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WO2023009712A1 - Heteroaryloxy thiazolo azines as jak2 inhibitors - Google Patents

Heteroaryloxy thiazolo azines as jak2 inhibitors Download PDF

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Publication number
WO2023009712A1
WO2023009712A1 PCT/US2022/038661 US2022038661W WO2023009712A1 WO 2023009712 A1 WO2023009712 A1 WO 2023009712A1 US 2022038661 W US2022038661 W US 2022038661W WO 2023009712 A1 WO2023009712 A1 WO 2023009712A1
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optionally substituted
nitrogen
sulfur
compound
oxygen
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WO2023009712A9 (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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Ajax Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • JAK2 INHIBITORS RELATED APPLICATIONS [0001] This application claims priority to and benefit of U.S. Application No.63/226,888, filed July 29, 2021, the entire contents of which are hereby incorporated by reference.
  • BACKGROUND [0002] Janus kinase 2 (JAK2) 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.
  • JAK2V617F is the most prevalent mutation in myeloproliferative neoplasms, occurring in approx. 70% of all patients, and in up to 95% of patients with polycythemia vera.
  • JAK2V617F is the most prevalent mutation in myeloproliferative neoplasms, occurring in approx. 70% of all patients, and in up to 95% of patients with polycythemia vera.
  • Even less common mutations, such as in MPL and CALR have been shown to effect activation of JAK2, thereby initiating and/or driving disease progression. (Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev):82).
  • JAK2 polymorphisms in JAK2 have been linked to various autoimmune diseases and inflammatory conditions, such as psoriasis and inflammatory bowel disease.
  • Inhibitors of JAKs e.g., JAK2 are classified based on their binding mode.
  • Type I inhibitors are those that bind the ATP- binding site in the active conformation of the kinase domain, thereby blocking catalysis (Vainchenker, W. et al.).
  • 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.
  • 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 I: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, W, X, Y, Z, and R a are as defined herein.
  • DETAILED DESCRIPTION Compounds and Definitions Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.
  • each stereocenter 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. [0008] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • 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., C 1-6 ). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C 1-5 ). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C 1-4 ). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C 1-3 ), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C 1-2 ).
  • 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., C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 1- 3, or C 1-2 ).
  • 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 C 3 -C 8 hydrocarbon, or an optionally substituted C 7 -C 10 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., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ).
  • 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., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ).
  • 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., C 6-14 ), 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 ⁇ 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[1,2- a]pyrimidinyl, imidazo[1,2-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, 4H– quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)–one, and benzoisoxazolyl.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.
  • Heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized 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)).
  • 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.
  • 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.
  • a patient or subject displays one or more symptoms of a disorder or condition.
  • a patient or subject has been diagnosed with one or more disorders or conditions.
  • a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • Substituted or optionally substituted As described herein, compounds of this disclosure may contain “optionally substituted” moieties. In general, 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 refers to at least or Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes 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 ) 0–2 R ⁇ , –(haloR ⁇ ), –(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR ⁇ , –(CH 2 ) 0–2 CH(OR ⁇ ) 2 , -O(haloR ⁇ ), –CN, – N 3 , –(CH 2 ) 0–2 C(O)R ⁇ , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR ⁇ , –(CH 2 ) 0–2 SR ⁇ , –(CH 2 ) 0–2 SH, – (CH 2 ) 0–2 NH 2 , –(CH 2 ) 0
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2 ) 2–3 O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, – R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, 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(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , – C(O)CH 2 C(O)R ⁇ , -S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2, –C(S)NR ⁇ 2, –C(NH)NR ⁇ 2, or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 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
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, – R ⁇ , -(haloR ⁇ ), –OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or -NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, 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.
  • W is CR w or N;
  • X is CR x or N;
  • Y is CR y or N;
  • Z is –O- or –NR z -;
  • R w , R x , and R y are each independently hydrogen, halogen, -OR 1 , -N(R 1 ) 2 , -SR 1 , optionally substituted C 1-6 aliphatic, or –CN;
  • R z is hydrogen or optionally substituted C 1-6 aliphatic; each R 1 is independently hydrogen or optionally substituted C 1-6 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
  • the present disclosure provides a compound of Formula IB: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, R a , R x , and R y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IC: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, R a , R w , and R y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula ID:
  • the present disclosure provides a compound of Formula IE: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, R a , and R y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IF: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, R a , and R w are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0035] In some embodiments, the present disclosure provides a compound of Formula IG:
  • Ring A, Ring B, L, Z, R a , R w , R x , and R y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, W, X, Y, Z, and R a are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and: R b is hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -NO 2 , -C(O)R’, -C(O)OR, -C(O)N(R) 2 , - OC(O)R’, -OC(O)N(R) 2 , -OC(O)OR, -OSO 2 R, -OSO 2 N(R) 2 , -N(R)C(O)R’, -N(R)SO 2 R’, - SO 2 R’, -SO 2 N(R) 2 , -SO 3 R’, optionally substituted C 1-6
  • the present disclosure provides a compound of Formula III: or a pharmaceutically acceptable salt thereof, wherein Ring A, L, W, X, Y, Z, and R a are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and: R 2 is –N(R) 2 , –N(R)C(O)R’, –C(O)N(R) 2 , or –N(R)C(O)N(R) 2 ; each R is independently hydrogen, optionally substituted C 1-6 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 heterocycly
  • the present disclosure provides a compound of Formula IV: or a pharmaceutically acceptable salt thereof, wherein Ring A, L, W, X, Y, Z, and R a are as defined above for Formula I 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 B1 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
  • W is CR w . In some embodiments, W is N. [0040] In some embodiments of any of Formulae I, II, III, and IV, X is CR x . In some embodiments, X is N. [0041] In some embodiments of any of Formulae I, II, III, and IV, Y is CR y . In some embodiments, Y is N. [0042] In some embodiments of any of Formulae I, II, III, and IV, W is CR w or N, X is CR x or N, and Y is CR y or N, and at least one of W, X, and Y is N.
  • W is CR w or N
  • X is CR x or N
  • Y is CR y or N
  • one and only one of W, X, and Y is N.
  • W is CR w or N
  • X is CR x or N
  • Y is CR y or N, and no more than two of W, X, and Y is N.
  • Z is –O-.
  • Z is –NR z -.
  • Z is –NH-.
  • R w is hydrogen, halogen, or optionally substituted C 1-6 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 C 1-6 aliphatic.
  • Y is N, W is CR w , and R w is –OR 1 wherein R 1 is optionally substituted C 1-6 aliphatic.
  • R w is –N(R 1 ) 2 .
  • R w is –SR 1 .
  • R w is –SR 1 , wherein R 1 is optionally substituted C 1-6 aliphatic.
  • Y is N, W is CR w , and R w is – SR 1 wherein R 1 is optionally substituted C 1-6 aliphatic.
  • R w is optionally substituted C 1-6 aliphatic.
  • R w is optionally substituted straight-chain or branched C 1-6 aliphatic (i.e., optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R w is optionally substituted C 1-6 alkyl. In some embodiments, R w is optionally substituted C 1-4 alkyl. In some embodiments, R w is optionally substituted C 1-2 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, -CN, or optionally substituted C 1-6 aliphatic.
  • R x is hydrogen, -CN, or optionally substituted C 1-6 aliphatic.
  • R x is hydrogen, - CN, or optionally substituted C 1-6 alkyl.
  • R x is hydrogen or optionally substituted C 1-6 aliphatic.
  • R x is hydrogen or C 1-6 alkyl.
  • R x is hydrogen.
  • R x is halogen.
  • R x is fluoro. In some embodiments, R x is chloro. In some embodiments, R x is –OR 1 . In some embodiments, R x is –OR 1 , wherein R 1 is optionally substituted C 1-6 aliphatic. In some embodiments, R x is –N(R 1 ) 2 . In some embodiments, R x is –SR 1 . In some embodiments, R x is – SR 1 , wherein R 1 is optionally substituted C 1-6 aliphatic. In some embodiments, R x is optionally substituted C 1-6 aliphatic.
  • R x is optionally substituted straight-chain or branched C 1-6 aliphatic (i.e., optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R x is optionally substituted C 1-6 alkyl. In some embodiments, R x is optionally substituted C 1–4 alkyl. In some embodiments, R x is optionally substituted C 1-2 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 C 1-6 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 C 1-6 aliphatic.
  • W is N, Y is CR y , and R y is —OR 1 wherein R 1 is optionally substituted C 1-6 aliphatic.
  • R y is –N(R 1 ) 2 .
  • R y is –SR 1 .
  • R y is –SR 1 , wherein R 1 is optionally substituted C 1-6 aliphatic.
  • W is N, Y is CR y , and R y is –SR 1 wherein R 1 is optionally substituted C 1-6 aliphatic. In some embodiments, R y is optionally substituted C 1-6 aliphatic.
  • R y is optionally substituted straight-chain or branched C 1-6 aliphatic (i.e., optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R y is optionally substituted C 1-6 alkyl. In some embodiments, R y is optionally substituted C 1-4 alkyl. In some embodiments, R y is optionally substituted C 1-2 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. In some embodiments, R z is optionally substituted C 1-6 aliphatic. In some embodiments, R z is optionally substituted straight-chain or branched C 1-6 aliphatic (i.e., optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R z is optionally substituted C 1-6 alkyl. In some embodiments, R z is optionally substituted C 1–4 alkyl. In some embodiments, R z is unsubstituted C 1-4 alkyl.
  • R z is optionally substituted C 1-2 alkyl. In some embodiments, R z is unsubstituted C 1-2 alkyl.
  • each R 1 is independently hydrogen or optionally substituted C 1–4 aliphatic. In some embodiments, each R 1 is independently hydrogen or optionally substituted C 1-2 aliphatic. In some embodiments, each R 1 is hydrogen. In some embodiments, each R 1 is independently optionally substituted C 1-6 aliphatic.
  • each R 1 is independently optionally substituted straight-chain or branched C 1-6 aliphatic (i.e., optionally substituted acyclic C 1-6 aliphatic). In some embodiments, each R 1 is independently optionally substituted C 1-4 aliphatic. In some embodiments, each R 1 is independently optionally substituted straight-chain or branched C 1–4 aliphatic (i.e., optionally substituted acyclic C 1–4 aliphatic). In some embodiments, each R 1 is independently optionally substituted C 1-2 aliphatic. In some embodiments, each R 1 is independently hydrogen or C 1-6 alkyl. In some embodiments, each R 1 is independently hydrogen or C 1–4 alkyl.
  • each R 1 is independently hydrogen or C 1-2 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 , -NO 2 , -C(O)R°, - C(O)OR°, -C(O)NR° 2 , -OC(O)R°, -OC(O)NR° 2 , –OC(O)OR°, -OS(O) 2 R°, -OS(O) 2 NR° 2 , - N(R°)C(O)R°, -N(R°)S(O) 2 R°, -S(O) 2 R°, -SO 2 NR
  • 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 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 or pyridazinonyl. 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[1,5-a]pyridinyl.
  • Ring A is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0056] In some embodiments, Ring A is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted C 3-7 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.
  • 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. [0057] In some embodiments, 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.
  • 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. In some embodiments, 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.
  • 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 C 1-3 straight or branched hydrocarbon chain.
  • L is a bivalent C 1-2 straight or branched hydrocarbon chain.
  • L is methylene (i.e., -CH 2 -).
  • L is – CH 2 CH 2 -.
  • L is –CH 2 CH 2 CH 2 -. In some embodiments, L is a covalent bond or –CH 2 -.
  • R a is halogen, optionally substituted C 1-6 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 C 1-6 aliphatic, 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.
  • R a is optionally substituted C 1-6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, 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.
  • 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. [0063] In some embodiments, R a is optionally substituted C 1-6 aliphatic. In some embodiments, R a is optionally substituted straight-chain or branched C 1-6 aliphatic (i.e., optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R a is C 1-6 aliphatic optionally substituted with one or more -O(C 1-6 alkyl).
  • R a is optionally substituted C 1-6 alkyl. In some embodiments, R a is C 1-6 alkyl optionally substituted with one or more -O(C 1-6 alkyl). In some embodiments, R a is optionally substituted C 1-4 alkyl. In some embodiments, R a is C 1-4 alkyl optionally substituted with one or more -O(C 1-6 alkyl). In some embodiments, R a is –CH 3 , -CH 2 CH 2 OCH 3 , or -CH(CH 3 ) 2 . [0064] In some embodiments, 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.
  • R a is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl.
  • R a is 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl optionally substituted with one or more –OH.
  • R a is optionally substituted C 3 -C 6 cycloalkyl.
  • R a is C 3 -C 6 cycloalkyl optionally substituted with one or more –OH.
  • R a is optionally substituted C 3 cycloalkyl. In some embodiments, R a is optionally substituted C 4 cycloalkyl. In some embodiments, R a is C4 cycloalkyl optionally substituted with one or more –OH. In some embodiments, R a is optionally substituted C 5 cycloalkyl. In some embodiments, R a is optionally substituted C 6 cycloalkyl. In some embodiments, R a is optionally substituted C 7 cycloalkyl. [0067] In some embodiments, 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 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more –O(C 1-6 alkyl). In some embodiments, R a is optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more –O(C 1-6 alkyl).
  • R a is optionally substituted 3-membered saturated monocyclic heterocyclyl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is optionally substituted 4-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 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 optionally substituted with one or more –O(C 1-6 alkyl).
  • 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 tetrahydropyranyl. In some embodiments, R a is optionally substituted 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0068] In some embodiments, 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.
  • 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. [0069] In some embodiments, R a is selected from the group consisting of: . [0070] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, is –R a (i.e., L is a covalent bond).
  • is –(C 1-3 alkylene)-R a i.e., L is a C 1-3 straight or branched hydrocarbon chain).
  • is –(C 1- 2 alkylene)-R a i.e., L is a C 1-2 straight or branched hydrocarbon chain).
  • is —CH 2 -R a i.e., L is a C 1 hydrocarbon chain).
  • is – CH 2 CH 2 -R a i.e., L is a C 2 straight hydrocarbon chain).
  • is – CH 2 CH 2 CH 2 -R a i.e., L is a C 3 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 , -NO 2 , -C(O)R’, -C(O)OR, -C(O)N(R) 2 , - OC(O)R’, -OC(O)N(R) 2 , -OC(O)OR, -OSO 2 R, -OSO 2 N(R) 2 , -N(R)C(O)R’, -N(R)SO 2 R’, - SO 2 R’, -SO 2 N(R) 2 , -SO 3 R’, optionally substituted C 1-6 aliphatic, optionally substituted 3- to 6- membered saturated or partially unsatur
  • each occurrence of R b is independently optionally substituted C 1-6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each occurrence of R b is independently optionally substituted C 1-4 alkyl, optionally substituted C 3 -C 4 cycloalkyl, or optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each occurrence of R b is independently C 1-4 alkyl optionally substituted with one or more halogen, C 3 -C 4 cycloalkyl, or 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each occurrence of R b is independently C 3-4 cycloalkyl or C 1–4 alkyl optionally substituted with one or more halogen. [0072] In some embodiments, R b is hydrogen. [0073] In some embodiments, R b is halogen. In some embodiments, R b is fluoro, chloro, bromo, or iodo. In some embodiments, R b is fluoro.
  • R b is chloro.
  • R b is -CN, -OR, -SR, -N(R) 2 , -NO 2 , -C(O)R’, -C(O)OR, - C(O)N(R) 2 , -OC(O)R’, -OC(O)N(R) 2 , -OC(O)OR, -OSO 2 R, -OSO 2 N(R) 2 , -N(R)C(O)R’, - N(R)SO 2 R’, -SO 2 R, -SO 2 N(R) 2 , or -SO 3 R’.
  • R b is optionally substituted C 1-6 aliphatic. In some embodiments, R b is optionally substituted straight-chain or branched C 1-6 aliphatic (i.e., optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R b is optionally substituted C 1-6 alkyl. In some embodiments, R b is optionally substituted C 1–4 alkyl. In some embodiments, R b is C 1–4 alkyl optionally substituted with one or more halogen. In some embodiments, R b is selected from the group consisting of –CH 3 , –CF 3 , and –C(CH 3 ) 3 .
  • R b is optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R b is optionally substituted C 3 -C 6 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.
  • 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.
  • R b is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R b is optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is pyrazolyl. In some embodiments, R b is optionally substituted 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • 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 , -NO 2 , -C(O)R°, -C(O)OR°, -C(O)NR° 2
  • 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(O)NR° 2 , -N(R°)C(O)R°, and -N(R°)C(O)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(O)NR° 2 , -N(R°)C(O)R°, and -N(R°)C(O)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.
  • Ring B is optionally substituted 9- to 10-membered bicyclic aryl.
  • Ring B is optionally substituted 9-membered bicyclic aryl (e.g., a 5-membered carbocycle fused to a phenyl ring).
  • 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. [0090] In some embodiments, 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.
  • 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. [0091] In some embodiments, Ring B is optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0092] In some embodiments, Ring B is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring B is optionally substituted C 3-7 cycloalkyl.
