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  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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  • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence.
• epigenetic regulation is mediated by selective and reversible modification (e.g. , methylation) of DNA and proteins (e.g. , histones) that control the conformational transition between transcriptionally active and inactive states of chromatin.
• methylation e.g. , methylation
• proteins e.g. , histones
• methyltransferases e.g., CARM1 (co-activator-associated arginine methyltransferase 1 ; PRMT4)
• CARM1 co-activator-associated arginine methyltransferase 1 ; PRMT4
• PRMT4 co-activator-associated arginine methyltransferase 1
• CARM1 is an attractive target for modulation given its role in the regulation of diverse biological processes. It has now been found that compounds described herein, and pharmaceutically acceptable salts and compositions thereof, are effective as inhibitors of CARM1. Such compounds have the general Formula (I):
• R 1 , R 2a , R 2b , R 3 , Ring A and Ring B are as defined herein.
• compositions are further provided comprising a compound described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and, optionally, a pharmaceutically acceptable excipient.
• compounds described herein inhibit the activity of CARMl .
• methods of inhibiting CARMl are provided which comprise contacting CARMl with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• the CARMl may be purified or crude, and may be present in a cell, tissue, or a subject. Thus, such methods encompass inhibition of CARMl activity both in vitro and in vivo.
• the CARMl is wild-type CARMl .
• the CARMl is overexpressed.
• the CARMl is a mutant.
• the CARMl is in a cell. In certain embodiments, the CARMl is in a tissue.
• the CARMl is in a biological sample. In certain embodiments, the CARMl is in an animal, e.g., a human. In some embodiments, the CARMl is expressed at normal levels in a subject, but the subject would benefit from
• CARMl inhibition e.g., because the subject has one or more mutations in an CARMl substrate that causes an increase in methylation of the substrate with normal levels of CARMl.
• the CARMl is in a subject known or identified as having abnormal CARMl activity (e.g., overexpression).
• the CARMl is in a subject known or identified as having aberrant CARMl activity.
• a provided compound is selective for CARMl over other methyltransferases.
• a provided compound is at least about 10-fold selective, at least about 20-fold selective, at least about 30-fold selective, at least about 40-fold selective, at least about 50- fold selective, at least about 60-fold selective, at least about 70-fold selective, at least about 80-fold selective, at least about 90-fold selective, or at least about 100-fold selective relative to one or more other methyltransferases.
• methods of modulating gene expression or activity in a cell comprise contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical
• the cell is cultured in vitro.
• cell is in an animal, e.g., a human.
• methods of modulating transcription in a cell comprise contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
• the cell is cultured in vitro.
• the cell is in an animal, e.g., a human.
• methods of treating a CARMl -mediated disorder comprise administering to a subject suffering from a CARMl -mediated disorder an effective amount of a compound described herein ⁇ e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
• the CARMl -mediated disorder is a proliferative disorder.
• compounds described herein are useful for treating cancer.
• compounds described herein are useful for treating breast cancer or prostate cancer.
• the CARMl -mediated disorder is a metabolic disorder.
• Compounds described herein are also useful for the study of CARMl in biological and pathological phenomena, the study of intracellular signal transduction pathways mediated by CARMl, and the comparative evaluation of new CARMl inhibitors.
• the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
• Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by 13 C or 14 C are within the scope of the disclosure.
• Such compounds are useful, for example, as analytical tools or probes in biological assays.
• Ci_ 3 alkyl is intended to encompass, C ls C 2 , C 3 , Ci_ 3 , Ci_2, and C 2 - 3 alkyl.
• Alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 3 carbon atoms (“Ci_ 3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“Ci_ 2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of Ci_ 3 alkyl groups include methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ),and isopropyl (C 3 ). Alkyl groups may be substituted or unsubstituted as described herein.
• Haloalkyl refers to an alkyl group, as defined herein, substituted with one or more halogen atoms, e.g., 1, 2, 3, 4, 5, 6, or 7 halogen atoms independently selected from the group consisting of fluoro, bromo, chloro, and iodo. Haloalkyl encompasses perhaloalkyl as defined herein.
• Perhaloalkyl refers to a substituted alkyl group as defined herein wherein all of the hydrogen atoms are independently replaced by a halogen. In some embodiments, at least one of the hydrogen atoms is replaced with fluoro. In some embodiments, at least one of the hydrogen atoms is replaced with chloro.
• perhaloalkyl groups examples include - CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CCI3, -CFCI2, -CF 2 C1, and the like.
• haloalkyl groups include all of the aforementioned perhaloalkyl groups, as well as groups such as - CH 2 F, -CHF 2 , -CH2CI, CHC1 2 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , - CH2CH2CI, -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2 , - CH2CH2CI, -CH(CH 3 )CHF 2 , -CH(CH 3 )CF 2
• alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 3 carbon atoms and one carbon-carbon double bond (“C 2 _ 3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”). In some
• an alkenyl group has 3 carbon atoms ("C 3 alkenyl”).
• C 2 _ 3 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), and 2-propenyl (C 3 ).
• Alkenyl groups may be substituted or unsubstituted as described herein.
• Alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 3 carbon atoms and one carbon-carbon triple bond ("C 2 _ 3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C 2 alkynyl”). In some embodiments, an alkynyl group has 3 carbon atoms (“C 3 alkynyl”). Examples of C 2 _ 3 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), and 2-propynyl (C 3 ). Alkynyl groups may be substituted or unsubstituted as described herein.
• Carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic monocyclic hydrocarbon group having from 3 to 6 ring carbon atoms ("C 3 _ 6 carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
• a carbocyclyl group has 3 to 4 ring carbon atoms ("C 3 ⁇ carbocyclyl”).
• a carbocyclyl group has 3 to 5 ring carbon atoms ("C 3 _5 carbocyclyl”).
• a carbocyclyl group has 3 to 3 ring carbon atoms.
• carbocyclyl group has 4 to 6 ring carbon atoms ("C4_ 6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C 5 _6 carbocyclyl”).
• Exemplary C 3 _ 6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
• Heterocyclyl refers to a radical of a 4-6 membered monocyclic non-aromatic ring system having ring carbon atoms and 1, 2, or 3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("4-6 membered heterocyclyl").
• the point of attachment can be a carbon or nitrogen atom, as valency permits.
• a heterocyclyl group is a 4-membered monocyclic non-aromatic ring system having ring carbon atoms and 1 ring heteroatom, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("4-membered heterocyclyl").
• a heterocyclyl group is a 5 - membered monocyclic non-aromatic ring system having ring carbon atoms and 1, 2, or 3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- membered heterocyclyl").
• a heterocyclyl group is a 6- membered monocyclic non-aromatic ring system having ring carbon atoms and 1, 2, or 3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("6- membered heterocyclyl").
• Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
• Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, and pyrrolidin-2-one.
• Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
• Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
• Exemplary 6- membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
• Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
• Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinanyl.
• alkylene is the divalent moiety of alkyl
• alkenylene is the divalent moiety of alkenyl
• alkynylene is the divalent moiety of alkynyl, as defined herein.
• substituted means that at least one hydrogen present on a group ⁇ e.g., a carbon or nitrogen atom) is replaced with a substituent as defined herein and results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
• a “substituted” group may have a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent may be the same or different at each position.
• Halo or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), or iodine (iodo, -I).
• “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response, and the like, and are
• Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds describe herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
• organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
• Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci_ 4 alkyl) 4 salts.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, quaternary salts.
• a "subject" to which administration is contemplated includes, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other non-human animals, for example, non-human mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs), birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys), rodents (e.g., rats and/or mice), reptiles, amphibians, and fish.
• non-human mammals e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys);
• the non-human animal is a mammal.
• the non-human animal may be a male or female at any stage of development.
• a non-human animal may be a transgenic animal.
• Treating encompasses an action that occurs while a subject is suffering from a condition which reduces the severity of the condition or retards or slows the progression of the condition ("therapeutic treatment”).
• Treating also encompasses an action that occurs before a subject begins to suffer from the condition and which inhibits or reduces the severity of the condition (“prophylactic treatment”).
• an "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, e.g., treat the condition.
• the effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
• An effective amount encompasses therapeutic and prophylactic treatment.
• a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
• a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
• the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
• a prophylactically effective amount of a compound is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence.
• a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
• the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
• methyltransferase represents transferase class enzymes that are able to transfer a methyl group from a donor molecule to an acceptor molecule, e.g. , an amino acid residue of a protein or a nucleic base of a DNA molecule.
• Methytransferases typically use a reactive methyl group bound to sulfur in S-adenosyl methionine (SAM) as the methyl donor.
• SAM S-adenosyl methionine
• a methyltransferase described herein is a protein methyltransferase.
• a methyltransferase described herein is a histone methyltransferase.
• Histone methyltransferases are histone -modifying enzymes, (including histone-lysine N-methyltransferase and histone-arginine N-methyltransferase), that catalyze the transfer of one or more methyl groups to lysine and arginine residues of histone proteins.
• a methyltransferase described herein is a histone-arginine N-methyltransferase.
