[go: up one dir, main page]

WO2023009709A1 - Pyrazolo pipérazines en tant qu'inhibiteurs de jak2 - Google Patents

Pyrazolo pipérazines en tant qu'inhibiteurs de jak2 Download PDF

Info

Publication number
WO2023009709A1
WO2023009709A1 PCT/US2022/038657 US2022038657W WO2023009709A1 WO 2023009709 A1 WO2023009709 A1 WO 2023009709A1 US 2022038657 W US2022038657 W US 2022038657W WO 2023009709 A1 WO2023009709 A1 WO 2023009709A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
nitrogen
sulfur
oxygen
independently selected
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2022/038657
Other languages
English (en)
Inventor
Craig E. Masse
Jeremy R. Greenwood
Jiayi Xu
Sayan Mondal
Phani GHANAKOTA
Fiona Michelle MCROBB
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ajax Therapeutics Inc
Original Assignee
Ajax Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ajax Therapeutics Inc filed Critical Ajax Therapeutics Inc
Publication of WO2023009709A1 publication Critical patent/WO2023009709A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • JAK2 INHIBITORS RELATED APPLICATIONS [0001] This application claims priority to and benefit of U.S. Application No. 63/226,892, 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, Z, R a , R x , R 1 , R 1’ , R 2 , R 2’ , R 3 , R 3’ , R 4 , and R 4’ are as defined herein.
  • structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure.
  • 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.
  • 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 ).
  • 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 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., C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 1- 3, or C 1-2 ).
  • 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., C6-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
  • the term “aryl” may be used interchangeably with the term “aryl ring”.
  • “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons.
  • Heteroaryl refers to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 ⁇ 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 .
  • 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 Ro 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 ) 0-2 NHR ⁇ , –(CH 2 )
  • 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 ⁇ ,
  • 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.
  • Z is –O- or –NR z -;
  • R x is hydrogen, halogen, -OR 5 , -N(R 5 ) 2 , -SR 5 , optionally substituted C 1-6 aliphatic, or –CN;
  • R z is hydrogen or optionally substituted C 1-6 aliphatic;
  • R 1 , R 1’ , R 2 , R 2’ , R 3 , and R 3’ are each independently hydrogen or optionally substituted C 1-6 aliphatic;
  • R 4 and R 4’ are each independently hydrogen or optionally substituted C 1-6 aliphatic, or R 4 and R 4’ are taken together to form an oxo;
  • each R 5 is independently hydrogen or optionally substituted C 1-6 aliphatic;
  • Ring A is optionally substituted
  • the present disclosure provides a compound of Formula IB: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, R a , and R 1 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 IB: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, R a , and R 1 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 , and R 1 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:
  • Ring A, Ring B, L, Z, R a , R x , R 1 , R 1’ , R 2 , R 2’ , R 3 , R 3’ , R 4 , and R 4’ 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 2 R’, -SO 2 N
  • Ring A, L, Z, R a , R x , R 1 , R 1’ , R 2 , R 2’ , R 3 , R 3’ , R 4 , and R 4’ are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and: R 6 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- membere
  • the present disclosure provides a compound of Formula IV: or a pharmaceutically acceptable salt thereof, wherein Ring A, L, Z, R a , R x , R 1 , R 1’ , R 2 , R 2’ , R 3 , R 3’ , R 4 , and R 4’ 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 hetero
  • Z is –O-. In some embodiments, Z is –NR z -. In some embodiments, Z is –NH-.
  • R x is hydrogen, halogen, or optionally substituted C 1-6 aliphatic. In some embodiments, R x is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R x is hydrogen or C 1-6 alkyl. In some embodiments, R x is hydrogen. In some embodiments, R x is halogen. In some embodiments, R x is fluoro.
  • 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 –CN. [0037] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV, R z is hydrogen. In some embodiments, R z is optionally substituted C 1-6 aliphatic.
  • 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. In some embodiments, R z is optionally substituted C 1-2 alkyl. In some embodiments, R z is unsubstituted C 1-2 alkyl.
  • R 1 is hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is optionally substituted C 1-6 aliphatic. In some embodiments, R 1 is optionally substituted C 1-6 alkyl. In some embodiments, R 1 is optionally substituted C 1-4 alkyl. In some embodiments, R 1 is optionally substituted C 1-2 alkyl. In some embodiments, R 1 is methyl. [0039] In some embodiments of any of Formulae I, II, III, and IV, R 1’ is hydrogen or optionally substituted C 1-6 alkyl.