  • 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.
  • Ring B is optionally substituted 3- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 5-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 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. [0095] In some embodiments, Ring B is optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • 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. In some embodiments, Ring B is optionally substituted 9-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B is optionally substituted 10-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0096] In some embodiments, Ring B is optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0097] In some embodiments, Ring B is , wherein R 2 is as defined in Formula III and described in classes and subclasses herein, both singly and in combination.
  • Ring B is [0099] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, R 2 is –N(R)C(O)R’, –C(O)N(R) 2 , or –N(R)C(O)N(R) 2 , wherein R and R’ are as defined in Formula III and described in classes and subclasses herein, both singly and in combination. In some embodiments, R 2 is –N(R)C(O)R’ or –C(O)N(R) 2 . [0100] In some embodiments, R 2 is –N(R)C(O)R’.
  • R 2 is – N(H)C(O)R’. In some embodiments, R 2 is –N(R)C(O)(optionally substituted C 1-6 aliphatic). In some embodiments, R 2 is –N(H)C(O)(optionally substituted C 1-6 aliphatic). In some embodiments, R 2 is –N(R)C(O)(C 1-6 aliphatic). In some embodiments, R 2 is –N(H)C(O)(C 1-6 aliphatic). In some embodiments, R 2 is –N(R)C(O)(straight-chain or branched C 1-6 aliphatic).
  • R 2 is –N(H)C(O)(straight-chain or branched C 1-6 aliphatic). In some embodiments, R 2 is –N(R)C(O)(optionally substituted C 1-6 alkyl). In some embodiments, R 2 is – N(H)C(O)(optionally substituted C 1-6 alkyl). In some embodiments, R 2 is –N(R)C(O)(C 1-6 alkyl). In some embodiments, R 2 is –N(H)C(O)(C 1-6 alkyl). In some embodiments, R 2 is – N(R)C(O)(optionally substituted C 1-4 alkyl).
  • R 2 is –N(H)C(O)(optionally substituted C 1–4 alkyl). In some embodiments, R 2 is –N(R)C(O)(C 1–4 alkyl). In some embodiments, R 2 is –N(H)C(O)(C 1–4 alkyl). In some embodiments, R 2 is –N(R)C(O)(optionally substituted C 1-2 alkyl). In some embodiments, R 2 is –N(H)C(O)(optionally substituted C 1-2 alkyl). In some embodiments, R 2 is –N(R)C(O)(C 1-2 alkyl).
  • R 2 is – N(H)C(O)(C 1-2 alkyl). In some embodiments, R 2 is –N(R)C(O)CH 3 . In some embodiments, R 2 is –N(H)C(O)CH 3 . In some embodiments, R 2 is –N(R)C(O)(optionally substituted C 3-7 carbocyclyl). In some embodiments, R 2 is –N(H)C(O)(optionally substituted C 3-7 carbocyclyl). In some embodiments, R 2 is –N(R)C(O)(optionally substituted C 3-7 cycloalkyl).
  • R 2 is –N(H)C(O)(optionally substituted C 3-7 cycloalkyl). In some embodiments, R 2 is –N(R)C(O)(C 3-6 cycloalkyl). In some embodiments, R 2 is –N(H)C(O)(C 3-6 cycloalkyl). [0101] In some embodiments, R 2 is –C(O)N(R) 2 . In some embodiments, R 2 is – C(O)N(R)(C 1-6 aliphatic). In some embodiments, R 2 is –C(O)N(H)(C 1-6 aliphatic).
  • R 2 is –C(O)N(R)(straight-chain or branched C 1-6 aliphatic). In some embodiments, R 2 is –C(O)N(H)(straight-chain or branched C 1-6 aliphatic). In some embodiments, R 2 is –C(O)N(R)(C 1-6 alkyl). In some embodiments, R 2 is –C(O)N(H)(C 1-6 alkyl). In some embodiments, R 2 is –C(O)N(R)(C 1–4 alkyl). In some embodiments, R 2 is – C(O)N(H)(C 1-4 alkyl).
  • R 2 is –C(O)N(R)(C 1-2 alkyl). In some embodiments, R 2 is –C(O)N(H)(C 1-2 alkyl). [0102] In some embodiments, R 2 is –N(R) 2 . In some embodiments, R 2 is –N(H)(R). [0103] In some embodiments, R 2 is –N(R)C(O)N(R) 2 .
  • R 2 is – N(R)C(O)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(O)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(O)N(R) 2 .
  • R 2 is –N(H)C(O)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(O)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 C 1-6 aliphatic.
  • R is hydrogen.
  • R is optionally substituted C 1-6 aliphatic.
  • R is optionally substituted straight-chain or branched C 1-6 aliphatic (i.e., optionally substituted acyclic C 1-6 aliphatic).
  • R is optionally substituted C 1-6 alkyl.
  • R is optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl.
  • 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.
  • 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 C 1-6 aliphatic.
  • R’ is optionally substituted straight-chain or branched C 1-6 aliphatic (i.e., optionally substituted acyclic C 1-6 aliphatic). In some embodiments, R’ is optionally substituted C 1-6 alkyl. In some embodiments, R’ is optionally substituted C 1-4 alkyl. In some embodiments, R’ is unsubstituted C 1-4 alkyl. In some embodiments, R’ is optionally substituted C 1-2 alkyl. In some embodiments, R’ is unsubstituted C 1-2 alkyl. In some embodiments, R’ is methyl. In some embodiments, R’ is 3- to 7-membered saturated or partially unsaturated carbocyclyl.
  • R’ is optionally substituted C 3-6 cycloalkyl.
  • Ring B is , wherein Ring B1 and Ring B2 are defined as in Formula IV 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.
  • 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.
  • 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. [0110] In some embodiments, Ring B1 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl.
  • Ring B1 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. [0111] In some embodiments, 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 B1 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. In some embodiments, Ring B1 is optionally substituted 5- to 6-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0112] In some embodiments, 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. [0114] In some embodiments, 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.
  • 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. In some embodiments, Ring B3, when not fused to an aromatic Ring B2, is 3- to 7-membered saturated monocyclic carbocyclyl. In some embodiments, Ring B3 is 3- to 7-membered partially saturated monocyclic carbocyclyl. In some embodiments, 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.
  • Ring B3 is 3- to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0120] In some embodiments, the present disclosure provides compounds selected from Table 1: or a pharmaceutically acceptable salt thereof.
  • 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.
  • biochemical or cellular assays e.g., the JAK2 Binding Assay or SET2-pSTAT5 Cellular Assay described herein
  • ADME absorption, distribution, metabolism, and excretion
  • plasma protein binding profiles e.g.,
  • 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 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, Ring B, L, W, X, Y, and R a are as defined above for Formula I 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, Ring B, L, W, X, Y, and R a are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • intermediate A.3 is prepared by a process comprising contacting intermediate A.1 with intermediate A.2 in the presence of a suitable base (e.g., Cs 2 CO 3 or NaOH).
  • a suitable base e.g., Cs 2 CO 3 or NaOH.
  • compound A is prepared by a process comprising contacting intermediate A.3 with intermediate A.4 in the presence of a suitable base (e.g., NaH, K 3 PO 4 , or Cs 2 CO 3 ).
  • compound A is prepared by a process comprising contacting intermediate A.3 with intermediate A.4 in the presence of a suitable base (e.g., NaH, K 3 PO 4 , or Cs 2 CO 3 ), a suitable metal complex (e.g., CuI), and optionally a suitable ligand (e.g., picolinic acid).
  • a suitable base e.g., NaH, K 3 PO 4 , or Cs 2 CO 3
  • a suitable metal complex e.g., CuI
  • a suitable ligand e.g., picolinic acid
  • provided compounds are prepared according to the following Scheme: wherein LG is a suitable leaving (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, W, X, Y, and R a are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • LG is a suitable leaving (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, W, X, Y, and R a are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • intermediate B.2 is prepared by a process comprising contacting intermediate B.1 with thiophosgene in the presence of a suitable base (e.g., NaHCO 3 ).
  • compound B is prepared by a process comprising contacting intermediate B.2 with intermediate B.3 in the presence of a suitable base (e.g., Cs 2 CO 3 or NaH).
  • a suitable base e.g., Cs 2 CO 3 or NaH.
  • provided compounds e.g., compounds of Formula I wherein Z is –NH-
  • LG is a suitable leaving (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, W, X, Y, and R a are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • compound C is prepared by a process comprising contacting intermediate C.1 with intermediate C.2 in the presence of a suitable base (e.g., Cs 2 CO 3 or NaH).
  • a suitable base e.g., Cs 2 CO 3 or NaH.
  • provided compounds e.g., compounds of Formula I
  • LG is a suitable leaving (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, W, X, Y, Z, and R a are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • compound D is prepared by a process comprising contacting intermediate D.1 with intermediate D.2 in the presence of a suitable base.
  • compound D is prepared by a process comprising contacting intermediate D.1 with intermediate D.2 in the presence of a suitable base, a suitable metal complex (e.g., a palladium complex), and optionally a suitable ligand.
  • a suitable metal complex e.g., a palladium complex
  • 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, Ring B, L, W, X, Y, and R a are as defined above for Formula I 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, Ring B, L, W, X, Y, and R a are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • intermediate E.3 is prepared by a process comprising contacting intermediate E.1 with intermediate E.2 in the presence of a suitable base.
  • compound E is prepared by a process comprising contacting intermediate E.3 with intermediate E.4 in the presence of a suitable base.
  • compound E is prepared by a process comprising contacting intermediate E.3 with intermediate E.4 in the presence of a suitable base, a suitable metal complex, and optionally a suitable ligand.
  • a provided compound is obtained by a process comprising a purification method described in the Examples section. In some such embodiments, a compound is the 1 st 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 I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV).
  • a provided composition is a pharmaceutical composition that comprises and/or delivers a compound provided herein (e.g., compounds of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV) 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.
  • Provided pharmaceutical 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. [0133] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage.
  • the expression “unit dosage form” as used herein 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.
  • 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. [0137] 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.
  • 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).
  • JAK-STAT3 pathway Jaffer, T., Ma, D. Transl. Cancer Res.2016, 5(Suppl.4), S616-S628).
  • EXAMPLES [0144] As described in the Examples below, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
  • Compounds 1.3 and/or 1.4 can also be used to prepare compounds I-11, I-12, I-18, I- 27, and I-32 using methods described herein.
  • Example 2 N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)amino)thiazolo[4,5-c]pyridin-6-yl)oxy)pyridin-2-yl)acetamide
  • Int-1 and/or Int-1.4 can be used to prepare compounds I-7, I-17, I-19, and I-30 using methods described herein.
  • Int-6 was prepared from Int-6.5, following the procedure described in the synthesis of Int-4. The product was used without purification. MS(ES): m/z 208.3 [M+H] + . [0207] Int-6 and/or Int-6.5 can be used to prepare compounds I-10 and I-15 using methods described herein. Preparation of Intermediate Int-7: 2-isothiocyanato-4,4-dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine [0208] Synthesis of compound Int-7.2.
  • reaction mixture was stirred for 5 min followed by addition of acetonitrile (2.5 mL, 48.37 mmol, 1.0 equiv).
  • acetonitrile 2.5 mL, 48.37 mmol, 1.0 equiv.
  • the reaction mixture stirred for 10 min and compound Int-7.3 (6.20 g, 48.37 mmol, 1.0 equiv) in THF (30 mL) was added to it.
  • the reaction mixture was stirred at 5 °C for 6 h. It was poured over cold saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Int-7 and/or Int-7.5 can be used to prepare compounds I-21 and I-36 using methods described herein.
  • Int-9 and/or Int-9.2 can be used to prepare compounds I-25 and I-26 using methods described herein.
  • Int-12 and/or Int-12.2 can be used to prepare compounds I-33 and I-35 using methods described herein.
  • Synthesis of compound Int-13.1 To a solution of 3-(benzyloxy)cyclobutan-1-one (10 g, 56.75 mmol, 1.0 equiv) in methanol (100 mL) was added sodium borohydride (6.4 g, 170.2 mmol, 3.0 equiv) in small portions at 0 °C.
  • JAK2 binding Assay JAK2 (JH1domain-catalytic, Y1007F,Y1008F) kinase was expressed as N-terminal fusion to the DNA binding domain of NFkB in transiently transfected HEK293 cells and subsequently tagged with DNA for qPCR detection. 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 1x binding buffer (1x PBS, 0.05% Tween 20, 0.1% BSA, 1 mmol/L DTT). Test compound was prepared as 111x 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.
  • JAK Family Selectivity Assays Provided compounds are evaluated for selectivity by comparing their JAK2 binding affinity (K d ) in the above JAK2 Binding Assay with their binding affinity (K d ) for one or more other kinases. 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.
  • blocking buffer SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT
  • Binding reactions are assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT).
  • Test compounds are prepared as 111X 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 (1x PBS, 0.05% Tween 20). The beads are then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 ⁇ M non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes.
  • the kinase concentration in the eluates is measured by qPCR. 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.
  • SET2-pSTAT5 Cellular 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 ⁇ L 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% CO 2 incubator for 4 hours.
  • the cells are spun, and the cell pellets are re-suspended with 100 ⁇ L cold PBS. Then, the cells are spun again at 4 °C and 4000 rpm for 5 min. PBS is aspirated, and 25 ⁇ L 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.
  • lysis buffer with protease and phosphatase inhibitor cocktail
  • MSD Meso-scale discovery
  • PBS 40 ⁇ L/well
  • 1x MSD Wash Buffer Tris-buffered saline with 0.1% Tween® 20 detergent, TBST
  • the MSD plates are then blocked with 150 ⁇ L 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 ⁇ L/well of 1x MSD Wash Buffer (TBST).
  • Sample lysates are then added to MSD plates (25 ⁇ L/well) and shaken for 1 h at room temperature and 600 rpm.
  • the MSD plate is washed three times with 150 ⁇ L/well of 1x MSD Wash Buffer (TBST).
  • Detection antibody prepared in Antibody Detection buffer, 1% BSA in 1xTBST 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 ⁇ L/well of 1x MSD Wash Buffer (TBST).
  • a secondary detection antibody (prepared in Antibody Detection buffer, 1% BSA in 1xTBST) 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 ⁇ L/well of 1x MSD Wash Buffer (TBST).
  • MSD reading buffer (1x) is added to the plates (150 ⁇ L/well), and they are diluted from 4x with water.
  • the plates are imaged using an MSD imaging instrument according to the manufacturer’s instructions.
  • Caco2 Permeability Assay [0248] Preparation of Caco-2 Cells: 50 ⁇ L and 25 mL of cell culture medium are added to each well of a Transwell® insert and reservoir, respectively.
  • HTS Transwell® plates are incubated at 37 °C, 5% CO 2 for 1 hour before cell seeding.
  • Caco-2 cell cells are diluted to 6.86 ⁇ 105 cells/mL with culture medium, and 50 ⁇ L 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% CO 2 , 95% relative humidity. Cell culture medium is replaced every other day, beginning no later than 24 hours after initial plating.
  • Preparation of Stock Solutions 10 mM stock solutions of test compounds are prepared in DMSO.
  • the stock solutions of positive controls are prepared in DMSO at the concentration of 10 mM.
  • TEER Transepithelial electrical resistance
  • TEER Transepithelial electrical resistance across the monolayer
  • the Plate is returned to the incubator once the measurement is done.
  • a TEER value greater than 230 ohm•cm 2 indicates a well-qualified Caco-2 monolayer.
  • 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 ⁇ M 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 ⁇ M working solutions.
  • the final concentration of DMSO in the incubation system is 0.5%.
  • Time 0 samples are prepared by transferring 50 ⁇ L of 5 ⁇ M working solution to wells of the 96-deepwell plate, followed by the addition of 200 ⁇ L cold methanol containing appropriate internal standards (IS). The plates are incuabted at 37 °C for 2 hours. At the end of the incubation, 50 ⁇ L 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).
  • 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 ⁇ L 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% CO 2 incubator overnight.
  • Test compounds are dissolved at 10 mM DMSO stock solution.45 ⁇ L of stock solution is then transferred to a 384 PP-plate.
  • a 3-fold, 10-point dilution is performed via transferring 15 ⁇ L compound into 30 ⁇ L DMSO by using TECAN (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.
  • Hepatocyte Stability Assay 10 mM stock solutions of test compound and positive control are prepared in DMSO. Stock solutions are diluted to 100 ⁇ M by combining 198 ⁇ L of 50% acetonitrile/50% water and 2 ⁇ L 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 ⁇ 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 0.5 ⁇ 106 viable cells/mL.
  • a portion of the hepatocytes at 0.5 ⁇ 106 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 ⁇ L hepatocytes are dispensed into each well of a 96-well non-coated plate. The plate is placed in the incubator for approximately 10 minutes.
  • test compounds are calculated as follows, wherein INJ VOL is injection volume, DF is dilution factor, and STD is standard: Plasma Protein Binding Assay [0255]
  • Working solutions of test compounds and control compound are prepared in DMSO at the concentration of 200 ⁇ M, and then the working solutions are spiked into plasma. The final concentration of compound is 1 ⁇ M. 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 ⁇ L of plasma sample and dialyzed against equal volume of dialysis buffer (PBS).