• R 1 is hydrogen, -CHO, or unsubstituted Ci_3alkyl
• each instance of R 2a and R 2b is independently hydrogen, halogen, unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl;
• R is unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, or halogen;
• Ring A is of formula (A-i), (A-ii), or (A-iii):
• each instance of R A1 and R ⁇ is independently unsubstituted Ci_ 3 alkyl, Ci_ haloalkyl, or unsubstituted cyclopropyl;
• R ⁇ is unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, halogen, or -CN;
• R A4 is hydrogen, unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, halogen, or -CN; and R A5 is unsubstituted Ci_ 3 alkyl or Ci_ 3 haloalkyl;
• Ring B is any one of formula (i) to (xxviii):
• q is 1 , 2, or 3 and w is 1 ; or q is 2 and w is 0 or 2; x is 1 and y is 1 or 2;
• n 0, 1 , or 2;
• Li is -NH-, substituted or unsubstituted C 2 alkylene, substituted or unsubstituted C 2 alkenylene, or substituted or unsubstituted C 2 alkynylene;
• R N1A is substituted or unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C 3 _ 6 carbocyclyl, or substituted or unsubstituted 4- to 6-membered heterocyclyl;
• R N1B is hydrogen, substituted or unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C 3 _ 6 carbocyclyl, or substituted or unsubstituted 4- to 6- membered heterocyclyl; or
• R N1A and R N1B are joined to form a substituted or unsubstituted 4- to 6- membered heterocyclyl;
• each instance of R N2 and R B8 is independently substituted or unsubstituted Ci_ 3 alkyl or Ci_ 3 haloalkyl, or R N2 and R B8 are joined to form a substituted or
• R B1A is substituted or unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C 3 _ 6 carbocyclyl, or substituted or unsubstituted 4- to 6-membered heterocyclyl;
• R B1B is hydrogen, substituted or unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C 3 _ 6 carbocyclyl, or substituted or unsubstituted 4- to 6- membered heterocyclyl; or
• R B1A and R B1B are joined to form a substituted or unsubstituted 4- to 6- membered heterocyclyl
• R B2 is hydrogen, halogen, -OR B2A , substituted or unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl, wherein R B2A i s substituted or unsubstituted Ci_ 3 alkyl or Ci_ 3 haloalkyl; or R B1 and R B2 are joined to form a substituted or unsubstituted 4- to 6- membered heterocyclyl;
• each instance of R is independently hydrogen, unsubstituted Ci_ 3 alkyl, or Ci_
• R B4A is substituted or unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C 3 _ 6 carbocyclyl, or substituted or unsubstituted 4- to 6-membered heterocyclyl;
• R B4B is hydrogen, substituted or unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C 3 _ 6 carbocyclyl, or substituted or unsubstituted 4- to 6- membered heterocyclyl; or
• R B4A and R B4B are joined to form a substituted or unsubstituted 4- to 6- membered heterocyclyl
• R is unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, C 3 _6carbocylyl unsubstituted or substituted with 1 or 2 R D1 groups; or 4-6 membered heterocyclyl unsubstituted or substituted with 1 or 2 R D1 groups; and R is hydrogen, unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, C3_ 6 carbocylyl unsubstituted or substituted with 1 or 2 R D1 groups, or 4-6 membered heterocyclyl unsubstituted or substituted with 1 or 2 R D1 groups; or
• R" 1A and R" 1D are joined to form an 4- to 6- membered heterocyclyl unsubstituted or substituted with 1 or 2 R D1 groups;
• each instance of R is independently halogen, -CN, -OR , unsubstituted Ci_3 alkyl, or Ci_ 3 haloalkyl, wherein R D1A is hydrogen, unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl.
• the compound of Formula (I) is a stereoisomer of Formula:
• the compound of Formula (I) is a stereoisomer of Formula:
• R 1 is hydrogen, -CHO, or unsubstituted Ci_ 3 alkyl.
• R 1 is hydrogen. In certain embodiments, R 1 is -CHO. In certain embodiments, R 1 is unsubstituted Ci_ 3 alkyl, i.e. , unsubstituted Ci alkyl (-C3 ⁇ 4), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• each instance of R 2a and R 2b is independently hydrogen, halogen, unsubstituted Ci_ 3 alkyl, or C ⁇ haloalkyl. [0040] In certain embodiments, at least one instance of R 2a and R 2b is hydrogen. In certain embodiments, each instance of R 2a and R 2b is hydrogen.
• At least one instance of R 2a and R 2b is halogen, i.e., at least one instance of R 2a and R 2b is -F, -CI, -Br, or -I.
• R 2a is halogen and R 2b is halogen, i.e., each instance of R 2a and R 2b is independently -F, -CI, -Br, or -I.
• at least one instance of R 2a and R 2b is -F or -CI.
• R 2a is -F or -CI.
• R 2b is -F or -CI.
• R a is -CI and R is -CI. In certain embodiments, R a is -F and R is -F.
• At least one instance of R 2a and R 2b is unsubstituted Ci_ 3 alkyl, i.e., unsubstituted Ci alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• at least one instance of R 2a and R 2b is -CH 3 .
• R 2a and R 2b is Ci_ 3 haloalkyl, e.g., Ci haloalkyl (-CF 3 , -CC1 3 , -CFC1 2 , -CF 2 C1, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 ), C 2 haloalkyl (- CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC
• R 2b is hydrogen and R 2a is halogen, unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl.
• R 2b is hydrogen and R 2a is halogen, i.e., R 2b is hydrogen and R 2a is -F, -CI, -Br, or -I.
• R 2b is hydrogen and R 2a is unsubstituted Ci_ 3 alkyl, i.e., unsubstituted Ci alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• R 2b is hydrogen and R 2a is Ci_ 3 haloalkyl, e.g., Ci haloalkyl (-CF 3 , -CC1 3 , -CFC1 2 , -CF 2 C1, -CH 2 F, - CHF 2 , -CH 2 C1, CHC1 2 ), C 2 haloalkyl (-CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2 , - CH 2 C1), or
• R 2a is hydrogen and R 2b is halogen, unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl.
• R 2a is hydrogen and R 2b is halogen, i.e., R 2a is hydrogen and R 2b is -F, -CI, -Br, or -I.
• R 2a is hydrogen and R 2b is unsubstituted Ci_ 3 alkyl, i.e., unsubstituted Ci alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH or -CH(CH ) 2 ).
• R 2a is hydrogen and R 2b is Ci_ 3 haloalkyl, e.g., Ci haloalkyl (-CF 3 , -CCI 3 , -CFCI 2 , -CF 2 C1, -CH 2 F, - CHF 2 , -CH 2 CI, CHCI 2 ), C 2 haloalkyl (-CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2 , - CH 2 CH 2 C1),
• R 2a is hydrogen and R 2b is -CI. In certain embodiments,
• R a is hydrogen and R is -F. In certain embodiments, R a is hydrogen and R is -CF 3 .
• R is unsubstituted Ci_ 3 alkyl, Ci_
• R is unsubstituted Ci_ 3 alkyl, i.e.,
• Ci alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (- CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• R is Ci_ 3 haloalkyl, e.g., C ⁇ haloalkyl (-CF 3 , -CCI 3 , -CFCI 2 , -CF 2 CI, -CH 2 F, -CHF 2 , -CH 2 CI, CHCI 2 ), C 2 haloalkyl (-CF 2 CF 3 , - CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (- CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2 , - CH 2 CH 2 CH 2 C1), or C 3
• R is -CH 3 .
• R is halogen, i.e., -F, -CI, -Br, or -I.
• R is -F or -CI.
• R 2a , R 2b , and R 3 are contemplated herein.
• each of R 2a and R 3 is the same group. In certain embodiments, R 2a and R 3 are different groups. In certain embodiments, each of R 2a and R 3 is halogen, e.g., R 2a is -CI and R 3 is -CI, or R 2a is -F and R 3 is -F, or R 2a is -CI and
• R is -F, or R a is -F and R is -CI.
• R a is halogen and R is unsubstituted C 1-3 alkyl, e.g., wherein R 2a is -CI and R 3 is -CH 3 , or R 2a is -F and R 3 is -CH 3 .
• R 2a is Ci_ 3 haloalkyl and R 3 is unsubstituted Ci_ 3 alkyl, e.g., R 2a is - CF 3 and R 3 is -CH 3 .
• R 2a is hydrogen and R 3 is unsubstituted Ci_ 3 alkyl, e.g., wherein R 2a is hydrogen and R 3 is -CH 3 .
• R 2a is halogen ⁇ e.g., -F or -CI
• R 2b is hydrogen
• R 3 is unsubstituted Ci_ 3 alkyl ⁇ e.g., -CH ).
• R 2a is -CI
• R 2b is hydrogen
• R 3 is -CH 3
• R 2a is -F
• R 2b is hydrogen
• R 3 is -CH 3
• R 2a is halogen (e.g., -F or -CI)
• R 2b is hydrogen
• R 3 is halogen (e.g., -F or -CI).
• R 2a is -CI
• R 2b is hydrogen
• R 3 is -CI
• R 2a is -F
• R 2b is hydrogen
• R 3 is -CI
• R 2a is -F
• R 2b is hydrogen
• R 3 is -F
• R 2a is Ci_ 3 haloalkyl (e.g., -CF 3 ), R 2b is hydrogen, and R 3 is unsubstituted Ci_ 3 alkyl (e.g., -CH ).
• R 2a is -CF
• R 2b is hydrogen
• R is -CH 3 to provide a com ound of Formula:
• each of R 2a and R 2b is hydrogen, and R 3 is unsubstituted Ci_ 3 alkyl (e.g., -CH 3 ).
