WO2023009708A1 - Hétéroaryloxy triazolo-azines et imidazo-azines en tant qu'inhibiteurs de jak2 - Google Patents

Hétéroaryloxy triazolo-azines et imidazo-azines en tant qu'inhibiteurs de jak2 Download PDF

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Publication number
WO2023009708A1
WO2023009708A1 PCT/US2022/038654 US2022038654W WO2023009708A1 WO 2023009708 A1 WO2023009708 A1 WO 2023009708A1 US 2022038654 W US2022038654 W US 2022038654W WO 2023009708 A1 WO2023009708 A1 WO 2023009708A1
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Prior art keywords
optionally substituted
nitrogen
sulfur
oxygen
independently selected
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PCT/US2022/038654
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English (en)
Inventor
Craig E. Masse
Jeremy R. Greenwood
Jiayi Xu
Sayan Mondal
Phani GHANAKOTA
Fiona Michelle MCROBB
Nicholas BOYLES
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Ajax Therapeutics, Inc.
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Publication of WO2023009708A1 publication Critical patent/WO2023009708A1/fr

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    • 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

Definitions

  • Janus kinase 2 is a non-receptor tyrosine kinase involved in the JAK-STAT signaling pathway, which plays a role in cell processes such as immunity, cell division, and cell death.
  • Dysfunction of the JAK-STAT pathway is implicated in various diseases, including cancer and other proliferative diseases, as well as diseases of the immune system.
  • essentially all BCR-ABL1 -negative myeloproliferative neoplasms are associated with mutations that activate JAK2.
  • JAK2 ⁇ i 6 ⁇ 7F is the most prevalent mutation in myeloproliferative neoplasms, occurring in approx.
  • Inhibitors of JAKs are classified based on their binding mode. All currently approved JAK inhibitors are Type I inhibitors, which are those that bind the ATP- binding site in the active conformation of the kinase domain, thereby blocking catalysis (Vainchenker, W. et al.). However, increased phosphorylation of the JAK2 activation loop is observed with Type I inhibitors and may lead to acquired resistance in certain patients (Meyer S. C., Levine, R. L. Clin. Cancer Res. 2014, 20(8):2051-9).
  • Type II inhibitors bind the ATP -binding site of the kinase domain in the inactive conformation and, therefore, may avoid hyperphosphorylation observed with Type I inhibitors (Wu, S. C. et al. Cancer Cell 2015 Jul 13, 28(1):29-41).
  • the present disclosure provides compounds useful for inhibiting JAK2.
  • provided compounds are useful for, among other things, treating and/or preventing diseases, disorders, or conditions associated with JAK2.
  • the present disclosure provides a compound of Formula 1-1 or 1-2:
  • Ring A, Ring B, L, V, W, X, Y, Z, R a , R x , and R y are as defined herein.
  • structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure.
  • the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomic, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure.
  • Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and/or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.
  • structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by 13 C- or 14 C-enriched carbon, are within the scope of this disclosure.
  • Aliphatic refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic 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 “carbocyclic” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., Ci- 6 ).
  • aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, and alkynyl groups and hybrids thereof.
  • aliphatic refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation that has a single point of attachment to the rest of the molecule.
  • Alkyl refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., Ci-12, Ci-10, Ci-8, Ci- 6 , Ci-4, Ci- 3, or C1-2).
  • exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.
  • Carbocyclyl The terms “carbocyclyl,” “carbocycle,” and “carbocyclic ring” as used herein, refer to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as described herein.
  • Carbocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl.
  • “carbocyclyl” refers to an optionally substituted monocyclic C3-C8 hydrocarbon, or an optionally substituted C7-C10 bicyclic 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.
  • the term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3-6 carbons.
  • Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • cycloalkenyl refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • Alkenyl refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3).
  • alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.
  • Alkynyl refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3).
  • exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
  • Aryl refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C6-14), 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”.
  • “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons.
  • Heteroaryl refers to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 p 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, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l,2- ajpyrimidinyl, imidazo[l,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl.
  • 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 (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms).
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 H quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, and benzoisoxazolyl.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroxazin
  • Heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen.
  • Heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted 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, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl.
  • a heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.
  • a bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings.
  • Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3- dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl.
  • a bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).
  • a spirocyclic ring system e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).
  • Partially Unsaturated when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.
  • Patient or subject refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • animals e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans.
  • a patient is a human.
  • a patient or a subject is suffering from or susceptible to one or more disorders or conditions
  • Substituted or optionally substituted As described herein, compounds of this disclosure may contain “optionally substituted” moieties.
  • the term “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 either explicit or implicit from the structure (e.g., refers to at least . , p y g p y 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 provided herein.
  • Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents.
  • Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 )O-2R ⁇ , -(haloR*), -(CH 2 )o-20H, -(CH 2 )O-20R ⁇ , -(CH 2 )O-
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -0(CR * 2 ) 2-3 0-, 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(0)OH, -C(0)OR*, -NH 2 , -NHR*, -NR* 2, or -N0 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, -CHzPh, -0(CH 2 )o-iPh, or a 3- to 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 ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ ,
  • each R ⁇ is independently hydrogen, Ci- 6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 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- to 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(0)OH, -C(0)OR*, -NH 2 , -NHR*, -NR* 2, or -N0 2 , wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci ⁇ i aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • treat refers to any administration of a therapy that partially or completely alleviates, ameliorates, relieves, 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.
  • 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.