  • PBS dialysis buffer
  • the assay is performed in duplicate.
  • the dialysis plate is sealed and incubated in an incubator at 37 °C with 5% CO 2 at 100 rpm for 6 hours.
  • 50 ⁇ L of samples from both buffer and plasma chambers are transferred to wells of a 96-well plate.
  • 50 ⁇ L of plasma is added to each buffer samples and an equal volume of PBS is supplemented to the collected plasma sample.

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Abstract

The present disclosure provides heteroaryloxy thiazolo azine compounds and compositions thereof useful for inhibiting JAK2.

Description

HETEROARYLOXY THIAZOLO AZINES AS JAK2 INHIBITORS RELATED APPLICATIONS [0001] This application claims priority to and benefit of U.S. Application No.63/226,888, filed July 29, 2021, the entire contents of which are hereby incorporated by reference. BACKGROUND [0002] Janus kinase 2 (JAK2) 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. For example, essentially all BCR-ABL1-negative myeloproliferative neoplasms are associated with mutations that activate JAK2. In particular, JAK2V617F is the most prevalent mutation in myeloproliferative neoplasms, occurring in approx. 70% of all patients, and in up to 95% of patients with polycythemia vera. (Vainchenker, W., Kralovics, R. Blood 2017, 129(6):667-79). Even less common mutations, such as in MPL and CALR, have been shown to effect activation of JAK2, thereby initiating and/or driving disease progression. (Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev):82). Furthermore, polymorphisms in JAK2 have been linked to various autoimmune diseases and inflammatory conditions, such as psoriasis and inflammatory bowel disease. (O’Shea, J. J. et al., Ann. Rheum. Dis. 2013 Apr, 72:ii111-ii115). Increased signaling through JAK2, as well as other members of the JAK family, is also associated with atopic dermatitis. (Rodrigues, M. A. and Torres, T. J. Derm. Treat. 2019, 31(1):33-40). [0003] Inhibitors of JAKs (e.g., JAK2) 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, on the other hand, 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). SUMMARY [0004] The present disclosure provides compounds useful for inhibiting JAK2. In some embodiments, provided compounds are useful for, among other things, treating and/or preventing diseases, disorders, or conditions associated with JAK2. [0005] In some embodiments, the present disclosure provides a compound of Formula I:
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, W, X, Y, Z, and Ra are as defined herein. DETAILED DESCRIPTION Compounds and Definitions [0006] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0007] Unless otherwise stated, 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. For example, 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. For example, in some case, 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. [0008] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by 13C- or 14C-enriched carbon, are within the scope of this disclosure. [0009] Aliphatic: The term “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. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C1-6). In some embodiments, 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. In some embodiments, “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. [0010] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, 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., C1-12, C1-10, C1-8, C1-6, C1-4, C1- 3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl. [0011] 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. In some embodiments, “carbocyclyl” (or “cycloaliphatic”) 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. The term “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. [0012] Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, 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). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. [0013] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, 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. [0014] Aryl: The term “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”. In some embodiments, “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. [0015] Heteroaryl: The terms “heteroaryl” and “heteroar–”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer 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 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Exemplary 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[1,2- a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. The terms “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, 4H– quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)–one, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted. [0016] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. [0017] 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. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-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. Examples of such 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)). [0018] Partially Unsaturated: As used herein, the term “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. [0019] Patient or subject: As used herein, the term “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. [0020] Substituted or optionally substituted: As described herein, compounds of this disclosure may contain “optionally substituted” moieties. In general, 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.,
Figure imgf000008_0001
refers to at least
Figure imgf000008_0002
refers to at least
Figure imgf000008_0004
or
Figure imgf000008_0003
Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, 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. [0021] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4R°, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0– 4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; – C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; – OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; – SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; – C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; – S(O)2NR°2; -(CH2)0–4S(O)(NH)R°; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; – N(OR°)R°; –C(NH)NR°2; –P(O)2R°; -P(O)R°2; -OP(O)R°2; –OP(O)(OR°)2; –SiR°3; –(C1–4 straight or branched alkylene)O–N(R°)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1– 6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 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 a 3- to 12- membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. [0022] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms) are independently halogen, –(CH2)0–2R ●, –(haloR ●), –(CH2)0–2OH, –(CH2)0–2OR ●, –(CH2)0–2CH(OR ●)2, -O(haloR ●), –CN, – N3, –(CH2)0–2C(O)R ●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR ●, –(CH2)0–2SR ●, –(CH2)0–2SH, – (CH2)0–2NH2, –(CH2)0–2NHR ●, –(CH2)0–2NR ● 2, –NO2, –SiR ● 3, –OSiR ● 3, -C(O)SR ●, –(C1–4 straight or branched alkylene)C(O)OR ●, or –SSR ● wherein each R ● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S. [0023] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O (“oxo”), =S, =NNR* 2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R* 2))2–3O–, or –S(C(R* 2))2–3S–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 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. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR* 2)2–3O–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 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. [0024] Suitable substituents on the aliphatic group of R* include halogen, – R ●, -(haloR ●), -OH, –OR ●, –O(haloR ●), –CN, –C(O)OH, –C(O)OR ●, –NH2, –NHR ●, –NR ● 2, or –NO2, wherein each R ● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0025] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, – C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R† is independently hydrogen, C1–6 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. [0026] Suitable substituents on the aliphatic group of R† are independently halogen, – R ●, -(haloR ●), –OH, –OR ●, –O(haloR ●), –CN, –C(O)OH, –C(O)OR ●, –NH2, –NHR ●, –NR ● 2, or -NO2, wherein each R ● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0027] Treat: As used herein, the term “treat” (also “treatment” or “treating”) 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. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. Provided Compounds [0028] The present disclosure provides a compound of Formula I:
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof, wherein: W is CRw or N; X is CRx or N; Y is CRy or N; Z is –O- or –NRz-; Rw, Rx, and Ry are each independently hydrogen, halogen, -OR1, -N(R1)2, -SR1, optionally substituted C1-6 aliphatic, or –CN; Rz is hydrogen or optionally substituted C1-6 aliphatic; each R1 is independently hydrogen or optionally substituted C1-6 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 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; L is a covalent bond or a bivalent C1-3 straight or branched hydrocarbon chain; and Ra is hydrogen, halogen, optionally substituted C1-6 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. [0029] In some embodiments, the present disclosure provides a compound of Formula IA:
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, Ra, Rw, and Rx are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0030] In some embodiments, the present disclosure provides a compound of Formula IB:
Figure imgf000013_0002
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, Ra, Rx, and Ry are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0031] In some embodiments, the present disclosure provides a compound of Formula IC:
Figure imgf000013_0003
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, Ra, Rw, and Ry are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0032] In some embodiments, the present disclosure provides a compound of Formula ID:
Figure imgf000014_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, Ra, and Rx are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0033] In some embodiments, the present disclosure provides a compound of Formula IE:
Figure imgf000014_0002
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, Ra, and Ry are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0034] In some embodiments, the present disclosure provides a compound of Formula IF:
Figure imgf000014_0003
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, Ra, and Rw are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0035] In some embodiments, the present disclosure provides a compound of Formula IG:
Figure imgf000015_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, Ra, Rw, Rx, and Ry are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0036] In some embodiments, the present disclosure provides a compound of Formula II:
Figure imgf000015_0002
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, W, X, Y, Z, and Ra are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and: Rb is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, - OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)SO2R’, - SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6 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, and sulfur; each R is independently hydrogen, optionally substituted C1-6 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 C1-6 aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl. [0037] In some embodiments, the present disclosure provides a compound of Formula III:
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof, wherein Ring A, L, W, X, Y, Z, and Ra are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and: R2 is –N(R)2, –N(R)C(O)R’, –C(O)N(R)2, or –N(R)C(O)N(R)2; each R is independently hydrogen, optionally substituted C1-6 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 C1-6 aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl. [0038] In some embodiments, the present disclosure provides a compound of Formula IV:
Figure imgf000016_0002
or a pharmaceutically acceptable salt thereof, wherein Ring A, L, W, X, Y, Z, and Ra are as defined above for Formula I 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 B1 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. [0039] In some embodiments of any of Formulae I, II, III, and IV, W is CRw. In some embodiments, W is N. [0040] In some embodiments of any of Formulae I, II, III, and IV, X is CRx. In some embodiments, X is N. [0041] In some embodiments of any of Formulae I, II, III, and IV, Y is CRy. In some embodiments, Y is N. [0042] In some embodiments of any of Formulae I, II, III, and IV, W is CRw or N, X is CRx or N, and Y is CRy or N, and at least one of W, X, and Y is N. In some embodiments, W is CRw or N, X is CRx or N, and Y is CRy or N, and one and only one of W, X, and Y is N. In some embodiments, W is CRw or N, X is CRx or N, and Y is CRy or N, and no more than two of W, X, and Y is N. [0043] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, Z is –O-. In some embodiments, Z is –NRz-. In some embodiments, Z is –NH-. [0044] In some embodiments of any of Formulae I, IA, IC, IF, IG, II, III, and IV, Rw is hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, Rw is hydrogen. In some embodiments, Rw is halogen. In some embodiments, Rw is fluoro. In some embodiments, Rw is chloro. In some embodiments, Rw is –OR1. In some embodiments, Rw is – OR1, wherein R1 is optionally substituted C1-6 aliphatic. In some embodiments, Y is N, W is CRw, and Rw is –OR1 wherein R1 is optionally substituted C1-6 aliphatic. In some embodiments, Rw is –N(R1)2. In some embodiments, Rw is –SR1. In some embodiments, Rw is –SR1, wherein R1 is optionally substituted C1-6 aliphatic. In some embodiments, Y is N, W is CRw, and Rw is – SR1 wherein R1 is optionally substituted C1-6 aliphatic. In some embodiments, Rw is optionally substituted C1-6 aliphatic. In some embodiments, Rw is optionally substituted straight-chain or branched C1-6 aliphatic (i.e., optionally substituted acyclic C1-6 aliphatic). In some embodiments, Rw is optionally substituted C1-6 alkyl. In some embodiments, Rw is optionally substituted C1-4 alkyl. In some embodiments, Rw is optionally substituted C1-2 alkyl. In some embodiments, Rw is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, Rw is –CN. [0045] In some embodiments of any of Formulae I, IA, IB, ID, IG, II, III, and IV, Rx is hydrogen, halogen, -CN, or optionally substituted C1-6 aliphatic. In some embodiments, Rx is hydrogen, -CN, or optionally substituted C1-6 aliphatic. In some embodiments, Rx is hydrogen, - CN, or optionally substituted C1-6 alkyl. In some embodiments, Rx is hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, Rx is hydrogen or C1-6 alkyl. In some embodiments, Rx is hydrogen. In some embodiments, Rx is halogen. In some embodiments, Rx is fluoro. In some embodiments, Rx is chloro. In some embodiments, Rx is –OR1. In some embodiments, Rx is –OR1, wherein R1 is optionally substituted C1-6 aliphatic. In some embodiments, Rx is –N(R1)2. In some embodiments, Rx is –SR1. In some embodiments, Rx is – SR1, wherein R1 is optionally substituted C1-6 aliphatic. In some embodiments, Rx is optionally substituted C1-6 aliphatic. In some embodiments, Rx is optionally substituted straight-chain or branched C1-6 aliphatic (i.e., optionally substituted acyclic C1-6 aliphatic). In some embodiments, Rx is optionally substituted C1-6 alkyl. In some embodiments, Rx is optionally substituted C1–4 alkyl. In some embodiments, Rx is optionally substituted C1-2 alkyl. In some embodiments, Rx is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, Rx is –CN. [0046] In some embodiments of any of Formulae I, IB, IC, IE, IG, II, III, and IV, Ry is hydrogen, halogen, or optionally substituted C1-6 aliphatic. In some embodiments, Ry is hydrogen. In some embodiments, Ry is halogen. In some embodiments, Ry is fluoro. In some embodiments, Ry is chloro. In some embodiments, Ry is –OR1. In some embodiments, Ry is – OR1, wherein R1 is optionally substituted C1-6 aliphatic. In some embodiments, W is N, Y is CRy, and Ry is –OR1 wherein R1 is optionally substituted C1-6 aliphatic. In some embodiments, Ry is –N(R1)2. In some embodiments, Ry is –SR1. In some embodiments, Ry is –SR1, wherein R1 is optionally substituted C1-6 aliphatic. In some embodiments, W is N, Y is CRy, and Ry is –SR1 wherein R1 is optionally substituted C1-6 aliphatic. In some embodiments, Ry is optionally substituted C1-6 aliphatic. In some embodiments, Ry is optionally substituted straight-chain or branched C1-6 aliphatic (i.e., optionally substituted acyclic C1-6 aliphatic). In some embodiments, Ry is optionally substituted C1-6 alkyl. In some embodiments, Ry is optionally substituted C1-4 alkyl. In some embodiments, Ry is optionally substituted C1-2 alkyl. In some embodiments, Ry is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, Ry is –CN. [0047] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, Rz is hydrogen. In some embodiments, Rz is optionally substituted C1-6 aliphatic. In some embodiments, Rz is optionally substituted straight-chain or branched C1-6 aliphatic (i.e., optionally substituted acyclic C1-6 aliphatic). In some embodiments, Rz is optionally substituted C1-6 alkyl. In some embodiments, Rz is optionally substituted C1–4 alkyl. In some embodiments, Rz is unsubstituted C1-4 alkyl. In some embodiments, Rz is optionally substituted C1-2 alkyl. In some embodiments, Rz is unsubstituted C1-2 alkyl. [0048] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, each R1 is independently hydrogen or optionally substituted C1–4 aliphatic. In some embodiments, each R1 is independently hydrogen or optionally substituted C1-2 aliphatic. In some embodiments, each R1 is hydrogen. In some embodiments, each R1 is independently optionally substituted C1-6 aliphatic. In some embodiments, each R1 is independently optionally substituted straight-chain or branched C1-6 aliphatic (i.e., optionally substituted acyclic C1-6 aliphatic). In some embodiments, each R1 is independently optionally substituted C1-4 aliphatic. In some embodiments, each R1 is independently optionally substituted straight-chain or branched C1–4 aliphatic (i.e., optionally substituted acyclic C1–4 aliphatic). In some embodiments, each R1 is independently optionally substituted C1-2 aliphatic. In some embodiments, each R1 is independently hydrogen or C1-6 alkyl. In some embodiments, each R1 is independently hydrogen or C1–4 alkyl. In some embodiments, each R1 is independently hydrogen or C1-2 alkyl. [0049] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, 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(O)R°, - C(O)OR°, -C(O)NR°2, -OC(O)R°, -OC(O)NR°2, –OC(O)OR°, -OS(O)2R°, -OS(O)2NR°2, - N(R°)C(O)R°, -N(R°)S(O)2R°, -S(O)2R°, -SO2NR°2, and -S(O)2OR°, and (ii) optionally substituted on a substitutable nitrogen atom with one or more groups selected from –R†, –NR† 2, – C(O)R†, –C(O)OR†, -S(O)2R†, and -S(O)2NR†2. In some embodiments, 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†. In some embodiments, 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†. [0050] In some embodiments, Ring A is optionally substituted with one or more Rb (i.e., in addition to being substituted with –L-Ra), wherein Rb is as defined in Formula II above and described in classes and subclasses herein. In some embodiments, Ring A is substituted with zero, one, two, three, four, or five Rb, as valency allows. [0051] In some embodiments, 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.
[0052] In some embodiments, 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.
[0053] In some embodiments, Ring A is optionally substituted phenyl.
[0054] In some embodiments, 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. In some embodiments, 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 or pyridazinonyl. In some embodiments, Ring A is optionally substituted pyridonyl.
