WO2024059186A1 - Dérivés de n-((isoquinolin-6-yl)méthyl)-1 h-pyrazole-4-carboxamide en tant qu' inhibiteurs de la kallicréine plasmatique pour le traitement de l'angioœdème héréditaire - Google Patents

Dérivés de n-((isoquinolin-6-yl)méthyl)-1 h-pyrazole-4-carboxamide en tant qu' inhibiteurs de la kallicréine plasmatique pour le traitement de l'angioœdème héréditaire Download PDF

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WO2024059186A1
WO2024059186A1 PCT/US2023/032723 US2023032723W WO2024059186A1 WO 2024059186 A1 WO2024059186 A1 WO 2024059186A1 US 2023032723 W US2023032723 W US 2023032723W WO 2024059186 A1 WO2024059186 A1 WO 2024059186A1
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methyl
amino
compound
dimethylisoquinolin
optionally substituted
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PCT/US2023/032723
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Nikolaos PAPAIOANNOU
Sarah Jocelyn FINK
Jeremy Mark Travins
John Mark Ellard
Alastair Rae
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Takeda Pharmaceutical Company Limited
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • 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
    • C07D498/04—Ortho-condensed systems

Definitions

  • Plasma Kallikrein (PKa) is a serine protease zymogen in blood that is converted to its catalytically active form by coagulation factor Xlla, and contributes to the innate inflammatory response and intrinsic cascade of blood coagulation.
  • the mechanisms that lead to the activation of this pathway in vivo include interactions with polyphosphates released from activated platelets and deficiency of Cl inhibitor (Cl -INH), the primary physiological inhibitor of PKa.
  • Cl inhibitor Cl inhibitor
  • PKa- mediated cleavage of high-molecular weight kininogen generates the potent vasodilator and pro- inflammatory nonapeptide bradykinin (BK), which activates the bradykinin 2 receptor.
  • Bl and B2 receptors are expressed by vascular, glial, and neuronal cell types, with the highest levels of retinal expression detected in the ganglion cell layer and inner and outer nuclear layers. Activation of Bl and B2 receptors causes vasodilation and increases vascular permeability.
  • PKa is also associated with a number of disorders, such as hereditary angioedema (HAE), an autosomal dominant disease characterized by painful, unpredictable, recurrent attacks of inflammation affecting the hands, feet, face, abdomen, urogenital tract, and the larynx.
  • HAE hereditary angioedema
  • Prevalence for HAE is uncertain but is estimated to be approximately 1 case per 50,000 persons without known differences among ethnic groups.
  • HAE is caused by deficient (Type I) or dysfunctional (Type II) levels of Cl -INH, which inhibits PKa, bradykinin, and other serine proteases in the blood.
  • HAE hereditary angioedema
  • the present disclosure is based on, at least in part, the development of a number of compounds which bind to plasma kallikrein and effectively inhibit its activity. Accordingly, provided herein are compounds and uses thereof for targeting plasma kallikrein and/or treating plasma kallikrein-mediated diseases and disorders. [0004] In some embodiments, the present invention provides a compound of Formula (I): Cy B — L'— Cy A — L— Cy c
  • the present invention provides a compound of Formula (I): Cy B — U— Cy A — L— Cy c
  • the present invention also provides methods of using compounds of Formulae (I)-(XVI-c).
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyclyl,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • cycloaliphatic refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • aryl refers to monocyclic and bicyclic ring systems having a total of five to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
  • the term “aryl” may be used interchangeably with the term “aryl ring”.
  • an 8-10 membered bicyclic aryl group is an optionally substituted naphthyl ring.
  • “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar-” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 7t electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (or in the case of a bivalent fused heteroarylene ring system, at least one radical or point of attachment is on a heteroaromatic ring).
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4/7- quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one.
  • heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heterocyclyl As used herein, the terms “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10- membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro- 2//-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in A-substitutcd pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocyclyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • a bivalent carbocycle is “carbocycylene”
  • a bivalent aryl ring is “arylene”
  • a bivalent benzene ring is “phenylene”
  • a bivalent heterocycle is “heterocyclylene”
  • a bivalent heteroaryl ring is “heteroarylene”
  • a bivalent alkyl chain is “alkylene”
  • a bivalent alkenyl chain is “alkenylene”
  • a bivalent alkynyl chain is “alkynylene”
  • compounds of the invention may, when specified, contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are in a polycyclic ring system, substituents may, unless otherwise indicated, replace a hydrogen on any individual ring (e.g., ).
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, -CH 2 -(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 )o- 2 R*, -(haloR*), -(CH 2 )o- 2 OH, -(CH 2 )o- 2 OR*, -(CH 2 )o- 2 CH(OR*) 2 ; -O(haloR’), - CN, -N3, -(CH 2 )O- 2 C(0)R*, -(CH 2 )O- 2 C(0)OH, -(CH 2 )O- 2 C(0)OR*, -(CH 2 )O- 2 SR*, -(CH 2 )O- 2 SH, - (CH 2 )O- 2 NH 2 , -(CH 2 )O- 2 NHR*, -(CH 2 )O- 2 NR* 2 , -NO 2 , -SiR*
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR # 2 ) 2 -3O-, wherein each independent occurrence of R # is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R # include halogen, -R*, - (haloR*), - OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR*, -NR* 2 , or -NO 2 , wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R f , -NR’h, -C(O)R f , -C(O)OR f , -C(O)C(O)R f , -C(O)CH 2 C(O)R f , -S(O) 2 R f , - S(O) 2 NR T 2 , -CfSjNR’h, -C(NH)NR 1 ’2, or -N(R t )S(O)2R t ; wherein each R ?
  • Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R', taken together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R' are independently halogen, -R*, - (haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR*, -NR* 2 , or -NO 2 , wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “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 lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • the neutral forms of the compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • 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 including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • oxo means an oxygen that is double bonded to a carbon atom, thereby forming a carbonyl.
  • a “dosing regimen” is a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
  • a “reference” compound is one that is sufficiently similar to a particular compound of interest to permit a relevant comparison.
  • information about a reference compound is obtained simultaneously with information about a particular compound.
  • information about a reference compound is historical.
  • information about a reference compound is stored, for example in a computer-readable medium.
  • comparison of a particular compound of interest with a reference compound establishes identity with, similarity to, or difference of the particular compound of interest relative to the compound.
  • therapeutic agent refers to any agent that has a therapeutic effect and/or elicits a desired biological and/or pharmacological effect, when administered to a subject.
  • the term “therapeutically effective amount” refers to an amount of a therapeutic agent that confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • the “therapeutically effective amount” refers to an amount of a therapeutic agent effective to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventative effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease, and/or also lessening the severity or frequency of symptoms of the disease.
  • a therapeutically effective amount is commonly administered in a dosing regimen that may comprise multiple unit doses.
  • a therapeutically effective amount (and/or an appropriate unit dose within an effective dosing regimen) may vary, for example, depending on route of administration, on combination with other pharmaceutical agents.
  • the specific therapeutically effective amount (and/or unit dose) for any particular subject may depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific therapeutic agent employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and/or rate of excretion or metabolism of the specific therapeutic agent employed; the duration of the treatment; and like factors as is well known in the medical arts.
  • treatment refers to any administration of a substance (e.g., provided compositions) that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition.
  • a substance e.g., provided compositions
  • Such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition.
  • such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
  • treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and/or condition.
  • a provided compound is of Formula (I): Cy B — L'— Cy A — L— Cy c
  • Cy A is phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein Cy A is substituted with 0-4 -R A groups; each R A is independently selected from oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, - NO 2 , -N(R)2, -N(R)C(O)R, -N(R)C(O) 2 R, -N(R)S(O) 2 R, -OR, -OC(O)R, -OC(O
  • L’ is a covalent bond or an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NR Z -, -S-, -SO- , -SO2-, -S(NH)(O)-, or cyclopropylene; each R z is independently selected from hydrogen, -(CH2)o-30R, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group; wherein: each of R B1 and R B2 is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl;
  • R B3 is hydrogen or C1-6 aliphatic
  • R B4 is -N(R X ) 2 ; each R x is independently selected from hydrogen, -C(O)R, -C(O)2R, or optionally substituted C1-6 aliphatic. wherein no more than one of R B1 or R B2 is hydrogen; or wherein:
  • R B5 is hydrogen or Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl; each of R B6 and R B7 is independently hydrogen or an optionally substituted Ci-6 aliphatic;
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR Z -, -N(NO)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
  • Cy c is selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10-membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cy c is substituted with 0-6 -L c -R c groups; each L c is independently selected from a covalent bond or an optionally substituted C1-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-; and each R c is independently selected from oxo, halogen, -CN, -C(O)R, -C(O) 2 R, -C(O)N(R)2,
  • a provided compound is of Formula (!'):
  • Cy A Cy A , Cy c , L, and L’ is defined and described in classes and subclasses herein, both singly and in combination; and Cy B is an optionally substituted 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • Cy A is phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or an 8- to 12- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is phenylene, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is phenylene, wherein Cy A is substituted with 0-2 -R A groups. [0045] In some embodiments, Cy A is a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is a 6-membered monocyclic heteroarylene having 1-3 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 R A groups. In some embodiments, Cy A is a pyridinediyl substituted with 0-3 R A groups. In some embodiments, Cy A is a pyrimidinediyl substituted with 0-2 R A groups. In some embodiments, Cy A is a pyridazinediyl substituted with 0-2 R A groups. In some embodiments, Cy A is a pyrazinediyl substituted with 0-2 R A groups. In some embodiments, Cy A is a pyrazinediyl substituted with 0-2 R A groups. In some embodiments, Cy A is a triazinediyl substitute
  • Cy A is a 5-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-2 -R A groups.