  • R 1’ is hydrogen. In some embodiments, R 1’ is optionally substituted C 1-6 aliphatic. In some embodiments, R 1’ is optionally substituted C 1-6 alkyl. In some embodiments, R 1’ is optionally substituted C 1-4 alkyl. In some embodiments, R 1’ is optionally substituted C 1-2 alkyl. In some embodiments, R 1’ is methyl. [0040] In some embodiments of any of Formulae I, II, III, and IV, R 2 is hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, R 2 is optionally substituted C 1-6 alkyl.
  • R 2 is optionally substituted C 1-4 alkyl. In some embodiments, R 2 is optionally substituted C 1-2 alkyl. In some embodiments, R 2 is methyl.
  • R 2’ is hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, R 2’ is hydrogen. In some embodiments, R 2’ is optionally substituted C 1-6 aliphatic. In some embodiments, R 2’ is optionally substituted C 1-6 alkyl. In some embodiments, R 2’ is optionally substituted C 1-4 alkyl. In some embodiments, R 2’ is optionally substituted C 1-2 alkyl. In some embodiments, R 2’ is methyl.
  • R 3 is hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is optionally substituted C 1-6 aliphatic. In some embodiments, R 3 is optionally substituted C 1-6 alkyl. In some embodiments, R 3 is optionally substituted C 1-4 alkyl. In some embodiments, R 3 is optionally substituted C 1-2 alkyl. In some embodiments, R 3 is methyl. [0043] In some embodiments of any of Formulae I, II, III, and IV, R 3’ is hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, R 3’ is hydrogen.
  • R 3’ is optionally substituted C 1-6 aliphatic. In some embodiments, R 3’ is optionally substituted C 1-6 alkyl. In some embodiments, R 3’ is optionally substituted C 1-4 alkyl. In some embodiments, R 3’ is optionally substituted C 1-2 alkyl. In some embodiments, R 3’ is methyl. [0044] In some embodiments of any of Formulae I, II, III, and IV, R 4 is hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is optionally substituted C 1-6 aliphatic. In some embodiments, R 4 is optionally substituted C 1-6 alkyl.
  • R 4 is optionally substituted C 1-4 alkyl. In some embodiments, R 4 is optionally substituted C 1-2 alkyl. In some embodiments, R 4 is methyl.
  • R 4’ is hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, R 4’ is hydrogen. In some embodiments, R 4’ is optionally substituted C 1-6 aliphatic. In some embodiments, R 4’ is optionally substituted C 1-6 alkyl. In some embodiments, R 4’ is optionally substituted C 1-4 alkyl. In some embodiments, R 4’ is optionally substituted C 1-2 alkyl. In some embodiments, R 4’ is methyl.
  • R 4 and R 4’ are taken together to form an oxo. In some embodiments, both R 4 and R 4’ are hydrogen. [0047] In some embodiments, all of R 1 , R 1’ , R 2 , R 2’ , R 3 , and R 3’ are hydrogen. In some embodiments, R 1 is optionally substituted C 1-6 alkyl, and R 1’ , R 2 , R 2’ , R 3 , and R 3’ are hydrogen. In some embodiments, R 1 is methyl, and R 1’ , R 2 , R 2’ , R 3 , and R 3’ are hydrogen.
  • each R 5 is independently hydrogen or optionally substituted C 1-4 aliphatic. In some embodiments, each R 5 is independently hydrogen or optionally substituted C 1-2 aliphatic. In some embodiments, each R 5 is hydrogen. In some embodiments, each R 5 is independently optionally substituted C 1-6 aliphatic. In some embodiments, each R 5 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 5 is independently optionally substituted C 1-4 aliphatic.
  • each R 5 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 5 is independently optionally substituted C 1-2 aliphatic. In some embodiments, each R 5 is independently hydrogen or C 1-6 alkyl. In some embodiments, each R 5 is independently hydrogen or C 1-4 alkyl. In some embodiments, each R 5 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, -Ro, -CN, -ORo, -SRo, -N(Ro) 2 , -NO 2 , -C(O)Ro, -C(O)OR°, - C(O)NRo 2 , -OC(O)Ro, -OC(O)NRo 2 , –OC(O)OR°, -OS(O) 2 Ro, -OS(O) 2 NRo 2 , -N(Ro)C(O)Ro, - N(Ro)S(O) 2 Ro, -S(O) 2 Ro, -SO 2 NRo 2 , and -S(O) 2 ORo, and (ii) optionally substituted on a substitutable nitrogen
  • Ring A is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, and Ro, 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 Ro, 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 Ro, 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.
  • 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 -.
  • 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, 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 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 6-membered saturated monocyclic heterocyclyl having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 8-membered saturated, spirocyclic, bicyclic 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.
  • 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 optionally substituted C 1-6 alkyl. In some embodiments, R a is optionally substituted C 1-4 alkyl. In some embodiments, R a is –CH 3 . [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 optionally substituted C 3-6 cycloalkyl.
  • R a is optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl.
  • R a is optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclyl.
  • R a is optionally substituted cyclobutyl (e.g., cyclobutyl optionally substituted with –OH). In some embodiments, R a is optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R a is optionally substituted 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R a is optionally substituted 7-membered saturated or partially unsaturated monocyclic carbocyclyl. [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 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 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 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.