• R 2a is hydrogen
• R 2b is hydrogen
• R 3 is - CH to provide a compound of Formula:
• each of R 2a , R 2b , and R 3 is halogen (e.g., -F or -CI).
• halogen e.g., -F or -CI.
• each of R a , R , and R is -CI, or each of R a , R , and R is -F to provide a compound ofFormulae:
• each of R 2a and R 2b is independently halogen (e.g., -F or -CI), R 3 is unsubstituted Ci_ 3 alkyl (e.g., -CH 3 ).
• R 2a is -CI
• R 2b is -CI
• R 3 is -CH or R 2a is -F
• R 2b is -F
• R 3 is -CH 3
• Ring A is of formula (A-i), (A-ii), or (A-iii):
• each instance of R A1 and R ⁇ is independently unsubstituted Ci_ 3 alkyl or Ci_
• R ⁇ is unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, halogen, or -CN;
• R is hydrogen, unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, halogen, or -CN;
• R A5 is unsubstituted C h alky! or Ci_ 3 haloalkyl.
• Ring A is of Formula (A-i):
• each instance of R A1 a anndd RR ⁇ i iss iinnddependently unsubstituted C ⁇ alkyl, Ci_ 3 haloalkyl, or unsubstituted cyclopropyl.
• At least one instance of R A1 and R ⁇ is unsubstituted Ci_ 3alkyl, i.e., unsubstituted Ci alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• at least one of R A1 and R ⁇ is -CH 3 .
• at least one of R A1 and R ⁇ is -CH 2 CH 3 .
• R A1 and R ⁇ is Ci_3haloalkyl, e.g., Ci haloalkyl (-CF 3 , -CCI 3 , -CFC1 2 , -CF 2 C1, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 ), C 2 haloalkyl (- CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2
• At least one of R A1 and R ⁇ is unsubstituted cyclopropyl.
• R A1 and R ⁇ are the same group, e.g., in certain embodiments, R A1 and R ⁇ are each -CH 3 . However, in certain embodiments, R A1 and R ⁇ are different groups, e.g., in certain embodiments, R A1 is -CH 3 and R ⁇ is -CH 2 CH 3 , or in certain embodiments, R A1 is -CH 2 CH 3 and R ⁇ is -CH 3 , or in certain embodiments, R A1 is unsubstituted cyclopropyl and R ⁇ is -CH 3i or in certain embodiments, R ⁇ is unsubstituted cyclopropyl and R A1 is -CH 3 .
• Ring A is selected from the group consisting of:
• Ring A is of Formula (A-ii):
• R is unsubstituted Ci_ 3 alkyl, i.e., unsubstituted Ci alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or - CH(CH 3 ) 2 ).
• R ⁇ is Ci_ 3 haloalkyl, e.g., C ⁇ haloalkyl Ci haloalkyl (- CF 3 , -CCI3, -CFCI2, -CF2CI, -CH 2 F, -CHF 2 , -CH2CI, CHCI2), C 2 haloalkyl (-CF 2 CF 3 , - CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (- CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2 , - CH 2 CH 2 CH 2 C1), or
• R ⁇ is halogen, i.e., -F, -CI, -Br, or -I. In certain embodiments, R ⁇ is -CN. In certain embodiments, R ⁇ is -CN provided R A4 is is not also -CN.
• R A4 is hydrogen.
• R A4 is unsubstituted Ci_ 3 alkyl, i.e., unsubstituted Ci alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• R A4 is Ci_ 3 haloalkyl, e.g., Ci haloalkyl (-CF 3 , -CCI 3 , -CFC1 2 , -CF 2 C1, -CH 2 F, -CHF 2 , -CH 2 C1, CHCI 2 ), C 2 haloalkyl (-CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , - CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2 , - CH 2 CH 2 C1,
• R A4 is halogen, i.e., -F, -CI, -Br, or -I. In certain embodiments, R A4 is -CN. In certain embodiments, R A4 is -CN provided R ⁇ is is not also - CN.
• R A5 is unsubstituted Ci_ 3 alkyl, i.e., unsubstituted Ci alkyl
• R A5 is Ci_ 3 haloalkyl, e.g., C ⁇ haloalkyl (-CF , -CC1 3 , -
• R ⁇ is halogen, -CN, unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl, and R A4 is hydrogen.
• R ⁇ is halogen (i.e., -F, -CI, -
• R A4 is hydrogen.
• R ⁇ is -CN and R A4 is hydrogen.
• R is unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ) and R is hydrogen.
• R A5 is unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• R ⁇ is unsubstituted Ci_ 3 alkyl or Ci_ 3 haloalkyl and R A4 is halogen or -CN.
• R A4 is unsubstituted Ci_ 3 alkyl or Ci_ 3 haloalkyl and R ⁇ is halogen or -CN.
• R ⁇ is unsubstituted Ci_ 3 alkyl (e.g., -CH , - CH 2 CH 3 ) and R A4 is halogen (i.e., -F, -CI, -Br, or -I).
• R ⁇ is unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ) and R A4 is -CN.
• R A5 is unsubstituted Ci_ 3 alkyl (e.g., -CH , -CH 2 CH 3 ).
• Ring A is selected from the group consisting of:
• R ⁇ is unsubstituted Ci_ 3 alkyl, i.e., unsubstituted Ci alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or - CH(CH 3 ) 2 ).
• R is Ci_ 3 haloalkyl, e.g., C ⁇ haloalkyl (-CF , -CC1 3 , - CFC1 2 , -CF 2 C1, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 ), C 2 haloalkyl (-CF 2 CF 3 , -CH 2 CF 3 , - CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , - CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2 , - CH 2 CH 2 C1,
• R ⁇ is halogen, i.e., -F, -CI, -Br, or -I.
• R A5 is unsubstituted Ci_ 3 alkyl, i.e., unsubstituted Ci alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or - CH(CH ) 2 ).
• R A5 is Ci_ 3 haloalkyl, e.g., Ci haloalkyl (-CF , -CC1 3 , - CFC1 2 , -CF 2 C1, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 ), C 2 haloalkyl (-CF 2 CF 3 , -CH 2 CF 3 , - CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , - CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2 , - CH 2 CH 2 C1,
• R ⁇ is halogen, -CN, unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl
• R A5 is unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• R ⁇ is halogen (i.e., -F, -CI, -Br, or -I)
• R A5 is unsubstituted Ci_ 3 alkyl (e.g., -CH , -CH 2 CH ).
• R ⁇ is -CN and R A5 is unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ). In certain embodiments, R ⁇ is unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , - CH 2 CH 3 ) and R A5 is unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ). In certain embodiments, R ⁇ and R ⁇ are the same group. In certain embodiments, R ⁇ and R A5 are different groups.
• Ring A is:
• Ring A is of Formula (A-i), (A-ii), or (A-iii), R 1 is -CH , and each R 2a and R 2b is hydrogen, provided is a compound of Formula:
• Ring A is of Formula (A-i), (A-ii), or (A-iii), R 1 is -CH R 2a is -CI, and R 2b is hydrogen, provided is a compound of Formula:
• Ring A is of Formula (A-i), (A-ii), or (A-iii), R 1 is -CH 3 , R 2a is -F, and R 2b is hydrogen, provided is a compound of Formulae:
• Ring A is of Formula (A-i), (A-ii), or (A-iii), R 1 is -CH R 2a is -CF 3 , and R 2b is hydrogen, provided is a compound of Formulae:
• Ring A is of Formula (A-i), (A-ii), or (A-iii), R 1 is -CH 3 , R 2a is -CI, and R 2b is -CI, provided is a compound of Formulae:
• each instance of "substituted" preceding a group refers to a group, e.g., substituted C 2 alkylene, substituted C 2 alkenylene, or substituted C 2 alkynylene in the instance of L ls and substituted Ci_ 3 alkyl, substituted C3-6 carbocyclyl, substituted 4- to 6-membered heterocyclyl, and substituted 5- to 6-membered ring, in the instance of various Ring B recitations, refers to a group substituted with 1, 2, or 3 R groups, as valency permits. In certain embodiments, such groups are substituted with 1 or 2 R C1 groups.
• R D1A and R C1B are joined to form an 4- to 6- membered heterocyclyl unsubstituted or substituted with 1 or 2 R D1 groups; and wherein each instance of R D1 is independently halogen, -CN, -OR D1A , unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl, wherein R D1A is hydrogen, unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl.
• At least one instance of R is unsubstituted Ci_ 3 alkyl, i.e., unsubstituted Ci alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (- CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• Such embodiments are particularly envisioned for substitution on a C 3 _6 carbocyclyl, 4- to 6-membered heterocyclyl, or 5- to 6-membered ring.
• R is Ci_ 3 haloalkyl, e.g., C haloalkyl (-CF 3 , -CCI 3 , -CFC1 2 , -CF 2 C1, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 ), C 2 haloalkyl (- CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 halo
• At least one instance of R is halogen, i.e., -F, -CI, -Br, or -I. In certain embodiments, at least one instance of R is -F or -CI. Such embodiments are also particularly envisioned for substitution on a C 3 _ 6 carbocyclyl, 4- to 6-membered heterocyclyl, or 5- to 6-membered ring.
• At least one instance of R is -CN.
• Ci_3 alkyl groups are contemplated substituted by -CN.