  • Cy A is thiazolediyl, wherein Cy A is substituted with 0-1 -R A groups.
  • Cy A is an unsubstituted thiadiazol ediyl.
  • Cy A is an unsubstituted oxadiazolediyl.
  • Cy A is an unsubstituted triazolediyl.
  • Cy A is pyrrolediyl, wherein Cy A is substituted with 0-2 -R A groups. In some embodiments, Cy A is pyrazolediyl, wherein Cy A is substituted with 0-2 -R A groups. In some embodiments, Cy A is imidazolediyl, wherein Cy A is substituted with 0-2 -R A groups. In some embodiments, Cy A is unsubstituted pyrazolediyl. In some embodiments, Cy A is unsubstituted imidazolediyl.
  • Cy A is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is an 8- to 12-membered bicyclic heteroarylene having 1- 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is an 8- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 9- to 10- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is an 8-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is an 8-membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is an 8-membered bicyclic heteroarylene having 2 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 9-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is a 9-membered bicyclic heteroarylene having 1-4 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is a 9-membered bicyclic heteroarylene having 2 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 9- membered bicyclic heteroarylene having 3 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is a 9-membered bicyclic heteroarylene having 4 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 10-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is a 10-membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups. In some embodiments, Cy A is a 10-membered bicyclic heteroarylene having 1 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 7- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 9-membered bicyclic heteroarylene having 3-4 heteroatoms independently selected from oxygen and nitrogen, wherein Cy A is substituted with 0-1 -R A groups.
  • Cy A is a 10-membered bicyclic heteroarylene having 3-4 heteroatoms independently selected from oxygen and nitrogen, wherein Cy A is substituted with 0-1 -R A groups.
  • Cy A is selected from the group consisting of:
  • Cy A is selected from the group consisting of wherein * represents the point of attachment to L’.
  • Cy A is selected from the group consisting of wherein * represents the point of attachment to L’.
  • Cy A is selected from the group consisting of wherein * represents the point of attachment to L’.
  • Cy A is selected from the group consisting of: wherein * represents the point of attachment to L’.
  • Cy A is: wherein * represents the point of attachment to L’.
  • Cy A is phenylene, 5-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1- 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or 8- to 10-membered bicyclic arylene, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is selected from the group consisting of phenylene, thiazolediyl, pyrimidinediyl, pyridazinediyl, triazinediyl, thiadi azolediyl, oxadiazolediyl, triazolediyl, pyrrolediyl, pyrazolediyl, imidazolediyl, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is selected from the group consisting of:
  • Cy A is not a 6-membered monocyclic heteroarylene having 1- 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, Cy A is not a 6-membered monocyclic heteroarylene having 1-2 nitrogen heteroatoms. In some embodiments, Cy A is not a pyridinediyl or pyrazinediyl substituted with 0-3 R A groups. In some embodiments, Cy A is not a pyridinediyl substituted with 0-3 R A groups. In some embodiments, Cy A is a not pyrazinediyl substituted with 0-2 R A groups. In some embodiments, Cy A is not some embodiments, Cy A is not some embodiments, Cy A is not . In some embodiments, Cy A is not . In some embodiments, Cy A is not . In some embodiments, Cy A is not . In some embodiments, Cy A is not . In some embodiments, Cy A is not . In some embodiments, Cy A is not . In some embodiments
  • Cy A is phenylene, 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1- 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or 8- to 10-membered bicyclic arylene, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is selected from the group consisting of:
  • Cy A is not a 5-membered monocyclic heteroarylene having 1- 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, Cy A is not a 5-membered monocyclic heteroarylene having 1 nitrogen and 1 sulfur heteroatoms. In some embodiments, Cy A is not a thiazolediyl or pyrazinediyl substituted with 0-3 R A groups.
  • Cy A is not
  • Cy A is substituted with 0 -R A groups (i.e., Cy A is unsubstituted).
  • Cy A is phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is not a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur substituted with 0-4 -R A groups.
  • each R A is independently selected from oxo, halogen, -CN, - C(O)R, -C(O) 2 R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O) 2 R, -N(R)S(O) 2 R, -OR, - OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O) 2 R, -S(O)N(R) 2 , -S(O) 2 N(R) 2 , or an optionally substituted group selected from C1-6 aliphatic,
  • each R A is independently selected from oxo, halogen, -CN, - C(O) 2 R, -N(R) 2 , -OR, -SR, -S(O)R, -S(O) 2 R, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
  • each R A is independently selected from oxo, halogen, -C(O)2R, -OR, -C(O)N(R) 2 , or an optionally substituted C1-6 aliphatic.
  • each R A is independently selected from halogen, -OR, or an optionally substituted C1-6 aliphatic. In some embodiments, each R A is independently selected from halogen or an optionally substituted C1-6 aliphatic. In some embodiments, each R A is independently selected from fluorine or methyl.
  • substituents on an optionally substituted R A group are independently halogen, -(CH2)o-40R°, or -(CH2)O--IN(R 0 )2, wherein each R° is independently as defined above and described in classes and subclasses herein.
  • each R° is independently hydrogen or methyl.
  • each R° is hydrogen.
  • references herein to embodiments in which “a single instance” of a substituent is defined are not limited to monosubstituted embodiments.
  • a single instance of R A is oxo includes embodiments in which at least one instance of R A is oxo and which may comprise one or more additional R A groups as defined herein.
  • a single instance of R A is oxo. In some embodiments, a single instance of R A is halogen. In some embodiments, a single instance of R A is fluorine. In some embodiments, a single instance of R A is chlorine. In some embodiments, a single instance of R A is -CN.
  • a single instance of R A is -C(O)2R. In some embodiments, a single instance of R A is -C(O)2R, wherein R is hydrogen, methyl, or ethyl. In some embodiments, a single instance of R A is -C(O)2H. In some embodiments, a single instance of R A is -C(O)2CHa. In some embodiments, a single instance of R A is -C(O)2CH2CH3. In some embodiments, a single instance of R A is -C(O)N(R)2. In some embodiments, a single instance of R A is -C(O)NH2.
  • a single instance of R A is -N(R)2. In some embodiments, a single instance of R A is -OR.
  • a single instance of R A is Ci-6 aliphatic substituted with halogen.
  • R A is -CHF2.
  • R A is -CF3.
  • a single instance of R A is Ci-6 aliphatic substituted with - (CH 2 )O-40R°, wherein R° is selected from hydrogen or C1-6 aliphatic.
  • a single instance of R A is -CH2OH.
  • a single instance of R A is -CH2OCH3.
  • a single instance of R A is C1-6 aliphatic substituted with -(CH2)o-4N(R°)2, wherein each R° is independently selected from hydrogen or C1-6 aliphatic.
  • a single instance of R A is -CH2NH2.
  • a single instance of R A is C1-6 aliphatic substituted with -(CH2)o-4C(0)OR°, wherein R° is selected from hydrogen or 0
  • a single instance of R A is j n some o embodiments, a single instance of R A is
  • a single instance of R A is methyl, ethyl, or propyl. In some embodiments, a single instance of R A is methyl.
  • a single instance of R A is optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, a single instance of R A is optionally substituted cyclopropyl.
  • a single instance of R A is optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R A is optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen and nitrogen. In some embodiments, a single instance of R A is optionally substituted oxetanyl. In some embodiments, a single instance of R A is oxetanyl optionally substituted with halogen or -(CH2)o-40R°. In some embodiments, a single instance of R A is pyrrolidinyl.
  • each R A is independently selected from halogen, -CN, - C(O)R, -C(O) 2 R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O) 2 R, -N(R)S(O) 2 R, -OR, - OC(O)R, -OC(O)N(R) 2 , -SR, -S(O)R, -S(O) 2 R, -S(O)N(R) 2 , -S(O) 2 N(R) 2 , or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or
  • R A is not oxo.
  • L’ is a covalent bond or an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NR Z -, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
  • L’ is a covalent bond.
  • L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NR Z -, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
  • L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, - NR Z -, -SO2-. In some embodiments, L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)- or -NR Z . In some embodiments, L’ is an optionally substituted C2-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -C(O)-, and 1 or 2 additional methylene units are independently replaced with -NR Z .
  • L’ is an optionally substituted C3-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -C(O)-, and 1 or 2 additional methylene units are independently replaced with -NR Z .
  • L’ is an optionally substituted C1-4 hydrocarbon chain, wherein 1 methylene unit is replaced -NR Z .
  • L’ is an optionally substituted C1-3 hydrocarbon chain, wherein 1 methylene unit is replaced -NR Z .
  • L’ is an optionally substituted C2-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -SO2-, and 1 or 2 additional methylene units are independently replaced with -NR Z .
  • L’ is an optionally substituted C3-4 hydrocarbon chain, wherein 1 methylene unit is replaced with -SO2-, and 1 or 2 additional methylene units are independently replaced with -NR Z .
  • L’ is an optionally substituted Ci-4 hydrocarbon chain, wherein 1 methylene unis is optionally and independently replaced with -NR Z -.
  • L’ is optionally substituted with halogen. In some embodiments, L’ is optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or Ci-6 aliphatic and may be further substituted with halogen. In some embodiments, L’ is optionally substituted with -CF3.