  • R a is optionally substituted 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is optionally substituted 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [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. In some embodiments, R a is optionally substituted 7- to 10- membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R a is optionally substituted 7- to 8-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is optionally substituted 2-oxaspiro[3.3]heptanyl. [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, II, III, and IV, s –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 C3 straight hydrocarbon chain).
  • 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 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 unsaturated monocyclic carbocyclyl, optional
  • each occurrence of R b is independently optionally substituted C 1-6 aliphatic or optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, each occurrence of R b is independently optionally substituted C 1-4 alkyl or optionally substituted C 3 -C 4 cycloalkyl. 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. In some embodiments, each occurrence of R b is independently C 1-4 alkyl or C 3-4 cycloalkyl. [0072] In some embodiments, R b is hydrogen.
  • R b is halogen. In some embodiments, R b is fluoro, chloro, bromo, or iodo. In some embodiments, R b is fluoro. In some embodiments, R b is chloro.
  • R b is -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 C 1- 4 alkyl. In some embodiments, R b is selected from the group consisting of –CH 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. [0077] In some embodiments, R b is optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R b is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R b is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • optionally substituted [0080]
  • [0082] is selected from the group consisting of: , , , , [0083]
  • 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, -Ro, -CN, -ORo, -SRo, -N(Ro) 2
  • Ring B is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, -Ro, -CN, -ORo, -N(Ro) 2 , -C(O)NRo 2 , -N(Ro)C(O)Ro, and -N(Ro)C(O)NRo 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(Ro) 2 , -C(O)NRo 2 , -N(Ro)C(O)Ro, and -N(Ro)C(O)NRo 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 6 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 . In some embodiments, Ring B is .
  • R 6 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.
  • R 6 is –N(R)C(O)R’ or –C(O)N(R) 2 .
  • R 6 is –N(R)C(O)R’.
  • R 6 is – N(H)C(O)R’.
  • R 6 is –N(R)C(O)(optionally substituted C 1-6 aliphatic). In some embodiments, R 6 is –N(H)C(O)(optionally substituted C 1-6 aliphatic). In some embodiments, R 6 is –N(R)C(O)(C 1-6 aliphatic). In some embodiments, R 6 is –N(H)C(O)(C 1-6 aliphatic). In some embodiments, R 6 is –N(R)C(O)(straight-chain or branched C 1-6 aliphatic). In some embodiments, R 6 is –N(H)C(O)(straight-chain or branched C 1-6 aliphatic).
  • R 6 is –N(R)C(O)(optionally substituted C 1-6 alkyl). In some embodiments, R 6 is – N(H)C(O)(optionally substituted C 1-6 alkyl). In some embodiments, R 6 is –N(R)C(O)(C 1-6 alkyl). In some embodiments, R 6 is –N(H)C(O)(C 1-6 alkyl). In some embodiments, R 6 is – N(R)C(O)(optionally substituted C 1-4 alkyl). In some embodiments, R 6 is –N(H)C(O)(optionally substituted C 1-4 alkyl).
  • R 6 is –N(R)C(O)(C 1-4 alkyl). In some embodiments, R 6 is –N(H)C(O)(C 1-4 alkyl). In some embodiments, R 6 is –N(R)C(O)(optionally substituted C 1-2 alkyl). In some embodiments, R 6 is –N(H)C(O)(optionally substituted C 1-2 alkyl). In some embodiments, R 6 is –N(R)C(O)(C 1-2 alkyl). In some embodiments, R 6 is – N(H)C(O)(C 1-2 alkyl). In some embodiments, R 6 is –N(R)C(O)CH 3 .
  • R 6 is –N(H)C(O)CH 3 . In some embodiments, R 6 is –N(R)C(O)(optionally substituted C 3-7 carbocyclyl). In some embodiments, R 6 is –N(H)C(O)(optionally substituted C 3-7 carbocyclyl). In some embodiments, R 6 is –N(R)C(O)(optionally substituted C 3-7 cycloalkyl). In some embodiments, R 6 is –N(H)C(O)(optionally substituted C 3-7 cycloalkyl). In some embodiments, R 6 is –N(R)C(O)(C 3-6 cycloalkyl).
  • R 6 is –N(H)C(O)(C 3-6 cycloalkyl). In some embodiments, R 6 is –N(R)C(O)(cyclopropyl). In some embodiments, R 6 is – N(H)C(O)(cyclopropyl). [0101] In some embodiments, R 6 is –C(O)N(R) 2 . In some embodiments, R 6 is – C(O)N(R)(C 1-6 aliphatic). In some embodiments, R 6 is –C(O)N(H)(C 1-6 aliphatic).
  • R 6 is –C(O)N(R)(straight-chain or branched C 1-6 aliphatic). In some embodiments, R 6 is –C(O)N(H)(straight-chain or branched C 1-6 aliphatic). In some embodiments, R 6 is –C(O)N(R)(C 1-6 alkyl). In some embodiments, R 6 is –C(O)N(H)(C 1-6 alkyl). In some embodiments, R 6 is –C(O)N(R)(C 1-4 alkyl). In some embodiments, R 6 is – C(O)N(H)(C 1-4 alkyl).
  • R 6 is –C(O)N(R)(C 1-2 alkyl). In some embodiments, R 6 is –C(O)N(H)(C 1-2 alkyl). [0102] In some embodiments, R 6 is –N(R) 2 . In some embodiments, R 6 is –N(H)(R). [0103] In some embodiments, R 6 is –N(R)C(O)N(R) 2 .
  • R 6 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 6 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 6 is –N(H)C(O)N(R) 2 .