  • dashed bonds are each independently a single or double bond, as valency permits, such that the bicyclic ring system comprising V, X, Y, and W is aromatic;
  • V is CR V or N
  • W is CR W or N
  • X is C or N
  • Y is C or N; wherein at least one of V, W, X, and Y is N;
  • Z is -O- or -NR Z -;
  • R v , R w , R x , and R y are each independently hydrogen, halogen, -OR 1 , -N(R 1 )2, -SR 1 , optionally substituted Ci- 6 aliphatic, or-CN;
  • R z is hydrogen or optionally substituted Ci- 6 aliphatic; each R 1 is independently hydrogen or optionally substituted Ci- 6 aliphatic;
  • Ring A is optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • Ring B is optionally substituted phenyl, optionally substituted 9- to 16-membered bicyclic or tricyclic aryl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 7- to 16-membered saturated or partially unsaturated bicyclic or tricyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms
  • L is a covalent bond or a bivalent C1-3 straight or branched hydrocarbon chain; and R a is hydrogen, halogen, optionally substituted Ci- 6 aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the present disclosure provides a compound of Formula 1-1 : or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula 1-2: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-2 and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IA: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, R a , R v , R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IB:
  • Ring A, Ring B, L, Z, R a , R w , R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IC:
  • Ring A, Ring B, L, Z, R a , R w , R x , and R y are as defined above for Formula 1-2 and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula ID:
  • Ring A, Ring B, L, Z, R a , R v , R w , R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IE:
  • Ring A, Ring B, L, Z, R a , R v , R w , R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II-l :
  • R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination; and:
  • R b is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -NO2, -C(0)R ⁇ -C(0)OR, -C(0)N(R) 2 , - OC(0)R ⁇ -OC(0)N(R) 2 , -OC(0)OR, -OSO2R, -0S0 2 N(R) 2 , -N(R)C(0)R ⁇ -N(R)S0 2 R ⁇ - SOzR’, -S0 2 N(R) 2 , -SChR’, optionally substituted Ci- 6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen
  • the present disclosure provides a compound of Formula II-2:
  • Ring A, Ring B, L, V, W, X, Y, Z, R a , R b , R x , and R y are as defined above for Formula 1-2 and described in classes and subclasses herein, both singly and in combination; and:
  • R b is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -NO2, -C(0)R ⁇ -C(0)0R, -C(0)N(R) 2 , - 0C(0)R ⁇ -0C(0)N(R) 2 , -0C(0)0R, -0S0 2 R, -0S0 2 N(R) 2 , -N(R)C(0)R ⁇ -N(R)S0 2 R ⁇ - SOzR’, -S0 2 N(R) 2 , -SCbR’, optionally substituted Ci- 6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms
  • the present disclosure provides a compound of Formula III- 1 :
  • Ring A, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination; and:
  • R 2 is -N(R)2, -N(R)C(0)R ⁇ -C(0)N(R)2, or -N(R)C(0)N(R) 2 ; each R is independently hydrogen, optionally substituted Ci- 6 aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently optionally substituted Ci- 6 aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl.
  • the present disclosure provides a compound of Formula III-2:
  • Ring A, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-2 and described in classes and subclasses herein, both singly and in combination; and:
  • R 2 is -N(R)2, -N(R)C(0)R ⁇ -C(0)N(R)2, or -N(R)C(0)N(R) 2 ; each R is independently hydrogen, optionally substituted Ci- 6 aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently optionally substituted Ci- 6 aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl.
  • the present disclosure provides a compound of Formula IV- 1 :
  • Ring A, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination; and:
  • Ring B1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring B 1 is fused to Ring B2;
  • Ring B2 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring B2 is optionally (i) further fused to Ring B3, or (ii) Ring B2 and Ring B3 combine to form a spirocycle; and
  • Ring B3 when present, is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the present disclosure provides a compound of Formula IV-2:
  • Ring A, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-2 and described in classes and subclasses herein, both singly and in combination; and:
  • Ring B1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring B 1 is fused to Ring B2;
  • Ring B2 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring B2 is optionally (i) further fused to Ring B3, or (ii) Ring B2 and Ring B3 combine to form a spirocycle; and Ring B3, when present, is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • V is CR V . In some embodiments, V is N.
  • W is CR W . In some embodiments, W is N.
  • X is C. In some embodiments, X is N.
  • Y is C. In some embodiments, Y is N.
  • one and only one of V, W, X, and Y is N.
  • two of V, W, X, and Y are N.
  • no more than two of V, W, X, and Y are N.
  • three of V, W, X, and Y are N.
  • no more than three of V, W, X, and Y are N.
  • Z is -0-. In some embodiments, Z is -NR Z -. In some embodiments, Z is - NH-.
  • R v is hydrogen, halogen, or optionally substituted Ci-6 aliphatic.
  • R v is hydrogen.
  • R v is halogen.
  • R v is fluoro.
  • R v is chloro.
  • R v is -OR 1 .
  • R v is -OR 1 , wherein R 1 is optionally substituted Ci-6 aliphatic.
  • R v is -N ⁇ R 1 ⁇ .
  • R v is -SR 1 .
  • R v is - SR 1 , wherein R 1 is optionally substituted Ci-6 aliphatic.
  • R v is optionally substituted Ci-6 aliphatic. In some embodiments, R v is optionally substituted straight-chain or branched Ci-6 aliphatic (i.e., optionally substituted acyclic Ci-6 aliphatic). In some embodiments, R v is optionally substituted Ci-6 alkyl. In some embodiments, R v is optionally substituted Ci-4 alkyl. In some embodiments, R v is optionally substituted C1-2 alkyl. In some embodiments, R v is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, R v is -CN.
  • R w is hydrogen, halogen, or optionally substituted Ci-6 aliphatic.
  • R w is hydrogen.
  • R w is halogen.
  • R w is fluoro.
  • R w is chloro.
  • R w is -OR 1 .
  • R w is -OR 1 , wherein R 1 is optionally substituted Ci-6 aliphatic.
  • R w is -N ⁇ R 1 ⁇ .
  • R w is -SR 1 . In some embodiments, R w is -SR 1 , wherein R 1 is optionally substituted Ci-6 aliphatic. In some embodiments, R w is optionally substituted Ci-6 aliphatic. In some embodiments, R w is optionally substituted straight-chain or branched Ci-6 aliphatic (i.e., optionally substituted acyclic Ci-6 aliphatic). In some embodiments, R w is optionally substituted Ci-6 alkyl. In some embodiments, R w is optionally substituted Ci-4 alkyl. In some embodiments, R w is optionally substituted C1-2 alkyl. In some embodiments, R w is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, R w is -CN.
  • R x is hydrogen, halogen, or optionally substituted Ci-6 aliphatic. In some embodiments, R x is hydrogen or optionally substituted Ci- 6 aliphatic. In some embodiments, R x is hydrogen or Ci- 6 alkyl. In some embodiments, R x is hydrogen. In some embodiments, R x is halogen. In some embodiments, R x is fluoro. In some embodiments, R x is chloro. In some embodiments, R x is -OR 1 .
  • R x is -OR 1 , wherein R 1 is optionally substituted Ci- 6 aliphatic. In some embodiments, R x is In some embodiments, R x is - SR 1 . In some embodiments, R x is -SR 1 , wherein R 1 is optionally substituted Ci- 6 aliphatic. In some embodiments, R x is optionally substituted Ci- 6 aliphatic. In some embodiments, R x is optionally substituted straight-chain or branched Ci- 6 aliphatic (i.e., optionally substituted acyclic Ci- 6 aliphatic). In some embodiments, R x is optionally substituted Ci- 6 alkyl.
  • R x is optionally substituted Ci-4 alkyl. In some embodiments, R x is optionally substituted C1-2 alkyl. In some embodiments, R x is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, R x is -CN.
  • R y is hydrogen, halogen, or optionally substituted Ci- 6 aliphatic.
  • R y is hydrogen.
  • R y is halogen.
  • R y is fluoro.
  • R y is chloro.
  • R y is -OR 1 .
  • R y is -OR 1 , wherein R 1 is optionally substituted Ci- 6 aliphatic.
  • V is N, Y is CR y , and R y is -OR 1 wherein R 1 is optionally substituted Ci- 6 aliphatic.
  • R y is -N(R X )2.