  • L’ is selected from the group consisting of: and 0 , wherein # represents the point of attachment to Cy B .
  • L’ is selected from the group consisting of: , wherein # represents the point of attachment to Cy B .
  • L’ is wherein # represents the point of attachment to Cy B . In some embodiments, L’ is O , wherein # represents the point of attachment to Cy B .
  • L’ is a covalent bond or an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -NR Z -, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
  • L’ is a covalent bond or an optionally substituted Ci-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
  • L’ is selected from the group consisting of:
  • L’ is not O , wherein # represents the point of attachment to Cy B .
  • L’ is a covalent bond or an optionally substituted C2-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NR Z -, -S-, -SO-, -SO2-, -S(NH)(O)-, or cyclopropylene.
  • L’ is not -O-.
  • Cy B is an optionally substituted 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, Cy B is an optionally substituted 10-membered heteroaryl having 1 nitrogen heteroatom. In some embodiments, Cy B is optionally substituted isoquinolinyl. In some embodiments, Cy B is optionally substituted . in some embodiments, Cy B is optionally substituted with halogen; -(CH2)o-4R°; -(CH2)o-40R°; or -(CH2)o-4N(R°)2. In some such embodiments, R° is hydrogen or C1-6 aliphatic.
  • Cy B wherein no more than one of R B1 or R B2 is hydrogen. In some embodiments, wherein R B1 is not hydrogen. In some embodiments, , wherein R B2 is not hydrogen. In some embodiments,
  • Cy B is , wherein R B1 and R B2 are not hydrogen.
  • R B1 is hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, R B1 is hydrogen or C1-6 aliphatic. In some embodiments, R B1 is hydrogen. In some embodiments, R B1 is C1-6 aliphatic. In some embodiments, R Bi is methyl. In some embodiments, R B1 is ethyl. In some embodiments, R B1 is methyl, optionally substituted with halogen. In some embodiments, R B1 is -CF3.
  • R B1 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, R B1 is an optionally substituted cyclopropyl. In some embodiments, R B1 is cyclopropyl. In some embodiments, R B1 is cyclopropyl, optionally substituted with -(CH2)O-4R 0 , wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R Bi is In some embodiments, R B1 is methyl, ethyl, -CF3, or
  • R B2 is hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, R B2 is hydrogen or C1-6 aliphatic. In some embodiments, R B2 is hydrogen. In some embodiments, R B2 is C1-6 aliphatic. In some embodiments, R B2 is methyl. In some embodiments, R B2 is ethyl. In some embodiments, R B2 is methyl, optionally substituted with halogen. In some embodiments, R B2 is -CF3.
  • R B2 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, R B2 is an optionally substituted cyclopropyl. In some embodiments, R B2 is cyclopropyl. In some embodiments, R B2 is cyclopropyl, optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R B2 is
  • R B1 and R B2 are the same. In some embodiments, R B1 and R B2 are different. In some embodiments, R B1 is hydrogen and R B2 is Ci-6 aliphatic. In some embodiments, R B1 is Ci-6 aliphatic and R B2 is hydrogen. In some embodiments, R B1 and R B2 are Ci-6 aliphatic. In some embodiments, R B1 is hydrogen and R B2 is methyl. In some embodiments, R B1 is methyl and R B2 is hydrogen. In some embodiments, R B1 and R B2 are methyl.
  • R B1 is methyl, ethyl, -CF3, or and R B2 is hydrogen, methyl, ethyl, -CF3, or In some embodiments, R B1 is hydrogen, methyl, ethyl, -CF3, or and R B2 is methyl, ethyl, -CF3, or In some embodiments, R B1 is methyl, ethyl, -CF3, or , and R B2 is methyl, ethyl, - .
  • the sizes of the R B1 and/or R B2 groups influence potency without loss of binding efficiency.
  • the relative size of a group can be determined from the van der Waals surface and/or molecular volume calculated for that group.
  • the van der Waals surface is a closed surface, and hence, it contains volume. This volume is called the molecular volume, or van der Waals volume, and is usually given in A 3 .
  • a straightforward way of calculating A-values on the computer is by numerical integration, i.e., by surrounding the van der Waals envelope with a grid of small bricks and summing up the bricks whose centers are within the van der Waals envelope of the molecule (i.e., are within a van der Waals radius from atom nucleus) (see, for example, Whitley, “Van der Waals surface graphs and molecular shape,” Journal of Mathematical Chemistry (1998) 23:377-397).
  • the relative size of a group can also be measured from the “A-value” for a given group.
  • the A-value is a measure of the effective size of a given group.
  • the “A-value” refers to the conformational energies (-G 0 values) as determined for a substituted cyclohexane and the relative axial-equatorial disposition of the substituent (see Table 1, provided below, and pages 695-697 of Eliel and Wilen, Chapter 11 entitled “Configuration and Confirmation of Cyclic Molecules” of Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New
  • R B1 is selected from a moiety with an A-value that is greater than about 1.0 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value that is greater than about 1.5 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value that is greater than about 1.70 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value that is greater than about 2.0 kcal/mol (e.g., as shown in Table 1).
  • R B1 is selected from a moiety with an A-value that is greater than about 2.25 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value that is greater than about 2.5 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value that is greater than about 2.75 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value that is greater than about 3.0 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value that is greater than about 4.0 kcal/mol (e.g., as shown in Table 1).
  • R B1 is selected from a moiety with an A-value between about 0.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 0.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 1.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A- value between about 1.5 and about 5.0 (e.g., as shown in Table 1).
  • R B1 is selected from a moiety with an A-value between about 1.70 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 2.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 2.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 2.5 and about 5.0 (e.g., as shown in Table 1).
  • R B1 is selected from a moiety with an A- value between about 3.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 4.0 and about 5.0 (e.g., as shown in Table 1).
  • R B1 is selected from a moiety with an A-value between about 0.25 and about 4.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 0.25 and about 3.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 0.25 and about 2.5 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A- value between about 0.25 and about 2.0 (e.g., as shown in Table 1).
  • R B1 is selected from a moiety with an A-value between about 0.5 and about 2.5 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 1.0 and about 2.5 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 1.0 and about 2.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A-value between about 1.5 and about 2.0 (e.g., as shown in Table 1). In some embodiments, R B1 is selected from a moiety with an A- value between about 1.5 and about 2.5 (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A-value that is greater than about 1.0 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value that is greater than about 1.5 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value that is greater than about 1.70 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value that is greater than about 2.0 kcal/mol (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A-value that is greater than about 2.25 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value that is greater than about 2.5 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value that is greater than about 2.75 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value that is greater than about 3.0 kcal/mol (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value that is greater than about 4.0 kcal/mol (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A-value between about 0.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 0.5 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 1.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A- value between about 1.5 and about 5.0 (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A-value between about 1.70 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 2.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 2.25 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 2.5 and about 5.0 (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A- value between about 3.0 and about 5.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 4.0 and about 5.0 (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A-value between about 0.25 and about 4.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 0.25 and about 3.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 0.25 and about 2.5 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A- value between about 0.25 and about 2.0 (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A-value between about 0.5 and about 2.5 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 1.0 and about 2.5 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 1.0 and about 2.0 (e.g., as shown in Table 1). In some embodiments, R B2 is selected from a moiety with an A-value between about 1.5 and about 2.0 (e.g., as shown in Table 1).
  • R B2 is selected from a moiety with an A- value between about 1.5 and about 2.5 (e.g., as shown in Table 1).
  • R B3 is hydrogen or Ci-6 aliphatic. In some embodiments, R B3 is hydrogen. In some embodiments, R B3 is Ci-6 aliphatic. In some embodiments, R B3 is methyl, ethyl, or propyl. In some embodiments, R B3 is methyl.
  • R B4 is -N(R x )i. In some embodiments, R B4 is -NH2. In some embodiments, R B4 is -NHR X .
  • each R x is independently selected from hydrogen, -C(O)R, - C(O)2R, or optionally substituted C1-6 aliphatic. In some embodiments, each R x is hydrogen. In some embodiments, each R x is independently selected from -C(O)R, -C(O)2R, or optionally substituted C1-6 aliphatic. In some embodiments, one R x is hydrogen, and the other is selected from -C(O)R, -C(O)2R, or optionally substituted C1-6 aliphatic.
  • R x is -C(O)R. In some embodiments, R x is -C(O)R, wherein R is C1-6 aliphatic. In some embodiments, R x -C(O)CH3 In some embodiments, R x is -C(O)2R. In some embodiments, R x is -C(O)2R, wherein R is optionally substituted C1-6 aliphatic. In some embodiments, R x is -C(O)2R, wherein R is C1-6 aliphatic optionally substituted with -(CH2)o-4Ph. In some embodiments, R x is -C(O)2CH2Ph.
  • R x is -C(O)2R, wherein R is C1-6 aliphatic. In some embodiments, R x is -C(O)2R, wherein R is methyl, ethyl, isopropyl, or isobutyl. In some embodiments, R x is -C(O)2CH2CH3. In some embodiments, R x is - C(O)C(CH3)2. In some embodiments, R x is -C(O)CH2C(CH3)2. In some embodiments, R x is optionally substituted C1-6 aliphatic. In some embodiments, R x is C1-6 aliphatic. In some embodiments, R x is methyl, ethyl, or propyl. In some embodiments, R x is methyl.
