetrahydrofur-3-yloxy or (S)-tetrahydrofur-3-yloxy; and / or R 4c is hydrogen or -OR 1a or R 4c -OR 1a or R 4c is hydrogen, hydroxyl, or methoxy; and / or R 4d is optionally substituted with hydrogen, halo, or 1, 2, or 3 substituents Q; 1-6 alkyl; or R 4d 3. The compound of claim 2, wherein is hydrogen, fluoro, or methyl.

12. (1)R 5a is optionally substituted with hydrogen, halo, or 1, 2, or 3 substituents Q; 1-6 alkyl; or R 5a is hydrogen, fluoro, or methyl; and / or R 5b is hydrogen or C optionally substituted with 1, 2 or 3 substituents Q 1-6 alkyl; or R 5b is hydrogen, methyl, difluoromethyl, trifluoromethyl, or 1,1-difluoro-2-hydroxyethyl; or R 5b is trifluoromethyl or 1,1-difluoro-2-hydroxyethyl; and / or R 5c is hydrogen; and / or R 5d is hydrogen, nitro, or amino; or R 5d is amino; and / or R 5e is hydrogen, or (2)R 6a is (i) hydrogen or halo; or (ii) each optionally substituted with 1, 2, or 3 substituents Q; 6-14 is aryl or heteroaryl; or R 6a is (i) hydrogen or halo; or (ii) phenyl or bicyclic heteroaryl, each optionally substituted with 1, 2, or 3 substituents Q; or R 6a is hydrogen, bromo, 2-(hydroxymethyl)phenyl, 2-(aminomethyl)phenyl, 2-(methylamino-methyl)phenyl, 2-(2-aminoethyl)phenyl, or 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl; and / or R 6b is (i) hydrogen; or (ii) each optionally substituted with 1, 2, or 3 substituents Q, 6-14 is aryl or heteroaryl; or R 6b is (i) hydrogen; or (ii) phenyl or bicyclic heteroaryl, each optionally substituted with 1, 2, or 3 substituents Q; or R 6b is hydrogen, 2-(hydroxymethyl)phenyl, 2-(aminomethyl)phenyl, 2-(methylamino-methyl)phenyl, 2-(2-amino-ethyl)phenyl, or 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl; and / or R 6c 5. The compound of claim 4, wherein is hydrogen.

13. R E1 is hydrogen; or R E1 C optionally substituted with one or more substituents Q 1-6 is alkyl; and / or Y E But, bond, C 1-6 Alkylene, or -N(R E3 )-; or Y E is a bond; or Y E C optionally substituted with one or more substituents Q 1-6 alkylene; or Y E is methanediyl optionally substituted with one or more substituents Q; or Y E -N(R E3 )- and optionally R E3 is hydrogen; and / or 2. The compound of claim 1, wherein m is an integer equal to 1.

14. Lが、-Z L -(R L -WITH L ) z -; (In the formula, Each R L are independently selected from the group consisting of C, ... 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; each Z L are independently a bond, -C(O)-, -C(O)O-, or -C(O)NR 1b -, -C(O)S-, -C(NR 1a )NR 1b -, -C(S)-, -C(S)O-, -C(S)NR 1b -, -O-, -OC(O)O-, -OC(O)NR 1b -, -OC(O)S-, -OC(NR 1a )NR 1b -, -OC(S)-, -OC(S)O-, -OC(S)NR 1b -, -OS(O)-, -OS(O) 2 -, -OS(O)NR 1b -, -OS(O) 2 NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b -, -NR 1a C(O)S-, -NR 1a C(NR 1d )NR 1b -, -NR 1a C(S)NR 1b -, -NR 1a S(O)NR 1b -, -NR 1a S(O) 2 NR 1b -, -S-, -S(O)-, -S(O) 2 -, -S(O)NR 1b - or -S(O) 2 NR 1b - and; and z is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 2. The compound of claim 1 having the structure:

15. Each R L are independently selected from the group consisting of C, ... 1-10 Alkylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; or Each R L independently represent methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, ethyne-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,3-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,3-diyl, cycloheptane-1,4-diyl, bicyclo [2.2.2]octane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, pyrazole-1,3-diyl, pyrazole-1,4-diyl, imidazole-1,4-diyl, 1,2,3-triazole-1,4-diyl, pyrimidine-2,4-diyl, pyrimidine-2,5-diyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazine-1,7-diyl, pyrazolidine-1,3-diyl, pyrazolidine-1,4-diyl, 1,3-dioxane-2,5-diyl, piperazine-1,4-diyl, piperidine-1,3-diyl, piperidine-1,4-diyl, or 3,9-diazaspiro[5.5]undecane-3,9-diyl; and / or each Z L are independently a bond, -C(O)-, or -C(O)NR 1b -, -O-, -OC(O)NR 1b -, -NR 1b - or -NR 1a C(O)NR 1b -is; or each Z L are, independently, bonds, -C(O)-, -C(O)O-, -C(O)NH-, -OC(O)NH-, -O-, -NH-, -N(CH 3 )-, or -NHC(O)NH-; and / or 15. The compound of claim 14, wherein z is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.

16. L, 【Chemistry 20】 2. The compound of claim 1, wherein:

17. The compound is 3-((3-((7-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)amino)phenyl)amino)piperidine-2,6-dione A1; 3-(3-((2-(4-(7-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B1; 3-(3-((2-(4-(9-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B2; 3-(3-((2-(4-(11-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B3; 3-(4-((2-(4-(7-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B4; 3-(4-((2-(4-(9-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B5; 3-(4-((2-(4-(11-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B6; 3-(3-(2-(4-(9-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethoxy)phenyl)piperidine-2,6-dione B7; 3-(4-((2-(4-(5-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)pentyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B8; 3-(3-((2-(4-(5-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)pentyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)piperidine-2,6-dione B9; (R)-1-(4-(2-(4-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)piperazin-1-yl)-2-oxoethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione C1; (R)-1-(4-(2-(4-(9-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione C2; (R)-1-(4-(2-(4-(11-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione C3; (R)-1-(3-(2-(4-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)piperazin-1-yl)-2-oxoethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dioneC4; (R)-1-(3-(2-(4-(9-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione C5; (R)-1-(3-(2-(4-(11-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dioneC6; 3-(6-((2-(4-(7-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)-piperidine-2,6-dione D1; 3-(6-((2-(4-(9-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)-piperidine-2,6-dione D2; 3-(6-((2-(4-(11-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)-piperidine-2,6-dione D3; 3-(7-((2-(4-(7-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)-piperidine-2,6-dione D4; 3-(7-((2-(4-(9-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)-piperidine-2,6-dione D5; 3-(7-((2-(4-(11-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione D6; (R)-1-(6-((2-(4-(11-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione D7; (R)-1-(6-((2-(4-(9-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione D8; (S)-1-(7-((2-(4-(9-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)nonyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione D9; (R)-1-(7-((2-(4-(11-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)undecyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione D10; or (R)-1-(7-((2-(4-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)piperazin-1-yl)-2-oxoethyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione D11; 2. The compound of claim 1, wherein:

18. 18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and a pharmaceutically acceptable excipient.

19. 20. A pharmaceutical composition comprising a compound of any one of claims 1 to 17 for use in the treatment, prevention, or amelioration of one or more symptoms of a disorder, disease, or condition mediated by Son of Sevenless homolog 1 (SOS1), or a disorder, disease, or condition mediated by Ras, or a proliferative disease.

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