WO2023086319A1 - 6-he tero aryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors - Google Patents

6-he tero aryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors Download PDF

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Publication number
WO2023086319A1
WO2023086319A1 PCT/US2022/049220 US2022049220W WO2023086319A1 WO 2023086319 A1 WO2023086319 A1 WO 2023086319A1 US 2022049220 W US2022049220 W US 2022049220W WO 2023086319 A1 WO2023086319 A1 WO 2023086319A1
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optionally substituted
compound
nitrogen
sulfur
oxygen
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French (fr)
Inventor
Craig E. Masse
Jeremy R. Greenwood
Jiayi Xu
Sayan Mondal
Phani GHANAKOTA
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Ajax Therapeutics Inc
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Ajax Therapeutics Inc
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Priority to CA3234638A priority Critical patent/CA3234638A1/en
Priority to EP22826728.2A priority patent/EP4430042B1/en
Priority to AU2022388555A priority patent/AU2022388555A1/en
Priority to DK22826728.2T priority patent/DK4430042T3/da
Priority to JP2024526576A priority patent/JP7782035B2/ja
Priority to CN202280074285.6A priority patent/CN118201928A/zh
Publication of WO2023086319A1 publication Critical patent/WO2023086319A1/en
Anticipated expiration legal-status Critical
Priority to JP2025153429A priority patent/JP2025178324A/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • Janus kinase 2 is a non-receptor tyrosine kinase involved in the JAK-STAT signaling pathway, which plays a role in cell processes such as immunity, cell division, and cell death.
  • Dysfunction of the JAK-STAT pathway is implicated in various diseases, including cancer and other proliferative diseases, as well as diseases of the immune system.
  • essentially all BCR -ABL1-negative myeloproliferative neoplasms are associated with mutations that activate JAK2.
  • JAK2V617F is the most prevalent mutation in myeloproliferative neoplasms, occurring in approx.
  • Inhibitors of JAKs are classified based on their binding mode. All currently approved JAK inhibitors are Type I inhibitors, which are those that bind the ATP- binding site in the active conformation of the kinase domain, thereby blocking catalysis (Vainchenker, W. et al.). However, increased phosphorylation of the JAK2 activation loop is observed with Type I inhibitors and may lead to acquired resistance in certain patients (Meyer S. C., Levine, R. L. Clin. Cancer Res. 2014, 20(8):2051-9).
  • Type II inhibitors bind the ATP -binding site of the kinase domain in the inactive conformation and, therefore, may avoid hyperphosphorylation observed with Type I inhibitors (Wu, S. C. et al. Cancer Cell 2015 Jul 13, 28(1):29-41).
  • the present disclosure provides compounds useful for inhibiting JAK2.
  • provided compounds are useful for, among other things, treating and/or preventing diseases, disorders, or conditions associated with JAK2.
  • the present disclosure provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Ring A, n, L, W, X, Y, Z, R 1 , R 2 , R a , and R c are as defined herein.
  • the present disclosure provides a compound of Formula II or a pharmaceutically acceptable salt thereof, wherein Ring A, n, W, X, Y, Z, R 1 , R 2 , and R c are as defined herein.
  • the present disclosure provides a compound of Formula III
  • Ring A, L, Z, R 2 , R 4 , R a , and R x are as defined herein.
  • the present disclosure provides a compound of Formula IV or a pharmaceutically acceptable salt thereof, wherein Ring A, L, Z, R’, R 2 , R a , and R x are as defined herein.
  • structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure.
  • the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomic, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure.
  • Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and/or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.
  • structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • Aliphatic refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., 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, alkynyl groups and hybrids thereof.
  • alkyl 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 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 ).
  • Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.
  • Carbocyclyl The terms “carbocyclyl,” “carbocycle,” and “carbocyclic ring” as used herein, refer to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as described herein.
  • Carbocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl.
  • “carbocyclyl” refers to an optionally substituted monocyclic C 3 -C 8 hydrocarbon, or an optionally substituted C 7 -C 10 bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • the term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3-6 carbons.
  • Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • cycloalkenyl refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • Alkenyl refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ).
  • alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.
  • Alkynyl refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ).
  • exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
  • Aryl refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C 6-14 ), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
  • the term “aryl” may be used interchangeably with the term “aryl ring”.
  • “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons.
  • Heteroaryl and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 71 electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroaryl and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 71 electrons shared in a
  • heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l,2- a]pyrimidinyl, imidazo[l,2-a]pyridinyl, thienopyrimidinyl, triazol opyridinyl, 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]-l,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 quatemized form of a basic nitrogen.
  • Heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl.
  • a heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.
  • a bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings.
  • Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3- dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl.
  • a bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).
  • a spirocyclic ring system e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).
  • Partially Unsaturated when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.
  • Patient or subject refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • animals e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans.
  • a patient is a human.
  • a patient or a subject is suffering from or susceptible to one or more disorders or conditions
  • Substituted or optionally substituted As described herein, compounds of this disclosure may contain “optionally substituted” moieties.
  • the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent (i.e., as described below for optionally substituted groups). “Substituted” applies to one or more hydrogens that are either explicit or an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein.
  • Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents.
  • Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 ) 0-2 R ⁇ , -(haloR ⁇ ), -(CH 2 ) 0-2 0H, -(CH 2 ) 0-2 0R e , -(CH 2 )o-
  • 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, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening
  • 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, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition.
  • 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.