  • Cy B is selected from the group consisting of:
  • Cy B is selected from the group consisting of: [0121] In some embodiments, Cy B is selected from the group consisting of:
  • R B5 is hydrogen or Ci-6 aliphatic or an optionally substituted
  • R B5 is hydrogen. In some embodiments, R B3 is Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, R B5 is Ci-6 aliphatic. In some embodiments, R B5 is methyl, ethyl, or propyl. In some embodiments, R B5 is methyl. In some embodiments, R B5 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl. In some embodiments, R B3 is an optionally substituted cyclopropyl. In some embodiments, R B3 is cyclopropyl, optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments,
  • R B6 is hydrogen or an optionally substituted Ci-6 aliphatic. In some embodiments, R B6 is hydrogen. In some embodiments, R B6 is an optionally substituted Ci-6 aliphatic. In some embodiments, R B6 is Ci-6 aliphatic or optionally substituted -(CH2)o-4N(R°)2, wherein each R° is independently hydrogen or Ci-6 aliphatic.
  • R B7 is hydrogen or an optionally substituted Ci-6 aliphatic. In some embodiments, R B7 is hydrogen. In some embodiments, R B7 is an optionally substituted Ci-6 aliphatic. In some embodiments, R B7 is Ci-6 aliphatic. In some embodiments, R B7 is C1-3 aliphatic. In some embodiments, R B7 is methyl, ethyl, or propyl. In some embodiments, R B7 is methyl.
  • Cy B is selected from the group consisting of:
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR Z -, - N(N0)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR 7 -, - N(NO)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR Z -, - N(N0)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or a 5-membered saturated or partially unsaturated heterocyclene having 1 nitrogen heteroatom, optionally substituted with - (CH 2 )O-40R 0 or -OSiR°3, wherein R° is as defined above and described in classes and subclasses herein.
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR 7 -, -N(N0)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or a pyrrolidinediyl optionally substituted with -(CH2)o-40R° or -OSiR°3, wherein each R° is independently as defined above and described in classes and subclasses herein. In some such embodiments, each R° is independently hydrogen of C1-6 aliphatic.
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR Z -, -N(N0)-, -S-, or an optionally substituted cyclopropylene.
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR Z -, or -S-.
  • L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -O-, -NR Z -, -N(NO)-, or -S-.
  • L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -O-, -NR Z -, -N(N0)-, -S-, or an optionally substituted cyclopropylene.
  • L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -O-, -NR Z -, or -S-. In some embodiments, L is an optionally substituted C1-2 hydrocarbon chain, wherein 1 methylene unit is replaced with -C(O)-, -O-, -NR Z -, -N(N0)-, or -S-.
  • L is an optionally substituted Ci hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-, -NR Z -, or -O-. In some embodiments, L is an optionally substituted Ci hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -C(O)-.
  • L is a Ci hydrocarbon chain, optionally substituted with halogen; -(CH 2 )o-4R°; -(CH 2 )o-40R°; -(CH 2 )o-4C(0)OR°; -(CH 2 )o-4N(R°) 2 ; or -(CH 2 )o- 4N(R°)C(O)OR°, wherein each R° is independently hydrogen or C1-6 aliphatic.
  • L is . In some embodiments, L is . In some embodiments, L is a Ci hydrocarbon chain, substituted with halogen. In some embodiments, L is , . In some embodiments, L is a Ci hydrocarbon chain, substituted with -(CH 2 )o-4R°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, L is . In some embodiments, L is , wherein % represents the point of attachment to Cy c . In some embodiments, L is , wherein % represents the point of attachment to Cy c . In some embodiments, L is a Ci hydrocarbon chain, substituted with
  • L is . In some embodiments, L is In some embodiments, L is a Ci hydrocarbon chain, substituted with -(CH2)o-4C(0)OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, L is In some embodiments, L is In some embodiments, L is a Ci hydrocarbon chain, substituted with -(CH2)o-4N(R°)2, wherein each R° is independently hydrogen or C1-6 aliphatic. In some embodiments, L is In some embodiments, L is a
  • Ci hydrocarbon chain substituted with -(CH2)o-4N(R°)C(0)OR°, wherein R° is hydrogen or Ci-6 aliphatic.
  • R° is hydrogen or Ci-6 aliphatic.
  • L is an optionally substituted C2 hydrocarbon chain, wherein 1 methylene unit is optionally replaced with -NR Z -, -O-, -N(N0)-, -S-.
  • L is a C2 hydrocarbon chain optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is independently replaced with -NR Z -, -O-, -N(N0)-, -S-.
  • L is a C2 hydrocarbon chain optionally substituted with -
  • L is a C2 hydrocarbon chain optionally substituted with -
  • L is , wherein % represents the point of attachment to Cy c In some embodiments, L is wherein % represents the point of attachment to
  • L is wherein % represents the point of attachment to
  • L is , wherein % represents the point of attachment to Cy c . In some embodiments, L is , wherein % represents the point of attachment to
  • L is a C2 hydrocarbon chain optionally substituted with - (CH2)O-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is replaced with -S-.
  • L is , wherein % represents the point of attachment to Cy c .
  • L is a C2 hydrocarbon chain optionally substituted with - (CH2)O-4R°, wherein R° is hydrogen or Ci-6 aliphatic, and wherein 1 methylene unit is replaced
  • L is , wherein % represents the point of attachment to Cy c .
  • L is a C2 hydrocarbon chain optionally substituted with - (CH2)O-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is replaced with -NR Z -.
  • L is a C2 hydrocarbon chain optionally substituted with - (CH2)o-4R°, wherein R° is hydrogen or C1-6 aliphatic, and wherein 1 methylene unit is replaced with -NR Z -, wherein R z is hydrogen, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group.
  • L is , wherein % represents the point of attachment to
  • L is , wherein % represents the point of attachment to
  • L is wherein % represents the point of attachment to
  • L is , wherein % represents the point of attachment ° ⁇ N to Cy c In some embodiments, L is wherein % represents the point of attachment to
  • L is , wherein % represents the point of attachment to i H r
  • L is i , wherein % represents the point of attachment to Cy c .
  • L is an optionally substituted C3 hydrocarbon chain, wherein 1 or 2 methylene units are optionally and independently replaced with -C(O)-, -NR Z -, or -O-. In some embodiments, L is an optionally substituted C3 hydrocarbon chain, wherein 1 or 2 methylene units are optionally and independently replaced with -C(O)- or -NR Z -. In some embodiments, L is a C3 hydrocarbon chain optionally substituted with -(CH2)o-4R°, wherein R° is hydrogen or C1-6 aliphatic and may be further substituted with halogen, wherein 1 or 2 methylene units are optionally and independently replaced with -C(O)- or -NR Z -. In some embodiments, L
  • O is H , wherein % represents the point of attachment to Cy c .
  • L is i , wherein % represents the point of attachment to Cy c .
  • L is CF 3 , wherein % represents the point of attachment to Cy c .
  • L is optionally substituted , wherein % represents the point of attachment to Cy c . In some embodiments, L is optionally substituted wherein % represents the point of attachment to Cy c . In some embodiments, optionally substituted with -(CH2)o-40R° or -OSiR°3, wherein % represents the point of attachment to Cy c . In some embodiments, L is optionally substituted , wherein % represents the point of attachment to Cy In some embodiments, L is optionally substituted with -(CH2)o-40R° or -OSiR°3, wherein % represents the point of attachment to Cy c .
  • % represents the point of attachment to Cy c .
  • L is not , wherein % represents the point of attachment to Cy .
  • L is not , wherein % represents the point of attachment to Cy
  • L is selected from the group consisting of:
  • L is selected from the group consisting of: wherein % represents the point of attachment to Cy c .
  • L is selected from the group consisting of:
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR Z -, - N(N0)- -S-, -SO-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6- membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • L is not -NHS(O)2- % , wherein % represents the point of attachment to Cy c .
  • each R z is independently selected from hydrogen, -(CH2)o- 3OR, -(CH2)O-3C(0)OR, or an optionally substituted C1-6 aliphatic group.
  • R z is hydrogen.
  • R z is selected from -(CH2)o-30R, -(CH2)o-3C(0)OR, or an optionally substituted C1-6 aliphatic group.
  • R z is -(CH2)o-30R.
  • R z is -(CH2)o-3C(0)OR.
  • R z is -C(O)OH.
  • R z is -C(O)OCH3.
  • R z is -C(O)OCH2CH3. In some embodiments, R z is an optionally substituted C1-6 aliphatic group. In some embodiments, R z is a Ci-6 aliphatic group optionally substituted with halogen. In some embodiments, R z is -CH2CF3. In some embodiments, R z is a C1-6 aliphatic group. In some embodiments, R z is methyl, ethyl, or propyl. In some embodiments, R z is methyl.
  • Cy c is selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10- membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is phenyl, wherein Cy c is substituted with 0-5 -L c -R c groups.
  • Cy c is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 - L c -R c groups.
  • Cy c is 5-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 - L c -R c groups.
  • Cy c is 5-membered heteroaryl having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 - L c -R c groups.
  • Cy c is 5-membered heteroaryl having 1 nitrogen heteroatom and 1 sulfur heteroatom, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is 5-membered heteroaryl having 2 nitrogen heteroatoms, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is pyrazolyl or thiazolyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is pyrazolyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is thiazolyl, wherein Cy c is substituted with 0-4 -L c -R c groups.
  • Cy c is 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 - L c -R c groups. In some embodiments, Cy c is 6-membered heteroaryl having 1-3 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is 6-membered heteroaryl having 1-2 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 - L c -R c groups.