[0055] In some embodiments, 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[1,5-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. [0056] In some embodiments, 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. [0057] In some embodiments, 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. In some embodiments, 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. [0058] In some embodiments, 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. [0059] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, L is a covalent bond. In some embodiments, L is a bivalent C1-3 straight or branched hydrocarbon chain. In some embodiments, L is a bivalent C1-2 straight or branched hydrocarbon chain. In some embodiments, L is methylene (i.e., -CH2-). In some embodiments, L is – CH2CH2-. In some embodiments, L is –CH2CH2CH2-. In some embodiments, L is a covalent bond or –CH2-. [0060] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, Ra is halogen, optionally substituted C1-6 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. In some embodiments, Ra is optionally substituted C1-6 aliphatic, 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. In some embodiments, Ra is optionally substituted C1-6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0061] In some embodiments, Ra is hydrogen. In some embodiments, Ra is not hydrogen. [0062] In some embodiments, Ra is halogen. In some embodiments, Ra is fluoro, chloro, bromo, or iodo. In some embodiments, Ra is fluoro. In some embodiments, Ra is chloro. [0063] In some embodiments, Ra is optionally substituted C1-6 aliphatic. In some embodiments, Ra is optionally substituted straight-chain or branched C1-6 aliphatic (i.e., optionally substituted acyclic C1-6 aliphatic). In some embodiments, Ra is C1-6 aliphatic optionally substituted with one or more -O(C1-6 alkyl). In some embodiments, Ra is optionally substituted C1-6 alkyl. In some embodiments, Ra is C1-6 alkyl optionally substituted with one or more -O(C1-6 alkyl). In some embodiments, Ra is optionally substituted C1-4 alkyl. In some embodiments, Ra is C1-4 alkyl optionally substituted with one or more -O(C1-6 alkyl). In some embodiments, Ra is –CH3, -CH2CH2OCH3, or -CH(CH3)2. [0064] In some embodiments, Ra is optionally substituted phenyl. [0065] In some embodiments, Ra is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0066] In some embodiments, Ra is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ra is 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl optionally substituted with one or more –OH. In some embodiments, Ra is optionally substituted C3-C6 cycloalkyl. In some embodiments, Ra is C3-C6 cycloalkyl optionally substituted with one or more –OH. In some embodiments, Ra is optionally substituted C3 cycloalkyl. In some embodiments, Ra is optionally substituted C4 cycloalkyl. In some embodiments, Ra is C4 cycloalkyl optionally substituted with one or more –OH. In some embodiments, Ra is optionally substituted C5 cycloalkyl. In some embodiments, Ra is optionally substituted C6 cycloalkyl. In some embodiments, Ra is optionally substituted C7 cycloalkyl. [0067] In some embodiments, Ra 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, Ra is 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more –O(C1-6 alkyl). In some embodiments, Ra is optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more –O(C1-6 alkyl). In some embodiments, Ra is optionally substituted 3-membered saturated monocyclic heterocyclyl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is optionally substituted 4-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is oxetanyl. In some embodiments, Ra is optionally substituted 5-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is tetrahydrofuranyl optionally substituted with one or more –O(C1-6 alkyl). In some embodiments, Ra is optionally substituted 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ra is tetrahydropyranyl. In some embodiments, Ra is optionally substituted 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0068] In some embodiments, Ra 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, Ra 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, Ra is optionally substituted 7- to 8-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0069] In some embodiments, Ra is selected from the group consisting of:
Figure imgf000025_0001
. [0070] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, is –Ra (i.e., L is a covalent bond). In some embodiments,
Figure imgf000025_0002
is –(C1-3 alkylene)-Ra (i.e., L is a C1-3 straight or branched hydrocarbon chain). In some embodiments,
Figure imgf000026_0001
is –(C1- 2 alkylene)-Ra (i.e., L is a C1-2 straight or branched hydrocarbon chain). In some embodiments,
Figure imgf000026_0004
is –CH2-Ra (i.e., L is a C1 hydrocarbon chain). In some embodiments,
Figure imgf000026_0002
is – CH2CH2-Ra (i.e., L is a C2 straight hydrocarbon chain). In some embodiments,
Figure imgf000026_0003
is – CH2CH2CH2-Ra (i.e., L is a C3 straight hydrocarbon chain). [0071] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, up to five occurrences of Rb may be present, as allowed by valency rules, and is each independently halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, - OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)SO2R’, - SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6 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, and sulfur. In some embodiments, each occurrence of Rb is independently optionally substituted C1-6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each occurrence of Rb is independently optionally substituted C1-4 alkyl, optionally substituted C3-C4 cycloalkyl, or optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each occurrence of Rb is independently C1-4 alkyl optionally substituted with one or more halogen, C3-C4 cycloalkyl, or 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each occurrence of Rb is independently C3-4 cycloalkyl or C1–4 alkyl optionally substituted with one or more halogen. [0072] In some embodiments, Rb is hydrogen. [0073] In some embodiments, Rb is halogen. In some embodiments, Rb is fluoro, chloro, bromo, or iodo. In some embodiments, Rb is fluoro. In some embodiments, Rb is chloro. [0074] In some embodiments, Rb is -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, - C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, - N(R)SO2R’, -SO2R, -SO2N(R)2, or -SO3R’. [0075] In some embodiments, Rb is optionally substituted C1-6 aliphatic. In some embodiments, Rb is optionally substituted straight-chain or branched C1-6 aliphatic (i.e., optionally substituted acyclic C1-6 aliphatic). In some embodiments, Rb is optionally substituted C1-6 alkyl. In some embodiments, Rb is optionally substituted C1–4 alkyl. In some embodiments, Rb is C1–4 alkyl optionally substituted with one or more halogen. In some embodiments, Rb is selected from the group consisting of –CH3, –CF3, and –C(CH3)3. [0076] In some embodiments, Rb is optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Rb is optionally substituted C3-C6 cycloalkyl. In some embodiments, Rb is optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Rb is cyclopropyl. In some embodiments, Rb is optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Rb is optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Rb is optionally substituted 6-membered saturated or partially unsaturated monocyclic carbocyclyl. [0077] In some embodiments, Rb is optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0078] In some embodiments, Rb is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rb is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rb is optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rb is pyrazolyl. In some embodiments, Rb is optionally substituted 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0079] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, optionally substituted
Figure imgf000027_0001
In some embodiments, optionally substituted
Figure imgf000028_0001
is optionally substituted
Figure imgf000028_0002
Figure imgf000028_0003
[0080] In some embodiments,
Figure imgf000028_0004
Figure imgf000028_0005
[0081] In some embodiments,
Figure imgf000029_0001
Figure imgf000029_0002
[0082] In some embodiments,
Figure imgf000029_0003
is selected from the group consisting of:
Figure imgf000029_0004
[0083] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, 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, -NO2, -C(O)R°, -C(O)OR°, -C(O)NR°2, -OC(O)R°, -OC(O)NR°2, –OC(O)OR°, -OS(O)2R°, -OS(O)2NR°2, -N(R°)C(O)R°, -N(R°)C(O)NR°2, - N(R°)S(O)2R°, -S(O)2R°, -SO2NR°2, and -S(O)2OR°, and (ii) optionally substituted on a substitutable nitrogen atom with one or more groups selected from –R†, –NR†2, –C(O)R†, – C(O)OR†, -S(O)2R†, and -S(O)2NR†2. In some embodiments, 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(O)NR°2, -N(R°)C(O)R°, and -N(R°)C(O)NR°2, and (ii) optionally substituted on a substitutable nitrogen with –R†. In some embodiments, Ring B is optionally substituted on a substitutable carbon atom with one or more groups independently selected from -N(R°)2, -C(O)NR°2, -N(R°)C(O)R°, and -N(R°)C(O)NR°2. [0084] In some embodiments, 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. In some embodiments, 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. [0085] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.
[0086] In some embodiments, 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.
[0087] In some embodiments, Ring B is optionally substituted phenyl. [0088] In some embodiments, 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). [0089] In some embodiments, 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. In some embodiments, 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. [0090] In some embodiments, 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. [0091] In some embodiments, Ring B is optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0092] In some embodiments, 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. [0093] In some embodiments, Ring B is optionally substituted 7- to 16-membered saturated or partially unsaturated bicyclic or tricyclic carbocyclyl. [0094] In some embodiments, 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. In some embodiments, 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. [0095] In some embodiments, 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. In some embodiments, 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. [0096] In some embodiments, Ring B is optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0097] In some embodiments, Ring B is
Figure imgf000034_0001
, wherein R2 is as defined in Formula III and described in classes and subclasses herein, both singly and in combination. [0098] In some embodiments, Ring B is
Figure imgf000034_0002
[0099] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, R2 is –N(R)C(O)R’, –C(O)N(R)2, or –N(R)C(O)N(R)2, wherein R and R’ are as defined in Formula III and described in classes and subclasses herein, both singly and in combination. In some embodiments, R2 is –N(R)C(O)R’ or –C(O)N(R)2. [0100] In some embodiments, R2 is –N(R)C(O)R’. In some embodiments, R2 is – N(H)C(O)R’. In some embodiments, R2 is –N(R)C(O)(optionally substituted C1-6 aliphatic). In some embodiments, R2 is –N(H)C(O)(optionally substituted C1-6 aliphatic). In some embodiments, R2 is –N(R)C(O)(C1-6 aliphatic). In some embodiments, R2 is –N(H)C(O)(C1-6 aliphatic). In some embodiments, R2 is –N(R)C(O)(straight-chain or branched C1-6 aliphatic). In some embodiments, R2 is –N(H)C(O)(straight-chain or branched C1-6 aliphatic). In some embodiments, R2 is –N(R)C(O)(optionally substituted C1-6 alkyl). In some embodiments, R2 is – N(H)C(O)(optionally substituted C1-6 alkyl). In some embodiments, R2 is –N(R)C(O)(C1-6 alkyl). In some embodiments, R2 is –N(H)C(O)(C1-6 alkyl). In some embodiments, R2 is – N(R)C(O)(optionally substituted C1-4 alkyl). In some embodiments, R2 is –N(H)C(O)(optionally substituted C1–4 alkyl). In some embodiments, R2 is –N(R)C(O)(C1–4 alkyl). In some embodiments, R2 is –N(H)C(O)(C1–4 alkyl). In some embodiments, R2 is –N(R)C(O)(optionally substituted C1-2 alkyl). In some embodiments, R2 is –N(H)C(O)(optionally substituted C1-2 alkyl). In some embodiments, R2 is –N(R)C(O)(C1-2 alkyl). In some embodiments, R2 is – N(H)C(O)(C1-2 alkyl). In some embodiments, R2 is –N(R)C(O)CH3. In some embodiments, R2 is –N(H)C(O)CH3. In some embodiments, R2 is –N(R)C(O)(optionally substituted C3-7 carbocyclyl). In some embodiments, R2 is –N(H)C(O)(optionally substituted C3-7 carbocyclyl). In some embodiments, R2 is –N(R)C(O)(optionally substituted C3-7 cycloalkyl). In some embodiments, R2 is –N(H)C(O)(optionally substituted C3-7 cycloalkyl). In some embodiments, R2 is –N(R)C(O)(C3-6 cycloalkyl). In some embodiments, R2 is –N(H)C(O)(C3-6 cycloalkyl). [0101] In some embodiments, R2 is –C(O)N(R)2. In some embodiments, R2 is – C(O)N(R)(C1-6 aliphatic). In some embodiments, R2 is –C(O)N(H)(C1-6 aliphatic). In some embodiments, R2 is –C(O)N(R)(straight-chain or branched C1-6 aliphatic). In some embodiments, R2 is –C(O)N(H)(straight-chain or branched C1-6 aliphatic). In some embodiments, R2 is –C(O)N(R)(C1-6 alkyl). In some embodiments, R2 is –C(O)N(H)(C1-6 alkyl). In some embodiments, R2 is –C(O)N(R)(C1–4 alkyl). In some embodiments, R2 is – C(O)N(H)(C1-4 alkyl). In some embodiments, R2 is –C(O)N(R)(C1-2 alkyl). In some embodiments, R2 is –C(O)N(H)(C1-2 alkyl). [0102] In some embodiments, R2 is –N(R)2. In some embodiments, R2 is –N(H)(R). [0103] In some embodiments, R2 is –N(R)C(O)N(R)2. In some embodiments, R2 is – N(R)C(O)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. In some embodiments, R2 is –N(R)C(O)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. In some embodiments, R2 is –N(H)C(O)N(R)2. In some embodiments, R2 is –N(H)C(O)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. In some embodiments, R2 is –N(H)C(O)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. [0104] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, each R is independently hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is optionally substituted straight-chain or branched C1-6 aliphatic (i.e., optionally substituted acyclic C1-6 aliphatic). In some embodiments, R is optionally substituted C1-6 alkyl. In some embodiments, 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. [0105] In some embodiments of any of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV, R’ is optionally substituted C1-6 aliphatic. In some embodiments, R’ is optionally substituted straight-chain or branched C1-6 aliphatic (i.e., optionally substituted acyclic C1-6 aliphatic). In some embodiments, R’ is optionally substituted C1-6 alkyl. In some embodiments, R’ is optionally substituted C1-4 alkyl. In some embodiments, R’ is unsubstituted C1-4 alkyl. In some embodiments, R’ is optionally substituted C1-2 alkyl. In some embodiments, 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. [0106] In some embodiments, Ring B is
Figure imgf000036_0001
, wherein Ring B1 and Ring B2 are defined as in Formula IV 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. [0107] In some embodiments, 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. [0108] In some embodiments, Ring B1 is optionally substituted phenyl. In some embodiments, when Ring B1 is phenyl, Ring B2 contains at least one heteroatom. [0109] In some embodiments, 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. [0110] In some embodiments, 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. [0111] In some embodiments, 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. In some embodiments, 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. In some embodiments, Ring B1 is optionally substituted 5- to 6-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0112] In some embodiments, 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. [0113] In some embodiments, Ring B2 is optionally substituted phenyl. In some embodiments, when Ring B2 is phenyl, Ring B1 contains at least one heteroatom. [0114] In some embodiments, 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. [0115] In some embodiments, 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. [0116] In some embodiments, 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. 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 heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B2 is optionally substituted 5- to 6-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0117] In some embodiments, 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. In some embodiments, Ring B1 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring B2 is optionally substituted 6-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, and Ring B2 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0118] In some embodiments, Ring B2 is further fused to Ring B3. In some embodiments, Ring B2 and Ring B3 combine to form a spirocycle. [0119] In some embodiments, Ring B3, when present, is optionally substituted phenyl. In some embodiments, Ring B3 is 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B3 is 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring B3, when not fused to an aromatic Ring B2, is 3- to 7-membered saturated monocyclic carbocyclyl. In some embodiments, Ring B3 is 3- to 7-membered partially saturated monocyclic carbocyclyl. In some embodiments, 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. [0120] In some embodiments, the present disclosure provides compounds selected from Table 1:
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
or a pharmaceutically acceptable salt thereof.
[0121] In some embodiments, the present disclosure encompasses the recognition that provided compounds display certain desirable characteristics, e.g., as compared to other known compounds. For example, in some embodiments, 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. In some embodiments, provided compounds display certain desirable characteristics in one or more assays described herein, e.g., compared to other known compounds. [0122] In some embodiments, provided compounds are provided and/or utilized in 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). [0123] It will be appreciated that throughout the present disclosure, unless otherwise indicated, reference to a compound of Formula I is intended to also include Formulae IA, IB, IC, ID, IE, IF, IG, II, III, and IV, and compound species of such formulas disclosed herein. Preparing Provided Compounds [0124] Provided compounds may generally be made by the processes described in the ensuing schemes and examples. [0125] In some embodiments, provided compounds (e.g., compounds of Formula I wherein Z is –NH-) are prepared according to the following Scheme:
Figure imgf000045_0001
wherein LG1 is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo), LG2 is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo), and Ring A, Ring B, L, W, X, Y, and Ra are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. Accordingly, in some embodiments, intermediate A.3 is prepared by a process comprising contacting intermediate A.1 with intermediate A.2 in the presence of a suitable base (e.g., Cs2CO3 or NaOH). In some embodiments, compound A is prepared by a process comprising contacting intermediate A.3 with intermediate A.4 in the presence of a suitable base (e.g., NaH, K3PO4, or Cs2CO3). In some embodiments, compound A is prepared by a process comprising contacting intermediate A.3 with intermediate A.4 in the presence of a suitable base (e.g., NaH, K3PO4, or Cs2CO3), a suitable metal complex (e.g., CuI), and optionally a suitable ligand (e.g., picolinic acid). [0126] In some embodiments, provided compounds (e.g., compounds of Formula I wherein Z is –NH-) are prepared according to the following Scheme:
Figure imgf000046_0001
wherein LG is a suitable leaving (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, W, X, Y, and Ra are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. Accordingly, in some embodiments, intermediate B.2 is prepared by a process comprising contacting intermediate B.1 with thiophosgene in the presence of a suitable base (e.g., NaHCO3). In some embodiments, compound B is prepared by a process comprising contacting intermediate B.2 with intermediate B.3 in the presence of a suitable base (e.g., Cs2CO3 or NaH). [0127] In some embodiments, provided compounds (e.g., compounds of Formula I wherein Z is –NH-) are prepared according to the following Scheme:
Figure imgf000046_0002
wherein LG is a suitable leaving (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, W, X, Y, and Ra are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. Accordingly, in some embodiments, compound C is prepared by a process comprising contacting intermediate C.1 with intermediate C.2 in the presence of a suitable base (e.g., Cs2CO3 or NaH). [0128] In some embodiments, provided compounds (e.g., compounds of Formula I) are prepared according to the following Scheme:
Figure imgf000047_0001
wherein LG is a suitable leaving (e.g., halogen, e.g., fluoro, chloro, or bromo) and Ring A, Ring B, L, W, X, Y, Z, and Ra are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. Accordingly, in some embodiments, compound D is prepared by a process comprising contacting intermediate D.1 with intermediate D.2 in the presence of a suitable base. In some embodiments, compound D is prepared by a process comprising contacting intermediate D.1 with intermediate D.2 in the presence of a suitable base, a suitable metal complex (e.g., a palladium complex), and optionally a suitable ligand. [0129] In some embodiments, provided compounds (e.g., compounds of Formula I wherein Z is –NH-) are prepared according to the following Scheme:
Figure imgf000047_0002
wherein LG1 is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo), LG2 is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, or bromo), and Ring A, Ring B, L, W, X, Y, and Ra are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. Accordingly, in some embodiments, intermediate E.3 is prepared by a process comprising contacting intermediate E.1 with intermediate E.2 in the presence of a suitable base. In some embodiments, compound E is prepared by a process comprising contacting intermediate E.3 with intermediate E.4 in the presence of a suitable base. In some embodiments, compound E is prepared by a process comprising contacting intermediate E.3 with intermediate E.4 in the presence of a suitable base, a suitable metal complex, and optionally a suitable ligand. [0130] In some embodiments, a provided compound is obtained by a process comprising a purification method described in the Examples section. In some such embodiments, a compound is the 1st eluting isomer. In some such embodiments, a compound is the 2nd eluting isomer. In some embodiments, a compound is the 3rd eluting isomer. In some embodiments, a compound is the 4th eluting isomer. In some embodiments, a compound is the 5th, 6th, 7th, 8th, or more eluting isomer. Compositions [0131] The present disclosure also provides compositions comprising a compound provided herein with one or more other components. In some embodiments, provided compositions comprise and/or deliver a compound described herein (e.g., compounds of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV). [0132] In some embodiments, a provided composition is a pharmaceutical composition that comprises and/or delivers a compound provided herein (e.g., compounds of Formulae I, IA, IB, IC, ID, IE, IF, IG, II, III, and IV) 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. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and/or anti-statics, etc. Provided pharmaceutical 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. [0133] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein 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. In some embodiments, 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.