  • the present disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: W is CR w or N; X is CR x or N; Y is CR y or N; Z is –O- or –NR z -; R w , R x , and R y are each independently hydrogen, halogen, -OR 3 , -N(R 3 ) 2 , -SR 3 , optionally substituted C 1-6 aliphatic, or –CN; R z is hydrogen or optionally substituted C 1-6 aliphatic; R 1 is –N(R) 2 , –N(R)C(O)R’, -C(O)N(R) 2 , –N(R)C(O)N(R) 2 , or –N(R)C
  • the present disclosure provides a compound of Formula I-A: or a pharmaceutically acceptable salt thereof, wherein Ring A, n, L, Z, R 1 , R 2 , R a , R c , R x , and R y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I-B: or a pharmaceutically acceptable salt thereof, wherein Ring A, n, L, Z, R 1 , R 2 , R a , R c , and R y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula I-C: or a pharmaceutically acceptable salt thereof, wherein Ring A, n, L, Z, R 1 , R 2 , R a , R c , and R x 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 I-D: or a pharmaceutically acceptable salt thereof, wherein Ring A, n, L, W, X, Y, Z, R 1 , R 2 , R a , and R c 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, -O(CH 2 ) m R, -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, -OSO2R, -OSO2N(R) 2 , -N(R)C(O)R’, - N(R)SO2R’, -SO2R’, -SO2R’, -
  • the present disclosure provides a compound of Formula I-E: or a pharmaceutically acceptable salt thereof, wherein Ring A, L, W, X, Y, Z, R 1 , R 2 , and R a are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein: W is CR w or N; X is CR x or N; Y is CR y or N; Z is –O- or –NR z -; R w , R x , and R y are each independently hydrogen, halogen, -OR 3 , -N(R 3 ) 2 , -SR 3 , optionally substituted C 1-6 aliphatic, or –CN; R z is hydrogen or optionally substituted C 1-6 aliphatic; R 1 is –N(R) 2 , –N(R)C(O)R’, -C(O)N(R) 2 , –N(R)C(O)N(R) 2 , or –N(R)C(O)OR; each R c is independently selected from halogen, -CN, -CO 2 R, -C(O)N(
  • the present disclosure provides a compound of Formula II-A: or a pharmaceutically acceptable salt thereof, wherein Ring A, n, Z, R 1 , R 2 , R c , R x , and R y are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II-B: or a pharmaceutically acceptable salt thereof, wherein Ring A, n, Z, R 1 , R 2 , R c , and R y are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II-C: or a pharmaceutically acceptable salt thereof, wherein Ring A, n, Z, R 1 , R 2 , R c , and R x are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II-D: or a pharmaceutically acceptable salt thereof, wherein Ring A, W, X, Y, Z, R 1 , and R 2 are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula II-E: or a pharmaceutically acceptable salt thereof, wherein n, W, X, Y, Z, R 1 , R 2 , and R c are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and Ring A1 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 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring A1 is fused to Ring A2; Ring A2 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 7-membere
  • the present disclosure provides a compound of Formula II-F: or a pharmaceutically acceptable salt thereof, wherein Ring A2, n, W, X, Y, Z, R 1 , R 2 , and R c are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula III: or a pharmaceutically acceptable salt thereof, wherein: Z is –O- or –NR z -; R x is hydrogen, halogen, -OR 3 , -N(R 3 ) 2 , -SR 3 , optionally substituted C 1-6 aliphatic, or –CN; R z is hydrogen or optionally substituted C 1-6 aliphatic; R 2 is optionally substituted C 1-6 aliphatic; R 3 is hydrogen or optionally substituted C 1-6 aliphatic; R 4 is halogen, –OR, -N(R) 2 , 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 A is optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted
  • the present disclosure provides a compound of Formula IV: or a pharmaceutically acceptable salt thereof, wherein: Z is –O- or –NR z -; R x is hydrogen, halogen, -OR 3 , or –CN; R z is hydrogen or optionally substituted C 1-6 aliphatic; R 2 is optionally substituted C 1-6 aliphatic; R 3 is hydrogen or optionally substituted C 1-6 aliphatic; selected from (i) or (ii): wherein Ring A is further substituted at least once, and at least one substituent on Ring A is C 1-6 haloalkyl; L is a covalent bond or a bivalent C 1-3 straight or branched hydrocarbon chain; R a is hydrogen, 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
  • W is CR w . In some embodiments, W is N.
  • X is CR x . In some embodiments, X is N.
  • Y is CR y . In some embodiments, Y is N.
  • W is CR w or N
  • X is CR x or N
  • Y is CR y or N, and no more than one of W, X, and Y is N.
  • W is CR w or N
  • X is CR x or N
  • Y is CR y or N, and no more than two of W, X, and Y is N.
  • Z is –O-. In some embodiments, Z is –NR z -. In some embodiments, Z is –NH-.
  • R w is hydrogen, halogen, or optionally substituted C 1-6 aliphatic. In some embodiments, R w is hydrogen. In some embodiments, R w is halogen.
  • R w is fluoro. In some embodiments, R w is chloro. In some embodiments, R w is –OR 2 . In some embodiments, R w is – OR 2 , wherein R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, Y is N, W is CR w , and R w is –OR 2 wherein R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, R w is –N(R 2 ) 2 . In some embodiments, R w is –SR 2 . In some embodiments, R w is –SR 2 , wherein R 2 is optionally substituted C 1-6 aliphatic.
  • Y is N
  • W is CR w
  • R w is – SR 2 wherein R 2 is optionally substituted C 1-6 aliphatic.
  • R w is optionally substituted C 1-6 aliphatic.
  • R w is optionally substituted straight-chain or branched C 1-6 aliphatic (i.e., optionally substituted acyclic C 1-6 aliphatic).
  • R w is optionally substituted C 1-6 alkyl.
  • R w is optionally substituted C 1-4 alkyl.
  • R w is optionally substituted C 1-2 alkyl.
  • R w is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, R w is –CN. [0052] In some embodiments of any of Formulae I, I-A, I-C, I-D, I-E, II, II-A, II-C, II-D, II- E, II-F, III, and IV, R x is hydrogen, halogen, -CN, -OR 2 , or optionally substituted C 1-6 aliphatic. In some embodiments, R x is hydrogen, halogen, -CN, -O(C 1-4 alkyl), or C 1-4 alkyl optionally substituted with one or more halogen.
  • R x is hydrogen, halogen, -OR 2 , or optionally substituted C 1-6 aliphatic. In some embodiments, R x is hydrogen, halogen, -O(C 1-4 alkyl), or C 1-4 alkyl optionally substituted with one or more halogen. In some embodiments, R x is hydrogen, halogen, or optionally substituted C 1-6 aliphatic. In some embodiments, R x is hydrogen, halogen, -CN, or OR 2 . In some embodiments, R x is hydrogen, halogen, -CN, or O(C 1- 4 alkyl). In some embodiments, R x is halogen or –CN. In some embodiments, R x is hydrogen.
  • R x is halogen. In some embodiments, R x is fluoro. In some embodiments, R x is chloro. In some embodiments, R x is –OR 2 . In some embodiments, R x is – OR 2 , wherein R 2 is optionally substituted C 1-6 aliphatic (e.g., optionally substituted C 1-6 alkyl). In some embodiments, R x is -O(C 1-4 alkyl). In some embodiments, R x is –OCH 3 . In some embodiments, R x is –N(R 2 ) 2 . In some embodiments, R x is –SR 2 .
  • R x is – SR 2 , wherein R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, R x is optionally substituted C 1-6 aliphatic. In some embodiments, 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 (e.g., C 1-6 alkyl optionally substituted with one or more fluoro). In some embodiments, R x is optionally substituted C 1-4 alkyl (e.g., C 1-4 alkyl optionally substituted with one or more fluoro).
  • R x is optionally substituted C 1-2 alkyl (e.g., C 1-2 alkyl optionally substituted with one or more fluoro). In some embodiments, R x is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro, e.g., -CHF2). In some embodiments, R x is –CN. [0053] In some embodiments of any of Formulae I, I-A, I-B, I-D, I-E, II, II-A, II-B, II-D, II- E, II-F, R y is hydrogen, halogen, or optionally substituted C 1-6 aliphatic. In some embodiments, R y is hydrogen.
  • R y is halogen. In some embodiments, R y is fluoro. In some embodiments, R y is chloro. In some embodiments, R y is –OR 2 . In some embodiments, R y is –OR 2 , wherein R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, W is N, Y is CR y , and R y is –OR 2 wherein R 2 is optionally substituted C 1-6 aliphatic. In some embodiments, R y is –N(R 2 ) 2 . In some embodiments, R y is –SR 2 .
  • R y is –SR 2 , wherein R 2 is optionally substituted C 1-6 aliphatic.
  • W is N
  • Y is CR y
  • R y is –SR 2 wherein R 2 is optionally substituted C 1-6 aliphatic.
  • R y is optionally substituted C 1-6 aliphatic.
  • R y is optionally substituted straight-chain or branched C 1-6 aliphatic (i.e., optionally substituted acyclic C 1-6 aliphatic).
  • R y is optionally substituted C 1-6 alkyl.
  • R y is optionally substituted C 1-4 alkyl.