  • R 6 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 6 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. In some embodiments, R’ is cyclopropyl.
  • 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. In some embodiments, when Ring B1 is phenyl, Ring B2 contains at least one heteroatom.
  • Ring B1 is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is unsubstituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B1 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, when Ring B1 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, Ring B2 contains at least one heteroatom. In some embodiments, when Ring B2 is not aromatic, Ring B1 is optionally substituted 5- to 6-membered saturated monocyclic carbocyclyl. In some embodiments, Ring B1 is optionally substituted 5- to 6-membered partially saturated monocyclic carbocyclyl.
  • Ring B1 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B2 when Ring B2 is not aromatic, Ring B1 is optionally substituted 5- to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B1 is optionally substituted 5- to 6-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B2 is an optionally substituted ring selected from 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B2 is optionally substituted phenyl. In some embodiments, when Ring B2 is phenyl, Ring B1 contains at least one heteroatom.
  • Ring B2 is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B2 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B2 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B2 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, when Ring B2 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, Ring B1 contains at least one heteroatom. In some embodiments, when Ring B1 (and Ring B3, if present) is not aromatic, Ring B2 is optionally substituted 5- to 6-membered saturated monocyclic carbocyclyl. In some embodiments, Ring B2 is optionally substituted 5- to 6-membered partially saturated monocyclic carbocyclyl.
  • Ring B2 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B1 when Ring B1 (and Ring B3, if present) is not aromatic, Ring B2 is optionally substituted 5- to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B2 is optionally substituted 5- to 6-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B1 and Ring B2 are both optionally substituted 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B1 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • Ring B2 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B1 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • Ring B2 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring B2 is further fused to Ring B3.
  • 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. 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:
  • the present disclosure encompasses the recognition that provided compounds display certain desirable characteristics, e.g., as compared to other known compounds.
  • provided compounds are more potent in one or more biochemical or cellular assays (e.g., the JAK2 Binding Assay or SET2-pSTAT5 Cellular Assay described herein) and/or have one or more other characteristics that make them more suitable for drug development, such as better selectivity over other kinases and/or better ADME (absorption, distribution, metabolism, and excretion) properties including but not limited to better permeability, cytotoxicity, hepatocyte stability, solubility, and/or plasma protein binding profiles (e.g., based on assays described in the ensuing examples), than other known compounds.
  • provided compounds display certain desirable characteristics in one or more assays described herein, e.g., compared to other known compounds.
  • provided compounds are provided and/or utilized in a salt form (e.g., a pharmaceutically acceptable salt form).
  • a salt form e.g., a pharmaceutically acceptable salt form.
  • Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated.
  • Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19(1977).
  • provided compounds are prepared according to the following Scheme: wherein PG is a suitable protecting group (e.g., Cbz); LG 1 is a first suitable leaving group (e.g., halogen, e.g., chloro or bromo); LG 2 is a second suitable leaving group (e.g., halogen, e.g., chloro or bromo); and Ring A, Ring B, L, Z, R 1 , R 1’ , R 2 , R 2’ , R 3 , R 3’ , R 4 , R 4’ , R x , and R a are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • PG is a suitable protecting group (e.g., Cbz)
  • LG 1 is a first suitable leaving group (e.g., halogen, e.g., chloro or bromo)
  • LG 2 is a second suitable leaving group (e.g., halogen, e.
  • 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., K3PO4).
  • intermediate A.3 is prepared by a process comprising contacting intermediate A.2 in the presence of a suitable base (e.g., K3PO4), a suitable metal complex (e.g., a palladium complex such as methanesulfonato (di-tert-butyl)phenylphosphino(2′- amino-1,1′-biphenyl-2-yl)palladium(II)), and, optionally, a suitable ligand.
  • a suitable metal complex e.g., a palladium complex such as methanesulfonato (di-tert-butyl)phenylphosphino(2′- amino-1,1′-biphenyl-2-yl)palladium(II)
  • a suitable ligand e.g
  • a compound of Formula I is prepared by a process comprising subjecting intermediate A.3 to suitable deprotection conditions, followed by contacting the resulting compound with intermediate A.4, optionally in the presence of a suitable base (e.g., K 2 CO 3 ).