  • R y is -SR 1 .
  • R y is -SR 1 , wherein R 1 is optionally substituted Ci- 6 aliphatic.
  • V is N, Y is CR y , and R y is -SR 1 wherein R 1 is optionally substituted Ci- 6 aliphatic.
  • R y is optionally substituted Ci- 6 aliphatic.
  • R y is optionally substituted straight-chain or branched Ci- 6 aliphatic (i.e., optionally substituted acyclic Ci- 6 aliphatic). In some embodiments, R y is optionally substituted Ci- 6 alkyl. In some embodiments, R y is optionally substituted Ci-4 alkyl. In some embodiments, R y is optionally substituted C1-2 alkyl. In some embodiments, R y is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, R y is -CN.
  • R z is hydrogen.
  • R z is optionally substituted Ci- 6 aliphatic.
  • R z is optionally substituted straight-chain or branched Ci- 6 aliphatic (i.e., optionally substituted acyclic Ci- 6 aliphatic).
  • R z is optionally substituted Ci- 6 alkyl.
  • R z is optionally substituted Ci-4 alkyl.
  • R z is unsubstituted Ci-4 alkyl.
  • R z is optionally substituted C1-2 alkyl. In some embodiments, R z is unsubstituted C1-2 alkyl.
  • each R 1 is independently hydrogen or optionally substituted Ci-4 aliphatic. In some embodiments, each R 1 is independently hydrogen or optionally substituted C1-2 aliphatic. In some embodiments, each R 1 is hydrogen. In some embodiments, each R 1 is independently optionally substituted Ci- 6 aliphatic. In some embodiments, each R 1 is independently optionally substituted straight-chain or branched Ci- 6 aliphatic (i.e., optionally substituted acyclic Ci- 6 aliphatic).
  • each R 1 is independently optionally substituted Ci-4 aliphatic. In some embodiments, each R 1 is independently optionally substituted straight-chain or branched Ci-4 aliphatic (i.e., optionally substituted acyclic Ci-4 aliphatic). In some embodiments, each R 1 is independently optionally substituted C1-2 aliphatic. In some embodiments, each R 1 is independently hydrogen or Ci- 6 alkyl. In some embodiments, each R 1 is independently hydrogen or Ci-4 alkyl. In some embodiments, each R 1 is independently hydrogen or C1-2 alkyl.
  • Ring A is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, R°, -CN, -OR°, -SR°, -N(R°)2, -NO2, -C(0)R°, -C(0)OR°, -C(0)NR°2, -OC(0)R°, -0C(0)NR° 2 , -OC(0)OR°, -0S(0) 2 R°, - 0S(0) 2 NR°2, -N(R°)C(0)R°, -N(R 0 )S(0) 2 R°, -S(0) 2 R°, -S0 2 NR°2, and -S(0) 2 OR°, and (ii) optionally substituted on a substitutable nitrogen atom with one
  • Ring A is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, and R°, and (ii) optionally substituted on a substitutable nitrogen atom with one or more groups selected from -R ⁇ . In some embodiments, Ring A is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from halogen and R°, and (ii) optionally substituted on a substitutable nitrogen atom with one or more groups selected from -R ⁇ .
  • Ring A is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from R°, and (ii) optionally substituted on a substitutable nitrogen atom with one or more groups selected from - R ⁇ .
  • Ring A is optionally substituted with one or more R b (i.e., in addition to being substituted with -L-R a ), wherein R b is as defined in Formula II-l above and described in classes and subclasses herein.
  • Ring A is substituted with zero, one, two, three, four, or five R b , as valency allows.
  • Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is optionally substituted phenyl.
  • Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted pyrazolyl.
  • Ring A is optionally substituted 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted pyridonyl.
  • Ring A is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 8-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted tetrahydropyrazolo[l,5-a]pyridinyl. In some embodiments, Ring A is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted C3-7 cycloalkyl. In some embodiments, Ring A is optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted 6- membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted 7-membered saturated or partially unsaturated monocyclic carbocyclyl.
  • Ring A is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 3- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 7- membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 9-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • L is a covalent bond.
  • L is a bivalent C1-3 straight or branched hydrocarbon chain.
  • L is a bivalent C1-2 straight or branched hydrocarbon chain.
  • L is methylene (i.e., -CH2-).
  • L is -CH2CH2-.
  • L is -CH2CH2CH2-.
  • L is a covalent bond or -CH2-.
  • R a is halogen, optionally substituted Ci- 6 aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R a is optionally substituted Ci- 6 aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is optionally substituted Ci- 6 alkyl or optionally substituted 3- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R a is hydrogen. In some embodiments, R a is not hydrogen. [0068] In some embodiments, R a is halogen. In some embodiments, R a is fluoro, chloro, bromo, or iodo. In some embodiments, R a is fluoro. In some embodiments, R a is chloro.
  • R a is optionally substituted Ci- 6 aliphatic. In some embodiments, R a is optionally substituted straight-chain or branched Ci- 6 aliphatic (i.e., optionally substituted acyclic Ci- 6 aliphatic). In some embodiments, R a is optionally substituted Ci- 6 alkyl. In some embodiments, R a is optionally substituted Ci-4 alkyl. In some embodiments, R a is -CHS.
  • R a is optionally substituted phenyl.
  • R a is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0072] In some embodiments, R a is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl.
  • R a is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R a is optionally substituted 4- to 6- membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R a is optionally substituted 3- membered saturated monocyclic heterocyclyl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • R a is optionally substituted 4-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R a is oxetanyl. In some embodiments, R a is optionally substituted 5-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is tetrahydrofuranyl. In some embodiments, R a is optionally substituted 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is optionally substituted 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R a is optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is optionally substituted 7- to 10- membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is optionally substituted 7- to 8-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R a is selected from the group consisting of: ,
  • ⁇ R a is -R a (i.e., L is a covalent bond).
  • ⁇ is -CFh-R 3 (i.e., L is a Ci hydrocarbon chain).
  • is -CH2CH2-R a i.e., L is a C2 straight hydrocarbon chain).
  • R b up to five occurrences of R b may be present, as allowed by valency rules, and is each independently halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(0)R’, -C(0)OR, - C(0)N(R)2, -0C(0)R ⁇ -0C(0)N(R)2, -OC(0)OR, -OSO2R, -0S0 2 N(R) 2 , -N(R)C(0)R’, - N(R)S02R’, -SCkR’, -S0 2 N(R) 2 , -SCbR’, optionally substituted Ci- 6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocycly
  • each occurrence of R b is independently optionally substituted Ci-6 aliphatic or optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, each occurrence of R b is independently optionally substituted Ci-4 alkyl or optionally substituted C3-C4 cycloalkyl. In some embodiments, each occurrence of R b is independently C3-4 cycloalkyl or Ci-4 alkyl optionally substituted with one or more halogen. In some embodiments, each occurrence of R b is independently Ci-4 alkyl or C3-C4 cycloalkyl.