  • R y is optionally substituted C 1-2 alkyl. In some embodiments, R y is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, R y is –CN. [0054] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II- C, II-D, II-E, II-F, 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 –N(R)C(O)N(R) 2 or –N(R)C(O)OR. In some embodiments, R 1 is – N(R) 2 , –N(R)C(O)R’, or -C(O)N(R) 2 . In some embodiments, R 1 is –N(R)C(O)R’ or - C(O)N(R) 2 .
  • R 1 is –N(R)C(O)R’, -C(O)N(R) 2 , –N(R)C(O)N(R) 2 , or – N(R)C(O)OR.
  • n is 1, 2, or 3.
  • R 1 is –N(R)C(O)N(R) 2 or –N(R)C(O)OR.
  • R 1 is –N(R) 2 .
  • R 1 is –N(H)(R). In some embodiments, R 1 is –NH2. In some embodiments, when R 1 is –N(R) 2 , then n is 1, 2, or 3. [0058] In some embodiments, R 1 is –N(R)C(O)R’. In some embodiments, R 1 is – N(H)C(O)R’. In some embodiments, R 1 is –N(R)C(O)(optionally substituted C 1-6 aliphatic). In some embodiments, R 1 is –N(H)C(O)(optionally substituted C 1-6 aliphatic). In some embodiments, R 1 is –N(R)C(O)(C 1-6 aliphatic).
  • R 1 is –N(H)C(O)(C 1-6 aliphatic). In some embodiments, R 1 is –N(R)C(O)(straight-chain or branched C 1-6 aliphatic). In some embodiments, R 1 is –N(H)C(O)(straight-chain or branched C 1-6 aliphatic). In some embodiments, R 1 is –N(R)C(O)(optionally substituted C 1-6 alkyl). In some embodiments, R 1 is – N(H)C(O)(optionally substituted C 1-6 alkyl).
  • R 1 is –N(R)C(O)R’, wherein R’ of R 1 is C 1-6 alkyl optionally substituted with halogen, -OH, –O(C 1-6 alkyl), - NH(CH2) 2 O(C 1-6 alkyl), -NH(C 1-4 haloalkyl), or an optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is –N(H)C(O)R’, wherein R’ of R 1 is C 1-6 alkyl optionally substituted with halogen, -OH, –O(C 1-6 alkyl), -NH(CH2) 2 O(C 1-6 alkyl), -NH(C 1-4 haloalkyl), or an optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is –N(R)C(O)(C 1-6 alkyl).
  • R 1 is –N(H)C(O)(C 1-6 alkyl).
  • R 1 is –N(R)C(O)(optionally substituted C 1-4 alkyl). In some embodiments, R 1 is –N(H)C(O)(optionally substituted C 1-4 alkyl). In some embodiments, R 1 is – N(R)C(O)R’, wherein R’ of R 1 is C 1-4 alkyl optionally substituted with halogen, -OH, –O(C 1-6 alkyl), -NH(CH2) 2 O(C 1-6 alkyl), -NH(C 1-4 haloalkyl), or an optionally substituted 3- to 7- membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is –N(H)C(O)R’, wherein R’ of R 1 is C 1-4 alkyl optionally substituted with halogen, -OH, –O(C 1-6 alkyl), -NH(CH2) 2 O(C 1-6 alkyl), - NH(C 1-4 haloalkyl), or an optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is –N(R)C(O)(C 1-4 alkyl).
  • R 1 is – N(H)C(O)(C 1-4 alkyl).
  • R 1 is –N(R)C(O)(C 1-2 alkyl). In some embodiments, R 1 is –N(H)C(O)(C 1-2 alkyl). In some embodiments, R 1 is –N(R)C(O)CH 3 . In some embodiments, R 1 is –N(H)C(O)CH 3 . In some embodiments, R 1 is –N(R)C(O)(optionally substituted C 3-7 cycloalkyl). In some embodiments, R 1 is –N(H)C(O)(optionally substituted C 3-7 cycloalkyl). In some embodiments, R 1 is –N(R)C(O)(optionally substituted cyclopropyl).
  • R 1 is –N(H)C(O)(optionally substituted cyclopropyl). In some embodiments, when R 1 is –N(R)C(O)R’, then n is 1, 2, or 3. [0059] In some embodiments, R 1 is -C(O)N(R) 2 . In some embodiments, R 1 is – C(O)N(R)(C 1-6 aliphatic). In some embodiments, R 1 is –C(O)N(H)(C 1-6 aliphatic). In some embodiments, R 1 is –C(O)N(R)(straight-chain or branched C 1-6 aliphatic).
  • R 1 is –C(O)N(H)(straight-chain or branched C 1-6 aliphatic). In some embodiments, R 1 is –C(O)N(R)(C 1-6 alkyl). In some embodiments, R 1 is –C(O)N(H)(C 1-6 alkyl). In some embodiments, R 1 is –C(O)N(R)(C 1-4 alkyl). In some embodiments, R 1 is – C(O)N(H)(C 1-4 alkyl). In some embodiments, R 1 is –C(O)N(R)(C 1-2 alkyl). In some embodiments, R 1 is –C(O)N(H)( C 1-2 alkyl).
  • R 1 is –C(O)N(R)CH 3 . In some embodiments, R 1 is –C(O)N(H)(R). In some embodiments, when R 1 is -C(O)N(R) 2 , then n is 1, 2, or 3. [0060] In some embodiments, R 1 is –N(R)C(O)N(R) 2 . In some embodiments, R 1 is – N(H)C(O)N(R) 2 . In some embodiments, R 1 is –N(H)C(O)N(optionally substituted C 1-6 aliphatic) 2 .
  • R 1 is –N(H)C(O)N(optionally substituted C 1-6 alkyl) 2 . In some embodiments, R 1 is –N(H)C(O)N(optionally substituted C 1-4 alkyl) 2 . In some embodiments, R 1 is –N(H)C(O)N(optionally substituted C 1-2 alkyl) 2 . In some embodiments, R 1 is –N(R)C(O)NH(R). In some embodiments, R 1 is –N(H)C(O)NH(R). In some embodiments, R 1 is –N(H)C(O)NH(optionally substituted C 1-6 aliphatic).
  • R 1 is – N(H)C(O)NH(optionally substituted C 1-6 alkyl). In some embodiments, R 1 is – N(H)C(O)NH(optionally substituted C 1-4 alkyl). In some embodiments, R 1 is – N(H)C(O)NH(optionally substituted C 1-2 alkyl). In some embodiments, R 1 is – N(H)C(O)NH(optionally substituted C 3-7 cycloaliphatic). In some embodiments, R 1 is – N(H)C(O)NH(optionally substituted C 3-7 cycloalkyl). In some embodiments, R 1 is – N(H)C(O)NH(optionally substituted cyclopropyl).
  • R 1 is – N(H)C(O)NH(optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 is –N(H)C(O)NH(optionally substituted 4- to 6- membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 is –N(H)C(O)NH(optionally substituted oxetanyl).
  • R 1 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 1 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 1 is –N(H)C(O)N(R) 2 , wherein the two R groups attached to the same nitrogen are taken together to form a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, C 1-6 alkyl, -OH, and –O(C 1-6 alkyl).
  • R 1 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 4- to 6-membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is –N(H)C(O)N(R) 2 , wherein the two R groups attached to the same nitrogen are taken together to form a 4- to 6- membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, C 1-6 alkyl, -OH, and –O(C 1-6 alkyl).