  • suitable deprotection conditions are known in the art; for example, when PG is Cbz, suitable deprotection conditions may comprise H 2 and a metal compound (e.g., Pd/C or Pd(OH 2 ) 2 ).
  • provided compounds are prepared according to the following Scheme: wherein PG is a suitable protecting group (e.g., Cbz); LG 1 is a first suitable leaving group (e.g., halogen, e.g., chloro or bromo); LG 2 is a second suitable leaving group (e.g., halogen, e.g., chloro or bromo); and Ring A, Ring B, L, Z, R 1 , R 1’ , R 2 , R 2’ , R 3 , R 3’ , R 4 , R 4’ , R x , and R a are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • PG is a suitable protecting group (e.g., Cbz)
  • LG 1 is a first suitable leaving group (e.g., halogen, e.g., chloro or bromo)
  • LG 2 is a second suitable leaving group (e.g., halogen, e.
  • intermediate B.3 is prepared by a process comprising contacting intermediate B.1 with intermediate B.2 in the presence of a suitable base.
  • intermediate B.3 is prepared by a process comprising contacting intermediate B.2 in the presence of a suitable base, a suitable metal complex (e.g., a palladium complex), and, optionally, a suitable ligand.
  • a compound of Formula I is prepared by a process comprising subjecting intermediate B.3 to suitable deprotection conditions, followed by contacting the resulting compound with intermediate B.4, optionally in the presence of a suitable base.
  • Suitable deprotection conditions are known in the art; for example, when PG is Cbz, suitable deprotection conditions may comprise H 2 and a metal compound (e.g., Pd/C or Pd(OH 2 ) 2 ).
  • a metal compound e.g., Pd/C or Pd(OH 2 ) 2 .
  • provided compounds e.g., compounds of Formula I wherein R 4 and R 4’ are taken together to form an oxo
  • PG is a suitable protecting group (e.g., Cbz)
  • Ring A, Ring B, L, Z, R 1 , R 1’ , R 2 , R 2’ , R 3 , R 3’ , R x , 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 subjecting intermediate C.1 to suitable deprotection conditions, followed by contacting the resulting compound with intermediate C.2 under suitable amide coupling conditions (e.g., in the presence of a suitable base and/or suitable coupling agent).
  • suitable deprotection conditions are known in the art; for example, when PG is Cbz, suitable deprotection conditions may comprise H 2 and a metal compound (e.g., Pd/C or Pd(OH 2 ) 2 ).
  • 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, 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, 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. [0131] 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. [0135] 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. 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. [0138] 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.
  • a hematological malignancy is leukemia (e.g., chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, or acute monocytic leukemia).
  • a hematological malignancy is lymphoma (e.g., Burkitt’s lymphoma, Hodgkin’s lymphoma, or non-Hodgkin’s lymphoma).
  • a non- Hodgkin’s lymphoma is a B-cell lymphoma.
  • a non-Hodgkin’s lymphoma is a NK/T-cell lymphoma (e.g., cutaneous T-cell lymphoma).
  • a hematological malignancy is myeloma (e.g., multiple myeloma).
  • a hematological malignancy is myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or myelofibrosis).
  • a hematological malignancy is myelodysplastic syndrome.
  • the present disclosure provides methods of treating an inflammatory disease, disorder, or condition (e.g., acute respiratory syndrome, hyperinflammation, and/or cytokine storm syndrome (including those associated with COVID- 19) or atopic dermatitis), comprising administering a provided compound or composition to a subject in need thereof.
  • an inflammatory disease, disorder, or condition e.g., acute respiratory syndrome, hyperinflammation, and/or cytokine storm syndrome (including those associated with COVID- 19) or atopic dermatitis
  • a provided compound or composition is administered as part of a combination therapy.
  • combination therapy refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents).
  • the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens.
  • “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination.
  • combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.
  • a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapies (e.g., an anti-cancer therapy and/or therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care).
  • additional therapies include, but are not limited to, BCL2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mivebresib), proteasome inhibitors (e.g., bortezomib), LSD1 inhibitors (e.g., IMG-7289), and CXCR2 inhibitors.
  • JAK2 inhibitors Useful combinations of a JAK2 inhibitor with BCL2, HDAC, BET, and proteasome inhibitors have been demonstrated in cells derived from cutaneous T-cell lymphoma patients (Yumeen, S., et al., Blood Adv. 2020, 4(10), 2213-2226).
  • CXCR2 activity has been shown to modulate signaling pathways involved in tumor growth, angiogenesis, and/or metastasis, including the JAK-STAT3 pathway (Jaffer, T., Ma, D. Transl. Cancer Res. 2016, 5(Suppl. 4), S616-S628).