  • Cy c is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is pyridinyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is pyrimidinyl, wherein Cy c is substituted with 0-3 -L c -R c groups. In some embodiments, Cy c is pyrazinyl, wherein Cy c is substituted with 0-3 -L c -R c groups. In some embodiments, Cy c is pyridazinyl, wherein Cy c is substituted with 0-3 -L c -R c groups.
  • Cy c is selected from the group consisting of:
  • Cy c is not
  • Cy c is an 8- to 10-membered bicyclic aryl, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is an 8-membered bicyclic aryl, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is a 9-membered bicyclic aryl, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is a 10-membered bicyclic aryl, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is indazolyl, benzotriazolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, tetrahydro-2//-benzo[/>][l,4]oxazinyl, or dihydro-2//- benzo[Z>][l,4]oxazinonyl, substituted with 0-6 -L c -R c groups.
  • Cy c is indazolyl, substituted with 0-5 -L c -R c groups. In some embodiments, Cy c is benzotriazolyl, substituted with 0-4 -L c -R c groups.
  • Cy c is naphthalenyl, substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is quinolinyl, substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is isoquinolinyl, substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is quinoxalinyl, substituted with 0-5 -L c -R c groups. In some embodiments, Cy c is quinazolinyl, substituted with 0-5 -L c -R c groups.
  • Cy c is tctrahydro-2//- benzo[Z>][l,4]oxazinyl, substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is dihydro-277-benzo[£>][l,4]oxazinonyl, substituted with 0-6 -L c -R c groups.
  • Cy c is a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 - L c -R c groups. In some embodiments, Cy c is a 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is a 9-membered heteroaryl having 1-4 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is a 9-membered heteroaryl having 1-4 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 - L c -R c groups. In some embodiments, Cy c is a 9-membered heteroaryl having 2-3 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is a 9-membered heteroaryl having 1 nitrogen heteroatom, wherein Cy c is substituted with 0-6 -L c - R c groups. In some embodiments, Cy c is a 9-membered heteroaryl having 2 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is a 9-membered heteroaryl having 3 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c - R c groups.
  • Cy c is a 9-membered heteroaryl having 4 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is a 9-membered heteroaryl having 1 oxygen heteroatom, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is a 9-membered heteroaryl having 1 sulfur heteroatom, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is a 9-membered heteroaryl having 1 nitrogen and 1 sulfur heteroatoms, wherein Cy c is substituted with 0-6 -L c - R c groups. In some embodiments, Cy c is a 9-membered heteroaryl having 1 nitrogen and 1 oxygen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is a 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 - L c -R c groups. In some embodiments, Cy c is a 10-membered heteroaryl having 1-2 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is a
  • Cy c is a 10-membered heteroaryl having 2 nitrogen heteroatoms, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is imidazopyridinyl, pyrazolopyridinyl, indazolyl, pyrrolopyridinyl, benzoimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotri azolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzooxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is imidazopyridinyl, wherein Cy c is substituted with 0-5 - L c -R c groups.
  • Cy c is pyrazolopyridinyl, wherein Cy c is substituted with 0-5 -L c -R c groups.
  • Cy c is indazolyl, wherein Cy c is substituted with 0-5 -L c -R c groups.
  • Cy c is pyrrolopyridinyl, wherein Cy c is substituted with 0-5 -L c -R c groups.
  • Cy c is benzoimidazolyl, wherein Cy c is substituted with 0-5 -L c -R c groups. In some embodiments, Cy c is triazolopyridinyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is imidazopyridazinyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is imidazopyrimidinyl, wherein Cy c is substituted with 0-4 -L c -R c groups.
  • Cy c is imidazopyrimidinonyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is benzotriazolyl, wherein Cy c is substituted with 0-4 -L c -R c groups. In some embodiments, Cy c is triazolopyrimidinyl, wherein Cy c is substituted with 0-3 -L c -R c groups. . In some embodiments, Cy c is triazolopyridazinyl, wherein Cy c is substituted with 0-3 -L c -R c groups.
  • Cy c is benzothiophenyl, wherein Cy c is substituted with 0-5 -L c - R c groups. In some embodiments, Cy c is benzothiozolyl, wherein Cy c is substituted with 0-4 - L c -R c groups. In some embodiments, Cy c is thienopyridinyl, wherein Cy c is substituted with 0-
  • Cy c is benzofuranyl, wherein Cy c is substituted with 0-
  • Cy c is benzooxazolyl, wherein Cy c is substituted with 0-4 -L c -R c groups.
  • Cy c is pyrazolopyrimidinyl, wherein Cy c is substituted with 0-4 -L c -R c groups.
  • Cy c is imidazopyrazinyl, wherein Cy c is substituted with 0-4 -L c -R c groups.
  • Cy c is quinolinyl, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is isoquinolinyl, wherein Cy c is substituted with 0-6 -L c -R c groups. In some embodiments, Cy c is quinazolinyl, wherein Cy c is substituted with 0-5 -L c -R c groups. In some embodiments, Cy c is naphthyridinyl, wherein Cy c is substituted with 0-5 -L c - R c groups.
  • Cy c is selected from the group consisting of: [0167] In some embodiments, Cy c is selected from the group consisting of:
  • Cy c is selected from the group consisting of:
  • Cy c is selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10- membered bicyclic aryl, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is not T (LC - RC)C - 5
  • Cy c is pyrazolopyridinyl, indazolyl, pyrrol opyridinyl, benzoimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotri azolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzooxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is not imidazopyridinyl substituted with 0-6 -L c -R c groups.
  • Cy c is selected from the group consisting of:
  • each L c is independently selected from a covalent bond or an optionally substituted Ci-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-.
  • a single instance of L c is a covalent bond.
  • a single instance of L c is an optionally substituted Ci-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-.
  • a single instance of L c is an optionally substituted Ci-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O- or -NR-.
  • L c is optionally substituted with -(CH2)o-4R°, wherein R° is independently as defined above and described in classes and subclasses herein.
  • R° is hydrogen or Ci-6 aliphatic.
  • a single instance of L c is selected from the group consisting of: *-NH-, *-NCHs-, *-O-, *-CH 2 -, *-CH 2 C(CH3) 2 -, *-CH 2 CH 2 -, *-CH 2 C(O)N(CH3)-, *-CH 2 C(O)N(CH3)CH 2 -, *-CF 2 -, *-CH(CH 3 )-, *-OCH 2 -, *-OCF 2 -, *-OC(CH 3 ) 2 -, *-CH 2 C(O)-, *-OCH 2 C(O)-, *-CH 2 C(O)NH-,*-CH 2 C(O)NHCH 2 -,*-N(CH 3 )C(O)-, *-C(CH 2 CH3)-, *-C(CHCH3)-, *-C(FCH3)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-NCH3-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-O-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH 2 C(CH3) 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH 2 CH 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH 2 C(O)N(CH3)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH 2 C(O)N(CH3)CH 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CF 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH(CH3)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-OCH 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *- OCF 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-OC(CH3) 2 -, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH 2 C(O)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-OCH2C(O)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH2C(0)NH-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-CH2C(O)NHCH2-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-N(CH3)C(0)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-C(CH2CH3)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-C(CHCH3)-, wherein * represents the point of attachment to Cy c .
  • a single instance of L c is *-C(FCH3)-, wherein * represents the point of attachment to Cy c .
  • each R c is independently selected from oxo, halogen, -CN, - C(O)R, -C(O) 2 R, -C(O)N(R)2, -NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O) 2 R, -N(R)S(O) 2 R, -OR, -OC(O)R, -OC(O)N(R)2, -SR, -S(O)R, -S(O) 2 R, -S(O)N(R) 2 , -S(O) 2 N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membere
  • each R c is independently selected from oxo, halogen, -CN, - C(O)2R, -C(O)N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • a single instance of R c is selected from oxo, halogen, -CN, -C(O)2R, -OR, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 6- to 12-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur.
  • a single instance of R c is oxo. In some embodiments, a single instance of R c is halogen. In some embodiments, a single instance of R c is fluorine. In some embodiments, a single instance of R c is chlorine. In some embodiments, a single instance of R c is bromine. In some embodiments, a single instance of R c is -CN. In some embodiments, a single instance of R c is -C(O)2R. In some embodiments, a single instance of R c is -COOH. In some embodiments, a single instance of R c is -C(O)OCH3.
  • a single instance of R c is -C(O)OCH2CH3. In some embodiments, a single instance of R c is -OR. In some embodiments, a single instance of R c is -OH. In some embodiments, a single instance of R c is -OMe. In some embodiments, a single instance of R c is -C(O)N(R)2. In some embodiments, a single instance of R c is -C(O)NH2. In some embodiments, a single instance of R c is -C(O)NHCH3. In some embodiments, a single instance of R c is -C(O)N(CH3)2. In some embodiments, a single instance of R c is -C(O)N(CH2CH3)2.
  • a single instance of R c is an optionally substituted Ci-6 aliphatic. In some embodiments, a single instance of R c is Ci-6 aliphatic optionally substituted with halogen. In some embodiments, a single instance of R c is Ci-6 aliphatic optionally substituted with fluorine. In some embodiments, a single instance of R c is -CF3. In some embodiments, a single instance of R c is -CHF2. In some embodiments, a single instance of R c is methyl. In some embodiments, a single instance of R c is ethyl. In some embodiments, a single instance of R c is isopropyl.
  • a single instance of R c is -CHCHCH3. In some embodiments, a single instance of R c is -CHC(CH3)2. In some embodiments, a single instance of R c is butyl. In some embodiments, a single instance of R c is n-butyl.