  • R 1 is selected from: In some embodiments, R 1 is not In some embodiments, when X is CH, then R 1 is not [0061] In some embodiments, R 1 is –N(R)C(O)OR. In some embodiments, R 1 is – N(H)C(O)OR. In some embodiments, R 1 is –N(H)C(O)OR, wherein R of R 1 is optionally substituted C 1-6 aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is –N(H)C(O)OR, wherein R of R 1 is optionally substituted C 1-6 alkyl or optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is –N(H)C(O)OR, wherein R of R 1 is C 1-6 alkyl optionally substituted with one or more –OH, –O(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , or 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is –N(H)C(O)OR, wherein R of R 1 is 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C 1-6 alkyl.
  • R 1 is selected from: [0062]
  • R 2 is optionally substituted straight-chain or branched C 1-6 aliphatic (i.e., optionally substituted acyclic C 1-6 aliphatic).
  • 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 unsubstituted C 1-4 alkyl. In some embodiments, R 2 is optionally substituted C 1-2 alkyl. In some embodiments, R 2 is unsubstituted C 1-2 alkyl. In some embodiments, R 2 is methyl.
  • each R 3 is independently hydrogen or optionally substituted C 1-4 aliphatic. In some embodiments, each R 3 is independently hydrogen or optionally substituted C 1- 2 aliphatic. In some embodiments, each R 3 is hydrogen. In some embodiments, each R 3 is independently optionally substituted C 1-6 aliphatic. In some embodiments, each R 3 is independently optionally substituted straight-chain or branched C 1-6 aliphatic (i.e., optionally substituted acyclic C 1-6 aliphatic).
  • each R 3 is independently optionally substituted C 1-4 aliphatic. In some embodiments, each R 3 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 3 is independently optionally substituted C 1-2 aliphatic. In some embodiments, each R 3 is independently hydrogen or C 1-6 alkyl. In some embodiments, each R 3 is independently hydrogen or C 1-4 alkyl. In some embodiments, each R 3 is independently hydrogen or C 1-2 alkyl. [0064] In some embodiments of Formula III, R 4 is halogen. In some embodiments, R 4 is fluoro.
  • R 4 is chloro. In some embodiments, R 4 is –OR. In some embodiments, R 4 is —OH or –O(optionally substituted C 1-6 alkyl). In some embodiments, R 4 is – OH or –O(C 1-6 alkyl). In some embodiments, R 4 is –OH or –OCH 3 . In some embodiments, R 4 is –N(R) 2 . In some embodiments, R 4 is –NH(R). In some embodiments, R 4 is –NH(optionally substituted C 1-6 alkyl).
  • R 4 is –NH(R), wherein R of R 4 is C 1-6 alkyl optionally substituted with one or more halogen or –O(C 1-6 alkyl). In some embodiments, R 4 is – NH(CH2) 2 F or –NH(CH2) 2 OCH 3 . In some embodiments, R 4 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, R 4 is optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 4 is 4- to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C 1-6 alkyl. In some embodiments, R 4 is tetrahydropyranyl or morpholinyl optionally substituted with one or more C 1-6 alkyl.
  • each R c is independently selected from halogen, -CN, -CO 2 R, -C(O)N(R) 2 , -NO 2 , - N(R) 2 , -OR, -SR, or optionally substituted C 1-6 alkyl, wherein each R of R c is independently hydrogen or C 1-6 alkyl.
  • R c is halogen (e.g., fluoro).
  • R c is -CN, -CO 2 R, -C(O)N(R) 2 , or -NO 2 . In some embodiments, R c is -N(R) 2 , - OR, or –SR. In some embodiments, R c is optionally substituted C 1-6 aliphatic (e.g., C 1-6 alkyl). [0066] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, II, II-A, II-B, II-C, II- E, and II-F, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
  • 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 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or optionally substituted 8- to 10- membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0068] In some embodiments, Ring A is optionally substituted phenyl. In some embodiments, Ring A is not optionally substituted phenyl. [0069] In some embodiments, Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • 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 pyrazolyl. In some embodiments, Ring A is optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 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]pyridyl or dihydro-4H-pyrazolo[5,1- c][1,4]oxazinyl.
  • Ring A is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0071] 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 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 not 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. [0072] 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. [0074] In some embodiments, Ring A is or [0075] In some embodiments of any of Formulae II, II-A, II-B, II-C, II-D, II-E, and II-F, Ring A 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 A 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 A is 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.
  • each ring in a bicyclic or polycyclic ring system of Ring A contains at least one heteroatom.
  • one and only one ring of a bicyclic or polycyclic ring system of Ring A contains no heteroatoms.
  • each ring in a bicyclic or polycyclic ring system of Ring A is aromatic.
  • one and only one ring of a bicyclic or polycyclic ring system of Ring A is aromatic.
  • no ring in a bicyclic or polycyclic ring system of Ring A is aromatic.
  • Ring A is optionally substituted 9- to 16-membered bicyclic or tricyclic aryl.
  • Ring A is optionally substituted 9- to 10-membered bicyclic aryl.
  • Ring A is optionally substituted 9-membered bicyclic aryl (e.g., a 5-membered carbocycle fused to a phenyl ring). In some embodiments, Ring A is not substituted indanyl (e.g., indanyl substituted with one or more halogens). In some embodiments, Ring A is optionally substituted 10-membered bicyclic aryl (e.g., naphthyl or a 6-membered carbocycle fused to a phenyl ring). [0079] In some embodiments, Ring A is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more oxo, halogen, or C 1-6 alkyl. 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 dihydro-1H-imidazo[1,2- b]pyrazolyl, In some embodiments, Ring A is optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more oxo, halogen, or C 1-6 alkyl.
  • Ring A is optionally substituted tetrahydropyrazolo[1,5-a]pyridyl, dihydropyrazolo[1,5-a]pyrazin-4(5H)-onyl, tetrahydropyrazolo[1,5-a]pyrimidinyl, or dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl.
  • Ring A is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C 1-6 alkyl.
  • Ring A is optionally substituted tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepinyl, tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepinyl, tetrahydropyrazolo[1,5-d][1,4]oxazepinyl, or tetrahydro-4H-pyrazolo[1,5-a]azepinyl. [0080] In some embodiments, Ring A is optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is optionally substituted 11-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is optionally substituted dihydrospiro[cyclobutane-1,4’-pyrrolo[1,2- b]pyrazolyl], dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyridyl], dihydro-5'H- spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine], or dihydro-4'H-spiro[cyclopropane-1,5'- pyrazolo[1,5-a]pyrimidinyl].
  • Ring A is optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A 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 A is optionally substituted 7-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 8-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is optionally substituted 9-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 10-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0082] In some embodiments, Ring A is optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is selected from: [0084] In some embodiments, Ring A is , wherein Ring A1 and Ring A2 are defined as in Formula II-E and described in classes and subclasses herein, both singly and in combination; and Ring A1 is fused to Ring A2; and Ring A2 is optionally (i) further fused to Ring A3 or (ii) Ring A2 and Ring A3 combine to form a spirocycle.
  • Ring A1 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 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A1 is optionally substituted phenyl.
  • Ring A2 contains at least one heteroatom.
  • Ring A1 is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A1 is unsubstituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A1 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A1 is optionally substituted pyrazole. In some embodiments, Ring A1 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0088] In some embodiments, Ring A1 is optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl.