• C 2 alkyl groups are contemplated substituted by 1 -CN group, e.g., of formula:
• at least one instance of R is -OR , wherein R is hydrogen, unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, C 3 _ 6 carbocylyl unsubstituted or substituted with 1 or 2 R D1 groups, or 4-6 membered heterocyclyl unsubstituted or substituted with 1 or 2 R D1 groups.
• Ci_3 alkyl groups are contemplated substituted by -OR .
• Ci_3 alkyl groups are contemplated substituted by 1 or 2 -OR groups, e.g., of formula:
• R is -OR , wherein R is hydrogen.
• R is -OR , wherein R is unsubstituted C 1-3 alkyl, i.e., unsubstituted Ci alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH3), or unsubstituted C3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• R C1 is -OR clB , wherein R C1B is Ci_ 3 haloalkyl, e.g., Ci haloalkyl (-CF 3 , -CCI3, -CFCI 2 , -CF 2 C1, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 ), C 2 haloalkyl (- CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2
• R C1 is -OR clB , wherein R C1B is -CF 3 , -CH 2 F, -CHF 2 , -CH 2 C1, - CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CHF 2 , or -CH(CH 3 )CF 3 .
• R C1 is -OR clB , wherein R C1B is C 3 _6carbocylyl or 4-6 membered heterocyclyl , each independently unsubstituted or substituted with 1 or 2 R D1 groups, wherein R D1 is independently halogen, -CN, -OR D1A , unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl, and wherein R D1A is hydrogen, unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl.
• R is -OR , wherein R is C3carbocylyl (e.g., cyclopropyl) unsubstituted or substituted with 1 or 2 R D1 groups.
• R C1 is -OR clB , wherein R C1B is 4- membered heterocyclyl (e.g., azetidinyl, oxetanyl), unsubstituted or substituted with 1 or 2 R D1 groups.
• R C1 is -OR clB , wherein R C1B is 5-membered
• R is -OR , wherein R is 6-membered heterocyclyl (e.g., tetrahydropyranyl), unsubstituted or substituted with 1 or 2 R D1 groups.
• R is -OR , wherein R is 6-membered heterocyclyl (e.g., tetrahydropyranyl), unsubstituted or substituted with 1 or 2 R D1 groups.
• such groups are unsubstituted by R .
• at least one instance of R D1 is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR D1A (e.g., -OH, -OCH3), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• At least one instance of R is -SR , wherein R is hydrogen, unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, C 3 _ 6 carbocylyl unsubstituted or substituted with 1 or 2 R D1 groups, or 4-6 membered heterocyclyl unsubstituted or substituted with 1 or 2 R D1 groups.
• R is -SR , wherein R is hydrogen.
• R C1 is -SR C1B , wherein R C1B is unsubstituted C 1-3 alkyl, i.e., unsubstituted Ci alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH3), or unsubstituted C3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• R C1B is unsubstituted C 1-3 alkyl, i.e., unsubstituted Ci alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH3), or unsubstituted C3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• R C1 is -SR C1B , wherein R C1B is Ci_ 3 haloalkyl, e.g., Ci haloalkyl (-CF 3 , -CCI 3 , -CFC1 2 , -CF 2 C1, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 ), C 2 haloalkyl (- CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , -
• R C1 is -SR C1B , wherein R C1B is -CF 3 , -CH 2 F, -CHF 2 , -CH 2 C1, -CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CHF 2 , or -CH(CH 3 )CF 3 .
• R C1 is -SR C1B , wherein R C1B is C 3 _6carbocylyl or 4-6 membered heterocyclyl , each independently unsubstituted or substituted with 1 or 2 R D1 groups, wherein R D1 is independently halogen, -CN, -OR D1A , unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl, and wherein R D1A is hydrogen, unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl.
• R is -SR , wherein R is C3carbocylyl (e.g., cyclopropyl) unsubstituted or substituted with 1 or 2 R D1 groups.
• R C1 is -SR C1B , wherein R C1B is 4- membered heterocyclyl (e.g., azetidinyl, oxetanyl), unsubstituted or substituted with 1 or 2 R D1 groups.
• R C1 is -SR C1B , wherein R C1B is 5-membered heterocyclyl (e.g., tetrahydrofuranyl), unsubstituted or substituted with 1 or 2 R D1 groups.
• R is -SR , wherein R is 6-membered heterocyclyl (e.g.,
• such groups are unsubstituted by R D1 .
• such groups are substituted, e.g., wherein at least one instance of R D1 is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR D1A (e.g., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• R C1A and R C1B do not join to form a cyclic ring structure, such that R is unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, C 3 _ 6 carbocylyl unsubstituted or substituted with 1 or 2 R D1 groups, or 4-6 membered heterocyclyl unsubstituted or substituted with 1 or 2 R D1 groups; and R C1B is hydrogen, unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, C 3 _6carbocylyl unsubstituted
• R is unsubstituted Ci_ 3 alkyl (e.g., -CH ), Ci_ 3 haloalkyl (e.g., -CF , -CH 2 F, -CHF 2 , -CH 2 C1, -CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CHF 2 , or -CH(CH 3 )CF 3 ), C 3 carbocylyl (e.g., cyclopropyl) unsubstituted or substituted with 1 or 2 R D1 groups, 4- membered heterocyclyl (e.g., azetidinyl, oxetanyl), unsubstituted or substituted with 1 or 2 R D1 groups, 5-membered heterocyclyl (e.g., tetrahydrofuranyl), unsubstituted or substituted with 1 or 2 R D1 groups, or 6-membered heterocyclyl (e.g.,
• such groups are unsubstituted by R D1 .
• such groups are substituted, e.g., wherein at least one instance of R D1 is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR D1A (e.g., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• R C1A and R C1B are joined to form an 4- to 6- membered heterocyclyl unsubstituted or substituted with 1 or 2 R D1 groups, e.g., for example, in certain embodiments, R and R are joined to form an 4- membered heterocyclyl (e.g., azetidinyl), unsubstituted or substituted with 1 or 2 R D1 groups, 5- membered heterocyclyl (e.g., pyrrolidinyl, pyrrolidin-2-one, oxazolidin-2-one), unsubstituted or
• 4- membered heterocyclyl e.g., pyrrolidinyl, pyrrolidin-2-one, oxazolidin-2-one
• such groups are unsubstituted by R D1 .
• such groups are substituted, e.g., wherein at least one instance of R D1 is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR D1A (i.e., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (-CH 3 , -CH 2 CH 3 ).
• R C1A is Ci_ 3 haloalkyl, e.g., Ci haloalkyl (-CF 3 , -CC1 3 , -CFC "11 2 2,
• C 2 haloalkyl -CF 2 CF 3 , -CH 2 CF 3 ,
• R is C 3 _ 6 carbocylyl or 4-6 membered heterocyclyl , each independently unsubstituted or substituted with 1 or 2 R D1 groups, wherein R D1 is
• R C1 is independently halogen, -CN, -OR D1A , unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl, and wherein R D1A is hydrogen, unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl.
• such groups are substituted, e.g., wherein at least one instance of R D1 is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR D1A (e.g., -OH, -OCF or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• R D1 is halogen (i.e., -F, -CI, -Br, or -I)
• -CN e.g., -OR D1A (e.g., -OH, -OCF or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• such groups are unsubstituted by R D1 .
• at least one instance of R D1 is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR D1A (e.g., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• At least one instance of R is -S(0) 2 R , wherein R is unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, C 3 _ 6 carbocylyl unsubstituted or substituted with 1 or 2 R D1 groups, or 4-6 membered heterocyclyl unsubstituted or substituted with 1 or 2 R D1 groups.
• At least one instance of R is -S(0) 2 R , wherein R is unsubstituted Ci_ 3 alkyl, i.e., unsubstituted Ci alkyl (-CH ), unsubstituted C 2 alkyl (-CH 2 CH ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• R is unsubstituted Ci_ 3 alkyl, i.e., unsubstituted Ci alkyl (-CH ), unsubstituted C 2 alkyl (-CH 2 CH ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• R is -S(0) 2 R , wherein R is Ci_ 3 haloalkyl, e.g., Ci haloalkyl (-CF 3 , -CC1 3 , -CFC1 2 , -CF 2 C1, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 ), C 2 haloalkyl (-CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , - CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH
• R is -S(0) 2 R , wherein R is C 3 _6carbocylyl or 4-6 membered heterocyclyl , each independently unsubstituted or substituted with 1 or 2 R D1 groups, wherein R D1 is independently halogen, -CN, -OR D1A , unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl, and wherein R is hydrogen, unsubstituted C
• At least one instance of R is -S(0) 2 R , wherein R U1A is C 3 carbocylyl (e.g., cyclopropyl) unsubstituted or substituted with 1 or 2 R m groups.
• at least one instance of R is -S(0) 2 R , wherein R is 4- membered heterocyclyl (e.g., azetidinyl, oxetanyl), unsubstituted or substituted with 1 or 2 R D1 groups.
• R C1 is -S(0) 2 R C1A , wherein R C1A is 5-membered heterocyclyl (e.g., tetrahydrofuranyl), unsubstituted or substituted with 1 or 2 R D1 groups.
• R C1 -S(0) 2 R C1A wherein R C1A is 6-membered heterocyclyl (e.g., tetrahydropyranyl), unsubstituted or substituted with 1 or 2 R D1 groups.
• such groups are unsubstituted by R D1 .