[0134] Provided 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.
Uses
[0135] The present disclosure provides uses for compounds and compositions described herein. In some embodiments, provided compounds and compositions are useful in medicine (e.g., as therapy). In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and/or control compounds in biological assays.
[0136] In some embodiments, 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. [0137] 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.
[0138] JAK (e.g., 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). Accordingly, in some embodiments, 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. In some embodiments, a disease, disorder or condition is associated with overexpression of JAK2. [0139] In some embodiments, the present disclosure provides methods of treating cancer, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating proliferative diseases, comprising administering a provided compound or composition to a subject in need thereof. [0140] In some embodiments, the present disclosure provides methods of treating a hematological malignancy, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, 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). In some embodiments, a hematological malignancy is lymphoma (e.g., Burkitt’s lymphoma, Hodgkin’s lymphoma, or non-Hodgkin’s lymphoma). In some embodiments, a non- Hodgkin’s lymphoma is a B-cell lymphoma. In some embodiments, a non-Hodgkin’s lymphoma is a NK/T-cell lymphoma (e.g., cutaneous T-cell lymphoma). In some embodiments, a hematological malignancy is myeloma (e.g., multiple myeloma). In some embodiments, a hematological malignancy is myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or myelofibrosis). In some embodiments, a hematological malignancy is myelodysplastic syndrome. [0141] In some embodiments, 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. [0142] In some embodiments, a provided compound or composition is administered as part of a combination therapy. As used herein, the term “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). In some embodiments, 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. In some embodiments, “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. For clarity, 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. [0143] For example, in some embodiments, 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). Exemplary 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. 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). A combination of a JAK2 inhibitor with a LSD1 inhibitor demonstrated good efficacy in a mouse model of myeloproliferative neoplasms (Jutzi, J.S., et al., HemaSphere 2018, 2(3), dx.doi.org/10.1097/HS9.0000000000000054). 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). EXAMPLES [0144] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Preparation of Provided Compounds Example 1: N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)oxy)pyridin-2-yl)acetamide
Figure imgf000052_0001
[0145] Synthesis of compound 1.1. To a solution of 5-bromo-3-nitropyridin-2(1H)-one (10.0 g, 45.66 mmol, 1.0 equiv) in DMF (100 mL) was added potassium carbonate (12.6 g, 91.32 mmol, 2.0 equiv) and stirred for 15 min. To the mixture was added methyl iodide (3.7 mL, 59.35 mmol, 1.3 equiv) and was stirred at room temperature for 1 h. The reaction mixture was poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1.1. MS(ES): m/z 233.03 [M]+. [0146] Synthesis of compound 1.2. A mixture of 1.1 (7.9 g, 33.90 mmol, 1.0 equiv) and iron powder (9.49 g, 169.5 mmol, 5.0 equiv) in acetic acid (80 mL) was stirred at 80 °C for 30 min. The reaction mixture was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. It was dissolved in ethyl acetate and washed with saturated sodium bicarbonate followed by water and brine solution. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 60% ethyl acetate in hexane) to afford 1.2. MS(ES): m/z 203.01 [M]+. [0147] Synthesis of compound 1.3. To a solution of 1.2 (4.0 g, 19.70 mmol, 1.0 equiv) in toluene (60 mL) and water (20 mL) was added cyclopropylboronic acid (5.08 g, 59.10 mmol, 3.0 equiv), potassium carbonate (5.43 g, 39.4 mmol, 2.0 equiv) and tricyclohexylphosphine (0.992 g, 3.54 mmol, 0.18 equiv). The reaction mixture was degassed by bubbling through a stream of argon for 10 min. Under argon atmosphere palladium(II) acetate (0.353 g, 1.57 mmol, 0.08 equiv) was added, again degassed for 5 min. The reaction mixture was stirred at 110 °C for 8 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1.7% methanol in hexane) to afford 1.3. MS(ES): m/z 165.1 [M+H]+. [0148] Synthesis of compound 1.4. To a solution of 1.3 (1.0 g, 6.09 mmol, 1.0 equiv) in dichloromethane (20 mL) was added a solution of sodium bicarbonate (2.58 g, 30.45 mmol, 5.0 equiv) in water (4 mL) followed by thiophosgene (1.75 g, 15.22 mmol, 2.5 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was poured over ice-water and extracted with dichloromethane. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1.4. MS(ES): m/z 207.3 [M+H]+. [0149] Synthesis of compound 1.5. To a solution of 2,4-dichloro-5-nitropyrimidine (4.0 g, 20.62 mmol, 1.0 equiv) in acetic acid (40 mL) was added iron powder (5.77 g, 103.1 mmol, 5.0 equiv). The reaction mixture was stirred at 80 °C for 30 min. The reaction mixture was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford a residue, which was dissolved in ethyl acetate and washed with saturated sodium bicarbonate followed by water and brine solution. The organic layer was separated dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by trituration in pentane to afford 1.5. MS(ES): m/z 164.8 [M]+. [0150] Synthesis of compound 1.6. A mixture of 1.5 (0.4 g, 2.44 mmol, 1.0 equiv), 1.5 (0.503 g, 2.44 mmol, 1.0 equiv) and cesium carbonate (1.58 g, 4.88 mmol, 2.0 equiv) in acetonitrile (4 mL) was stirred at 50 °C for 3 h. The reaction mixture was poured over ice-water and precipitated solids were collected by filtration and air dried to afford 1.6. MS(ES): m/z 334.5 [M]+. [0151] Synthesis of compound 1.7. To a solution of benzyl alcohol (17.05 g, 157.69 mmol, 1.0 equiv) in THF (250 mL) was added sodium hydride (12.61 g, 315.38 mmol, 2 equiv) at 0 °C and stirred for 1 h. To the reaction was added 2-chloro-4-nitropyridine (25 g, 157.69 mmol, 1.0 equiv) and stirred at 0 °C for 2 h. The reaction mixture was poured over ice, stirred 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 1.7. MS (ES): m/z 220.13 [M+H]+. [0152] Synthesis of compound 1.8. A solution of 1.7 (20 g, 91.05 mmol, 1.0 equiv) in THF (200 mL) was degassed by bubbling through a stream of argon for 10 min. Under argon atmosphere were added 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (4.34 g, 9.105 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (4.17 g, 4.55 mmol, 0.05 equiv), again degassed for 5 min. To the mixture was added lithium bis(trimethylsilyl)amide solution (1 M in THF, 182 mL, 182.1 mmol, 2.0 equiv) and the mixture was stirred at 65 °C for 1 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 solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3% methanol in dichloromethane) to afford 1.8. MS(ES): m/z 201.2 [M+H]+. [0153] Synthesis of compound 1.9. To a solution of 1.8 (11.2 g, 55.93 mmol, 1.0 equiv) in dichloromethane (110 mL) was added pyridine (6.3 mL, 78.30 mmol, 1.4 equiv) followed by acetic anhydride (6.34 mL, 67.11 mmol, 1.2 equiv) and stirred at room temperature for 1 h. The reaction mixture was poured over ice, stirred and extracted with dichloromethane. 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®, 1% methanol in dichloromethane) to afford 1.9. MS (ES): m/z 243.21 [M+H]+. [0154] Synthesis of compound 1.10. A mixture of compound 1.9 (6.1 g, 25.18 mmol, 1.0 equiv) and 10% palladium on carbon (2 g) in methanol (60 mL) was stirred under hydrogen for 2 h. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in dichloromethane) to afford 1.10. MS(ES): m/z 153.2 [M+H]+. [0155] Synthesis of I-1. To a solution of 1.6 (0.100 g, 0.299 mmol, 1.0 equiv) and 1.10 (0.068 g, 0.449 mmol, 1.5 equiv) in DMF (3 mL) was added sodium hydride (0.023 g, 0.598 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. It was cooled to room temperature and poured over ice-cold water, stirred 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 preparative HPLC to afford I-1. MS(ES): m/z: 450.4 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.74 (s, 1H), 10.69 (s, 1H), 8.82 (s, 1H), 8.48 (s, 1H), 8.33-8.31 (d, J = 5.6 Hz, 1H), 7.90 (s, 1H), 7.25 (s, 1H), 7.00-6.99 (d, J = 3.2 Hz, 1H), 3.56 (s, 3H), 2.09 (s, 3H), 1.79 (bs, 1H), 0.86- 0.85 (m, 2H), 0.60-0.59 (m, 2H). [0156] Compounds 1.3 and/or 1.4 can also be used to prepare compounds I-11, I-12, I-18, I- 27, and I-32 using methods described herein. Example 2: N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)amino)thiazolo[4,5-c]pyridin-6-yl)oxy)pyridin-2-yl)acetamide
Figure imgf000056_0001
[0157] Synthesis of compound 2.1. To a mixture of 2,4-dichloro-5-nitropyridine (4 g, 20.73 mmol, 1.0 equiv) and potassium carbonate (5.72 g, 41.46 mmol, 2.0 equiv) in DMF (30 mL) was added benzyl alcohol (2.23 g, 20.73 mmol, 1.0 equiv) and stirred at 100 °C for 4 h. The reaction mixture was poured over ice-cold water, stirred 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 (4% ethyl acetate in hexane) to afford 2.1. MS (ES): m/z 265.5 [M+H]+. [0158] Synthesis of compound 2.2. A mixture of 2.1 (1.2 g, 4.53 mmol, 1.0 equiv), 1.10 (0.827 g, 5.44 mmol, 1.2 equiv) and potassium carbonate (1.56 g, 11.32 mmol, 2.5 equiv) in DMF (15 mL) was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite®, poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1.5% methanol in dichloromethane) to afford 2.2. MS(ES): m/z 381.1 [M+H]+. [0159] Synthesis of compound 2.3. To a solution of 2.2 (0.810 g, 2.13 mmol, 1.0 equiv) in dichloromethane (20 mL) was added triflic acid (1.0 mL) at 0 °C and stirred for 30 min. The reaction mixture was poured over ice-cold saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by trituration in diethyl ether to afford 2.3. MS(ES): m/z: 291.2 [M+H]+. [0160] Synthesis of compound 2.4. To a solution of 2.3 (0.540 g, 1.86 mmol, 1.0 equiv) in acetonitrile (2 mL) was added phosphorous oxychloride (1.13 g, 7.44 mmol, 4.0 equiv) and stirred at 70 °C for 30 min. The reaction mixture was poured over ice-water, neutralized by saturated sodium bicarbonate, stirred 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®, 40% ethyl acetate in hexane) to afford 2.4. MS (ES): m/z 309.5 [M+H]+. [0161] Synthesis of compound 2.5. A mixture of 2.4 (0.400 g, 1.30 mmol, 1.0 equiv), iron powder (0.364 g, 6.5 mmol, 5.0 equiv) and ammonium chloride (0.351 g, 6.5 mmol, 5.0 equiv) in ethanol:water (8:2, 14 mL) was stirred at 80 °C for 2 h. The reaction mixture was poured over ice-water, filtered and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.0% methanol in dichloromethane) to afford 2.5. MS(ES): m/z 279.7 [M+H]+. [0162] Synthesis of compound 2.6. Compound 2.6 was prepared from 2.5, following the procedure described in the synthesis of 1.4. It was used in the next step without purification. MS(ES): m/z 321.5 [M+H]+. [0163] Synthesis of I-2. To a solution of 2.6 (0.080 g, 0.249 mmol, 1.0 equiv) and 1.3 (0.053 g, 0.324 mmol, 1.3 equiv) in THF (5 mL) was stirred at 60 °C for 1 h. The reaction mixture was concentrated under reduced pressure. It was dissolved in acetonitrile (5 mL) followed by addition of cesium carbonate (0.202 g, 0.622 mmol, 2.5 equiv) and stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature, poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.4% methanol in dichloromethane) to afford I-2. MS(ES): m/z: 449.0 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.69 (s, 1H), 10.57 (s, 1H), 8.56 (s, 1H), 8.52 (s, 1H), 8.24-8.23 (d, J = 5.6 Hz, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.23 (s, 1H), 6.83-6.82 (d, J = 5.6 Hz, 1H), 3.52 (s, 3H), 2.07 (s, 3H), 1.24 (bs, 1H), 0.87-0.85 (m, 2H), 0.61-0.60 (m, 2H). Example 3: N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)amino)thiazolo[4,5-b]pyrazin-6-yl)oxy)pyridin-2-yl)acetamide
Figure imgf000058_0001
[0164] Synthesis of compound 3.1. To a solution of 3,5-dibromopyrazin-2-amine (0.500 g, 1.98 mmol, 1.0 equiv) in acetone (10 mL) was added sodium hydroxide (0.198 g, 4.95 mmol, 2.5 equiv) at room temperature and stirred for 20 min followed by addition of 1.4 (0.489 g, 2.37 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was poured over ice-cold water, stirred 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 trituration with diethyl ether to afford 3.1. MS(ES): m/z: 379.2 [M+H]+. [0165] Synthesis of I-3. A mixture of 3.1 (0.200 g, 0.528 mmol, 1.0 equiv), 1.10 (0.160 g, 1.06 mmol, 2.0 equiv) and tripotassium phosphate (0.335 g, 1.584 mmol, 3.0 equiv) in dimethyl sulfoxide (6 mL) was degassed by bubbling through a stream of argon for 10 min. Under argon atmosphere, copper iodide (0.010 g, 0.052 mmol, 0.1 equiv) and picolinic acid (0.013 g, 0.106 mmol, 0.2 equiv) were added, again degassed for 5 min. The reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (3.2% methanol in dichloromethane) to afford I-3. MS(ES): m/z: 450.5 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.87 (s, 1H), 10.66 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.27-8.26 (d, J = 5.6 Hz, 1H), 7.83 (s, 1H), 7.29 (s, 1H), 6.90-6.89 (d, J = 3.6 Hz, 1H), 3.52 (s, 3H), 2.07 (s, 3H), 1.21 (bs, 1H), 0.87-0.85 (m, 2H), 0.59-0.58 (m, 2H). Example 4: N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3- yl)amino)thiazolo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide
Figure imgf000059_0001
[0166] Synthesis of compound 4.1. To a suspension of 5-fluoropyridin-2-amine (2 g, 17.84 mmol, 1.0 equiv) in water (8 mL) was added sulfuric acid (3.5 g, 35.68 mmol, 2.0 equiv) at 0 °C and stirred at room temperature for 10 min. To the mixture was added bromine (3.06 g, 19.26 mmol, 1.08 equiv) slowly. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture cooled to room temperature, poured into ice-water neutralized with 50% sodium hydroxide solution. Precipitated solid filtered, washed with sodium thiosulfate solution followed by water and dried well to afford 4.1. 1H NMR (DMSO-d6, 400 MHz): δ 7.99 (d, J = 2.4 Hz, 1H), 7.89-7.87 (m, 1H), 6.18 (bs, 2H). [0167] Synthesis of compound 4.2. Concentrated sulfuric acid (12 mL, 6vol) was added dropwise to potassium persulfate (11.86 g, 43.96 mmol, 4.0 equiv) at room temperature and stirred for 15 min. To the mixture was added 4.2 (2.1 g, 10.99 mmol, 1.0 equiv) portionwise maintaining temperature 30-40 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was transferred into crushed ice, stirred, neutralized with aqueous ammonium hydroxide and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (8% ethyl acetate in hexane) to afford 4.2.1H NMR (DMSO-d6, 400 MHz): δ 8.73-8.70 (m, 2H). [0168] Synthesis of compound 4.3. A mixture of 4.2 (0.870 g, 3.94 mmol, 1.0 equiv), 1.10 (0.599 g, 3.94 mmol, 1.0 equiv) and sodium carbonate (0.835 g, 7.88 mmol, 2.0 equiv) in DMF (10 mL) was stirred at room temperature for 1 h. It was poured over ice-water and precipitated compound was filtered, washed with water and dried well to afford 4.3. MS(ES): m/z 354.1 [M+H]+. [0169] Synthesis of compound 4.4. Compound 4.4 was prepared from 4.3 following the procedure described in the synthesis of 2.5. The product was purified by flash column chromatography on silica gel (Combiflash®, 1.7% methanol in dichloromethane). MS(ES): m/z 324.0 [M+H]+. [0170] Synthesis of I-4. A solution of 4.4 (0.100 g, 0.309 mmol, 1.0 equiv) and 1.4 (0.063 g, 0.309 mmol, 1.0 equiv) in THF (5 mL) was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMF (5 mL) and sodium hydride (0.037 g, 0.927 mmol, 3.0 equiv) was added at 0 °C. It was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature, poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2% methanol in dichloromethane) to afford I-4. MS(ES): m/z: 447.2 [M-H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.63 (s, 1H), 10.60 (s, 1H), 8.59 (s, 1H), 8.29-8.28 (d, J = 2.4 Hz, 1H), 8.24-8.20 (m, 2H), 7.67 (s, 1H), 7.25 (s, 1H), 6.73-6.71 (m, 1H), 3.53 (s, 3H), 2.04 (s, 3H), 1.82-1.79 (m, 1H), 0.89-0.85 (m, 2H), 0.60-0.58 (m, 2H). Example 5: N-(4-((6-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)thiazolo[4,5- c]pyridazin-3-yl)oxy)pyridin-2-yl)acetamide