  • Ring A1 when Ring A1 is optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, Ring A2 contains at least one heteroatom. In some embodiments, when Ring A2 is not aromatic, Ring A1 is optionally substituted 5- to 7-membered saturated monocyclic carbocyclyl. In some embodiments, Ring A1 is optionally substituted 5- to 7-membered partially saturated monocyclic carbocyclyl. [0089] In some embodiments, Ring A1 is optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A1 when Ring A2 is not aromatic, Ring A1 is optionally substituted 5- to 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A1 is optionally substituted 5- to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A1 fused to Ring A2 is [0091]
  • Ring A2 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 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A2 is optionally substituted phenyl. In some embodiments, when Ring A2 is phenyl, Ring A1 contains at least one heteroatom.
  • Ring A2 is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A2 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A2 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0094] In some embodiments, Ring A2 is optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl.
  • Ring A1 when Ring A2 is optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, Ring A1 contains at least one heteroatom. In some embodiments, when Ring A1 is not aromatic, Ring A2 is optionally substituted 5- to 7-membered saturated monocyclic carbocyclyl. In some embodiments, Ring A2 is optionally substituted 5- to 7-membered partially saturated monocyclic carbocyclyl. [0095] In some embodiments, Ring A2 is optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A2 when Ring A1 (and Ring A3, if present) is not aromatic, Ring A2 is optionally substituted 5- to 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A2 is optionally substituted 5- to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A2 is optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A2 is 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C 1-6 alkyl. In some embodiments, Ring A2 is optionally substituted pyrrolidine or imidazolidine. In some embodiments, Ring A2 is optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A2 is 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more oxo, halogen, and C 1-6 alkyl.
  • Ring A2 is optionally substituted piperidine, hexahydropyrimidine, morpholine, or piperazinone. In some embodiments, Ring A2 is optionally substituted 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A2 is 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C 1-6 alkyl. In some embodiments, Ring A2 is azepane, diazepane, or oxazepane.
  • optionally substituted Ring A2 fused to Ring A1 is selected from the group consisting of: [0097] In some embodiments, Ring A1 is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring A2 is an optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A1 is an optionally substituted 5- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • Ring A2 is an optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • Ring A1 is an optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • Ring A2 is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A1 is an optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • Ring A2 is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • Ring A1 is an optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur
  • Ring A2 is an optionally substituted 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A2 is further fused to Ring A3.
  • Ring A2 and Ring A3 combine to form a spirocycle. In some embodiments, when Ring A2 and Ring A3 combine to form a spirocycle, Ring A3 is 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. [0099] In some embodiments, Ring A3, when present, is optionally substituted phenyl. In some embodiments, Ring A3, when present, is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A3, when present, is optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A3, when not fused to an aromatic Ring A2, is 3- to 7-membered saturated monocyclic carbocyclyl. In some embodiments, Ring A3 is 3- to 7-membered partially saturated monocyclic carbocyclyl. In some embodiments, Ring A3 is optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl or cyclobutyl). In some embodiments, Ring A3 is 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A3 when not fused to an aromatic Ring A2, is 3- to 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A3 is 3- to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A2 fused to Ring A1 and combined to form a spirocycle with Ring A3 is selected from: [0101]
  • Ring A is optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, R ⁇ , -CN, -OR ⁇ , -O(CH 2 ) 1- 4 R o , -SR ⁇ , -N(R ⁇ ) 2 , -NO 2 , -C(O)R ⁇ , -C(O)OR°, -C(O)NR ⁇ 2 , -OC(O)R ⁇ , -OC(O)NR ⁇ 2 , – OC(O)OR°,
  • Ring A is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, R ⁇ , -OR ⁇ , and -O(CH2)1-4R o , 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 oxo, halogen, and R ⁇ , and (ii) optionally substituted on a substitutable nitrogen atom with one or more groups selected from –R ⁇ .
  • Ring A is optionally substituted with one or more R b (e.g., in addition to being substituted with –L-R a , when present), wherein R b is as defined in Formula I-D 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.
  • L is a covalent bond.
  • L is a bivalent C1-3 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 –C(CH 3 ) 2 -.
  • L is a covalent bond or –CH2-.
  • 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 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 hydrogen, halogen, optionally substituted C 1-6 aliphatic, 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 hydrogen. In some embodiments, R a is not hydrogen.
  • R a is halogen. In some embodiments, R a is fluoro, chloro, bromo, or iodo. In some embodiments, R a is fluoro.
  • R a is chloro.
  • R a is optionally substituted C 1-6 aliphatic.
  • R a is optionally substituted straight-chain or branched C 1-6 aliphatic (i.e., optionally substituted acyclic C 1-6 aliphatic).
  • R a is C 1-6 aliphatic optionally substituted with one or more halogen, -N(C 1-6 alkyl) 2 , –OH, or -O(optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl).
  • R a is optionally substituted C 1-6 alkyl.
  • R a is C 1-6 alkyl optionally substituted with one or more halogen, -N(C 1-6 alkyl) 2 , –OH, or -O(optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl). In some embodiments, R a is optionally substituted C 1-4 alkyl. In some embodiments, R a is C 1-4 alkyl optionally substituted with one or more halogen, -N(C 1-6 alkyl) 2 , –OH, or -O(optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl).
  • 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 5- to 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R a is optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R a is optionally substituted 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. In some embodiments, R a is optionally substituted 3- to 6-membered saturated monocyclic carbocyclyl. In some embodiments, R a is optionally substituted 3-membered saturated monocyclic carbocyclyl. In some embodiments, R a is optionally substituted 4-membered saturated monocyclic carbocyclyl. In some embodiments, R a is optionally substituted 5-membered saturated monocyclic carbocyclyl. In some embodiments, R a is optionally substituted 6-membered saturated monocyclic carbocyclyl.
  • R a is optionally substituted 7-membered saturated monocyclic carbocyclyl.
  • R a is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R a is optionally substituted 4- to 7- membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R a is optionally substituted 3- membered saturated monocyclic heterocyclyl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • R a is optionally substituted 4-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 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 optionally substituted pyrrolidinyl or tetrahydrofuranyl. In some embodiments, R a is optionally substituted 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R a is optionally substituted 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0112] 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 9-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is optionally substituted 7-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is optionally substituted 2-oxaspiro[3.3]heptanyl. In some embodiments, R a is optionally substituted 8-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R a is optionally substituted 9-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is optionally substituted 7-oxaspiro[3.5]nonanyl. In some embodiments, R a is optionally substituted 10-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0113] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, III, and IV, is –R a (i.e., L is a covalent bond).
  • is –(C 1- alkylene)-R a 3 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 C1 hydrocarbon chain).
  • is – CH 2 CH 2 -R a i.e., L is a C 2 straight hydrocarbon chain).
  • is – CH 2 CH 2 CH 2 -R a i.e., L is a C 3 straight hydrocarbon chain).
  • R b is – C(CH 3 ) 2 -R a (i.e., L is a C3 branched hydrocarbon chain).
  • R b up to five occurrences of R b may be present, as allowed by valency rules, and is each independently halogen, -CN, -OR, -O(CH 2 ) m R, -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 , -OSO 2 N(R) 2 , -
  • each occurrence of R b is independently halogen, optionally substituted C 1-6 aliphatic, -OR, or -O(CH 2 ) m R.
  • each occurrence of R b is independently halogen, optionally substituted C 1-6 alkyl, -OR, or –OCH 2 R, wherein R of 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.
  • each occurrence of R b is halogen or C 1-6 alkyl optionally substituted with one or more halogen. [0115] In some embodiments, one occurrence of R b is present.