• R D1 is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR D1A (e.g., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• R C1A and is unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, C 3 _ 6 carbocylyl unsubstituted or substituted with 1 or 2 R D1 groups, or 4-6 membered heterocyclyl unsubstituted or substituted with 1 or 2 R D1 groups
• R C1B is hydrogen, unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, C 3 _ 6 carbocylyl unsubstituted or substituted with 1 or 2 R D1 groups, or 4-6 membered heterocyclyl unsubstituted or substituted with 1 or 2 R D1 groups.
• R C1B is hydrogen or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 ).
• R is unsubstituted Ci_ 3 alkyl (e.g., -CH 3 ), Ci_ 3 haloalkyl (e.g., - CF 3 , -CH 2 F, -CHF 2 , -CH 2 C1, -CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CHF 2 , or -CH(CH 3 )CF 3 ), C 3 carbocylyl (e.g., cyclopropyl) unsubstituted or substituted with 1 or 2 R D1 groups, 4- membered heterocyclyl (e.g., azetidinyl, oxetanyl), unsubstituted or substituted with 1 or 2 R D1 groups, 5-membered heterocyclyl (e.g., t
• such groups are unsubstituted by R D1 .
• at least one instance of R D1 is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR D1A (i.e., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (-CH 3 , -CH 2 CH 3 ).
• R C1A and R C1B are joined to form an 4- to 6- membered heterocyclyl unsubstituted or substituted with 1 or 2 R D1 groups, e.g., for example, in certain embodiments, R C1A and R C1B are joined to form an 4- membered heterocyclyl (e.g., azetidinyl), unsubstituted or substituted with 1 or 2 R D1 groups, 5-membered heterocyclyl (e.g., pyrrolidinyl, pyrrolidin-2-one, oxazolidin-2-one), unsubstituted or substituted with 1 or 2 R D1 groups, or 6-membered heterocyclyl (e.g., morpholinyl, piperidinyl, piperazinyl), unsubstituted or substituted with 1 or 2
• such groups are unsubstituted by R .
• at least one instance of R D1 is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR D1A (e.g., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• Ring B Substituents Groups comprising -N(R N1A )(R N1B ), -N(R B1A )(R B1B ), and -
• R N1A , R B1A , or R B4A is unsubstituted Ci_3alkyl, Ci_3haloalkyl, C3- 6 carbocylyl unsubstituted or substituted with 1 or 2 R D1 groups, or 4-6 membered heterocyclyl unsubstituted or substituted with 1 or 2 R D1 groups; and R N1B , R B1B , or R B4B is hydrogen, unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, C 3 _ 6 carbocyly
• R N1B , R B1B , or R B4B is hydrogen or unsubstituted Ci_ 3 alkyl ⁇ e.g., -CH 3 ).
• R N1A , R B1A , or R B4A is unsubstituted Ci_ 3 alkyl (e.g., -CH 3 ), Ci_ 3 haloalkyl (e.g., -CF 3 , -CH 2 F, -CHF 2 , -CH 2 CI, -CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CHF 2 , or -CH(CH 3 )CF 3 ), C3carbocylyl (e.g., cyclopropyl) unsubstituted or substituted with 1 or 2 R D1 groups, 4- membered heterocyclyl (e.g., azetidinyl, oxetanyl), unsubstituted or substituted with 1 or 2 R D1 groups, 5-membered heterocyclyl (e.g., tetrahydrofuranyl), unsubstituted or substituted with 1 or 2 R
• such groups are unsubstituted by R D1 .
• at least one instance of R D1 is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR D1A (e.g., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• any recited instance of - N(R N1A )(R N1B ), -N(R B1A )(R B1B ), or -N(R B4A )(R B4B ) independently refers to a group selected from: for -N(R N1A )(R N1B );
• R N1A , R B1A , and R B4A are as defined herein.
• the two R groups attached to the amino (N) atom are joined to form an 4- to 6- membered heterocyclyl unsubstituted or substituted with 1 or 2 R D1 groups, e.g., for example, in certain embodiments, R N1A and R N1B (or R B1A and R B1B , or R B4A and R B4B ) are joined to form an 4- membered heterocyclyl (e.g., azetidinyl), unsubstituted or substituted with 1 or 2 R D1 groups, 5-membered heterocyclyl (e.g., pyrrolidinyl, pyrrolidin-2-one, oxazolidin-2-one), unsubstituted or substitute
• 4- membered heterocyclyl e.g., azetidinyl
• 5-membered heterocyclyl e.g., pyrrolidinyl, pyrrolidin-2-one, oxazolidin-2-
• such groups are unsubstituted by R D1 .
• at least one instance of R D1 is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR D1A (i.e., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (-CH 3 , -CH 2 CH 3 ).
• any recited instance of -N(R N1A )(R N1B ), - N(R B1A )(R B1B ), or -N(R B4A )(R B4B ) independently refers to a group selected from:
• R N1 , R B2 and/or L l s are present in Ring B groups of formula (iii), (v), (vi), vii), (viii), (ix), (x), (xii), (xiii), (xxii (xxvii), (xxviii), and (xxiv):
• R N1 , R B2 and L 1 are further contemplated herein.
• R is substituted or unsubstituted Ci_ 3 alkyl, i.e., a Ci_ 3 alkyl substituted by 1, 2, or 3 R groups as previously described herein, or an unsubstituted Ci_ 3 alkyl.
• R N1 is unsubstituted Ci_ 3 alkyl, i.e., C ⁇ alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• R N1 is unsubstituted Ci_ 3 alkyl of formula -CH 3 , -CH 2 CH 3 , or - CH(CH 3 ) 2 .
• R N1 is substituted Ci_ 3 alkyl, e.g., of formula:
• R N1 is Ci_3haloalkyl, e.g., Ci haloalkyl (-CF 3 , -CCI 3 , - CFC1 2 , -CF 2 CI, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 ), C 2 haloalkyl (-CF 2 CF 3 , -CH 2 CF 3 , - CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , - CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2 , - CH 2 CH 2 C1), or C 3 hal
• R N1 is -CF 3 , -CH 2 F, -CHF 2 , -CH 2 C1, -CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CHF 2 , or -CH(CH 3 )CF 3 .
• R N1 is substituted or unsubstituted C 3 _6carbocylyl. In certain embodiments, R N1 is substituted or unsubstituted C 3 carbocylyl (e.g., substituted or unsubstituted cyclopropyl). In certain embodiments, such groups are unsubstituted by R . In other embodiments, such groups are substituted, e.g., wherein at least one instance of R is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR clA (e.g., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl
• R N1 is substituted or unsubstituted 4-6 membered heterocyclyl.
• R N1 is a substituted or unsubstituted 4- membered heterocyclyl (e.g., azetidinyl), substituted or unsubstituted 5-membered heterocyclyl (e.g., pyrrolidinyl, pyrrolidin-2-one, oxazolidin-2-one), or substituted or unsubstituted 6-membered heterocyclyl (e.g., morpholinyl, piperidinyl, piperazinyl). In certain embodiments, such groups are unsubstituted by R .
• such groups are substituted, e.g., wherein at least one instance of R is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR (e.g., - OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• R is halogen (i.e., -F, -CI, -Br, or -I)
• -CN e.g., -OR (e.g., - OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• unsubstituted 6-membered heterocyclyl ⁇ e.g., tetrahydropyranyl
• such groups are unsubstituted by R .
• such groups are substituted, e.g., wherein at least one instance of R is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR ⁇ e.g., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl ⁇ e.g., -CH 3 , -CH 2 CH 3 ).
• R N1 is a substituted or unsubstituted 4- to 6- membered heterocyclyl comprising one oxygen ring heteroatom.
• R N1 is:
• R is:
• Ci_ 3 alkyl (a) substituted or unsubstituted Ci_ 3 alkyl (-CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 ); Ci_ 3 haloalkyl (-CF 3 , -CH 2 F, -CHF 2 , -CH 2 C1, -CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CHF 2 or -CH(CH 3 )CF 3 );
• R N1A is -CH 3 , CH 2 CH 3 , - CH(CH 3 ) 2 , -CF 3 , -CH 2 F, -CHF 2 , -CH 2 C1, -CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CHF 2 , or CH(CH 3 )CF 3 ;
• N(R N1A )(R N1B ) is:
• Ring B is of formula: [00143] In certain embodiments f formula iii wherein Rin B is of formula:
• Rin B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• G of is -CH 2 - to provide a cyclopropanated Ring B of formula:
• x is 1 and y is 1. In certain embodiments of formula (xxii), x is 1 and y is 2.
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula: N1
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula: (xxviii).
• Ring B is of formula:
• Ring B is of formula:
• Li is -NH-, substituted or unsubstituted C 2 alkylene, substituted or unsubstituted C 2 alkenylene, or substituted or unsubstituted C 2 alkynylene.
• Li is -NH-. In certain embodiments of formula (viii), Li is substituted or unsubstituted C 2 alkylene. In certain embodiments of formula (viii), Li is substituted or unsubstituted C 2 alkenylene. In certain embodiments of formula (viii), Li is substituted or unsubstituted C 2 alkynylene. In certain embodiments of formula (viii), Li is an unsubstituted C 2 alkylene, unsubstituted C 2 alkenylene, or unsubstituted C 2 alkynylene group.