  • a single instance of R c is an optionally substituted phenyl. In some embodiments, a single instance of R c is phenyl.
  • a single instance of R c is an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, a single instance of R c is an optionally substituted cyclopropyl. In some embodiments, a single instance of R c is cyclopropyl, optionally substituted with -(CH2)o-4R°, -(CH2)o-4N(R°)C(0)R°, or
  • R° is hydrogen or Ci-6 aliphatic (e.g., methyl).
  • R c is cyclopropyl.
  • R c is . In some embodiments, a single instance of R c is . In some embodiments, a single instance of R c is . In some embodiments, a single instance of R c is . In H ? some embodiments, a single instance of R c is A . In some embodiments, a single instance of R c is In some embodiments, Cy c is substituted with 1-6 -L c -R c groups, wherein a single instance of R c is cyclopropyl.
  • a single instance of R c is an optionally substituted 5- or 6- membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 5- or 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
  • a single instance of R c is an optionally substituted 5- membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 5-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 5-membered heteroaryl having 2 nitrogen heteroatoms. In some embodiments, a single instance of R c is an optionally substituted pyrazolyl.
  • a single instance of R c is pyrazolyl, optionally substituted with -(CH2)O-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl).
  • R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl).
  • a single instance of R c is an optionally substituted imidazolyl.
  • a single instance of R c is imidazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl).
  • a single instance of R c is an optionally substituted 5- membered heteroaryl having 1 nitrogen heteroatom and 1 sulfur heteroatom. In some embodiments, a single instance of R c is an optionally substituted thiazolyl. In some embodiments, a single instance of R c is thiazolyl. In some embodiments, a single instance of R c is an optionally substituted 5-membered heteroaryl having 1 nitrogen heteroatom and 1 oxygen heteroatom. In some embodiments, a single instance of R c is an optionally substituted oxazolyl. In some embodiments, a single instance of R c is oxazolyl.
  • a single instance of R c is an optionally substituted 5- membered heteroaryl having 3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 5-membered heteroaryl having 2 nitrogen heteroatoms and 1 oxygen heteroatom. In some embodiments, a single instance of R c is an optionally substituted oxadiazolyl. In some embodiments, a single instance of R c is oxadiazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl). In some embodiments, a single instance of R c is oxadiazolyl.
  • a single instance of R c is an optionally substituted 5- membered heteroaryl having 2 nitrogen heteroatoms and 1 sulfur heteroatom.
  • a single instance of R c is an optionally substituted thiadiazolyl.
  • a single instance of R c is thiadiazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl).
  • a single instance of R c is thiadiazolyl.
  • a single instance of R c is an optionally substituted 5- membered heteroaryl having 3 nitrogen heteroatoms.
  • a single instance of R c is an optionally substituted triazolyl.
  • a single instance of R c is triazolyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl or cyclopropyl).
  • a single instance of R c is triazolyl.
  • a single instance of R c is an optionally substituted 6- membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 6-membered heteroaryl having 1 nitrogen heteroatom. In some embodiments, a single instance of R c is an optionally substituted pyridinyl.
  • a single instance of R c is pyridinyl, optionally substituted with halogen or -(CH2)o- 4R 0 ; wherein R° is C1-6 aliphatic (e.g., methyl or cyclopropyl). In some embodiments, a single instance of R c is an optionally substituted pyridinonyl.
  • a single instance of R c is pyridinonyl, optionally substituted with halogen or -(CH2)o-4R°; wherein R° is C1-6 aliphatic (e.g., methyl, ethyl, or cyclopropyl), wherein R° may be further substituted with halogen (e.g., fluorine).
  • a single instance of R c is pyridinonyl.
  • a single instance of R c is an optionally substituted pyrimidinyl. In some embodiments, a single instance of R c is pyrimidinyl. In some embodiments, a single instance of R c is an optionally substituted pyrazinyl. In some embodiments, a single instance of R c is pyrazinyl.
  • a single instance of R c is an optionally substituted 6- membered heteroaryl having 2 nitrogen heteroatoms.
  • a single instance of R c is selected from the group consisting of
  • a single instance of R c is an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.
  • a single instance of R c is an optionally substituted 4- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, a single instance of R c is an optionally substituted 4- membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, a single instance of R c is an optionally substituted azetidinyl. In some embodiments, a single instance of R is x . In some embodiments, a single instance of R c is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom.
  • a single instance of R c is an optionally substituted pyrrolidinyl. In some embodiments, a single instance of R c is pyrrolidinyl, optionally substituted with -(CH2)o-4R°; wherein R° is Ci-6 aliphatic (e.g., methyl).
  • a single instance of R c is . In some embodiments, a single instance of R c is an optionally substituted pyrrolidinonyl. In some embodiments, a single instance of R c some embodiments, a single instance of R c is an optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, a single instance of R c is an optionally substituted piperidinyl. In some embodiments, a single instance of R c is In some embodiments, a single instance of R c is an optionally substituted piperidinonyl. In some embodiments, a single instance of R c is
  • a single instance of R c is an optionally substituted 4- membered saturated or partially unsaturated monocyclic heterocyclyl having 1 heteroatom selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 oxygen heteroatom. In some embodiments, a single instance of R c is an optionally substituted oxetanyl. In some embodiments, a single instance of R c is oxetanyl, optionally substituted with halogen or -(CH2)o-40R°, wherein R° is hydrogen or Ci-6 aliphatic (e.g., methyl).
  • a single instance of R c is In some embodiments, a single instance
  • a single instance of R c is an optionally substituted 5- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom and 1 oxygen heteroatom. In some embodiments, a single instance of R c is an optionally substituted oxazolidinonyl. In some embodiments, a single instance of R c
  • a single instance of R c is an optionally substituted 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 nitrogen heteroatom and 1 oxygen heteroatom. In some embodiments, a single instance of R c is an optionally substituted morpholinyl. In some embodiments, a single instance of R c is . In some embodiments, a single instance of R is an optionally substituted morpholinonyl. In some embodiments, a single instance of R c is o
  • a single instance of R c is an optionally substituted 6- to 12- membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 6-membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 6-membered saturated or unsaturated bicyclic heterocyclyl having 1 nitrogen heteroatom.
  • a single instance of R c is an optionally substituted azabicyclo[3.1.0]hexanyl.
  • a single instance of R c is azabicyclo[3.1.0]hexanyl, optionally substituted with halogen, -(CH2)o-4R°, -(CH2)o-40R°,
  • R° is hydrogen or Ci-6 aliphatic (e g., methyl), wherein R° may be further substituted with halogen (e.g., fluorine).
  • a single instance of R c is In some embodiments, a single instance of R c is . In some embodiments, a single instance of R c is ’
  • a single instance of R c is N O ⁇ F i n some embodiments, a single H instance of R c is H . In some embodiments, a single instance of R c is . In some embodiments, a single instance of R c is . In some embodiments, a single instance of R c is . In some embodiments, a single instance of R c . In some embodiments, a single instance of R c . In some embodiments, a single instance of R c is . , some embodiments, a single instance of R c is . In some embodiments, a single instance of R c is . In some embodiments, a single instance of R c is . In some embodiments, a single instance
  • a single instance of R c is an optionally substituted 7- membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a single instance of R c is an optionally substituted 7-membered saturated or unsaturated bicyclic heterocyclyl having 1 nitrogen heteroatom.
  • a single instance of R c is an optionally substituted 3- azabicyclo[3.1.1]heptanyl. In some embodiments, a single instance of R is
  • a single instance of R c is an optionally substituted 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl. In some embodiments, a single instance of R c is an optionally substituted 5- membered saturated or unsaturated bicyclic carbocyclyl. In some embodiments, a single instance of R c is an optionally substituted 5- membered saturated bicyclic carbocyclyl. In some embodiments, a single instance of R c is bicycle[l. l.l]pentanyl. In some embodiments, a single instance of R c is
  • a single instance of R c is an optionally substituted 7- to 10- membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, a single instance of R c is an optionally substituted 9-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, a single instance of R c is an optionally substituted 9-membered heteroaryl having 2 nitrogen heteroatoms. In some embodiments, a single instance of R c is an optionally substituted imidazopyridinyl.
  • a single instance of R c is [0209]
  • a provided compound is of Formula (Il-a) or (Il-b): or a pharmaceutically acceptable salt thereof, wherein each of Cy A , Cy c , L, L’, R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , and R B7 is defined and described in classes and subclasses herein, both singly and in combination.
  • a provided compound is of Formula (Ill-a), (Ill-b), (III-c), or
  • a provided compound is of Formula (III-a-1), (III-a-2), or (III- a-3):
  • a provided compound is of Formula (III-b-1), (III-b-2), or (III- b-3):
  • a provided compound is of Formula (IV), (IV-a), (IV-b), or
  • a provided compound is of Formula (V-a), (V-b), or (V-c):
  • a provided compound is of Formula (Vl-a), (Vl-b), or (VI-c):
  • a provided compound is of Formula (Vll-a), (Vll-b), or (VII- c):
  • a provided compound is of Formula (Vlll-a), (VIILb), or (VIII-c):
  • a provided compound is of Formula (IX-a), (IX-b), or (IX-c):
  • a provided compound is of Formula (X-a), (X-b), or (X-c): or a pharmaceutically acceptable salt thereof, wherein each of Cy A , Cy c , L’, R B1 , and R B2 is defined and described in classes and subclasses herein, both singly and in combination. It will be understood that the connection between Cy A and Cy c in each of Formula (X-a), (X-b), and (X-c) is a methylene.