  • 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.
  • R b is chloro.
  • R b is -CN, -OR, -O(CH 2 ) m R, -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 N(R) 2 , or -SO3R’.
  • R b is –CN. In some embodiments, R b is -N(R) 2 . In some embodiments, R b is -C(O)N(R) 2 . [0119] In some embodiments, R b is –OR. In some embodiments, R b is -OR, wherein R is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is –OR, wherein R is optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R b is –OR, wherein R is 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted with one or more C 1-6 alkyl (e.g., methyl).
  • R b is –OR, wherein R is optionally substituted azetidinyl or pyrrolidinyl.
  • R b is –OR, wherein R is azetidinyl or pyrrolidinyl optionally substituted with one or more C 1-6 alkyl (e.g., methyl).
  • R b is .
  • R b is -O(CH 2 ) m R. In some embodiments, R b is -OCH2R. In some embodiments, R b is -O(CH 2 ) m R, wherein R is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is -O(CH 2 ) m R, wherein R is optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R b is -O(CH 2 ) m R, wherein R is 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted with one or more C 1-6 alkyl (e.g., methyl).
  • R b is -O(CH 2 ) m R, wherein R is optionally substituted pyrrolidinyl.
  • R b is -O(CH 2 ) m R, wherein R is pyrrolidinyl optionally substituted with one or more C 1-6 alkyl (e.g., methyl).
  • 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 of halogen. In some embodiments, R b is –CH 3 , –CF 3 , or –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. [0123] 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. In some embodiments, R b is optionally substituted 3- to 6- membered saturated monocyclic heterocyclyl having 1-2 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.
  • m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.
  • optionally substituted is selected from the group consisting of: [0127]
  • Ring A when is then Ring A is further substituted with R b as defined and described in classes and subclasses herein, and at least one substituent on Ring A (i.e., either R b or –L-R a ) is C 1-6 haloalkyl (e.g., -CF 3 ). In some embodiments, is selected from the group consisting of: [0128] In some embodiments of any of Formulae II, II-A, II-B, II-C, II-D, II-E, and II-F, optionally substituted In some embodiments, optionally substituted
  • each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each R is independently hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently optionally substituted C 1-6 aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each R is independently is hydrogen, optionally substituted C 1-6 alkyl or optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • 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 C 1-6 alkyl optionally substituted with one or more –OH, –O(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , or 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R is optionally substituted C 1-4 alkyl.
  • R is optionally substituted C 1-2 alkyl.
  • R is optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl.
  • R is optionally substituted C 3-7 cycloalkyl.
  • R is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 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 is 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C 1-6 alkyl. In some embodiments, R is optionally substituted oxetanyl.
  • two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • two R groups attached to the same nitrogen are taken together to form a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted with one or more halogen, C 1-6 alkyl, -OH, or –O(C 1-6 alkyl).
  • two R groups attached to the same nitrogen are taken together to form an optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • two R groups attached to the same nitrogen are taken together to form a 4- to 6- membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, C 1-6 alkyl, -OH, and –O(C 1-6 alkyl).
  • each R’ is independently optionally substituted C 1-6 alkyl or optionally substituted C 3-7 cycloalkyl.
  • 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 C 1-6 alkyl optionally substituted with halogen, -OH, –O(C 1-6 alkyl), -NH(CH2) 2 O(C 1-6 alkyl), -NH(C 1-4 haloalkyl), or an optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R’ is optionally substituted C 1-4 alkyl.
  • R’ is optionally substituted C 1-2 alkyl.
  • R’ is methyl.
  • R’ is optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl.
  • R’ is optionally substituted C 3-7 cycloalkyl. In some embodiments, R’ is optionally substituted cyclopropyl. In some embodiments, R’ is cyclopropyl. [0136] In some embodiments of any of Formulae described herein, the compound is not: . [0137] In some embodiments, the compound is not: [0138] In some embodiments, the compound is not: [0139] In some embodiments, the compound is not: [0140] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, and I-E, when R 1 is and Y is N, then R x is not hydrogen.
  • Ring A when R 1 is , then Ring A is not pyrazolyl. In some embodiments, when Ring A is pyrazolyl, then R 1 is not –N(R)C(O)N(R) 2 . In some embodiments, when Ring A is pyrazolyl and Y is N, then R x is not hydrogen. [0141] In some embodiments of any of Formulae II, II-A, II-B, II-C, II-D, II-E, and II-F, Ring A is not . In some embodiments, when Ring , then R 1 is not –N(H)C(O)CH 3 . In some embodiments, when Ring , then X is not N and R x is not –CN.
  • R 4 is not tetrahydropyranyl. In some embodiments, when R 4 is tetrahydropyranyl and Y is N, then R x is not chloro. [0143] In some embodiments of Formula IV, when Y is N and R x is not hydrogen, then –L- [0144] 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, SET2-pSTAT5 Cellular Assay, hPBMC-GMCSF-STAT5 Assay, hPBMC-IL12-STAT4 Assay, or hPBMC-IL2-STAT5 Assay described herein) and/or have one or more other characteristics that make them more suitable for drug development, such as better selectivity over other kinases and/or better ADME (absorption, distribution, metabolism, and excretion) properties including but not limited to better permeability, cytotoxicity, hepatocyte stability, solubility, and/or plasma protein binding profiles (e.g., based on assays described in the ensuing examples), than other known compounds.
  • biochemical or cellular assays e.g., the JAK2 Binding As
  • provided compounds display certain desirable characteristics in one or more assays described herein, e.g., compared to other known compounds.
  • the present disclosure encompasses the recognition that 6- heteroaryloxy benzimidazoles and azabenzimidazoles (e.g., compounds described herein) display certain more desirable characteristics (such as better properties in one or more assays described herein) than corresponding 5-heteroaryloxy benzimidazoles and azabenzimidazoles.
  • provided compounds are provided and/or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated.
  • Provided compounds may generally be made by the processes described in the ensuing schemes and examples.
  • provided compounds are prepared according to the following Scheme: wherein PG is a suitable protecting group (e.g., p-methoxybenzyl, acetyl, methyl carbamate, etc.), and Ring A, n, L, W, X, Y, R, R 2 , R a , and R c 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., p-methoxybenzyl, acetyl, methyl carbamate, etc.)
  • Ring A, n, L, W, X, Y, R, R 2 , R a , and R c are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • intermediate A.3 is prepared by a process comprising contacting intermediate A.1 with intermediate A.2 in the presence of a suitable coupling agent and/or a suitable base (e.g., potassium tert-butoxide).
  • a process for preparing intermediate A.3 further comprises a deprotection step and/or a functionalization step (e.g., cyanation) under suitable conditions.
  • intermediate A.4 is prepared by a process comprising contacting intermediate A.3 with phenyl chloroformate in the presence of a suitable base (e.g., triethylamine).
  • compound A-1 is prepared by a process comprising contacting intermediate A.4 with RO-H, optionally in the presence of a suitable base (e.g., triethylamine).
  • compound A-1 is prepared by a process comprising contacting intermediate A.3 with RO-C(O)-Cl in the presence of a suitable base (e.g., triethylamine).
  • compound A-2 is prepared by a process comprising contacting intermediate A.4 with R 2 N-H, optionally in the presence of a suitable base (e.g., triethylamine).
  • compound A-2 is prepared by a process comprising contacting intermediate A.3 with R2N-C(O)-Cl in the presence of a suitable base (e.g., triethylamine).