  • methanesulfonato (di-tert-butyl)phenylphosphino(2′-amino-1,1′-biphenyl-2- yl)palladium(II) (0.277 g, 0.349 mmol, 0.4 equiv) was added, again degassed for 5 min.
  • the reaction mixture was stirred at room temperature for 12 h. It was poured over ice cold water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Example 2 N-(4-(((S)-2-((5-(tert-butyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-4- methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)pyridin-2-yl)acetamide and N-(4- (((R)-2-((5-(tert-butyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-4-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)pyridin-2-yl)acetamide
  • Example 3 N-(4-(((R)-2-((5-(tert-butyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3- yl)amino)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)pyridin-2- yl)cyclopropanecarboxamide and N-(4-(((S)-2-((5-(tert-butyl)-1-((S)-tetrahydrofuran-3-yl)-1H- pyrazol-3-yl)amino)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)pyridin-2- yl)cyclopropanecarboxamide [0171] Synthesis of compound 3.1.
  • the diastereomers were separated by HPLC (column: CHIRALPAK IC (250 mm x 4.6 mm, 5 ⁇ m); mobile phase: (A) 0.1% DEA in n-hexane, (B) 0.1% DEA in propane-2-ol:acetonitrile (70:30); flow rate: 20 mL/min) to afford first eluting fraction (I-3-a) and second eluting fraction (I-3-b).
  • HPLC column: CHIRALPAK IC (250 mm x 4.6 mm, 5 ⁇ m); mobile phase: (A) 0.1% DEA in n-hexane, (B) 0.1% DEA in propane-2-ol:acetonitrile (70:30); flow rate: 20 mL/min) to afford first eluting fraction (I-3-a) and second eluting fraction (I-3-b).
  • HPLC column: CHIRALPAK IC (250 mm x 4.6 mm, 5
  • Int-2 can be used to prepare compounds I-5-i and I-5-ii using methods described herein.
  • Preparation of Intermediate Int-3 1-((1r,3r)-3-(benzyloxy)cyclobutyl)-5-(tert-butyl)-1H- pyrazol-3-amine [0184] Synthesis of compound Int-3.1.
  • Int-3 can be used to prepare compounds I-6-i and I-6-ii, after deprotection using standard conditions, using methods described herein.
  • 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.
  • Binding affinity for other kinases is determined as follows: Kinase-tagged T7 phage strains are prepared in an E. coli host derived from the BL21 strain. E. coli are grown to log-phase and infected with T7 phage and incubated with shaking at 32 °C until lysis. The lysates are centrifuged and filtered to remove cell debris. The remaining kinases are produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection.
  • Streptavidin-coated magnetic beads are treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • the liganded beads are blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding.
  • Binding reactions are assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds are prepared as 11 IX stocks in 100% DMSO.
  • Kds are determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds are then diluted directly into the assays such that the final concentration of DMSO is 0.9%. All reactions are performed in polypropylene 384-well plate. Each has a final volume of 0.02 ml. The assay plates are incubated at room temperature with shaking for 1 hour and the affinity beads are washed with wash buffer (lx PBS, 0.05% Tween 20).
  • JAK2-selective compounds Compounds that exhibit a better binding affinity for JAK2 compared to one or more other kinases are considered to be JAK2-selective compounds.
  • provided compounds may be JAK2-selective over one or more of the following kinases: JAK1, JAK3, and Tyk2.
  • This assay measures inhibition of JAK2-mediated pSTAT5 signaling in constitutively active essential thrombocytopenia cells carrying the V617F mutation.
  • Cells are harvested from a flask into cell culture medium, and the number of cells is counted.
  • the cells are diluted with culture medium and 100 ⁇ 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. After 4 hours, the cells are spun, and the cell pellets are re-suspended with 100 ⁇ L cold PBS.
  • 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.
  • Meso-scale discovery is used to analyze plates as follows: a standard MSD plate is coated with capture antibody in PBS (40 ⁇ L/well) and is incubated at 4 °C overnight with shaking.
  • the MSD plate is washed three times with 150 ⁇ L/well of 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).
  • 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
  • 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 [0197] 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. Then, the 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. Digoxin and propranolol are used as control compounds in this assay.
  • 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 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%.
  • 75 ⁇ L of 5 ⁇ M 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 ⁇ L of HBSS (10 mM HEPES and 4% BSA, pH 7.4).
  • 235 ⁇ L of 5 ⁇ M 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 ⁇ L of HBSS (10 mM HEPES and 4% BSA, pH 7.4).
  • 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 [0204]
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de pyrazolo pipérazine et des compositions de ceux-ci utiles pour inhiber JAK2.
PCT/US2022/038657 2021-07-29 2022-07-28 Pyrazolo pipérazines en tant qu'inhibiteurs de jak2 Ceased WO2023009709A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163226892P 2021-07-29 2021-07-29
US63/226,892 2021-07-29