• Li is a substituted C 2 alkylene, substituted C 2 alkenylene, or substituted C 2 alkynylene group, e.g., substituted with 1 R group such as -OR ⁇ e.g., -OCH 3 .
• exemplary substituted L groups include:
• R is as defined herein, excluding hydrogen.
• q is 1, 2, or 3 and w is 1. In certain embodiments of formula (viii), q is 2 and w is 0 or 2.
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• R is hydrogen, halogen, -OR , substituted or unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl, and wherein R B2A i s substituted or unsubstituted Ci_ 3 alkyl or Ci_ 3 haloalkyl.
• R B2 is hydrogen. In certain embodiments, R B2 is halogen, e.g., -F, -CI, -Br, or -I. In certain embodiments, R is substituted or unsubstituted Ci_ 3 alkyl, i.e., a Ci_ 3 alkyl substituted by 1, 2, or 3 R groups as previously described herein, or an
• R is unsubstituted Ci_ 3 alkyl, i.e., C ⁇ alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -
• R is unsubstituted Ci_ 3 alkyl of formula -CH 3 , -
• R is substituted C _ 3 alkyl, e.g., of formula:
• R is C ⁇ haloalkyl, e.g., C ⁇ haloalkyl (-CF 3 , -CCI 3 , CFCI2, -CF2CI, -CH 2 F, -CHF 2 , -CH2CI, CHCI2), C 2 haloalkyl (-CF 2 CF 3 , -CH 2 CF 3 , - CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2 , - CH 2 CH 2 C1, -CH(CH 3
• R B2 is -CF 3 , -CH 2 F, -CHF 2 , -CH 2 C1, -CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CHF 2 , or -CH(CH 3 )CF 3 .
• R B2 is -OR B2A , wherein R B2A i s substituted or
• R B2A is substituted or unsubstituted Ci_ 3 alkyl, i.e., a Ci_ 3 alkyl substituted by 1, 2, or 3 R groups as previously described herein, or an unsubstituted Ci_ 3 alkyl. In certain embodiments, R B2A is
• Ci_ 3 alkyl i.e., C ⁇ alkyl (-CH ), unsubstituted C 2 alkyl (-CH 2 CH ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• R B2A is unsubstituted Ci_ 3 alkyl of formula -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .
• R B2A is substituted Ci_ 3 alkyl, e.g., of formula:
• R is hydrogen, -OR , -F, unsubstituted Ci_ 3 alkyl, Ci_
• Ci_ 3 alkyl substituted with -OR
• Rin B is of formula:
• R is hydrogen or -CH 3 CH 3 .
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• R l B2 i iss hhydrogen or halogen (e.g., -F, -CI,
• Ring B is of formula:
• Group R B1 and optionally group R B2 , are present in Ring B groups of formula (i), (ii), (iv), (xi), (xxiii), and (xxvi):
• R B1 is -N(R B1A )(R B1B ), wherein R B1A and R B1B are as defined herein.
• R is halogen, i.e., -F, -CI, -Br, or -I.
• R B1 is -CN.
• R B1 is -OR B1B or -SR B1B , wherein R B1B is hydrogen, substituted or unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C3-6 carbocyclyl, or substituted or unsubstituted 4- to 6-membered heterocyclyl.
• R B1 is -OR B1B or -SR B1B , wherein R B1B is substituted or unsubstituted Ci_ 3 alkyl or Ci_ 3 haloalkyl.
• R B1 is -OR B1B or -SR B1B , wherein R B1B is substituted or unsubstituted Ci_ 3 alkyl, i.e., a Ci_ 3 alkyl substituted by 1, 2, or 3 R groups as previously described herein, or an unsubstituted Ci_ 3 alkyl.
• R B1 is - OR B1B or -SR B1B , wherein R B1B is unsubstituted Ci_ 3 alkyl, i.e., C ⁇ alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• R B1 is -OR B1B or -SR B1B , wherein R B1B is unsubstituted Ci_ 3 alkyl of formula CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .
• R B1 is -OR B1B or -SR B1B , wherein R B1B is substituted Ci_ 3 alkyl, e.g., of formula:
• R B1 is substituted or unsubstituted C 1-3 alkyl, i.e., a Ci_ alkyl substituted by 1, 2, or 3 R groups as previously described herein, or an unsubstituted Ci_ 3 alkyl.
• R B1 is unsubstituted Ci_ 3 alkyl, i.e., Ci alkyl (-CH ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• R B1 is unsubstituted Ci_ 3 alkyl of formula -CH 3 , -CH 2 CH 3 , or - CH(CH ) 2 .
• R B1 is substituted Ci_ 3 alkyl, e.g., of formula:
• R B1 is Ci_ 3 haloalkyl, e.g., C ⁇ haloalkyl (-CF , -CC1 3 , - CFC1 2 , -CF 2 C1, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 ), C 2 haloalkyl (-CF 2 CF 3 , -CH 2 CF 3 , - CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2 , - CH 2 CH 2 CH 2 C1), or C 3
• R B1 is -CF 3 , -CH 2 F, -CHF 2 , -CH 2 C1, -CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CHF 2 , or -CH(CH 3 )CF 3 .
• R is substituted or unsubstituted C3_ 6 carbocylyl.
• R B1 is substituted or unsubstituted C 3 carbocylyl (e.g., substituted or unsubstituted cyclopropyl). In certain embodiments, such groups are unsubstituted by R .
• such groups are substituted, e.g., wherein at least one instance of R is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR clA (e.g., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl
• R is halogen (i.e., -F, -CI, -Br, or -I)
• -CN e.g., -OR clA (e.g., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl
• R B1 is substituted or unsubstituted 4-6 membered heterocyclyl.
• R B1 is a substituted or unsubstituted 4- membered heterocyclyl (e.g., azetidinyl), substituted or unsubstituted 5-membered heterocyclyl (e.g., pyrrolidinyl, pyrrolidin-2-one, oxazolidin-2-one), or substituted or unsubstituted 6-membered heterocyclyl (e.g., morpholinyl, piperidinyl, piperazinyl). In certain embodiments, such groups are unsubstituted by R .
• such groups are substituted, e.g., wherein at least one instance of R is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR (e.g., - OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• R is halogen (i.e., -F, -CI, -Br, or -I)
• -CN e.g., -OR (e.g., - OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• heterocyclyl e.g., azetidinyl, oxetanyl
• such groups are substituted, e.g., wherein at least one instance of R is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR clA (e.g., -OH, -OCH3), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• R B1 is:
• Ci_ 3 alkyl e.g., -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 ); or
• Ci_ 3 haloalkyl e.g., -CF 3 , -CCI 3 , -CFCI 2 , -CF 2 C1, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 , - CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1, - CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2 , - CH 2 CH 2 CH 2 C1, -CH(CH 3 )CHF 2 , -CH(CH 3 )CF 3 ); or
• R is hydrogen, halogen, -OR , substituted or unsubstituted Ci_ 3 alkyl, or Ci_ 3 haloalkyl, wherein R B2A is substituted or unsubstituted Ci_ 3 alkyl or Ci_ 3 haloalkyl.
• R B2 is hydrogen. In certain embodiments, R B2 is halogen, e.g., -F, -CI, -Br, or -I. In certain embodiments, R is substituted or unsubstituted Ci_ 3 alkyl, i.e., a Ci_ 3 alkyl substituted by 1, 2, or 3 R groups as previously described herein, or an
• R is unsubstituted Ci_ 3 alkyl, i.e., C ⁇ alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -
• R is unsubstituted Ci_ 3 alkyl of formula -CH , -
• R is substituted C _ 3 alkyl, e.g., of formula:
• R is Ci_3haloalkyl, e.g., C ⁇ haloalkyl (-CF 3 , -CCI 3 , - CFC1 2 , -CF2CI, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 ), C 2 haloalkyl (-CF 2 CF 3 , -CH 2 CF 3 , - CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 CHC1 2 , or C 3 haloalkyl (-CF 2 CF 2
• R B2 is -CF 3 , -CH 2 F, -CHF 2 , -CH 2 C1, -CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CHF 2 , or -CH(CH 3 )CF 3 .
• R B2 is -OR B2A , wherein R B2A i s substituted or
• R B2A is substituted or unsubstituted Ci_3alkyl, i.e., a Ci_3alkyl substituted by 1, 2, or 3 R groups as previously described herein, or an unsubstituted Ci_3alkyl. In certain embodiments, R B2A is
• Ci_3alkyl i.e., C ⁇ alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• R B2A is unsubstituted Ci_3alkyl of formula -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .
• R B2A is substituted Ci_3alkyl, e.g., of formula:
• R is hydrogen, -OR , -F, unsubstituted Ci_3 alkyl, Ci_
• Ci_3 alkyl substituted with -OR 1 CIB
• Ring B of formula (i), (ii), or (xxvi) various combinations of R B1 and R az are contemplated herein.
• R B1 and R B2 combinations are specifically contemplated:
• R B1 is -F and R B2 is -F; or c.
• R B1 is -OR B1B and R B2 is -OR B2A , and each instance of R B1B and R B2A is
• Ci_ 3 alkyl or Ci_ 3 haloalkyl independently substituted or unsubstituted Ci_ 3 alkyl or Ci_ 3 haloalkyl.
• R B1 and R B2 are joined to form a substituted or unsubstituted 4- to 6-membered heterocyclyl, e.g., a substituted or unsubstituted 4-membered heterocyclyl, a substituted or unsubstituted 5- membered heterocyclyl, or a substituted or unsubstituted 6-membered heterocyclyl.