  • a suitable base e.g., triethylamine.
  • provided compounds are prepared according to the following Scheme: wherein PG is a suitable protecting group (e.g., p-methoxybenzyl, acetyl, methyl carbamate, etc.), and Ring A, n, W, X, Y, R, R 2 , and R c are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • intermediate A.6 is prepared by a process comprising contacting intermediate A.5 with intermediate A.2 in the presence of a suitable coupling agent and/or a suitable base (e.g., potassium tert-butoxide).
  • a process for preparing intermediate A.6 further comprises a deprotection step and/or a functionalization step (e.g., cyanation) under suitable conditions.
  • intermediate A.7 is prepared by a process comprising contacting intermediate A.6 with phenyl chloroformate in the presence of a suitable base (e.g., triethylamine).
  • compound A-3 is prepared by a process comprising contacting intermediate A.7 with RO-H, optionally in the presence of a suitable base (e.g., triethylamine).
  • compound A-3 is prepared by a process comprising contacting intermediate A.6 with RO-C(O)-Cl in the presence of a suitable base (e.g., triethylamine).
  • compound A-4 is prepared by a process comprising contacting intermediate A.7 with R 2 N-H, optionally in the presence of a suitable base (e.g., triethylamine).
  • compound A-4 is prepared by a process comprising contacting intermediate A.6 with R2N-C(O)-Cl in the presence of a suitable base (e.g., triethylamine).
  • a suitable base e.g., triethylamine.
  • provided compounds are prepared according to the following Scheme: wherein LG is a suitable leaving group (e.g., halogen, e.g., chloro or bromo), and Ring A, n, L, W, X, Y, Z, R 1 , R 2 , R a , and R c are as defined above for Formulae I and/or II and described in classes and subclasses herein, both singly and in combination.
  • compound B-1 is prepared by a process comprising contacting intermediate B.1 with intermediate B.2 in the presence of a suitable base (e.g., K 3 PO 4 , K 2 CO 3 , or Cs 2 CO 3 ), and optionally in the presence of a suitable metal complex (e.g., a palladium complex such as tris(dibenzylideneacetone)dipalladium(0)) and/or a suitable ligand (e.g., 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene).
  • a suitable base e.g., K 3 PO 4 , K 2 CO 3 , or Cs 2 CO 3
  • a suitable metal complex e.g., a palladium complex such as tris(dibenzylideneacetone)dipalladium(0)
  • a suitable ligand e.g., 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene
  • compound B-2 is prepared by a process comprising contacting intermediate B.1 with intermediate B.3 in the presence of a suitable base (e.g., K 3 PO 4 , K 2 CO 3 , or Cs 2 CO 3 ), and optionally in the presence of a suitable metal complex (e.g., a palladium complex such as tris(dibenzylideneacetone)dipalladium(0)) and/or a suitable ligand (e.g., 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene).
  • a process for preparing compound B-1 or B-2 further comprises a deprotection step under suitable conditions.
  • a process for preparing compound B-1 or B-2 further comprises a funtionalization step (e.g., cyanation) under suitable conditions.
  • a funtionalization step e.g., cyanation
  • provided compounds are prepared according to the following Scheme: wherein Ring A, n, L, W, X, Y, R 1 , R 2 , R a , and R c are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.
  • compound C-1 is prepared by a process comprising contacting intermediate C.1 with intermediate C.2 in the presence of a suitable coupling agent and/or a suitable base (e.g., potassium tert-butoxide).
  • a process for preparing compound C-1 further comprises a deprotection and/or functionalization (e.g., cyanation) step under suitable conditions.
  • a deprotection and/or functionalization e.g., cyanation
  • provided compounds are prepared according to the following Scheme: wherein Ring A, n, W, X, Y, R 1 , R 2 , and R c are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • compound C-2 is prepared by a process comprising contacting intermediate C.3 with intermediate C.2 in the presence of a suitable coupling agent and/or a suitable base (e.g., potassium tert-butoxide).
  • 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, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II-C, II-D, II-E, II-F, 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, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV) and further comprises a pharmaceutically acceptable carrier.
  • a compound provided herein e.g., compounds of Formulae I, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV
  • 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.
  • provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage.
  • unit dosage form refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject.
  • each such unit contains a predetermined quantity of active agent.
  • a unit dosage form contains an entire single dose of the agent.
  • more than one unit dosage form is administered to achieve a total single dose.
  • administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect.
  • a unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.
  • a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents
  • a solid pharmaceutical composition e.g., a tablet, a capsule, or the like
  • a sustained release formulation containing a predetermined quantity of one or more active agents
  • a drug delivery device containing a predetermined amount of one or more active agents
  • 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.
  • 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.
  • provided compounds are useful as JAK2 inhibitors.
  • provided compounds are useful as Type II JAK2 inhibitors.
  • the present disclosure provides methods of inhibiting JAK2 in a subject comprising administering 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., F1000Research 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.
  • the present disclosure provides methods of treating a disease, disorder or condition associated with JAK2 in a subject in need thereof comprising administering to the subject a provided compound or composition.
  • a disease, disorder or condition is associated with overexpression of JAK2.
  • the present disclosure provides methods of treating cancer, comprising administering a provided compound or composition to a subject in need thereof.
  • the present disclosure provides methods of treating proliferative diseases, comprising administering a provided compound or composition to a subject in need thereof.
  • 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. In some embodiments, a non-Hodgkin’s lymphoma is a NK/T-cell lymphoma (e.g., cutaneous T-cell lymphoma). In some embodiments, a hematological malignancy is myeloma (e.g., multiple myeloma). In some embodiments, a hematological malignancy is myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or myelofibrosis).
  • myeloproliferative neoplasm e.g., polycythemia vera, essential thrombocytopenia, or myelofibrosis.
  • a hematological malignancy is myelodysplastic syndrome.
  • the present disclosure provides methods of treating an inflammatory disease, disorder, or condition (e.g., acute respiratory syndrome, hyperinflammation, and/or cytokine storm syndrome (including those associated with COVID- 19) or atopic dermatitis), comprising administering a provided compound or composition to a subject in need thereof.
  • a provided compound or composition is administered as part of a combination therapy.
  • the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents).
  • 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 BCL2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mivebresib), proteasome inhibitors (e.g., bortezomib), LSD1 inhibitors (e.g., IMG-7289), and CXCR2 inhibitors.
  • JAK2 inhibitors Useful combinations of a JAK2 inhibitor with BCL2, HDAC, BET, and proteasome inhibitors have been demonstrated in cells derived from cutaneous T-cell lymphoma patients (Yumeen, S., et al., Blood Adv. 2020, 4(10), 2213-2226).
  • CXCR2 activity has been shown to modulate signaling pathways involved in tumor growth, angiogenesis, and/or metastasis, including the JAK-STAT3 pathway (Jaffer, T., Ma, D. Transl. Cancer Res. 2016, 5(Suppl. 4), S616-S628).
  • JAK-STAT3 pathway Jaffer, T., Ma, D. Transl. Cancer Res. 2016, 5(Suppl. 4), S616-S628).
  • 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 or optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 5. The compound of any one of the preceding embodiments, wherein Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6.
  • 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. 7.