Figure imgf000060_0001
Figure imgf000061_0001
[0171] Synthesis of compound 5.1. To a solution of 6-chloropyridazin-3-amine (5 g, 38.60 mmol, 1.0 equiv) in methanol (50 mL) was added sodium bicarbonate (8.10 g, 96.5 mmol, 2.5 equiv) followed by addition of bromine (6.79 g, 42.46 mmol, 1.1 equiv) slowly at 0 °C. The reaction mixture was stirred at room temperature for 4 h. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (25% ethyl acetate in hexane) to afford 5.1.1H NMR (DMSO-d6, 400 MHz): δ 6.87 (bs, 2H), 2.38 (bs, 2H). [0172] Synthesis of compound 5.2. To a solution of 5.1 (1.0 g, 4.8 mmol, 1.0 equiv) in acetonitrile (10 mL) was added 1.4 (0.989 g, 4.8 mmol, 1.0 equiv) followed by cesium carbonate (2.34 g, 7.2 mmol, 1.5 equiv). The reaction mixture was stirred at 70 °C for 8 h. It was poured over ice-water. The precipitate was collected by filtration, rinsed with water and air dried to afford 5.2. It was used in the next step without purification. MS(ES): m/z 334.5 [M+H]+. [0173] Synthesis of compound 5.3. To a solution of 5.2 (0.500 g, 1.5 mmol, 1.0 equiv) in acetic acid (10 mL) was added sodium acetate (1.84 g, 22.5 mmol, 15 equiv) and stirred at 110 °C for 48 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (4% methanol in dichloromethane) to afford 5.3. MS(ES): m/z 316.2 [M+H]+. [0174] Synthesis of compound 5.4. A mixture of 5.3 (0.200 g, 0.634 mmol, 1.0 equiv), 2- chloro-4-fluoropyridine (0.417 g, 3.17 mmol, 5.0 equiv) and cesium carbonate (0.618 g, 1.902 mmol, 3.0 equiv) in DMSO (10 mL) was stirred at room temperature for 4 h. The reaction mixture was poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (2% methanol in dichloromethane) to afford 5.4. MS(ES): m/z 427.8 [M+H]+. [0175] Synthesis of I-5. A mixture of 5.4 (0.062 g, 0.145 mmol, 1.0 equiv), acetamide (0.042 g, 0.725 mmol, 5.0 equiv) and cesium carbonate (0.141 g, 0.435 mmol, 3.0 equiv) in 1,4- dioxane (5 mL) was degassed by bubbling through a stream of argon for 10 min. Under argon atmosphere, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.014 g, 0.029 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (0.013 g, 0.014 mmol, 0.1 equiv) were added, again degassed for 5 min. The reaction mixture was stirred at 120 °C for 3 h. It was cooled to room temperature, transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in dichloromethane) to afford I-5. MS(ES): m/z: 450.3 [M+H]+, 1H NMR (DMSO-d6, 400 MHz): δ 10.69 (s, 1H), 8.41 (bs, 3H), 7.45 (bs, 3H), 7.29 (s, 1H), 3.51 (s, 3H), 2.12 (s, 3H), 1.23 (bs, 1H), 0.84 (bs, 2H), 0.55 (bs, 2H). Preparation of Intermediate Int-1: (S)-5-(tert-butyl)-3-isothiocyanato-1-(tetrahydrofuran-3- yl)-1H-pyrazole
Figure imgf000062_0001
[0176] Synthesis of compound Int-1.1. To a round-bottom flask equipped with a Dean- Stark apparatus and a condenser was charged with 5-(tert-butyl)-1H-pyrazol-3-amine (5.0 g, 35.92 mmol, 1.0 equiv), 2, 5-hexanedione (4.09 g, 35.92 mmol, 1.0 equiv), toluene (100 mL) and a few drops of acetic acid (catalytic). The reaction mixture was heated to reflux for 3 hours. It was cooled rt and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 12% ethyl acetate in hexane as eluant) to afford Int-1.1. MS (ES): m/z 218.3 [M+H]+. [0177] Synthesis of compound Int-1.2 and Int-1.3. A mixture of Int-1.1 (2.5 g, 11.50 mmol, 1.0 equiv), (R)-tetrahydrofuran-3-yl methanesulfonate (1.91 g, 11.50 mmol, 1.0 equiv) and cesium carbonate (7.49 g, 23 mmol, 2.0 equiv) in DMF (15 mL) was stirred at 70 °C for 12 h under nitrogen. It was poured into ice-water, stirred 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®, 2% ethyl acetate in hexane as eluant) to afford Int- 1.2. MS (ES): m/z 287.4 [M+H]+ and Int-1.3. MS (ES): m/z 248.3 [M+H]+. [0178] Synthesis of compound Int-1.4. To a solution of Int-1.3 (0.120 g, 0.417 mmol, 1.0 equiv) in ethanol-water (2:1, 2 mL) was added hydroxylamine hydrochloride (0.287 g, 4.17 mmol, 10 equiv). The reaction mixture was stirred at 120 °C in a microwave reactor for 1 h. It was poured over ice-water, basified by 2 N sodium hydroxide and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford Int-1.4. MS (ES): m/z 210.3 [M+H]+. [0179] Synthesis of compound Int-1. To a solution of Int-1.4 (0.070 g, 0.334 mmol, 1.0 equiv) in dichloromethane (2 mL) was added a solution of sodium bicarbonate (0.140 g, 1.67 mmol, 5.0 equiv) in water (1 mL) followed by thiophosgene (0.096 g, 0.835 mmol, 2.5 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. It was poured over ice-water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford Int-1. MS (ES): m/z 252.3 [M+H]+. [0180] Int-1 and/or Int-1.4 can be used to prepare compounds I-7, I-17, I-19, and I-30 using methods described herein. Preparation of Intermediate Int-2: (R)-5-(tert-butyl)-3-isothiocyanato-1-(tetrahydrofuran-3- yl)-1H-pyrazole
Figure imgf000064_0001
[0181] Synthesis of compound Int-2. Compound Int-2 was prepared from Int-1.1, following the procedures described in the synthesis of Int-1. MS (ES): m/z 252.3 [M+H]+. [0182] Int-2 and/or Int-2.3 can be used to prepare compounds I-6, I-16, I-20, and I-31 using methods described herein. Preparation of Intermediate Int-3: 3-isothiocyanato-1-methyl-5-(trifluoromethyl)pyridin- 2(1H)-one
Figure imgf000064_0002
[0183] Synthesis of compound Int-3.2. A mixture of Int-3.1 (1.0 g, 4.81 mmol, 1.0 equiv), potassium carbonate (1.3 g, 9.62 mmol, 2.0 equiv) and methyl iodide (1.0 g, 7.21 mmol, 1.5 equiv) in DMF (15 mL) was stirred at 70 °C for 2 h. It was poured over 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®, 40% ethyl acetate in hexane as eluant) to afford Int-3.2. MS (ES): m/z 223.12 [M+H]+. [0184] Synthesis of compound Int-3.3. A flask charged with compound Int-3.2 (1.0 equiv), 10% palladium on carbon and methanol was vacuumed and purged with hydrogen three times. The mixture was stirred at rt under 1 atm hydrogen atmosphere for 1 h. The flask was vacuumed and purged with nitrogen three times before it was opened to air. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to obtain Int-3.3. MS (ES): m/z 193.14 [M+H]+. [0185] Synthesis of compound Int-3. To a solution of Int-3.3 (1.0 equiv) and triethylamine (3.0 equiv) in THF was added thiophosgene (1.2 equiv) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. It was 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 as eluant) to afford Int-3. MS (ES): m/z 192.15 [M+H]+. [0186] Int-3 and/or Int-3.3 can be used to prepare compound I-8 using methods described herein. Preparation of Intermediate Int-4: 5-cyclopropyl-3-isothiocyanato-1-(2-methoxyethyl)pyridin- 2(1H)-one
Figure imgf000065_0001
[0187] Synthesis of compound Int-4.1. A mixture of 5-bromo-3-nitropyridin-2(1H)-one (1.0 g, 4.57 mmol, 1.0 equiv) and potassium carbonate (1.57 g, 11.42 mmol, 2.5 equiv) in DMF (10 mL) was stirred for 15 min before the addition of 1-bromo-2-methoxyethane (0.698 g, 5.02 mmol, 1.1 equiv). The reaction mixture was stirred at 80 °C for 30 min. It was 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®, 7-8% ethyl acetate in hexane) to afford Int-4.1. MS(ES): m/z 278.1 [M+H]+. [0188] Synthesis of compound Int-4.2. A mixture of Int-4.1 (1.0 equiv), cyclopropylboronic acid (3.0 equiv), potassium phosphate (3.0 equiv) and tricyclohexylphosphine (0.2 equiv) in toluene and water was degassed by bubbling through a stream of argon for 10 min. Under argon atmosphere palladium(II) acetate (0.5 equiv) was added, and the mixture was degassed for additional 5 min. The reaction mixture was stirred at 100 °C for 2 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into 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®, 30% ethyl acetate in hexane) to afford Int 4.2. MS(ES): m/z 239.2 [M+H]+. [0189] Synthesis of compound Int-4.3. A mixture of compound Int-4.2 (1.0 equiv) and 10% palladium on carbon in methanol was stirred under hydrogen atmosphere (1 atm) at rt for 2 h. The mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford Int-4.3. MS(ES): m/z 209.3 [M+H]+. [0190] Synthesis of compound Int-4. To a solution of Int-4.3 (1.0 equiv) in dichloromethane was added a solution of sodium bicarbonate (5.0 equiv) in water followed by thiophosgene (2.5 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. It was poured over ice-water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford Int-4. MS(ES): m/z 251.3 [M+H]+. [0191] Int-4 and/or Int-4.3 can be used to prepare compounds I-9 and I-14 using methods described herein. Preparation of Intermediate (±)-Int-5. (±)-5-cyclopropyl-3-isothiocyanato-1-(tetrahydro-2H- pyran-3-yl)pyridin-2(1H)-one
Figure imgf000067_0001
[0192] Synthesis of compound Int-5.1. To a solution of 3,4-dihydro-2H-pyran (20 g, 238 mmol, 1.0 equiv) in DCM (200 mL) was added bromine (12.2 mL, 238 mmol, 1.0 equiv) in DCM (100 mL) at -78 °C dropwise. The reaction mixture was stirred at -78 °C for 2 h, and it was allowed to warm to room temperature stirring for 16 h. Triethylamine (66 mL, 476 mmol, 2.0 equiv) in DCM (100 mL) was added dropwise at room temperature and then stirred for 5 h. The reaction mixture was concentrated under reduced pressure to afford a residue, to which diethyl ether was added and the solid was removed by filtration. The filtrate was concentrated under reduced pressure to afford a residue which was purified by vacuum distillation (80 °C, 0.02 mmHg) to afford Int-5.1.1H NMR (400 MHz, CDCl3): 6.68 (s, 1H), 4.02-4.00 (t, J = 4 Hz, 2H), 2.45-2.42 (m, 2H), 2.06-2.00 (m, 2H). [0193] Synthesis of compound Int-5.2. A mixture of Int-5.1 (8 g, 49.08 mmol, 1.0 equiv), 3-aminopyridin-2(1H)-one (6.48 g, 58.89 mmol, 1.2 equiv) and potassium carbonate (13.6 g, 98.16 mmol, 2.0 equiv) in 1,4-dioxane (100 mL) was degassed by bubbling through a stream of argon for 15 min. Copper iodide (1.4 g, 7.40 mmol, 0.15 equiv) and 1,2- dimethylethylenediamine (1.60 mL, 14.72 mmol, 0.30 equiv) were added. The reaction mixture was degassed for 5 min and stirred at 110 °C for 12 h. It was cooled to room temperature, transferred into 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®, 1.2% methanol in DCM) to afford Int-5.2. MS(ES): m/z 193.09 [M+H]+. [0194] Synthesis of compound (±)-Int-5.3. A mixture of Int-5.2 (8 g, 41.62 mmol, 1.0 equiv) and palladium on charcoal (4 g) in methanol (100 mL) was stirred under hydrogen (1 atm) for 16 h at room temperature. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by trituration with n-pentane to afford (±)-Int-5.3. MS (ES): m/z 195.11 [M+H]+. [0195] Synthesis of compound (±)-Int-5.4. To a solution of (±)-Int-5.3 (2 g, 10.30 mmol, 1.0 equiv) in DCM (20 mL) at 0 °C was added triethylamine (4.33 mL, 30.9 mmol, 3.0 equiv) and acetic anhydride (1.55 mL, 16.49 mmol, 1.6 equiv). The reaction mixture was stirred at room temperature for 2 h. It was transferred into water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 0-5% methanol in DCM) to afford (±)-Int-5.4. MS (ES): m/z 237.12 [M+H]+. [0196] Synthesis of compound (±)-Int-5.5. To a solution of (±)-Int-5.4 (0.9 g, 3.81 mmol, 1.0 equiv) in DMF (10 mL) was added NBS (1.017 g, 5.71 mmol, 1.5 equiv), and the mixture was stirred at room temperature for 1 h. It was 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®, 60% ethyl acetate in hexane) to afford (±)- Int-31.5. MS(ES): m/z 316.2 [M+H]+. [0197] Synthesis of compound (±)-Int-5.6. Compound (±)-Int-5.6 was prepared from (±)- Int-5.5, following the procedure described in the synthesis of Int-4.2. The product was purified by flash column chromatography on silica gel (CombiFlash®, 100% ethyl acetate). MS(ES): m/z 277.3 [M+H]+. [0198] Synthesis of compound (±)-Int-5.7. To a solution of compound Int-5.6 (1.0 equiv) in methanol was added potassium carbonate (20.0 equiv). The reaction mixture was heated to reflux for 16 h. It was transferred into 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®, 2.0% methanol in DCM) to afford Int-5.7. MS(ES): m/z 235.3 [M+H]+. [0199] Synthesis of compound (±)-Int-5. Compound (±)-Int-5 was prepared from (±)-Int- 5.7, following the procedure described in the synthesis of Int-4. The product was used without purification. MS(ES): m/z 277.4 [M+H]+. [0200] (±)-Int-5 and/or (±)-Int-5.7 can be used to prepare compounds I-13-i, I-13-ii, I-29-i, and I-29-ii using methods described herein. Preparation of Intermediate Int-6: 6-cyclopropyl-4-isothiocyanato-2-methylpyridazin-3(2H)- one
Figure imgf000069_0001
[0201] Synthesis of compound Int-6.1. To a solution of 3,6-dichloropyridazin-4-amine (0.9 g, 5.49 mmol, 1.0 equiv) in THF (20 mL) was added sodium hydride (0.579 g, 12.07 mmol, 2.2 equiv) at 0 °C and stirred for 10 min. Pivaloyl chloride (0.7 mL, 5.76 mmol, 1.05 equiv) was added dropwise. The reaction mixture was stirred at room temperature for 15 min. It was transferred into ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford Int-6.1. MS (ES): m/z 230.6 [M+H]+. [0202] Synthesis of compound Int-6.2. A solution of Int-6.1 (1.1 g, 4.43 mmol, 1.0 equiv) in acetic acid (10 mL) was stirred at 110 °C for 3 h. It was transferred into ice, stirred and neutralized with saturated sodium bicarbonate solution. Precipitated solid was filtered out and dried well to afford Int-6.2. MS (ES): m/z 271.3 [M+H]+. [0203] Synthesis of compound Int-6.3. To a solution of Int-6.2 (0.7 g, 3.05 mmol, 1.0 equiv) in DMF (7 mL) was added potassium carbonate (0.841 g, 6.1 mmol, 2.0 equiv) at room temperature and stirred for 15 min followed by addition of methyl iodide (0.519 g, 3.66 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 16 h. It was 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 trituration with n-pentane to afford Int-6.3. MS(ES): m/z 244.6 [M+H]+. [0204] Synthesis of compound Int-6.4. To a solution of Int-6.3 (0.350 g, 1.44 mmol, 1.0 equiv) in dimethylacetamide (2 mL), water (1 mL) and ethanol (0.7 mL) was added cyclopropylboronic acid (0.27 g, 3.16 mmol, 2.2 equiv), cesium carbonate (0.938 g, 2.88 mmol, 2.0 equiv) and dichlorobis(triphenylphosphine)palladium(II) (0.090 g, 0.129 mmol, 0.09 equiv). The reaction mixture was heated in a microwave reactor at 150 °C for 30 min. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into water and extracted with DCM. 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 Int-6.4. MS(ES): m/z 250.3 [M+H]+. [0205] Synthesis of compound Int-6.5. To a solution of Int-6.4 (0.155 g, 0.621 mmol, 1.0 equiv) in methanol (2.5 mL) was added sodium methoxide solution (25% in methanol, 0.4 mL, 1.86 mmol, 3.0 equiv). The reaction mixture was stirred at 65 °C for 2 h. It was concentrated under reduced pressure. The residue was transferred into 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 to afford Int-6.5. MS(ES): m/z 166.2 [M+H]+. [0206] Synthesis of compound Int-6. Compound Int-6 was prepared from Int-6.5, following the procedure described in the synthesis of Int-4. The product was used without purification. MS(ES): m/z 208.3 [M+H]+. [0207] Int-6 and/or Int-6.5 can be used to prepare compounds I-10 and I-15 using methods described herein. Preparation of Intermediate Int-7: 2-isothiocyanato-4,4-dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine
Figure imgf000071_0001