  • R b is hydrogen
  • R b is halogen. In some embodiments, R b is fluoro, chloro, bromo, or iodo. In some embodiments, R b is fluoro. In some embodiments, R b is chloro.
  • R b is optionally substituted Ci-6 aliphatic. In some embodiments, R b is optionally substituted straight-chain or branched Ci-6 aliphatic (i.e., optionally substituted acyclic Ci-6 aliphatic). In some embodiments, R b is optionally substituted Ci-6 alkyl. In some embodiments, R b is optionally substituted Ci-4 alkyl. In some embodiments, R b is Ci-4 alkyl optionally substituted with one or more of halogen. In some embodiments, R b is Ci-4 alkyl. In some embodiments, R b is -CH3 or -C(CH3)3.
  • R b is optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R b is optionally substituted C3-C6 cycloalkyl. In some embodiments, R b is optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R b is cyclopropyl. In some embodiments, R b is optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R b is optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl.
  • R b is optionally substituted 6-membered saturated or partially unsaturated monocyclic carbocyclyl. [0083] In some embodiments, R b is optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R b is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • IP-2, IV- 1, and IV-2 optionally substituted In some embodiments, optionally substituted is optionally substituted In some embodiments, optionally substituted is optionally substituted In some embodiments, optionally substituted is optionally substituted In some embodiments, optionally substituted is optionally substituted
  • Ring B (including Ring B1 and/or Ring B2 and/or, when present, Ring B3) is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, R°, -CN, -OR°, -SR°, -N(R°)2, -NCte, -C(0)R°, - C(0)0R°, -C(0)NR°2, -0C(0)R°, -0C(0)NR°2, -0C(0)0R°, -0S(0) 2 R°, -0S(0) 2 NR°2, - N(R°)C(0)R°, -N(R°)C(0)NR°2, -N(R 0 )S(0) 2 R°, -S(0) 2 R°, -S(0) 2 R°,
  • Ring B is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, R°, -CN, -OR°, -N(R°)2, -C(0)NR°2, -N(R°)C(0)R°, and - N(R°)C(0)NR°2, and (ii) optionally substituted on a substitutable nitrogen with -R ⁇ .
  • Ring B is optionally substituted on a substitutable carbon atom with one or more groups independently selected from -N(R°)2, -C(0)NR°2, -N(R°)C(0)R°, and -N(R°)C(0)NR°2.
  • Ring B is optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 9- to 16-membered bicyclic or tricyclic aryl, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 7- to 16- membered saturated or partially unsaturated bicyclic or tricyclic carbocyclyl, optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 10- to 16- membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 8- to 10- membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is monocyclic. In some embodiments, Ring B is polycyclic (e.g., bicyclic or tricyclic). In some embodiments, Ring B is bicyclic. In some embodiments, each ring in a bicyclic ring system of Ring B contains at least one heteroatom. In some embodiments, one and only one ring of a bicyclic ring system of Ring B contains no heteroatoms. In some embodiments, each ring in a bicyclic ring system of Ring B is aromatic. In some embodiments, one and only one ring of a bicyclic ring system of Ring B is aromatic. In some embodiments, no ring in a bicyclic ring system of Ring B is aromatic.
  • Ring B is optionally substituted phenyl.
  • Ring B is optionally substituted 9- to 16-membered bicyclic or tricyclic aryl. In some embodiments, Ring B is optionally substituted 9- to 10-membered bicyclic aryl. In some embodiments, Ring B is optionally substituted 9-membered bicyclic aryl (e.g., a 5-membered carbocycle fused to a phenyl ring). In some embodiments, Ring B is optionally substituted 10-membered bicyclic aryl (e.g., naphthyl or a 6-membered carbocycle fused to a phenyl ring).
  • Ring B is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted pyridyl.
  • Ring B is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 8-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring B is optionally substituted C3-7 cycloalkyl. In some embodiments, Ring B is optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring B is optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring B is optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring B is optionally substituted 6- membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring B is optionally substituted 7-membered saturated or partially unsaturated monocyclic carbocyclyl.
  • Ring B is optionally substituted 7- to 16-membered saturated or partially unsaturated bicyclic or tricyclic carbocyclyl.
  • Ring B is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 3- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 7- to 10-membered fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 7-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 8-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 9-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 10-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is , wherein R 2 is as defined in Formula
  • Ring B is
  • R 2 is -N(R)C(0)R’ or -C(0)N(R) 2.
  • R 2 is -N(R)C(0)R ⁇ In some embodiments, R 2 is - N(H)C(0)R ⁇ In some embodiments, R 2 is -N(R)C(0)(optionally substituted Ci- 6 aliphatic). In some embodiments, R 2 is -N(H)C(0)(optionally substituted Ci- 6 aliphatic). In some embodiments, R 2 is -N(R)C(0)(CI-6 aliphatic). In some embodiments, R 2 is -N(H)C(0)(CI-6 aliphatic). In some embodiments, R 2 is -N(R)C(0)(straight-chain or branched Ci- 6 aliphatic).
  • R 2 is -N(H)C(0)(straight-chain or branched Ci- 6 aliphatic). In some embodiments, R 2 is -N(R)C(0)(optionally substituted Ci- 6 alkyl). In some embodiments, R 2 is - N(H)C(0)(optionally substituted Ci- 6 alkyl). In some embodiments, R 2 is -N(R)C(0)(CI-6 alkyl). In some embodiments, R 2 is -N(H)C(0)(CI-6 alkyl). In some embodiments, R 2 is - N(R)C(0)(optionally substituted Ci-4 alkyl). In some embodiments, R 2 is -N(H)C(0)(optionally substituted Ci-4 alkyl).
  • R 2 is -N(R)C(0)(CI-4 alkyl). In some embodiments, R 2 is -N(H)C(0)(CI-4 alkyl). In some embodiments, R 2 is -N(R)C(0)(optionally substituted Ci- 2 alkyl). In some embodiments, R 2 is -N(H)C(0)(optionally substituted Ci- 2 alkyl). In some embodiments, R 2 is -N(R)C(0)(Ci- 2 alkyl). In some embodiments, R 2 is - N(H)C(0)(CI- 2 alkyl). In some embodiments, R 2 is -N(R)C(0)CH3. In some embodiments, R 2 is -N(H)C(0)CH3.