Publications (1)

Publication Number Publication Date
WO2023009709A1 true WO2023009709A1 (fr) 2023-02-02

Family

ID=82942415

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2022/038657 Ceased WO2023009709A1 (fr) 2021-07-29 2022-07-28 Pyrazolo pipérazines en tant qu'inhibiteurs de jak2

Country Status (1)

Country Link
WO (1) WO2023009709A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013024078A1 (fr) * 2011-08-17 2013-02-21 F. Hoffmann-La Roche Ag Inhibiteurs de la tyrosine kinase de bruton
WO2020081450A1 (fr) * 2018-10-15 2020-04-23 Nurix Therapeutics, Inc. Composés bifonctionnels pour la dégradation de btk par l'intermédiaire d'une voie ubiquitine-protéasome
WO2020089455A1 (fr) * 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg 6,7-dihydro-4 h-pyrazolo[1,5-a]pyrazine indole-2-carboxamides actifs contre le virus de l'hépatite b (vhb)
WO2020097400A1 (fr) * 2018-11-07 2020-05-14 Dana-Farber Cancer Institute, Inc. Dérivés d'imidazopyridine et dérivés d'aza-imidazopyridine utilisés comme inhibiteurs de la janus kinase 2 et utilisations associées
WO2021091575A1 (fr) * 2019-11-08 2021-05-14 Nurix Therapeutics, Inc. Composés bifonctionnels pour la dégradation de btk par l'intermédiaire de la voie de l'ubiquitine-protéosome
WO2021113557A1 (fr) * 2019-12-04 2021-06-10 Nurix Therapeutics, Inc. Composés bifonctionnels pour la dégradation de la btk par l'intermédiaire de la voie de l'ubiquitine-protéosome
WO2021226261A1 (fr) * 2020-05-06 2021-11-11 Ajax Therapeutics, Inc. 6-hétéroaryloxy benzimidazoles et azabenzimidazoles en tant qu'inhibiteurs de jak2

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013024078A1 (fr) * 2011-08-17 2013-02-21 F. Hoffmann-La Roche Ag Inhibiteurs de la tyrosine kinase de bruton
WO2020081450A1 (fr) * 2018-10-15 2020-04-23 Nurix Therapeutics, Inc. Composés bifonctionnels pour la dégradation de btk par l'intermédiaire d'une voie ubiquitine-protéasome
WO2020089455A1 (fr) * 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg 6,7-dihydro-4 h-pyrazolo[1,5-a]pyrazine indole-2-carboxamides actifs contre le virus de l'hépatite b (vhb)
WO2020097400A1 (fr) * 2018-11-07 2020-05-14 Dana-Farber Cancer Institute, Inc. Dérivés d'imidazopyridine et dérivés d'aza-imidazopyridine utilisés comme inhibiteurs de la janus kinase 2 et utilisations associées
WO2021091575A1 (fr) * 2019-11-08 2021-05-14 Nurix Therapeutics, Inc. Composés bifonctionnels pour la dégradation de btk par l'intermédiaire de la voie de l'ubiquitine-protéosome
WO2021113557A1 (fr) * 2019-12-04 2021-06-10 Nurix Therapeutics, Inc. Composés bifonctionnels pour la dégradation de la btk par l'intermédiaire de la voie de l'ubiquitine-protéosome
WO2021226261A1 (fr) * 2020-05-06 2021-11-11 Ajax Therapeutics, Inc. 6-hétéroaryloxy benzimidazoles et azabenzimidazoles en tant qu'inhibiteurs de jak2