[0208] Synthesis of compound Int-7.2. To a solution of Int-7.1 (10 g, 99.88 mmol, 1.0 equiv) and methyl iodide (24.8 mL, 399.52 mmol, 4.0 equiv) in THF (200 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 219 mL, 219.7 mmol, 2.2 equiv) at -78 °C. The reaction mixture was stirred at room temperature for 16 h. It was poured over 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 as eluant) to afford Int-7.2. MS (ES): m/z 129.2 [M+H]+. [0209] Synthesis of compound Int-7.3. To a solution of diisopropylamine (4.88 g, 48.37 mmol, 1.0 equiv) in THF (100 mL) at -78°C was slowly added a solution of n-butyl lithium (2.5M in hexane, 24.2 mL, 60.46 mmol, 1.25 equiv). The reaction mixture was stirred for 5 min followed by addition of acetonitrile (2.5 mL, 48.37 mmol, 1.0 equiv). The reaction mixture stirred for 10 min and compound Int-7.3 (6.20 g, 48.37 mmol, 1.0 equiv) in THF (30 mL) was added to it. The reaction mixture was stirred at 5 °C for 6 h. It was poured over cold saturated ammonium chloride solution 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®, 20% ethyl acetate in hexane as eluant) to afford Int-7.3. MS (ES): m/z 170.2 [M+H]+. [0210] Synthesis of compound Int-7.4. To a solution of Int-7.3 (3.9 g, 23.05 mmol, 1.0 equiv) in ethanol (40 mL) was added hydrazine hydrochloride (2.35 g, 34.57 mmol, 1.5 equiv) followed by addition of potassium carbonate (4.77 g, 34.57 mmol, 1.5 equiv). The reaction mixture was heated to reflux for 16 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3-4% methanol in dichloromethane as eluant) to afford Int-7.4. MS (ES): m/z 184.26 [M+H]+. [0211] Synthesis of compound Int-7.5. To a solution of Int-7.4 (1.1 g, 6.0 mmol, 1.0 equiv) in THF (20 mL) was added thionyl chloride (2.15 mL, 30 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 2 h. It was poured over saturated sodium bicarbonate solution, stirred 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®, 2% methanol in dichloromethane as eluant) to afford Int-7.5. MS (ES): m/z 166.24 [M+H]+. [0212] Synthesis of compound Int-7. To a solution of Int-7.5 (1.0 equiv) and triethylamine (3.0 equiv) in THF was added thiophosgene (1.2 equiv) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. It was 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 to afford Int-7. MS (ES): m/z 208.3 [M+H]+. [0213] Int-7 and/or Int-7.5 can be used to prepare compounds I-21 and I-36 using methods described herein. Preparation of Intermediate Int-8: 5-cyclopropyl-3-isothiocyanato-1-(tetrahydro-2H-pyran-4- yl)pyridin-2(1H)-one
Figure imgf000072_0001
Figure imgf000073_0001
[0214] Synthesis of compound Int-8.1. To a solution of 3-nitropyridin-2(1H)-one (3 g, 14.28 mmol, 1.0 equiv) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (2.4 g, 17.14 mmol, 1.2 equiv) in dioxane (30 mL) was added copper acetate (2.60 g, 14.28 mmol, 1.0 equiv) and triethylamine (5.0 mL, 35.7 mmol, 2.5 equiv) under nitrogen. The reaction was stirred at 80 °C for 5 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were 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 Int-8.1. MS(ES): m/z 222.20 [M+H]+. [0215] Synthesis of compound Int-8.2. To a mixture of Int-8.1 (1.2 g, 5.40 mmol, 1.0 equiv) and 10% palladium on charcoal (0.5 g) in methanol (15 mL) was stirred under hydrogen (1 atm) for 3 h at room temperature. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 1.8% methanol in DCM) to afford Int-8.2. MS (ES): m/z 195.23 [M+H]+. [0216] Synthesis of compound Int-8.3. To a solution of Int-8.2 (0.500 g, 2.57 mmol, 1.0 equiv) and triethylamine (1.07 mL, 7.71 mmol, 3.0 equiv) in DCM (5 mL) at 0 °C was added acetic anhydride (0.51 mL, 5.14 mmol, 2.0 equiv) dropwise. The reaction mixture was stirred at room temperature for 2 h. It was poured into ice-water, stirred and extracted with DCM. 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®, 1.4% methanol in DCM) to afford Int-8.3. MS(ES): m/z 237.3 [M+H]+. [0217] Synthesis of compound Int-8.4. To a solution of Int-8.3 (0.4 g, 1.69 mmol, 1.0 equiv) in DMF (5 mL) was added NBS (0.448 g, 2.53 mmol, 1.5 equiv) and stirred at room temperature for 1 h. It was 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®, 80% ethyl acetate in hexane) to afford Int-8.4. MS(ES): m/z 316.2 [M+H]+. [0218] Synthesis of compound Int-8.5. Compound Int-8.5 was prepared from Int-8.4, following the procedure described in the synthesis of Int-4.2. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.4% methanol in DCM). MS(ES): m/z 277.3 [M+H]+. [0219] Synthesis of compound Int-8.6. To a solution of compound Int-8.5 (0.185 g, 0.669 mmol, 1.0 equiv) in methanol (5 mL) was added potassium carbonate (1.846 g, 13.38 mmol, 20.0 equiv). The reaction mixture was heated to reflux for 16 h. It was transferred into 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®, 2.0% methanol in DCM) to afford Int-8.6. MS(ES): m/z 235.3 [M+H]+. [0220] Synthesis of compound Int-8. Compound Int-8 was prepared from Int-8.6, following the procedure described in the synthesis of Int-4. The product was used without purification. MS(ES): m/z 277.4 [M+H]+. [0221] Int-8 and/or Int-8.6 can be used to prepare compounds I-22 and I-23 using methods described herein. Preparation of Intermediate Int-9: 1-isopropyl-3-isothiocyanato-5-(1H-pyrazol-1-yl)pyridin- 2(1H)-one
Figure imgf000075_0001
[0222] Synthesis of compound Int-9.1. A mixture of 5-bromo-1-isopropyl-3-nitropyridin- 2(1H)-one (0.3 g, 1.15 mmol, 1.0 equiv), 1,4-dioxane (12 mL), pyrazole (0.093 g, 1.38 mmol, 1.2 equiv) and potassium carbonate (0.396 g, 2.87 mmol, 2.5 equiv) was degassed by bubbling argon for 10 min and added 1,2-dimethylethylenediamine (0.015 g, 0.172 mmol, 0.15 equiv) and copper iodide (0.065 g, 0.345 mmol, 0.3 equiv). The reaction mixture was degassed for 5 min and was stirred at 100 °C for 12 h. It was cooled to room temperature, poured over water, 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®, 25% ethyl acetate in hexane as eluant) to afford Int-9.1. MS (ES): m/z 249.2 [M+H]+. [0223] Synthesis of compound Int-9.2. A mixture of compound Int-9.1 (0.150 g, 0.604 mmol, 1.0 equiv), methanol (5 mL) and 10% palladium on carbon (0.065 g) was stirred at rt under 1 atm hydrogen for 2 h. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to obtain Int-9.2. MS (ES): m/z 219.3 [M+H]+. [0224] Synthesis of compound Int-9. To a solution of Int-9.2 (1.0 equiv) in dichloromethane was added solution of sodium bicarbonate (5.0 equiv) in water followed by thiophosgene (2.5 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. It was poured over ice-water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain Int-9. MS (ES): m/z 261.3 [M+H]+. [0225] Int-9 and/or Int-9.2 can be used to prepare compounds I-25 and I-26 using methods described herein. Preparation of Intermediate Int-10: 5-cyclopropyl-1-isopropyl-3-isothiocyanatopyridin-2(1H)- one
Figure imgf000076_0001
[0226] Synthesis of compound Int-10.1. To a solution of 5-bromo-3-nitropyridin-2(1H)-one (5.0 g, 22.83 mmol, 1.0 equiv) in DMF (50 mL) was added potassium carbonate (6.6 g, 47.94 mmol, 2.1 equiv) and stirred for 15 min. To the mixture was added isopropyl bromide (3.36 g, 27.39 mmol, 1.2 equiv). The reaction mixture was stirred at 85 °C for 16 h. It was poured over 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®, 7-8% ethyl acetate in hexane as eluant) to afford Int-10.1. MS (ES): m/z 262.2 [M+H]+. [0227] Synthesis of compound Int-10.2. A mixture of Int-10.1 (1.0 equiv), cyclopropylboronic acid (3.0 equiv), potassium phosphate (3.0 equiv) and tricyclohexylphosphine (0.2 equiv) in toluene and water was degassed by bubbling argon for 10 min. Palladium(II) acetate (0.5 equiv) was added under argon, and degassed again for 5 min. The reaction mixture was stirred at 100 °C for 2 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was poured over water, 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®, 20% ethyl acetate in hexane as eluant) to afford Int-10.2. MS (ES): m/z 223.3 [M+H]+. [0228] Synthesis of compound Int-10.3. A flask charged with compound Int-10.2 (1.0 equiv), 10% palladium on carbon and methanol was vacuumed and purged with hydrogen three times. The mixture was stirred at rt under 1 atm hydrogen atmosphere for 1 h. The flask was vacuumed and purged with nitrogen three times before it was opened to air. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to obtain Int-10.3. MS (ES): m/z 193.3 [M+H]+. [0229] Synthesis of compound Int-10. Compound Int-10 was prepared from Int-10.3 following the procedure described in the synthesis of Int-9. The crude product was used in the next step without further purification. MS (ES): m/z 235.3 [M+H]+. [0230] Int-10 and/or Int-10.3 can be used to prepare compound I-28 using methods described herein. Preparation of Intermediate Int-11: 5-(tert-butyl)-1-((tetrahydrofuran-3-yl)methyl)-1H- pyrazol-3-amine
Figure imgf000077_0001
[0231] Synthesis of compound (±)-Int-11.2. To a solution of (tetrahydrofuran-3- yl)methanol ((±)-Int-11.1) (5.0 g, 48.96 mmol, 1.0 equiv) and triethylamine (20.5 mL, 146.88 mmol, 3.0 equiv) in dichloromethane (50 mL) at 0 °C was added MsCl (4.56 mL, 58.75 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 2 h. It was poured over ice- water, stirred and extracted with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate followed by brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (±)-Int-11.2. MS (ES): m/z 181.2 [M+H]+. [0232] Synthesis of compound (±)-Int-11.4. To a solution of Int-1.1 (1.0 equiv) and (±)- Int-11.2 (1.2 equiv) in DMF was added cesium carbonate (2.0 equiv), and the reaction mixture was stirred at 80 °C for 16 h. It was poured over ice-water, stirred 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 product was purified by flash column chromatography on silica gel (CombiFlash®, 8-12% ethyl acetate in hexane) to afford (±)-Int-11.4. MS (ES): m/z 302.3 [M+H]+. [0233] Synthesis of compound (±)-Int-11. A solution of (±)-Int-11.4 (1.0 equiv) and hydroxylamine hydrochloride (10 equiv) in ethanol-water (2/1, v/v) was stirred at 120 °C by a microwave reactor for 1 h. It was poured into ice-water and pH was adjusted to about 10 by the addition of 2 N aqueous sodium hydroxide solution. The mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (±)-Int-11. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2-3% methanol in dichloromethane) to afford (±)-Int-11. MS (ES): m/z 224.3 [M+H]+. [0234] (±)-Int-11 and/or the isothiocyanate thereof (prepared, e.g., by the process described for in the synthesis of Int-9) can be used to prepare compounds I-34-i and I-34-ii using methods described herein. Preparation of Intermediate Int-12: 5-(tert-butyl)-3-isothiocyanato-1-(oxetan-3-ylmethyl)-1H- pyrazole
Figure imgf000078_0001
[0235] Synthesis of compound Int-12.2 and Int-12.3. To a solution of Int-12.1 (0.4 g, 2.65 mmol, 1.0 equiv) in DMF (5 mL) was added sodium hydride (0.165 g, 3.45 mmol, 1.3 equiv) at 0 °C and stirred for 30 min. To the solution was added 5-(tert-butyl)-1H-pyrazol-3-amine (0.0.368 g, 2.65 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 16 h. It was poured over ice, stirred 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 preparative HPLC to obtain Int-12.2. MS (ES): m/z 210.3 [M+H]+ and Int-12.3. MS (ES): m/z 210.3 [M+H]+. [0236] Synthesis of compound Int-12. Compound Int-12 was prepared from Int-12.2 following the procedure described in the synthesis of Int-9. MS (ES): m/z 252.3 [M+H]+. [0237] Int-12 and/or Int-12.2 can be used to prepare compounds I-33 and I-35 using methods described herein. Preparation of Intermediate Int-13: 1-((1r,3r)-3-(benzyloxy)cyclobutyl)-5-(tert-butyl)-3- isothiocyanato-1H-pyrazole
Figure imgf000079_0001
[0238] Synthesis of compound Int-13.1. To a solution of 3-(benzyloxy)cyclobutan-1-one (10 g, 56.75 mmol, 1.0 equiv) in methanol (100 mL) was added sodium borohydride (6.4 g, 170.2 mmol, 3.0 equiv) in small portions at 0 °C. The reaction mixture was stirred at room temperature for 3 h. It was poured over ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford Int-13.1. MS (ES): m/z 179.3 [M+H]+. [0239] Synthesis of compound Int-13.2 To a solution of Int-13.1 (3.0 g, 16.83 mmol, 1.0 equiv) in DCM (30 mL) was added triethylamine (3.0 mL, 21.87 mmol, 1.3 equiv) at 0 °C followed by addition of methanesulfonyl chloride (1.7 mL, 21.87 mmol, 1.3 equiv). The reaction mixture was stirred at room temperature for 12 h. It was poured into ice-water, stirred and extracted with DCM. 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®, 20% ethyl acetate in hexane) to afford Int-13.2. MS (ES): m/z 257.3 [M+H]+. [0240] Synthesis of compound Int-13.3. A mixture of Int-1.1 (3.2 g, 12.48 mmol, 1.0 equiv), Int-13.2 (2.71 g, 12.48 mmol, 1.0 equiv) and cesium carbonate (8.13 g, 24.96 mmol, 2.0 equiv) in DMF (30 mL) was stirred at 80-90 °C for 12 h. It was poured into ice-water, stirred 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®, 8-12% ethyl acetate in hexane) to afford Int-13.3. MS (ES): m/z 378.5 [M+H]+. [0241] Synthesis of compound Int-13.4 A solution of Int-13.3 (1.0 equiv) and hydroxylamine hydrochloride (10 equiv) in ethanol:water (2:1) was stirred at 120 °C in a microwave reactor for 1 h. The reaction mixture was transferred into ice-water, followed by addition of a solution of sodium hydroxide (2 N), and the product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain Int-13.4. The product was purified by flash column chromatography on silica gel (CombiFlash®, 24-28% ethyl acetate in hexane). MS(ES): m/z 300.4 [M+H]+. [0242] Synthesis of compound Int-13. Compound Int-13 was prepared from Int-13.4 following the procedure described in the synthesis of compound Int-1. The product was used without purification. MS(ES): m/z 342.5 [M+H]+. [0243] Int-13 and/or Int-13.4 can be used to prepare compound I-37, after deprotection under standard conditions, using methods described herein. JAK2 Binding Assay [0244] JAK2 (JH1domain-catalytic, Y1007F,Y1008F) kinase was expressed as N-terminal fusion to the DNA binding domain of NFkB in transiently transfected HEK293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mmol/L DTT) to remove unbound ligand and to reduce nonspecific phage binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (1x PBS, 0.05% Tween 20, 0.1% BSA, 1 mmol/L DTT). Test compound was prepared as 111x 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. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05 % Tween 20). The beads were then re-suspended in elution buffer (1x PBS, 0.05 % Tween 20, 0.5 μmol/L non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluate was measured by qPCR. [0245] Results of the JAK2 JH1 Domain Binding Assay described above are presented in Table 2. Compounds denoted as “A” had a Kd < 10 nM; compounds denoted as “B” had a Kd ≥ 10 nM and < 50 nM; compounds denoted as “C” had a Kd ≥ 50 nM and < 1 µM; compounds denoted as “D” had a Kd ≥ 1 µM and < 5 µM; and compounds denoted as “E” had a Kd ≥ 5 µM. Table 2. Results of JAK2 Binding Assay
Figure imgf000081_0001
Figure imgf000082_0001
JAK Family Selectivity Assays [0246] Provided compounds are evaluated for selectivity by comparing their JAK2 binding affinity (Kd) in the above JAK2 Binding Assay with their binding affinity (Kd) for one or more other kinases. 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 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds are prepared as 111X 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 (1x PBS, 0.05% Tween 20). The beads are then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates is measured by qPCR. Compounds that exhibit a better binding affinity for JAK2 compared to one or more other kinases are considered to be JAK2-selective compounds. In some embodiments, provided compounds may be JAK2-selective over one or more of the following kinases: JAK1, JAK3, and Tyk2. SET2-pSTAT5 Cellular Assay [0247] 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 µL 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 µL cold PBS. Then, the cells are spun again at 4 °C and 4000 rpm for 5 min. PBS is aspirated, and 25 µL 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 (MSD) is used to analyze plates as follows: a standard MSD plate is coated with capture antibody in PBS (40 µL/well) and is incubated at 4 °C overnight with shaking. The MSD plate is washed three times with 150 µL/well of 1x MSD Wash Buffer (Tris-buffered saline with 0.1% Tween® 20 detergent, TBST). The MSD plates are then blocked with 150 µL 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 µL/well of 1x MSD Wash Buffer (TBST). Sample lysates are then added to MSD plates (25 µL/well) and shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 µL/well of 1x MSD Wash Buffer (TBST). Detection antibody (prepared in Antibody Detection buffer, 1% BSA in 1xTBST) 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 µL/well of 1x MSD Wash Buffer (TBST). A secondary detection antibody (prepared in Antibody Detection buffer, 1% BSA in 1xTBST) 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 µL/well of 1x MSD Wash Buffer (TBST). MSD reading buffer (1x) is added to the plates (150 µL/well), and they are diluted from 4x with water. The plates are imaged using an MSD imaging instrument according to the manufacturer’s instructions. Caco2 Permeability Assay [0248] Preparation of Caco-2 Cells: 50 μL 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 6.86х105 cells/mL with culture medium, and 50 μL 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. [0249] Preparation of Stock Solutions: 10 mM stock solutions of test compounds are prepared in DMSO. The stock solutions of positive controls are prepared in DMSO at the concentration of 10 mM. Digoxin and propranolol are used as control compounds in this assay. [0250] Assessment of Cell Monolayer Integrity: Medium is removed from the reservoir and each Transwell® insert and is replaced with prewarmed fresh cuture medium. Transepithelial electrical resistance (TEER) across the monolayer is measured using Millicell Epithelial Volt- Ohm measuring system (Millipore, USA). The Plate is returned to the incubator once the measurement is done. The TEER value isss calucated according to the following equation: TEER measurement (ohms) x Area of membrane (cm2) = TEER value (ohm•cm2). A TEER value greater than 230 ohm•cm2 indicates a well-qualified Caco-2 monolayer. [0251] 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 μM 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 μM working solutions. The final concentration of DMSO in the incubation system is 0.5%. To determine the rate of drug transport in the apical to basolateral direction. 