  • R 2 is -N(R)C(0)(optionally substituted C3-7 carbocyclyl). In some embodiments, R 2 is -N(H)C(0)(optionally substituted C3-7 carbocyclyl). In some embodiments, R 2 is -N(R)C(0)(optionally substituted C3-7 cycloalkyl). In some embodiments, R 2 is -N(H)C(0)(optionally substituted C3-7 cycloalkyl). In some embodiments, R 2 is -N(R)C(0)(C 3 - 6 cycloalkyl). In some embodiments, R 2 is -N(H)C(0)(C 3 - 6 cycloalkyl). [0107] In some embodiments, R 2 is -C(0)N(R)2. In some embodiments, R 2 is -
  • R 2 is -C(0)N(H)(CI- 6 aliphatic). In some embodiments, R 2 is -C(0)N(R)(straight-chain or branched Ci- 6 aliphatic). In some embodiments, R 2 is -C(0)N(H)(straight-chain or branched Ci- 6 aliphatic). In some embodiments, R 2 is -C(0)N(R)(CI- 6 alkyl). In some embodiments, R 2 is -C(0)N(H)(CI- 6 alkyl). In some embodiments, R 2 is -C(0)N(R)(CI-4 alkyl). In some embodiments, R 2 is -
  • R 2 is -C(0)N(R)(CI-2 alkyl). In some embodiments, R 2 is -C(0)N(H)(CI-2 alkyl).
  • R 2 is -N(R)2. In some embodiments, R 2 is -N(H)(R).
  • R 2 is -N(R)C(0)N(R)2. In some embodiments, R 2 is -
  • R 2 is -N(R)C(0)N(R)2, wherein the two R groups attached to the same nitrogen are taken together to form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is -N(R)C(0)N(R)2, wherein the two R groups attached to the same nitrogen are taken together to form an optionally substituted 3- to 5-membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is -N(H)C(0)N(R)2.
  • R 2 is -N(H)C(0)N(R)2, wherein the two R groups attached to the same nitrogen are taken together to form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is -N(H)C(0)N(R)2, wherein the two R groups attached to the same nitrogen are taken together to form an optionally substituted 3- to 5-membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each R is independently hydrogen or optionally substituted Ci- 6 aliphatic.
  • R is hydrogen.
  • R is optionally substituted Ci- 6 aliphatic.
  • R is optionally substituted straight-chain or branched Ci- 6 aliphatic (i.e., optionally substituted acyclic Ci- 6 aliphatic).
  • R is optionally substituted Ci- 6 alkyl.
  • R is optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl. In some embodiments, R is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R when attached to the same nitrogen atom are taken together form a 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R’ is optionally substituted Ci- 6 aliphatic.
  • R’ is optionally substituted straight-chain or branched Ci- 6 aliphatic (i.e., optionally substituted acyclic Ci- 6 aliphatic).
  • R’ is optionally substituted Ci- 6 alkyl.
  • R’ is optionally substituted Ci-4 alkyl.
  • R’ is unsubstituted Ci-4 alkyl.
  • R’ is optionally substituted C1-2 alkyl.
  • R’ is unsubstituted C1-2 alkyl. In some embodiments, R’ is methyl. In some embodiments, R’ is 3- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R’ is optionally substituted C3-6 cycloalkyl.
  • Ring B is , wherein Ring B1 and Ring B2 are defined as in Formula IV- 1 and described in classes and subclasses herein, both singly and in combination; and Ring B1 is fused to Ring B2; and Ring B2 is optionally (i) further fused to Ring B3 or (ii) Ring B2 and Ring B3 combine to form a spirocycle.
  • Ring B1 is an optionally substituted ring selected from 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B1 is optionally substituted phenyl. In some embodiments, when Ring B1 is phenyl, Ring B2 contains at least one heteroatom.
  • Ring B1 is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is unsubstituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B1 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, when Ring B1 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, Ring B2 contains at least one heteroatom. In some embodiments, when Ring B2 is not aromatic, Ring B1 is optionally substituted 5- to 6-membered saturated monocyclic carbocyclyl. In some embodiments, Ring B1 is optionally substituted 5- to 6-membered partially saturated monocyclic carbocyclyl.
  • Ring B1 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B2 when Ring B2 is not aromatic, Ring B1 is optionally substituted 5- to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B1 is optionally substituted 5- to 6-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B2 is an optionally substituted ring selected from 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B2 is optionally substituted phenyl. In some embodiments, when Ring B2 is phenyl, Ring B1 contains at least one heteroatom.
  • Ring B2 is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B2 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B2 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B2 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, when Ring B2 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, Ring B1 contains at least one heteroatom. In some embodiments, when Ring B1 (and Ring B3, if present) is not aromatic, Ring B2 is optionally substituted 5- to 6-membered saturated monocyclic carbocyclyl. In some embodiments, Ring B2 is optionally substituted 5- to 6-membered partially saturated monocyclic carbocyclyl.
  • Ring B2 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B1 when Ring B1 (and Ring B3, if present) is not aromatic, Ring B2 is optionally substituted 5- to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B2 is optionally substituted 5- to 6-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B1 and Ring B2 are both optionally substituted 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B1 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • Ring B2 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B1 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • Ring B2 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B2 is further fused to Ring B3. In some embodiments, Ring B2 and Ring B3 combine to form a spirocycle.
  • Ring B3, when present, is optionally substituted phenyl.
  • Ring B3 is 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B3 is 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl.
  • Ring B3, when not fused to an aromatic Ring B2, is 3- to 7-membered saturated monocyclic carbocyclyl.
  • Ring B3 is 3- to 7-membered partially saturated monocyclic carbocyclyl.
  • Ring B3 is 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B3, when not fused to an aromatic Ring B2, is 3- to 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B3 is 3- to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the present disclosure provides compounds selected from Table 1:
  • the present disclosure encompasses the recognition that provided compounds display certain desirable characteristics, e.g., as compared to other known compounds.
  • provided compounds are more potent in one or more biochemical or cellular assays (e.g., the JAK2 Binding Assay or SET2-pSTAT5 Cellular Assay described herein) and/or have one or more other characteristics that make them more suitable for drug development, such as better selectivity over other kinases and/or better ADME (absorption, distribution, metabolism, and excretion) properties including but not limited to better permeability, cytotoxicity, hepatocyte stability, solubility, and/or plasma protein binding profiles (e.g., based on assays described in the ensuing examples), than other known compounds.
  • provided compounds display certain desirable characteristics in one or more assays described herein, e.g., compared to other known compounds.
  • provided compounds are provided and/or utilized in a salt form (e.g., a pharmaceutically acceptable salt form).
  • a salt form e.g., a pharmaceutically acceptable salt form.
  • Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated.
  • Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19(1977).
  • Provided compounds may generally be made by the processes described in the ensuing schemes and examples.
  • provided compounds are prepared according to the following Scheme: wherein LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination.
  • LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination.
  • compound A-l is prepared by a process comprising contacting intermediate A.1-1 with intermediate A.2 in the presence of a suitable base (e.g., NaOtBu).
  • compound A-l is prepared by a process comprising contacting intermediate A.1-1 with intermediate A.2 in the presence of a suitable base (e.g., NaOtBu), a suitable metal complex (e.g., a palladium complex such as tris(dibenzylideneacetone)dipalladium(0)), and optionally a suitable ligand (e.g., 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene).