• R B1 is -OR B1B and R B2 is -OR B2A
• R B1B and R B2A are joined to form a substituted or unsubstituted 5- membered heterocyclyl ⁇ e.g., dioxolanyl) or substituted or unsubstituted 6- membered heterocyclyl ⁇ e.g., dioxanyl).
• Rin B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula: [00220] In certain embodiments of formula (iv), Ring B is of formula:
• Rin B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Rin B is of formula:
• Ring B Groups comprising R N2 , R 83 , R 84 , R 85 , R 86 , and/or R 87
• Groups R N2 , R B3 , R B4 , R B5 , R B6 , and/or R B7 are provided in Rin formula (xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx), and (xxi):
• R B4 , R B5 , R B6 , and R B7 are contemplated herein.
• At least one of R , R , R , and R is hydrogen. In certain embodiments, two of R B4 , R B5 , R B6 , and R B7 are hydrogen. In certain embodiments, each of R B4 , R B5 , R B6 , and R B7 is hydrogen.
• At least one of R B4 , R B5 , R B6 , and R B7 is halogen, i.e., -F, - CI, -Br, or -I. In certain embodiments, at least one of R B4 , R B5 , R B6 , and R B7 is -CN.
• R B4 , R B5 , R B6 , and R B7 is -OR B4B or - SR B4B , wherein R B4B is hydrogen, substituted or unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C 3 -6 carbocyclyl, or substituted or unsubstituted 4- to 6- membered heterocyclyl.
• At least one of R B4 , R B5 , R B6 , and R B7 is - OR B4B or -SR B4B , wherein R B4B is substituted or unsubstituted Ci_ 3 alkyl or C ⁇ haloalkyl
• at least one of R B4 , R B5 , R B6 , and R B7 is -OR B4B or -SR B4B , wherein R B4B is substituted or unsubstituted Ci_ 3 alkyl, i.e., a Ci_ 3 alkyl substituted by 1, 2, or 3 R C1 groups as previously described herein, or an unsubstituted Ci_ 3 alkyl.
• R B4 , R B5 , R B6 , and R B7 is -OR B4B or -SR B4B , wherein R B4B is unsubstituted Ci_ 3 alkyl, i.e., C ⁇ alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (- CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• R B4 , R B5 , R B6 , and R B7 is -OR B4B or -SR B4B , wherein R B4B is unsubstituted Ci_ 3 alkyl of formula -CH 3 , -CH 2 CH 3 , or - CH(CH 3 ) 2 .
• at least one of R B4 , R B5 , R B6 , and R B7 is -OR B4B or - SR B4B , wherein R B4B is substituted Ci_ 3 alkyl, e.g., of formula:
• At least one of R B4 , R B5 , R B6 , and R B7 is substituted or unsubstituted Ci_ 3 alkyl, i.e., a Ci_ 3 alkyl substituted by 1, 2, or 3 R groups as previously described herein, or an unsubstituted Ci_ 3 alkyl.
• At least one of R B4 , R B5 , R B6 , and R B7 is unsubstituted Ci_ 3 alkyl, i.e., C ⁇ alkyl (-CH 3 ), unsubstituted C 2 alkyl (- CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• at least one of R B4 , R B5 , R B6 , and R B7 is unsubstituted Ci_ 3 alkyl of formula -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .
• at least one of R B4 , R B5 , R B6 , and R B7 is substituted Ci_ 3 alkyl, e.g., of formula:
• R B4 , R B5 , R B6 , and R B7 is Ci_ 3 haloalkyl, e.g., Ci haloalkyl (-CF 3 , -CCI 3 , -CFCI 2 , -CF 2 C1, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 ), C 2 haloalkyl (-CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 F, - CH 2 CH 2 CC1 3
• At least one of R B4 , R B5 , R B6 , and R B7 is -CF 3 , -CH 2 F, -CHF 2 , -CH 2 C1, -CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CHF 2 , or -CH(CH 3 )CF 3 .
• R B4 , R B5 , R B6 , and R B7 is substituted or unsubstituted C 3 _ 6 carbocylyl. In certain embodiments, at least one of R B4 , R B5 , R B6 , and R B7 is substituted or unsubstituted C 3 carbocylyl (e.g., substituted or unsubstituted cyclopropyl). In certain embodiments, such groups are unsubstituted by R .
• such groups are substituted, e.g., wherein at least one instance of R is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR clA (e.g., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• R is halogen (i.e., -F, -CI, -Br, or -I)
• -CN e.g., -OR clA (e.g., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• R B4 , R B5 , R B6 , and R B7 is substituted or unsubstituted 4-6 membered heterocyclyl.
• at least one of R B4 , R B5 , R B6 , and R B7 is a substituted or unsubstituted 4- membered heterocyclyl (e.g., azetidinyl), substituted or unsubstituted 5-membered heterocyclyl (e.g., pyrrolidinyl, pyrrolidin-2-one, oxazolidin-2-one), or substituted or unsubstituted 6-membered heterocyclyl (e.g., morpholinyl, piperidinyl, piperazinyl).
• such groups are unsubstituted by R .
• such groups are substituted, e.g., wherein at least one instance of R C1 is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR clA (e.g., -OH, -OCH 3 ), or unsubstituted d_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• R B A is substituted or unsubstituted 4- membered heterocyclyl (e.g., azetidinyl, oxetanyl).
• R B A is substituted or unsubstituted 5-membered heterocyclyl (e.g., tetrahydrofuranyl).
• such groups are substituted, e.g., wherein at least one instance of R is halogen (i.e., -F, -CI, -Br, or -I), -CN, -OR (e.g., -OH, -OCH 3 ), or unsubstituted Ci_ 3 alkyl (e.g., -CH 3 , -CH 2 CH 3 ).
• R is halogen (i.e., -F, -CI, -Br, or -I)
• -CN e.g., -OH, -OCH 3
• Ci_ 3 alkyl e.g., -CH 3 , -CH 2 CH 3
• Ring B is of formula (xiv)
• R B5 and R B7 are contemplated, e.g., wherein:
• each instance of R B5 and R B7 is hydrogen
• each instance of R B5 and R B7 is independently -OR B4B ;
• R B5 is -N(R B4A )(R B4B ), -OR B4B , -SR B4B , halogen, substituted or unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C 3 carbocyclyl, or substituted or unsubstituted 4-6 membered heterocyclyl; and R B7 is hydrogen; or d.
• R B5 is hydrogen and R B7 is -N(R B4A )(R B4B ), -OR B4B , -SR B4B , substituted or unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, or substituted or unsubstituted C 3 carbocyclyl.
• Ring B is of formula (xv)
• R B5 , R B6 , and R B7 are contemplated, e.g., wherein:
• each instance of R B5 , R B6 , and R B7 is hydrogen;
• R B5 is -N(R B4A )(R B4B ), -OR B4B , -SR B4B , halogen, substituted or unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C 3 carbocyclyl, or substituted or unsubstituted 4-6 membered heterocyclyl, and R B6 and R B7 are hydrogen; or
• R B6 is -N(R B4A )(R B4B ), -OR B4B , -SR B4B , halogen, substituted or unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C 3 carbocyclyl, or substituted or unsubstituted 4-6 membered heterocyclyl, and R B5 and R B7 are hydrogen; or
• R B7 is -N(R B4A )(R B4B ), -OR B4B , -SR B4B , halogen, substituted or unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C 3 carbocyclyl, or substituted or unsubstituted 4-6 membered heterocyclyl, and R B5 and R B6 are hydrogen.
• Ring B is of formula (xvi)
• R B4 , R B6 and R B7 are contemplated, e.g., wherein:
• R B4 is -N(R B4A )(R B4B ), -OR B4B , -SR B4B , halogen, substituted or unsubstituted
• RR BB6b iiss --NN((RR B4 ' )(R ), -OR , -SR. , halogen, substituted or unsubstituted
• RR B7 i iss --NN((RR B4 ' )(R ), -OR , -SR. , halogen, substituted or unsubstituted
• RR BB44 aanndd RR BB66 aarr,e-N(R B4A )(R B4B ), -OR B4B , -SR B4B , halogen, substituted or
• Ci_ 3 alkyl unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C 3 carbocyclyl, or substituted or unsubstituted 4-6 membered heterocyclyl, and R B7 is hydrogen.
• Ring B is of formula (xvii)
• R B5 and R B6 are contemplated, e.g., wherein:
• R B5 is -N(R B4A )(R B4B ), -OR B4B , -SR B4B , halogen, substituted or unsubstituted Ci_3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C 3 carbocyclyl, or substituted or unsubstituted 4-6 membered heterocyclyl, and R B6 is hydrogen; or
• R B6 is -N(R B4A )(R B4B ), -OR B4B , -SR B4B , halogen, substituted or unsubstituted Ci_ 3 alkyl, Ci_ 3 haloalkyl, substituted or unsubstituted C 3 carbocyclyl, or substituted or unsubstituted 4-6 membered heterocyclyl, and R B5 is hydrogen.
• each instance of R is independently hydrogen, unsubstituted Ci_ 3 alkyl, or C ⁇ haloalkyl, provided at least one instance of R B3 is hydrogen. In certain embodiments, each instance of R B3 is hydrogen.