75 μL of 5 μM working solutions of test compounds are added to the Transwell® insert (apical compartment) and the wells in the receiver plate (basolateral compartment) are filled with 235 μL of HBSS (10 mM HEPES and 4% BSA, pH 7.4). To determine the rate of drug transport in the basolateral to apical direction, 235 μL of 5 μM working solutions of test compounds are added to the receiver plate wells (basolateral compartment) and then the Transwell® inserts (apical compartment) are filled with 75 μL of HBSS (10 mM HEPES and 4% BSA, pH 7.4). Time 0 samples are prepared by transferring 50 μL of 5 μM working solution to wells of the 96-deepwell plate, followed by the addition of 200 μL cold methanol containing appropriate internal standards (IS). The plates are incuabted at 37 °C for 2 hours. At the end of the incubation, 50 μL 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). Samples are vortexed for 5 minutes and then centrifuged at 3,220 g for 40 minutes. An aliquot of 100 µL of the supernatant is mixed with an appropriate volume of ultra-pure water before LC-MS/MS analysis. To determine the Lucifer Yellow leakage after 2 hour transport period, stock solution of Lucifer yellow is prepared in ultra-pure water and diluted with HBSS (10 mM HEPES, pH 7.4) to reach the final concentration of 100 μM. 100 μL of the Lucifer yellow solution is added to each Transwell® insert (apical compartment), followed by filling the wells in the receiver plate (basolateral compartment) with 300 μL of HBSS (10 mM HEPES, pH 7.4). The plates are incubated at 37 °C for 30 minutes.80 μL 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. Cytotoxicity Assay [0252] 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 μL 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 μL of stock solution is then transferred to a 384 PP-plate. A 3-fold, 10-point dilution is performed via transferring 15 μL compound into 30 μL DMSO by using TECAN (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 μL 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. Inhibition activity is calculated with the following formula: %Inhibition = 100 x (LumHC – LumSample) / (LumHC –LumLC), wherein HC is reading obtained from cells treated with 0.1% DMSO only and LC is reading from cells treated with 10 μL staurosporine. IC50 values are calculated using XLFit (equation 201). Hepatocyte Stability Assay [0253] 10 mM stock solutions of test compound and positive control are prepared in DMSO. Stock solutions are diluted to 100 μM by combining 198 μL of 50% acetonitrile/50% water and 2 μL 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 × 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 0.5×106 viable cells/mL. A portion of the hepatocytes at 0.5×106 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 μL hepatocytes are dispensed into each well of a 96-well non-coated plate. The plate is placed in the incubator for approximately 10 minutes. Aliquots of 2 μL of the 100 μM test compound and 2 μL positive control are added into respective wells of a non-coated 96-well plate to start the reaction. The final concentration of test compound is 1 μM. This assay is performed in duplicate. The plate is incubated in the incubator for the designed time points. 25 μL of contents are transferred and mixed with 6 volumes (150 μL) of cold acetonitrile with internal standard (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine and 200 nM diclofenac) to terminate the reaction at time points of 0, 15, 30, 60, 90 and 120 minutes. Samples are centrifuged for 25 minutes at 3,220 g and aliquots of 150 μL of the supernatants are used for LC-MS/MS analysis. Kinetic Solubility Assay [0254] Stock solutions of test compounds are prepared in DMSO at the concentration of 10 mM, and a stock solution of control compound is prepared in DMSO at the concentration of 30 mM. Diclofenac is used as positive control in the assay. 30 µL stock solution of each compound is placed into their a 96-well rack, followed by adding 970 µL of PBS at pH 4.0 and pH 7.4 into each vial of the cap-less solubility sample plate. This study is performed in duplicate. One stir stick is added to each vial and then vials are sealed using a molded PTDE/SIL 96-Well Plate Cover. 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:
Figure imgf000087_0001
Plasma Protein Binding Assay [0255] Working solutions of test compounds and control compound are prepared in DMSO at the concentration of 200 μM, and then the working solutions are spiked into plasma. The final concentration of compound is 1 μM. 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 μL of plasma sample and dialyzed against equal volume of dialysis buffer (PBS). The assay is performed in duplicate. The dialysis plate is sealed and incubated in an incubator at 37 °C with 5% CO2 at 100 rpm for 6 hours. At the end of incubation, 50 μL of samples from both buffer and plasma chambers are transferred to wells of a 96-well plate. 50 μL of plasma is added to each buffer samples and an equal volume of PBS is supplemented to the collected plasma sample. 400 μL of precipitation buffer acetonitrile containing internal standards (IS, 100 nM alprazolam, 200 nM labetalol, 200 nM imipramine and 2 μM ketoplofen) is added to precipitate protein and release compounds. Samples are vortexed for 2 minutes and centrifuged for 30 minutes at 3,220 g. Aliquot of 50 µL of the supernatant is diluted by 150 µL acetonitrile containing internal standards : ultra-pure H2O = 1 : 1, and the mixture is used for LC-MS/MS analysis. [0256] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMS 1. A compound of Formula I:
Figure imgf000089_0001
or a pharmaceutically acceptable salt thereof, wherein: W is CRw or N; X is CRx or N; Y is CRy or N; Z is –O- or –NRz-; Rw, Rx, and Ry are each independently hydrogen, halogen, -OR1, -N(R1)2, -SR1, optionally substituted C1-6 aliphatic, or –CN; Rz is hydrogen or optionally substituted C1-6 aliphatic; each R1 is independently hydrogen or optionally substituted C1-6 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 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; L is a covalent bond or a bivalent C1-3 straight or branched hydrocarbon chain; and Ra is hydrogen, halogen, optionally substituted C1-6 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.
2. The compound of claim 1, wherein at least one of W, X, and Y is N.
3. The compound of claim 1 or 2, wherein 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.
4. The compound of any one of the preceding claims, wherein 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.
5. The compound of any one of the preceding claims, wherein Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
6. The compound of any one of the preceding claims, wherein Ra is halogen, optionally substituted C1-6 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.
7. The compound of any one of the preceding claims, wherein Ra is optionally substituted C1-6 aliphatic, 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.
8. The compound of any one of the preceding claims, wherein Ra is optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, or optionally substituted 3- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
9. The compound of any one of the preceding claims, wherein:
Figure imgf000092_0001
Rb is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, - OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)SO2R’, - SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6 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, and sulfur; each R is independently hydrogen, optionally substituted C1-6 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 C1-6 aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl.
10. The compound of claim 9, wherein Rb is halogen, -CN, -OR, -SR, -N(R)2, -NO2, - C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, - N(R)C(O)R’, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6 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, and sulfur.
11. The compound of claim 9 or 10, wherein Rb is optionally substituted C1-6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
12. The compound of any one of claims 9-11, wherein Rb is C1-4 alkyl optionally substituted with one or more halogen, C3-C4 cycloalkyl, or 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
13. The compound of any one of claims 9-12, wherein
Figure imgf000093_0001
Figure imgf000093_0002
14. The compound of any one of claims 9-13, wherein
Figure imgf000093_0003
15. The compound of any one of claims 9-13, wherein
Figure imgf000093_0004
16. The compound of any one of the preceding claims, wherein L is a covalent bond.
17. The compound of any one of the preceding claims, wherein L is –CH2-.
18. The compound of any one of the preceding claims, wherein 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.
19. The compound of any one of the preceding claims, wherein Ring B is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
20. The compound of any one of the preceding claims, wherein Ring B is
Figure imgf000094_0001
, wherein: R2 is –N(R)2, –N(R)C(O)R’, –C(O)N(R)2, or –N(R)C(O)N(R)2; each R is independently hydrogen, optionally substituted C1-6 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 C1-6 aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl.
21. The compound of claim 20, wherein R2 is –N(R)C(O)R’ or –C(O)N(R)2.
22. The compound of claim 20 or 21, wherein R2 is –N(R)C(O)R’.
23. The compound of any one of claims 20-22, wherein R2 is –N(H)C(O)(optionally substituted C1-6 alkyl).
24. The compound of any one of claims 20-23, wherein R2 is –N(H)C(O)CH3.
25. The compound of any one of claims 1-17, wherein 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.
26. The compound of claim 25, wherein 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.
27. The compound of claim 25 or 26, wherein 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.
28. The compound of any one of claims 25-27, wherein Ring B is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
29. The compound of any one of the preceding claims, wherein: Ring B is
Figure imgf000096_0001
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 B1 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.
30. The compound of claim 29, wherein Ring B1 is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
31. The compound of claim 29 or 30, wherein Ring B2 is optionally substituted 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
32. The compound of any one of the preceding claims, wherein each R is independently hydrogen or optionally substituted C1-6 aliphatic.
33. The compound of any one of the preceding claims, wherein each R is hydrogen.
34. The compound of any one of the preceding claims, wherein R’ is optionally substituted C1-6 aliphatic.
35. The compound of any one of the preceding claims, wherein R’ is methyl.
36. The compound of any one of the preceding claims, wherein one of W, X, and Y is N.
37. The compound of any one of the preceding claims, wherein two of W, X, and Y are N.
38. The compound of any one of the preceding claims, wherein W is CRw.
39. The compound of claim 38, wherein Rw is hydrogen.
40. The compound of any one of claims 1-37, wherein W is N.
41. The compound of any one of the preceding claims, wherein X is CRx.
42. The compound of claim 41, wherein Rx is hydrogen, -CN, or optionally substituted C1-6 aliphatic.
43. The compound of any one of claims 1-40, wherein X is N.
44. The compound of any one of the preceding claims, wherein Y is CRy.
45. The compound of claim 44, wherein Ry is hydrogen.
46. The compound of any one of claims 1-43, wherein Y is N.
47. The compound of any one of the preceding claims, wherein Z is –O-.
48. The compound of any one of claims 1-46, wherein Z is –NRz-.
49. The compound of claim 48, wherein Rz is hydrogen.
50. The compound of any one of the preceding claims, wherein the compound is of Formula IA:
Figure imgf000098_0001
or a pharmaceutically acceptable salt thereof.
51. The compound of any one of claims 1-49, wherein the compound is of Formula IB:
Figure imgf000098_0002
or a pharmaceutically acceptable salt thereof.
52. The compound of any one of claims 1-49, wherein the compound is of Formula IC:
Figure imgf000099_0001
or a pharmaceutically acceptable salt thereof.
53. The compound of any one of claims 1-49, wherein the compound is of Formula ID:
Figure imgf000099_0002
or a pharmaceutically acceptable salt thereof.
54. The compound of any one of claims 1-49, wherein the compound is of Formula IE:
Figure imgf000099_0003
or a pharmaceutically acceptable salt thereof.
55. The compound of any one of claims 1-49, wherein the compound is of Formula IF:
Figure imgf000100_0003
or a pharmaceutically acceptable salt thereof.
56. The compound of any one of claims 1-49, wherein the compound is of Formula IG:
Figure imgf000100_0001
or a pharmaceutically acceptable salt thereof.
57. The compound of any one of the preceding claims, wherein the compound is of Formula II:
Figure imgf000100_0002
or a pharmaceutically acceptable salt thereof, wherein: Rb is hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, - OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)SO2R’, - SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6 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, and sulfur; each R is independently hydrogen, optionally substituted C1-6 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 C1-6 aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl.
58. The compound of any one of the preceding claims, wherein the compound is of Formula III:
Figure imgf000101_0001
or a pharmaceutically acceptable salt thereof, wherein: R2 is –N(R)2, –N(R)C(O)R’, –C(O)N(R)2, or –N(R)C(O)N(R)2; each R is independently hydrogen, optionally substituted C1-6 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 C1-6 aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl.
59. The compound of any one of the preceding claims, wherein the compound is of Formula IV:
Figure imgf000102_0001
or a pharmaceutically acceptable salt thereof, wherein: 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 B1 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.
60. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.
61. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
62. A method of inhibiting JAK2 in a subject comprising administering the compound of any one of claims 1-60 or the composition of claim 61.
63. A method of treating a disease, disorder, or condition associated with JAK2, comprising administering to a subject in need thereof the compound of any one of claims 1-60 or the composition of claim 61.
64. A method of treating cancer, comprising administering to a subject in need thereof the compound of any one of claims 1-60 or the composition of claim 61.
65. A method of treating a hematological malignancy, comprising administering to a subject in need thereof the compound of any one of claims 1-60 or the composition of claim 61.
66. The method of claim 65, wherein the hematological malignancy is leukemia or lymphoma.
67. A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof the compound of any one of claims 1-60 or the composition of claim 61.
68. The method of claim 67, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia or myelofibrosis.
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