  • a suitable base e.g., NaOtBu
  • a suitable metal complex e.g., a palladium complex such as tris(dibenzylideneacetone)dipalladium(0)
  • a suitable ligand e.g., 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
  • provided compounds are prepared according to the following Scheme: wherein LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-2 and described in classes and subclasses herein, both singly and in combination.
  • LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-2 and described in classes and subclasses herein, both singly and in combination.
  • compound A-2 is prepared by a process comprising contacting intermediate A.1-2 with intermediate A.2 in the presence of a suitable base.
  • compound A-2 is prepared by a process comprising
  • provided compounds are prepared according to the following Scheme: wherein LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination.
  • LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination.
  • compound B-1 is prepared by a process comprising contacting intermediate B.1-1 with intermediate B.2 in the presence of a suitable base.
  • provided compounds are prepared according to the following Scheme: wherein LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-2 and described in classes and subclasses herein, both singly and in combination.
  • LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-2 and described in classes and subclasses herein, both singly and in combination.
  • compound B-2 is prepared by a process comprising contacting intermediate B.1-2 with intermediate B.2 in the presence of a suitable base.
  • provided compounds are prepared according to the following Scheme: wherein LG 1 is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo); LG 2 is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo); and Ring A, L, R, R’, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination.
  • LG 1 is a suitable leaving group
  • LG 2 is a suitable leaving group
  • Ring A, L, R, R’, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination.
  • intermediate C.3-1 is prepared by a process comprising contacting intermediate C.1-1 with intermediate C.2 in the presence of a suitable base (e.g., t-BuOK).
  • compound C-l is prepared by a process comprising contacting intermediate C.3-1 with intermediate C.4 in the presence of a suitable base (e.g., CS2CO3).
  • compound C-l is prepared by a process comprising contacting intermediate C.3-1 with intermediate C.4 in the presence of a suitable base (e.g., CS2CO3), a suitable metal complex (e.g., a palladium complex such as tris(dibenzylideneacetone)dipalladium(0)), and optionally a suitable ligand (e.g., 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl).
  • a suitable base e.g., CS2CO3
  • a suitable metal complex e.g., a palladium complex such as tris(dibenzylideneacetone)dipalladium(0)
  • a suitable ligand e.g., 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.
  • provided compounds are prepared according to the following Scheme: wherein LG 1 is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo); LG 2 is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo); and Ring A, L, R, R’, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-2 and described in classes and subclasses herein, both singly and in combination.
  • LG 1 is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo)
  • LG 2 is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo)
  • intermediate C.3-2 is prepared by a process comprising contacting intermediate C.1-2 with intermediate C.2 in the presence of a suitable base.
  • compound C-2 is prepared by a process comprising contacting intermediate C.3-2 with intermediate C.4 in the presence of a suitable base.
  • compound C-2 is prepared by a process comprising contacting intermediate C.3-2 with intermediate C.4 in the presence of a suitable base, a suitable metal complex, and optionally a suitable ligand.
  • provided compounds are prepared according to the following Scheme: wherein LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-1 and described in classes and subclasses herein, both singly and in combination.
  • compound D-1 is prepared by a process comprising contacting intermediate D.1-1 with intermediate D.2 in the presence of a suitable base.
  • compound D-1 is prepared by a process comprising contacting intermediate D.1-1 with intermediate D.2 in the presence of a suitable base, a suitable metal complex, and optionally a suitable ligand.
  • provided compounds are prepared according to the following Scheme: wherein LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-2 and described in classes and subclasses herein, both singly and in combination.
  • LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, V, W, X, Y, Z, R a , R x , and R y are as defined above for Formula 1-2 and described in classes and subclasses herein, both singly and in combination.
  • compound D-2 is prepared by a process comprising contacting intermediate D.1-2 with intermediate D.2 in the presence of a suitable base.
  • compound D-2 is prepared by a process comprising
  • a provided compound is obtained by a process comprising a purification method described in the Examples section.
  • a compound is the 1 st eluting isomer.
  • a compound is the 2 nd eluting isomer.
  • a compound is the 3 rd eluting isomer.
  • a compound is the 4 th eluting isomer.
  • a compound is the 5 th , 6 th , 7 th , 8 th , or more eluting isomer.
  • compositions comprising a compound provided herein with one or more other components.
  • provided compositions comprise and/or deliver a compound described herein (e.g., compounds of Formulae 1-1, 1-2, IA, IB, IC, ID, IE, II- 1, II-2, III- 1 , III-2, IV- 1, and IV-2).
  • a provided composition is a pharmaceutical composition that comprises and/or delivers a compound provided herein (e.g., compounds of Formulae 1-1, 1-2, IA, IB, IC, ID, IE, II-l, II-2, III-l, III-2, IV- 1, and IV-2) and further comprises a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects.
  • provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and/or anti-statics, etc.
  • compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and/or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions.
  • Methods of preparing pharmaceutical compositions are well known in the art.
  • provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage.
  • unit dosage form refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent.
  • a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect.
  • a unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.
  • a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents
  • a solid pharmaceutical composition e.g., a tablet, a capsule, or the like
  • sustained release formulation containing a predetermined quantity of one or more active agents
  • a drug delivery device containing a predetermined amount of one or more active agents
  • compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of any disease or disorder described herein.
  • provided compounds and compositions are useful in medicine (e.g., as therapy).
  • provided compounds and compositions are useful in research as, for example, analytical tools and/or control compounds in biological assays.
  • the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with JAK2. [0146] In some embodiments, provided compounds are useful as JAK2 inhibitors. In some embodiments, provided compounds are useful as Type II JAK2 inhibitors. In some embodiments, the present disclosure provides methods of inhibiting JAK2 in a subject comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods of inhibiting JAK2 in a biological sample comprising contacting the sample with a provided compound or composition.
  • JAK e.g., JAK2
  • JAK2 has been implicated in various diseases, disorders, and conditions, such as myeloproliferative neoplasms (Vainchenker, W. et al., FlOOOResearch 2018, 7(F1000 Faculty Rev):82), atopic dermatitis (Rodrigues, M. A. and Torres, T. J. Derm. Treat. 2019, 31(1), 33-40.) and acute respiratory syndrome, hyperinflammation, and/or cytokine storm syndrome ( The Lancet. doi:10.1016/S0140-6736(20)30628-0).
  • the present disclosure provides methods of treating a disease, disorder or condition associated with JAK2 in a subject in need thereof comprising administering to the subject a provided compound or composition.
  • a disease, disorder or condition is associated with overexpression of JAK2.
  • the present disclosure provides methods of treating cancer, comprising administering a provided compound or composition to a subject in need thereof.
  • the present disclosure provides methods of treating proliferative diseases, comprising administering a provided compound or composition to a subject in need thereof.
  • the present disclosure provides methods of treating a hematological malignancy, comprising administering a provided compound or composition to a subject in need thereof.
  • a hematological malignancy is leukemia (e.g., chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, or acute monocytic leukemia).