• one instance of R is unsubstituted Ci_ 3 alkyl (e.g., -CH 3 ) or Ci_
• R B3 is hydrogen or -CH 3 , provided at least one instance of R B3 is hydrogen.
• each instance of R N2 and R B8 is independently substituted or unsubstituted Ci_ 3 alkyl or Ci_ 3 haloalkyl, or R N2
• R are joined to form a substituted or unsubstituted 5- to 6-membered ring.
• each instance of R N2 and R B8 is independently substituted or unsubstituted Ci_ 3 alkyl or C ⁇ haloalkyl.
• At least one of R N2 and R B8 is substituted or unsubstituted Ci_ 3 alkyl, i.e. , a Ci_ 3 alkyl substituted by 1 , 2, or 3 R groups as previously described herein, or an unsubstituted Ci_ 3 alkyl.
• at least one of R N2 and R B8 is unsubstituted Ci_ 3 alkyl, i.e., C ⁇ alkyl (-CH 3 ), unsubstituted C 2 alkyl (-CH 2 CH 3 ), or unsubstituted C 3 alkyl (-CH 2 CH 2 CH 3 or -CH(CH 3 ) 2 ).
• At least one of R N2 and R B8 is unsubstituted Ci_ 3 alkyl of formula -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In certain embodiments, at least one of R N2 and R B8 is substituted Ci_ 3 alkyl, e.g., of formula:
• R N2 and R B8 is Ci_ 3 haloalkyl, e.g., C ⁇ haloalkyl (-CF 3 , -CC1 3 , -CFC1 2 , -CF 2 C1, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 ), C 2 haloalkyl (- CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1), or C 3 haloalkyl (-CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH 2 C1), or C 3 haloalkyl (-CF
• At least one of R N2 and R B8 is -CF 3 , -CH 2 F, -CHF 2 , -CH 2 C1, -CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CHF 2 , or -CH(CH 3 )CF 3 .
• R N2 and R B8 are joined to form a substituted or unsubstituted 5- to 6-membered ring. In certain embodiments, R N2 and R B8 are joined to form a substituted or unsubstituted 5-membered ring. In certain embodiments, R N2 and R B8 are joined to form a substituted or unsubstituted 6-membered ring. In certain embodiments, R N2 and R B8 are joined to form an unsubstituted ring.
• each instance of R B8 and R N2 is independently -CH 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 3 , -CC1 3 , -CFC1 2 , -CF 2 C1, -CH 2 F, -CHF 2 , -CH 2 C1, CHC1 2 , -CF 2 CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CC1 3 , -CH 2 CHC1 2 , -CH 2 CH 2 C1, - CF 2 CF 2 CF 3 , -CH 2 CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 CHF 2 , - CH 2 CHF 2 , - CH 2 CH 2 F, - CH 2 CH 2 CC1 3 , - CH 2 CH
• Rin B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula: (xviii).
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B is of formula:
• Ring B groups contemplated herein include Ring B groups of formula (xxv) and (xxix).
• ing B is of formula: (xxv).
• Ring B is of formula:
• G of is -CH 2 - to provide a cyclopropanated Ring B of formula:
• Ring B is of formula:
• Ring B is of formula (i)
• Ring A is of formula (A-i)
• each of R A1 and R ⁇ is -CH 3
• Ring B is of formula (i), wherein Ring A is of formula (A- ii), and wherein R A5 is -CH 3 , R A4 is -Br, and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (ii), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (iii), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH provided is a compound of formula:
• Ring B is of formula (iv), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 provided is a compound of formula:
• Ring B is of formula (v), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (vi), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (vii), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (viii), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 provided is a compound of formula:
• Ring B is of formula (viii), wherein Ring A is of formula (A-iii), and wherein each of R ⁇ and R A5 is -CH 3 provided is a compound of formula:
• Ring B is of formula (ix), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH provided is a compound of formula:
• Ring B is of formula (ix), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CI, R A4 is hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (x), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 provided is a compound of formula:
• Ring B is of formula (x), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CI, R A4 is hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xi), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xii), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH provided is a compound of formula:
• Ring B is of formula (xiii), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xiv), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xiv), wherein Ring A is of formula (A-i), and wherein R A1 is -CH 3 and R ⁇ is -CH 2 CH , provided is a compound of formula:
• Ring B is of formula (xiv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH 3 , R A4 is -CI, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xiv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH 3 , R A4 is -Br, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xiv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH 3 , R A4 is -CN, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xiv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH 3 , R A4 is hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xiv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH 3 , R A4 is hydrogen, and R A5 is -CH 2 CH 3 , provided is a compound of formula:
• Ring B is of formula (xiv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CI, R A4 is hydrogen, and R A5 is -CH , provided is a compound of formula:
• Ring B is of formula (xiv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -Br, R A4 is hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xiv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CN, R A4 is hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xv), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xv), wherein Ring A is of formula (A-i), and wherein R A1 is -CH 3 and R ⁇ is -CH 2 CH , provided is a compound of formula:
• Ring B is of formula (xv), wherein Ring A is of formula (A-i), and wherein R A1 is -CH 2 CH and R ⁇ is -CH , provided is a compound of formula:
• Ring B is of formula (xv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH 3 , R A4 is -Br, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH 3 , R A4 is -CI, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -Br, R A4 is -hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -I, R A4 is -hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CI, R A4 is -hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CN, R A4 is -hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH 3 , R A4 is -hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CI, R A4 is -hydrogen, and R A5 is -CH 2 CH 3 , provided is a compound of formula:
• Ring B is of formula (xv), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH , R A4 is -hydrogen, and R A5 is -CH 2 CH , provided is a compound of formula:
• Ring B is of formula (xvi), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH provided is a compound of formula:
• Ring B is of formula (xvii), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CI, R A4 is -hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xviii), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH provided is a compound of formula:
• Ring B is of formula (xix), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 provided is a compound of formula:
• Ring B is of formula (xx), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxi), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxii), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH provided is a compound of formula:
• Ring B is of formula (xxii), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CI, R A4 is -hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxii), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -Br, R A4 is -hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxiii), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH provided is a compound of formula:
• Ring B is of formula (xxiv), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxv), wherein Ring A is of formula (A-i), and wherein eac A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxvi), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 provided is a compound of formula:
• Ring B is of formula (xxvi), wherein Ring A is of formula (A-i), and wherein R A1 is -CH 3 and nd R ⁇ is -CH , provided is a compound of formula:
• Ring B is of formula (xxvi), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH 3 , R A4 is -CI, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxvi), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH 3 , R A4 is -Br, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxvii), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxvii), wherein Ring A is of formula (A-i), and wherein R A1 is -CH 3 and R ⁇ is -CH 2 CH , provided is a compound of formula:
• Ring B is of formula (xxvii), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH , R A4 is -CI, and R A5 is -CH , provided is a compound of formula:
• Ring B is of formula (xxvii), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH 3 , R A4 is hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxvii), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH 3 , R A4 is hydrogen, and R A5 is -CH 2 CH 3 , provided is a compound of formula:
• Ring B is of formula (xxvii), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CI, R A4 is hydrogen, and R A5 is -CH 2 CH , provided is a compound of formula:
• Ring B is of formula (xxvii), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CI, R A4 is hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxvii), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -Br, R A4 is hydrogen, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxvii), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH 3 , R A4 is -Br, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxvii), wherein Ring A is of formula (A-ii), and wherein R ⁇ is -CH 3 , R A4 is -CN, and R A5 is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxviii), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• Ring B is of formula (xxix), wherein Ring A is of formula (A-i), and wherein each of R A1 and R ⁇ is -CH 3 , provided is a compound of formula:
• a compound of Formula (I) is selected from any one of the compounds provided in Table 1 , and pharmaceutically acceptable salts thereof.
• the compound of Formula (I) is not a compound or pharmaceutically acceptable salt thereof as disclosed in PCT/US2014/028463, the disclosure of which is incorporated herein by reference.
• compounds of Formula (I), wherein R 2a , R 2b , and R 3 are any of the following specific combinations:
• R 2a is hydrogen
• R 2b is hydrogen
• R 3 is -CH 3 ;
• R 2a is hydrogen
• R 2b is hydrogen
• R 3 is -F
• R 2a is hydrogen
• R 2b is hydrogen
• R 3 is -CI
• R 2a is -CI
• R 2b is hydrogen
• R 3 is -CI
• R 2a is -CI
• R 2b is hydrogen
• R 3 is -F
• R 2a is -F
• R 2b is hydrogen
• R 3 is -CI
• R 2a is -CI
• R 2b is hydrogen
• R 3 is -CH 3 ;
• R 2a is -F
• R 2b is hydrogen
• R 3 is -CH 3 ;
• R 2a is -CF 3
• R 2b is hydrogen
• R 3 is -CH 3
• R 2a is -CH 3
• R 2b is hydrogen
• R 3 is -CH 3
• R 2a is hydrogen
• R 2b is -CI
• R 3 is -CH 3 ;
• any one or all of the below compounds, and pharmaceutically acceptable salts thereof, are specifically excluded:

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• 2015
  • 2015-09-17 US US15/511,503 patent/US20170305922A1/en not_active Abandoned
  • 2015-09-17 JP JP2017514627A patent/JP2017530959A/ja not_active Withdrawn
  • 2015-09-17 WO PCT/US2015/050712 patent/WO2016044604A1/en not_active Ceased
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