  • a provided compound is of Formula (Xl-a), (Xl-b), or (XI-c): or a pharmaceutically acceptable salt thereof, wherein each of Cy A , Cy c , L’, R B1 , and R B2 is defined and described in classes and subclasses herein, both singly and in combination.
  • a provided compound is of Formula (Xll-a), (Xll-b), or (XII- c):
  • a provided compound is of Formula (Xlll-a), (XIILb), or (XIII-c):
  • a provided compound is of Formula (XlV-a), (XlV-b), or (XIV-c):
  • a provided compound is of Formula (XVI-a), (XVI-b), or (XVI-c):
  • a compound is 2-((2S,4R)-4-amino-l-(6-chloroimidazo[l,2- a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((l-amino-5,7-dimethylisoquinolin-6- yl)methyl)thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
  • a compound is not 2-((2S,4R)-4-amino-l-(6- chloroimidazo[l,2-a]pyridine-2-carbonyl)pyrrolidin-2-yl)-N-((l-amino-5,7-dimethylisoquinolin- 6-yl)methyl)thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
  • a compound is selected from:
  • a compound is selected from:
  • the present invention provides pharmaceutical compositions comprising a compound of Formulae (I)-(XVI-c) or a compound of Formulae (I)-(XVI-c) in combination with a pharmaceutically acceptable excipient (e.g., carrier).
  • a pharmaceutically acceptable excipient e.g., carrier
  • the pharmaceutical compositions include optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein.
  • a compound of Formulae (I)-(XVI-c) included in the pharmaceutical composition may be covalently attached to a carrier moiety, as described above.
  • a compound of Formulae (I)-(XVI-c) included in the pharmaceutical composition is not covalently linked to a carrier moiety.
  • a “pharmaceutically acceptable carrier,” as used herein refers to pharmaceutical excipients, for example, pharmaceutically, physiologically, acceptable organic or inorganic carrier substances suitable for enteral or parenteral application that do not deleteriously react with the active agent.
  • suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • the compounds of the invention can be administered alone or can be coadministered to the subject. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation).
  • test agent as described herein can be incorporated into a pharmaceutical composition for administration by methods known to those skilled in the art and described herein for provided compounds.
  • Compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms.
  • the compounds of the present invention can be administered by injection (e.g. intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally).
  • the compounds described herein can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally. It is also envisioned that multiple routes of administration (e.g., intramuscular, oral, transdermal) can be used to administer the compounds of the invention.
  • the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substance that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% to 70% of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • admixtures for the compounds of the invention are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. Ampoules are convenient unit dosages.
  • the compounds of the invention can also be incorporated into liposomes or administered via transdermal pumps or patches.
  • Pharmaceutical admixtures suitable for use in the present invention include those described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as well-known suspending agents.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • compositions provided by the present invention include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose.
  • a therapeutically effective amount i.e., in an amount effective to achieve its intended purpose.
  • the actual amount effective for a particular application will depend, inter alia, on the condition being treated.
  • such compositions when administered in methods to treat HAE, such compositions will contain an amount of active ingredient effective to achieve the desired result (e.g. inhibiting PKa and/or decreasing the amount of bradykinin in a subject).
  • the dosage and frequency (single or multiple doses) of compound administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g., the disease responsive to PKa inhibition); presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen.
  • Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of the invention.
  • the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of decreasing PKa enzymatic activity as measured, for example, using the methods described.
  • Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring PKa inhibition and adjusting the dosage upwards or downwards, as described above.
  • Dosages may be varied depending upon the requirements of the patient and the compound being employed.
  • the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side effects.
  • compounds provided herein display one or more improved pharmacokinetic (PK) properties (e.g., Cmax, tmax, Cmin, ti/2, AUC, CL, bioavailability, etc.) when compared to a reference compound.
  • PK pharmacokinetic
  • a reference compound is a PKa inhibitor known in the art.
  • a reference compound is a PKa inhibitor selected from those disclosed in PCT Publication Number WO 2019/178129.
  • the present disclosure provides compounds for use in medicine.
  • the present disclosure further provides the use of any compounds described herein for inhibiting the activity of PKa, which would be beneficial to treatment of PKa-mediated diseases and conditions.
  • Exemplary PKa-mediated disorders include edema, which refers to swelling in the whole body of a subject or a part thereof due to inflammation or injury when small blood vessels become leaky and releases fluid into nearby tissues.
  • the edema is HAE.
  • the edema occurs in eyes, e.g., diabetic macular edema (DME).
  • DME diabetic macular edema
  • the present disclosure provides methods of inhibiting the activity of PKa.
  • the application provides a method of inhibiting the activity of PKa in vitro via contacting any of the compounds described herein with PKa molecules in a sample, such as a biological sample.
  • the application provides a method of inhibiting the activity of PKa in vivo via delivering an effective amount of any of the compounds described herein to a subject in need of the treatment through a suitable route.
  • the methods comprise administering to a subject in need thereof (e.g., a subject such as a human patient with edema) any of the compounds described herein or a pharmaceutically acceptable salt thereof.
  • the methods comprise administering a compound of Formulae (I)-(XVI-c), or a pharmaceutically acceptable salt or composition thereof, to a subject in need thereof.
  • the method comprises administering a pharmaceutical composition comprising a compound of Formulae (I)- (XVI-c), or a pharmaceutically acceptable salt to a subject in need thereof.
  • the subject to be treated by any of the methods described herein is a human patient having, suspected of having, or at risk for edema, for example, HAE or diabetic macular edema (DME).
  • a subject having an edema can be identified by routine medical examination, e.g., laboratory tests.
  • a subject suspected of having an edema might show one or more symptoms of the disease/disorder.
  • a subject at risk for edema can be a subject having one or more of the risk factors associated with the disease, for example, deficiency in Cl -INH as for HAE.
  • provided herein are methods of alleviating one or more symptoms of HAE in a human patient who is suffering from an HAE attack. Such a patient can be identified by routine medical procedures. An effective amount of one or more of the provided compounds can be given to the human patient via a suitable route, for example, those described herein.
  • the compounds described herein may be used alone, or may be used in combination with other anti-HAE agents, for example, a Cl esterase inhibitor (e.g., Cinryze® or Berinert®), a PKa inhibitor (e.g., ecallantide or lanadelumab) or a bradykinin B2 receptor antagonist (e.g., Firazyr®).
  • a Cl esterase inhibitor e.g., Cinryze® or Berinert®
  • PKa inhibitor e.g., ecallantide or lanadelumab
  • a bradykinin B2 receptor antagonist e.g., Firazyr®
  • a human HAE patient who is in quiescent stage can be identified based on various factors, including history of HAE attack.
  • An effective amount of one or more of the compounds can be given to the human patient via a suitable route, for example, those described herein.
  • the compounds described herein may be used alone, or may be used in combination with other anti-HAE agents, for example, a Cl esterase inhibitor (e.g., Cinryze® or Berinert®), a PKa inhibitor (e.g, ecallantide or lanadelumab) or a bradykinin B2 receptor antagonist (e.g., Firazyr®).
  • prophylactic treatment of HAE in human patients having risk to HAE attacks with one or more of the compounds described herein are human subjects suffering from HAE (e.g., having history of HAE attacks).
  • patients suitable for such prophylactic treatment are human subjects where a physician determines a history of HAE attacks warrants a prophylactic approach (e.g., human subjects experiencing more than a particular average number of attacks over a time period, including by way of nonlimiting example, one, two, or more attacks per month).
  • patients suitable for the prophylactic treatment may be human subjects having no HAE attack history but bearing one or more risk factors for HAE (e.g, family history, genetic defects in Cl -INH gene, etc.)
  • prophylactic treatment may involve the compounds described herein as the sole active agent, or involve additional anti-HAE agents, such as those described herein.
  • a subject e.g., a human patient
  • the human patient is a diabetic having, suspected of having, or at risk for diabetic macular edema (DME).
  • DME is the proliferative form of diabetic retinopathy characterized by swelling of the retinal layers, neovascularization, vascular leak, and retinal thickening in diabetes mellitus due to leaking of fluid from blood vessels within the macula.
  • an effective amount of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof may be delivered into the eye of the subject where treatment is needed.
  • the compound may be delivered topically, by intraocular injection, or intravitreal injection.
  • a subject may be treated with the compound as described herein, either as the sole active agent, or in combination with another treatment for DME.
  • treatment for DME include laser photocoagulation, steroids, VEGF pathway targeting agents (e.g., Lucentis® (ranibizumab) or Eylea® (aflibercept)), and/or anti-PDGF agents.
  • the methods disclosed herein comprise administering to the subject an effective amount of a compound of Formulae (I)-(VLb), or a pharmaceutically acceptable salt or composition thereof.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • the subject being treated is an animal.
  • the animal may be of either sex and may be at any stage of development.
  • the subject is a mammal.
  • the subject being treated is a human.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the subject is a companion animal, such as a dog or cat.
  • the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat.
  • the subject is a zoo animal.
  • the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.
  • a rodent e.g., mouse, rat
  • dog e.g., dog
  • pig e.g., dog
  • non-human primate e.g., non-human primate.
  • the animal is a genetically engineered animal.
  • the animal is a transgenic animal.
  • Certain methods described herein may comprise administering one or more additional pharmaceutical agent(s) in combination with the compounds described herein.