  • a hematological malignancy is lymphoma (e.g., Burkitt’s lymphoma, Hodgkin’s lymphoma, or non-Hodgkin’s lymphoma).
  • a non- Hodgkin’s lymphoma is a B-cell lymphoma.
  • a non-Hodgkin’s lymphoma is a NK/T-cell lymphoma (e.g., cutaneous T-cell lymphoma).
  • a hematological malignancy is myeloma (e.g., multiple myeloma).
  • a hematological malignancy is myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or myelofibrosis).
  • a hematological malignancy is myelodysplastic syndrome.
  • the present disclosure provides methods of treating an inflammatory disease, disorder, or condition (e.g., acute respiratory syndrome, hyperinflammation, and/or cytokine storm syndrome (including those associated with COVID- 19) or atopic dermatitis), comprising administering a provided compound or composition to a subject in need thereof.
  • an inflammatory disease, disorder, or condition e.g., acute respiratory syndrome, hyperinflammation, and/or cytokine storm syndrome (including those associated with COVID- 19) or atopic dermatitis
  • a provided compound or composition is administered as part of a combination therapy.
  • combination therapy refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents).
  • the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens.
  • “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination.
  • combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.
  • a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapies (e.g., an anti-cancer therapy and/or therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care).
  • additional therapies include, but are not limited to, BCL2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mivebresib), proteasome inhibitors (e.g., bortezomib), LSD1 inhibitors (e.g., IMG-7289), and CXCR2 inhibitors.
  • JAK2 inhibitors Useful combinations of a JAK2 inhibitor with BCL2, HDAC, BET, and proteasome inhibitors have been demonstrated in cells derived from cutaneous T-cell lymphoma patients (Yumeen, S., et al., Blood Adv. 2020, 4(10), 2213-2226).
  • CXCR2 activity has been shown to modulate signaling pathways involved in tumor growth, angiogenesis, and/or metastasis, including the JAK-STAT3 pathway (Jaffer, T., Ma, D. Transl. Cancer Res. 2016, 5(Suppl. 4), S616-S628).
  • Example 1 /V-(4-((2-((4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin-2-yl)amino)- [l,2,4]triazolo[l,5-a]pyridin-7-yl)oxy)pyridin-2-yl)acetamide
  • Compound 1.12 can also be used to prepare compound 1-5 using methods described herein.
  • Example 2 A-(4-((2-((5-cyclopropyl- 1 -methyl-2-oxo- 1 ,2-dihydropyri din-3 - yl)amino)imidazo[ 1 ,2-c/]pyrimidin-6-yl)oxy)pyridin-2-yl)acetamide
  • reaction mixture was stirred at 80 °C in microwave for 2 h.
  • the reaction mixture was cooled to room temperature, poured into ice-water and extracted with ethyl acetate.
  • the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 3.7.
  • Compound 1-4 can be prepared using methods described herein, e.g., as described in the synthesis of 1-3.
  • Int-1 can be used to prepare compounds 1-7, 1-9, and 1-11 using methods described herein.
  • Int-2 can be used to prepare compounds 1-8, 1-10, and 1-12 using methods described herein.
  • Int-3 can be used to prepare compound 1-13 using methods described herein.
  • JAK2 JH1 domain-catalytic, Y1007F,Y1008F
  • JAK2 JH1 domain-catalytic, Y1007F,Y1008F
  • Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (lx PBS, 0.05% Tween 20, 0.1% BSA, 1 mmol/L DTT). Test compound was prepared as 11 lx stocks in 100% DMSO and directly diluted into the assay wells. All reactions were performed in polypropylene 384-well plates in a final volume of 0.02 mL.
  • Binding affinity for other kinases is determined as follows: Kinase-tagged T7 phage strains are prepared in an E. coli host derived from the BL21 strain. E. coli are grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates are centrifuged and filtered to remove cell debris. The remaining kinases are produced in HEK- 293 cells and subsequently tagged with DNA for qPCR detection.
  • Streptavidin-coated magnetic beads are treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • the liganded beads are blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding.
  • Binding reactions are assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds are prepared as 11 IX stocks in 100% DMSO.
  • Kds are determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds are then diluted directly into the assays such that the final concentration of DMSO is 0.9%. All reactions are performed in polypropylene 384-well plate. Each has a final volume of 0.02 ml. The assay plates are incubated at room temperature with shaking for 1 hour and the affinity beads are washed with wash buffer (lx PBS, 0.05% Tween 20).
  • JAK2-selective compounds Compounds that exhibit a better binding affinity for JAK2 compared to one or more other kinases are considered to be JAK2-selective compounds.
  • provided compounds may be JAK2-selective over one or more of the following kinases: JAK1, JAK3, and Tyk2.
  • This assay measures inhibition of JAK2-mediated pSTAT5 signaling in constitutively active essential thrombocytopenia cells carrying the V617F mutation.
  • Cells are harvested from a flask into cell culture medium, and the number of cells is counted.
  • the cells are diluted with culture medium and 100 pL of cell suspension (50000/well) is added into each well of a 96-well cell culture plate.
  • a solution of test compound is added to the assay plate.
  • the plates are covered with a lid and placed in a 37 °C 5% CO2 incubator for 4 hours. After 4 hours, the cells are spun, and the cell pellets are re-suspended with 100 pL cold PBS.
  • the cells are spun again at 4 °C and 4000 rpm for 5 min.
  • PBS is aspirated, and 25 pL lysis buffer (with protease and phosphatase inhibitor cocktail) is added to each cell pellet.
  • the cell lysate is shaken at 4 °C for 20 min to fully lyse the cells.
  • the cell lysate is spun at 4 °C and 4000 rpm for 15 min, and then the supernatant is transferred into a new plate and stored at -80 °C.
  • Meso-scale discovery is used to analyze plates as follows: a standard MSD plate is coated with capture antibody in PBS (40 pL/well) and is incubated at 4 °C overnight with shaking.
  • the MSD plate is washed three times with 150 pL/well of lx MSD Wash Buffer (Tris-buffered saline with 0.1% Tween® 20 detergent, TBST). The MSD plates are then blocked with 150 pL of blocking buffer (5% BSA in TBST) and shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 pL/well of lx MSD Wash Buffer (TBST). Sample lysates are then added to MSD plates (25 pL/well) and shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 pL/well of lx MSD Wash Buffer (TBST).
  • TBST 150 pL/well of lx MSD Wash Buffer
  • Detection antibody (prepared in Antibody Detection buffer, 1% BSA in lxTBST) is then added to the MSD plates, and they are shaken for 1 h at room temperature and 600 rpm.
  • the MSD plate is washed three times with 150 pL/well of lx MSD Wash Buffer (TBST).
  • a secondary detection antibody (prepared in Antibody Detection buffer, 1% BSA in lxTBST) is then added to the MSD plates, and they are shaken for 1 h at room temperature and 600 rpm.