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
"March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS
JAFFER, T.MA, D., TRANSL. CANCER RES., vol. 5, 2016, pages S616 - S628
JUTZI, J.S. ET AL.: "2", HEMASPHERE, no. 3, 2018
MEYER S. C.LEVINE, R. L., CLIN. CANCER RES., vol. 20, no. 8, 2014, pages 2051 - 9
O'SHEA, J. J. ET AL., ANN. RHEUM. DIS., vol. 72, April 2013 (2013-04-01), pages 111 - 115
RODRIGUES, M. A.TORRES, T. J., DERM. TREAT., vol. 31, no. 1, 2019, pages 33 - 40
S. M. BERGE ET AL., J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
THOMAS SORRELL: "Handbook of Chemistry and Physics", 1999, UNIVERSITY SCIENCE BOOKS
VAINCHENKER, W ET AL., FLOOORESEARCH, vol. 7, 2018, pages 82
VAINCHENKER, W.KRALOVICS, R., BLOOD, vol. 129, no. 6, 2017, pages 667 - 79
WU, S. C. ET AL., CANCER CELL, vol. 28, no. 1, 13 July 2015 (2015-07-13), pages 29 - 41
YUMEEN, S. ET AL., BLOOD ADV, vol. 4, no. 10, 2020, pages 2213 - 2226

Similar Documents

Publication Publication Date Title
CA3183656A1 (fr) 2-amino-3-cyano thiophenes anneles et leurs derives pour le traitement du cancer
US11970494B2 (en) 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
AU2020247451B2 (en) Imidazolonylquinoline compounds and therapeutic uses thereof
JP2023525047A (ja) Ｊａｋ２阻害薬としての６－ヘテロアリールオキシベンゾイミダゾール及びアザベンゾイミダゾール
US11304929B2 (en) Tosylacetate based compounds and derivatives thereof as PHGDH inhibitors
JP2023518609A (ja) 新規アミノピリミジン系ｅｇｆｒ阻害剤
US11213520B2 (en) Phenylpyrazolylacetamide compounds and derivatives as CDK8/CDK19 inhibitors
CN113365984A (zh) Lox抑制剂
JP2023515729A (ja) Ｃｄｋ９阻害剤としての多環式アミド系誘導体、その調製方法及び用途
WO2023009709A1 (fr) Pyrazolo pipérazines en tant qu'inhibiteurs de jak2
CN111163775B (zh) 作为cdk8/cdk19抑制剂的新型[1,6]萘啶化合物和衍生物
WO2023009712A1 (fr) Hétéroaryloxy thiazolo azines en tant qu'inhibiteurs de jak2
CN112243440A (zh) 可用作LOX抑制剂的六羟基吡咯并[3,4-c]吡咯衍生物
WO2023009708A1 (fr) Hétéroaryloxy triazolo-azines et imidazo-azines en tant qu'inhibiteurs de jak2
WO2025230890A1 (fr) Inhibiteurs de jak2 hétéroaromatiques 5,6 bicycliques
WO2024148247A2 (fr) Azaindazoles en tant qu'inhibiteurs de jak2
WO2025245175A1 (fr) Inhibiteurs hétéroaromatiques macrocycliques de jak2
WO2025210042A1 (fr) Combinaison de zongertinib avec un inhibiteur de sos1 destiné à être utilisé dans le traitement du cancer
CN118201928A (zh) 作为jak2抑制剂的6-杂芳基氧基苯并咪唑和氮杂苯并咪唑
JP2025528119A (ja) Ｊａｋ２阻害剤としての複素環式アミド及び尿素化合物
WO2025160079A1 (fr) Composés indazolo-amino-pyrimidinone
WO2025021218A1 (fr) Forme cystal d'inhibiteur biologique contenant du propénone, son procédé de préparation et son utilisation
EA046667B1 (ru) ПИРРОЛО[2,3-b]ПИРАЗИНЫ В КАЧЕСТВЕ ИНГИБИТОРА HPK1 И ИХ ПРИМЕНЕНИЕ
HK1197401A (en) Alkylated piperazine compounds as inhibitors of btk activity
HK1197401B (en) Alkylated piperazine compounds as inhibitors of btk activity

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22757433

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22757433

Country of ref document: EP

Kind code of ref document: A1