  • the additional pharmaceutical agent(s) may be administered at the same time as the compound of Formulae (I)- (XVI-c), or at different times than the compound of Formulae (I)-(XVI-c).
  • the compound of Formulae (I)-(XVl-c) and any additional pharmaceutical agent(s) may be on the same dosing schedule or different dosing schedules.
  • All or some doses of the compound of Formulae (I)-(XVI-c) may be administered before all or some doses of an additional pharmaceutical agent, after all or some does an additional pharmaceutical agent, within a dosing schedule of an additional pharmaceutical agent, or a combination thereof.
  • the timing of administration of the compound of Formulae (I)-(XVI-c) and additional pharmaceutical agents may be different for different additional pharmaceutical agents.
  • the additional pharmaceutical agent comprises an agent useful in the treatment of an edema, such as HAE or DME. Examples of such agents are provided herein.
  • Cy A is phenylene, a 5- to 6-membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, an 8- to 12-membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or an 8- to 10-membered bicyclic arylene, wherein Cy A is substituted with 0-4 -R A groups; each R A is independently selected from oxo, halogen, -CN, -C(O)R, -C(O)2R, -C(O)N(R)2, - NO2, -N(R)2, -N(R)C(O)R, -N(R)C(O) 2 R, -N(R)S(O) 2 R, -OR, -OC(O)R, -OC(O)N
  • L’ is a covalent bond or an optionally substituted C1-4 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -O-, -C(O)-, -NR Z -, -S-, -SO- , -SO2-, -S(NH)(O)-, or cyclopropylene; each R z is independently selected from hydrogen, -(CH 2 )o-30R, -(CH 2 )o-3C(0)OR, or an optionally substituted C1-6 aliphatic group; wherein: each of R B1 and R B2 is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl;
  • R B3 is hydrogen or C1-6 aliphatic
  • R B4 is -N(R X ) 2
  • each R x is independently selected from hydrogen, -C(O)R, -C(O) 2 R, or optionally substituted C1-6 aliphatic. wherein no more than one of R B1 or R B2 is hydrogen; or wherein:
  • R B5 is hydrogen or Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl; each of R B6 and R B7 is independently hydrogen or an optionally substituted Ci-6 aliphatic;
  • L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, -NR Z -, -N(NO)- -S-, -SO-, -SO2-, an optionally substituted cyclopropylene, or an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and
  • Cy c is selected from a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, 8- to 10-membered bicyclic aryl, a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12- membered saturated or partially unsaturated fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein Cy c is substituted with 0-6 -L c -R c groups; each L c is independently selected from a covalent bond or an optionally substituted C1-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with -C(O)-, -O-, or -NR-; and each R c is independently selected from oxo, halogen, -CN, -C(O)R,
  • VIILa (Vlll-b), or (VIILc):
  • each R x is independently selected from -C(O)R, -C(O)2R, or optionally substituted Ci-6 aliphatic.
  • R B5 is Ci-6 aliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocycyl.
  • Cy A is a 5- to 6- membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is selected from the group consisting of phenylene, thiazolediyl, pyridinediyl, pyrazinediyl, pyrimidinediyl, pyridazinediyl, triazinediyl, thiadiazolediyl, oxadiazolediyl, triazolediyl, pyrrolediyl, pyrazolediyl, imidazolediyl, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is an 8- to 12- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 10- membered bicyclic heteroarylene having 1-2 nitrogen heteroatoms, wherein Cy A is substituted with 0-4 -R A groups.
  • Cy A is a 7- to 12- membered bicyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-4 -R A groups.
  • each R A is independently selected from oxo, halogen, -C(O)2R, -OR, -C(O)N(R)2, or an optionally substituted C1-6 aliphatic.
  • Cy c is indazolyl, benzotri azolyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, tetrahydro- 2J/-benzo[Z>][l,4]oxazinyl, or dihydro-2/f-benzo[6][l,4]oxazinonyl, substituted with 0-6 -L c -R c groups.
  • Cy c is a 7- to 10- membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein Cy c is substituted with 0-6 -L c -R c groups.
  • Cy c is imidazopyridinyl, pyrazolopyridinyl, indazolyl, pyrrolopyridinyl, benzoimidazolyl, triazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrimidinonyl, benzotri azolyl, triazolopyrimidinyl, triazolopyridazinyl, benzothiophenyl, benzothiozolyl, thienopyridinyl, benzofuranyl, benzooxazolyl, pyrazolopyrimidinyl, imidazopyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, wherein Cy c is substituted with 0-6 -L c - R c groups.
  • L c is selected from the group consisting of: *-NH-, *-NCH 3 -, *-O-, *-CH 2 -, *-CH 2 C(CH 3 ) 2 -, *-CH 2 CH2-, *-CH 2 C(O)N(CH 3 )-, *-CH 2 C(O)N(CH 3 )CH 2 -, *-CF 2 -, *-CH(CH 3 )-, *-OCH 2 -, *-OCF 2 -, *-OC(CH 3 ) 2 -, *-CH 2 C(O)-, *-OCH 2 C(O)-, *-CH 2 C(O)NH-,*-CH 2 C(O)NHCH 2 -,*-N(CH 3 )C(O)-, *-C(CH 2 CH 3 )-, *- C(CHCH 3 )-, *-C(FCH 3 )-, wherein * represents the point of attachment
  • each R c is independently selected from oxo, halogen, -CN, -C(O)2R, -C(0)N(R)2, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- or 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 3 - to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; a 6- to 12- membered saturated or unsaturated bicyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur; a 5- to 12- membered saturated or unsaturated bicyclic carbocyclyl; or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • a pharmaceutical composition comprising a compound of any one of the preceding embodiments.
  • composition comprising a compound of any one of the preceding embodiments, further comprising a pharmaceutically acceptable excipient.
  • composition of embodiment 68 or 69, wherein the composition is suitable for oral administration.
  • a method of treating hereditary angioedema comprising administering to a patient in need thereof a compound or composition of any one of the preceding embodiments.
  • 75. A method of treating diabetic macular edema comprising administering to a patient in need thereof a compound or composition of any one of the preceding embodiments.
  • the Examples describe compounds comprising one or more stereocenters, where a particular stereocenter is designated “S*” or “R* ”
  • a particular stereocenter is designated “S*” or “R* ”
  • the depiction of the generally indicates that the exact configuration is unknown (e.g., for a compound with a single stereocenter, the depiction R*- or S*- indicates that either the R- or S- isomer was isolated, but the configuration at the stereocenter of the particular isomer isolated was not determined).
  • a compound denoted “(1S*,2S*)-” or “(1R*,2R*)-” would be understood to refer specifically to either the “(1S,2S)-” or “(1R,2R)-” isomer, but not the “(1 S,2R)-” or “(1R,2S)-” isomers.
  • a compound denoted “rac-(lS*,2S*)-” or “rac-(lR*,2R*)-” would be understood to include a racemic mixture of the “(1S,2S)-” and “(1R,2R)-” isomers.
  • a compound denoted “(1S*,2R*)-” or “(1R*,2S*)-” would be understood to refer specifically to either the “(1R,2S)-” or “(1S,2R)-” isomer, but not the “(1S,2S)-” or “(1R,2R)-” isomers.
  • a compound denoted “rac-(lR*,2S*)-” or “rac-(lS*,2R*)-” would be understood to include a racemic mixture of the “(1R,2S)-” and “(1S,2R)-” isomers.
  • the Examples include schemes that depict compounds with one or more stereocenters.
  • the symbol followed by a number appears adjacent to a stereocenter.
  • it is understood to include a mixture of both configurations (e.g., R- and S-) at that position.
  • the term “or” followed by a number appears adjacent to a stereocenter. In such cases, it is understood to denote either an “R-” or “S-” isomer, but the particular isomer was not determined.
  • the numbering following the symbol or term “or” refers to one stereocenter’s relation to another stereocenter in that compound.
  • two stereocenters in a compound are each denoted with the same number (e.g., two instances of “&1”), it is understood that the configurations are relative to each other (e.g., if the structure is drawn as (S,S) and both stereocenters are denoted “&1”, it is understood to include a mixture of the (S,S) and (R,R) isomers, but not the (S,R) or (R,S) isomers).
  • each stereocenter is denoted with a different number (e.g., one instance of “&1” and one instance of “&2”)
  • the configurations may be independent to each other (e.g., if the structure is drawn (S,S) and one stereocenter is denoted “&1” and one is denoted “&2,” it is understood to include a mixture of the (S,S), (S,R), (R,S), and (R,R) isomers).

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Abstract

La présente invention concerne des composés et des compositions de ceux-ci qui sont utiles en tant qu'inhibiteurs de la kallicréine plasmatique et qui présentent des caractéristiques souhaitables associées. La présente invention concerne des dérivés d'isoquinoline de formule (I) dans laquelle CyB a la formule (II) ou la formule (III) en tant qu'inhibiteurs de kallikréine plasmatique (PKa) destinés à être utilisés dans des méthodes de traitement de l'angioœdème héréditaire (HAE) ou de l'œdème maculaire diabétique (DME). Les composés préférés sont par exemple des dérivés de N-((isoquinolin-6-yl)méthyl)-lH- pyrazole-4-carboxamide et des composés similaires.
PCT/US2023/032723 2022-09-15 2023-09-14 Dérivés de n-((isoquinolin-6-yl)méthyl)-1 h-pyrazole-4-carboxamide en tant qu' inhibiteurs de la kallicréine plasmatique pour le traitement de l'angioœdème héréditaire WO2024059186A1 (fr)

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