  • the MSD plate is washed three times with 150 pL/well of lx MSD Wash Buffer (TBST).
  • MSD reading buffer (lx) is added to the plates (150 pL/well), and they are diluted from 4x with water.
  • the plates are imaged using an MSD imaging instrument according to the manufacturer’s instructions.
  • Preparation of Caco-2 Cells 50 pL and 25 mL of cell culture medium are added to each well of a Transwell® insert and reservoir, respectively. Then, the HTS Transwell® plates are incubated at 37 °C, 5% CO2 for 1 hour before cell seeding. Caco-2 cell cells are diluted to 6.86x105 cells/mL with culture medium, and 50 pL of cell suspension are dispensed into the filter well of the 96-well HTS Transwell® plate. Cells are cultivated for 14-18 days in a cell culture incubator at 37 °C, 5% CO2, 95% relative humidity. Cell culture medium is replaced every other day, beginning no later than 24 hours after initial plating.
  • Assay Procedure The Caco-2 plate is removed from the incubator and washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4), and then incubated at 37 °C for 30 minutes.
  • the stock solutions of control compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) to get 5 mM working solutions.
  • the stock solutions of the test compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES and 4% BSA, pH 7.4) to get 5 pM working solutions.
  • the final concentration of DMSO in the incubation system is 0.5%.
  • Time 0 samples are prepared by transferring 50 pL of 5 mM working solution to wells of the 96-deepwell plate, followed by the addition of 200 pL cold methanol containing appropriate internal standards (IS). The plates are incuabted at 37 °C for 2 hours. At the end of the incubation, 50 pL samples from donor sides (apical compartment for Ap Bl flux, and basolateral compartment for Bl Ap) and receiver sides (basolateral compartment for Ap Bl flux, and apical compartment for Bl Ap) are transferred to wells of a new 96-well plate, followed by the addition of 4 volume of cold acetonitrile or methanol containing appropriate internal standards (IS).
  • the plates are incubated at 37 °C for 30 minutes. 80 pL samples are removed directly from the apical and basolateral wells (using the basolateral access holes) and transferred to wells of new 96 wells plates.
  • the Lucifer Yellow fluorescence (to monitor monolayer integrity) signal is measured in a fluorescence plate reader at 485 nM excitation and 530 nM emission.
  • HEK293T cells are harvested from flask into cell culture medium, and then the cells are counted.
  • the cells are diluted with culture medium to the desired density, and 40 pL of cell suspension is added into each well of a 384-well cell culture plate.
  • the plates are covered with a lid and spun at room temperature at 1,000 RPM for 1 minute and then transferred into 37 °C 5% CO2 incubator overnight.
  • Test compounds are dissolved at 10 mM DMSO stock solution. 45 pL of stock solution is then transferred to a 384 PP-plate.
  • a 3-fold, 10-point dilution is performed via transferring 15 pL compound into 30 pL DMSO by using TEC AN (EVO200) liquid handler.
  • the plates are spun at room temperature at 1,000 RPM for 1 minute and shaken on a plate shaker for 2 minutes. 40 nL of diluted compound is transferred from compound source plate into the cell plate by using liquid handler Echo550. After compound treatment for 48 hours, CTG detection is performed for compound treatment plates: the plates are removed from incubators and equilibrated at room temperature for 15 minutes. 30 pL of CellTiter-Glo reagent is added into each well to be detected. The plates are then placed at room temperature for 30 min followed by reading on EnVision.
  • IC50 values are calculated using XLFit (equation 201).
  • Stock solutions are diluted to 100 pM by combining 198 pL of 50% acetonitrile/50% water and 2 pL of 10 mM stock solution. Verapamil is used as positive control in the assay.
  • Vials of cryopreserved hepatocytes are thawed in a 37 °C water bath with gently shaking. The contents are poured into the 50 mL thawing medium conical tube. Vials are centrifuged at 100 g for 10 minutes at room temperature. Thawing medium is aspirated and hepatocytes are re-suspended with serum-free incubation medium to yield -1.5 x 106 cells/mL.
  • Cell viability and density are counted using a Trypan Blue exclusion, and then cells are diluted with serum-free incubation medium to a working cell density of 0.5x106 viable cells/mL.
  • a portion of the hepatocytes at 0.5x106 viable cells/mL are boiled for 5 min prior to adding to the plate as negative control to eliminate the enzymatic activity so that little or no substrate turnover should be observed.
  • Aliquots of 198 pL hepatocytes are dispensed into each well of a 96-well non-coated plate. The plate is placed in the incubator for approximately 10 minutes.
  • the solubility sample plate is transferred to the Thermomixer comfort plate shaker and incubated at RT for 2 hours with shaking at 1100 rpm. After 2 hours incubation, stir sticks are removed using a big magnet and all samples from the solubility sample plate are transferred into the filter plate. All the samples are filtered by vacuum manifold. The filtered samples are diluted with methanol. Samples are analyzed by LC-MS/MS and quantified against a standard of known concentration in DMSO using LC coupled with Mass spectral peak identification and quantitation. The solubility values of the test compounds are calculated as follows, wherein INJ VOL is injection volume, DF is dilution factor, and STD is standard:
  • test compounds and control compound are prepared in DMSO at the concentration of 200 mM, and then the working solutions are spiked into plasma. The final concentration of compound is 1 mM. The final concentration of DMSO is 0.5%.
  • Ketoconazole is used as positive control in the assay. Dialysis membranes are soaked in ultrapure water for 60 minutes to separate strips, then in 20% ethanol for 20 minutes, finally in dialysis buffer for 20 minutes. The dialysis set up is assembled according to the manufacturer’s instruction. Each Cell is with 150 pL of plasma sample and dialyzed against equal volume of dialysis buffer (PBS). The assay is performed in duplicate.
  • PBS dialysis buffer
  • the dialysis plate is sealed and incubated in an incubator at 37 °C with 5% CO2 at 100 rpm for 6 hours.
  • 50 pL of samples from both buffer and plasma chambers are transferred to wells of a 96-well plate.
  • 50 pL of plasma is added to each buffer samples and an equal volume of PBS is supplemented to the collected plasma sample.
  • 400 pL of precipitation buffer acetonitrile containing internal standards (IS, 100 nM alprazolam, 200 nM labetalol, 200 nM imipramine and 2 pM ketoplofen) is added to precipitate protein and release compounds.
  • Samples are vortexed for 2 minutes and centrifuged for 30 minutes at 3,220 g.

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Abstract

La présente invention concerne des composés hétéroaryloxy triazolo-azines et imidazo-azines ainsi que des compositions de ceux-ci utiles pour inhiber JAK2.
PCT/US2022/038654 2021-07-29 2022-07-28 Hétéroaryloxy triazolo-azines et imidazo-azines en tant qu'inhibiteurs de jak2 WO2023009708A1 (fr)

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