  • R a is optionally substituted C 1-6 aliphatic, 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 or optionally substituted 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each R b is independently hydrogen, halogen, -CN, -OR, -O(CH 2 ) m R, -SR, -N(R) 2 , -NO 2 , - C(O)R’, -C(O)OR, -C(O)N(R) 2 , -OC(O)R’, -OC(O)N(R) 2 , -OC(O)OR, -OSO 2 R, - OSO 2 N(R) 2 , -N(R)C(O)R’, -N(R)SO 2 R’, -SO 2 R’, -SO 2 N(R) 2 , -SO 3 R’, optionally substituted C 1-6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membere
  • each R b is independently halogen, -CN, -OR, - O(CH 2 ) m R, -SR, -N(R) 2 , -NO 2 , -C(O)R’, -C(O)OR, -C(O)N(R) 2 , -OC(O)R’, -OC(O)N(R) 2 , - OC(O)OR, -OSO 2 R, -OSO 2 N(R) 2 , -N(R)C(O)R’, -N(R)SO 2 R’, -SO 2 R’, -SO 2 N(R) 2 , -SO 3 R’, optionally substituted C 1-6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen
  • R b is hydrogen, halogen, -CN, -OR, -O(CH 2 ) m R, -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 , -SO3R’, optionally substituted C 1-6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from
  • Ring A 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. 21.
  • Ring A 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. 22.
  • Ring A is 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more oxo, halogen, or C 1-6 alkyl.
  • Ring A is optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring Ring A1 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 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring A1 is fused to Ring A2; Ring A2 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 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5-
  • each R b is independently hydrogen, halogen, -CN, -OR, -O(CH 2 ) m R, -SR, -N(R) 2 , -NO 2 , - C(O)R’, -C(O)OR, -C(O)N(R) 2 , -OC(O)R’, -OC(O)N(R) 2 , -OC(O)OR, -OSO 2 R, - OSO 2 N(R) 2 , -N(R)C(O)R’, -N(R)SO 2 R’, -SO 2 R’, -SO 2 N(R) 2 , -SO 3 R’, optionally substituted C 1-6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membere
  • each R b is independently halogen, -CN, -OR, -O(CH 2 ) m R, -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 N(R) 2 , -SO3R’, optionally substituted C 1-6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen,
  • each R b is independently halogen, optionally substituted C 1-6 aliphatic, -OR, or -O(CH 2 ) m R. 33.
  • Ring A1 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 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring A1 is fused to Ring A2; Ring A2 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 7-membered saturated or partially uns
  • R 1 is – N(H)C(O)N(R) 2
  • each R of R 1 is independently hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or 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.
  • 50 The compound of any one of embodiments 1-47, wherein R 1 is –N(R)C(O)OR. 51.
  • R 1 is –N(H)C(O)OR, and R of R 1 is optionally substituted C 1-6 aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1 is –N(R)C(O)R’.
  • R 1 is –N(H)C(O)(optionally substituted C 1-6 aliphatic).
  • each R c is independently halogen.
  • 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. 60.
  • Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or optionally substituted 8- to 10-membered bicyclic heteroaryl 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.
  • 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.
  • R b is independently hydrogen, halogen, -CN, -OR, -O(CH 2 ) m R, -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 , -SO3R’, optionally substituted C 1-6 aliphatic
  • each R b is independently halogen, -CN, -OR, -O(CH 2 ) m R, -SR, -N(R) 2 , -NO 2 , -C(O)R’, -C(O)OR, -C(O)N(R) 2 , -OC(O)R’, -OC(O)N(R) 2 , - OC(O)OR, -OSO 2 R, -OSO 2 N(R) 2 , -N(R)C(O)R’, -N(R)SO 2 R’, -SO 2 R’, -SO 2 N(R) 2 , -SO 3 R’, optionally substituted C 1-6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen
  • each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each R is independently hydrogen or optionally substituted C 1-6 aliphatic.
  • each R’ is independently optionally substituted C 1-6 alkyl or optionally substituted C 3-7 cycloalkyl. 73. The compound of any one of the preceding embodiments, wherein each R’ is independently optionally substituted C 1-6 aliphatic. 74.
  • a compound of Formula IV or a pharmaceutically acceptable salt thereof, wherein: Z is –O- or –NR z -; R x is hydrogen, halogen, -OR 3 , or –CN; R z is hydrogen or optionally substituted C 1-6 aliphatic; R 2 is optionally substituted C 1-6 aliphatic; R 3 is hydrogen or optionally substituted C 1-6 aliphatic; selected from (i) or (ii): wherein Ring A is further substituted at least once, and at least one substituent on Ring A is C 1-6 haloalkyl; L is a covalent bond or a bivalent C 1-3 straight or branched hydrocarbon chain; R a is hydrogen, 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 carb
  • R a is optionally substituted C 1-6 aliphatic, 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.
  • L is a covalent bond.
  • a method of treating cancer comprising administering to a subject in need thereof the compound of any one of embodiments 1-88 or the composition of embodiment 89.
  • a method of treating a hematological malignancy comprising administering to a subject in need thereof the compound of any one of embodiments 1-88 or the composition of embodiment 89.
  • the method of embodiment 93, wherein the hematological malignancy is leukemia or lymphoma. 95.
  • a method of treating a myeloproliferative neoplasm comprising administering to a subject in need thereof the compound of any one of embodiments 1-88 or the composition of embodiment 89.
  • EXAMPLES [0167] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
  • Int-27.3-b was prepared from Int-27.2-b, following the same procedure.
  • Synthesis of compound Int-27-a and Int-27-b Compound Int-27-a was prepared from Int-27.3-a, following the procedure described in the synthesis of Int-13. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.1% methanol in DCM). MS(ES): m/z 287.32[M+H] + .
  • Int-27-b was prepared from Int-27.3-b in the same manner.
  • reaction mixture was stirred at 80 °C for 3 h. It was cooled to room temperature, transferred into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM) to afford compound 1.
  • Tris(dibenzylideneacetone)dipalladium(0) (0.131 g, 0.143 mmol, 0.15 equiv) and 1,1′-bis(diphenylphosphino)ferrocene (0.158 g, 0.286 mmol, 0.3 equiv) were added, and degassed for 5 min.
  • the reaction mixture was stirred at 190 °C in a microwave reactor for 2 h. It was cooled to room temperature, transferred into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford material.
  • Example 7 N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)azetidine-1- carboxamide
  • Synthesis of I-7 Compound I-7 was prepared from 6.1 and azetidine hydrochloride, following the procedure described in the synthesis of I-6. The product was purified by preparative HPLC. MS(ES): m/z: 540.4 [M+H] + .
  • Example 8 N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3- hydroxyazetidine-1-carboxamide
  • Synthesis of I-8 Compound I-8 was prepared from 6.1 and azetidin-3-ol hydrochloride, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM).
  • Example 9 N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3- methoxyazetidine-1-carboxamide
  • Synthesis of I-9 Compound I-9 was prepared from 6.1 and 3-methoxyazetidine hydrochloride, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM).
  • Example 11 N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)pyrrolidine-1- carboxamide
  • Synthesis of I-11 Compound I-11 was prepared from 6.1 and pyrrolidine, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.2% methanol in DCM). MS(ES): m/z: 554.3 [M+H] + .
  • Example 12 2-methoxyethyl (4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)- 1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate [0321] Synthesis of I-12.
  • Example 13 (R)-N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3- methoxypyrrolidine-1-carboxamide
  • Synthesis of I-13 Compound I-13 was prepared from 6.1 and (R)-3- methoxypyrrolidine, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.7% methanol in DCM).
  • Example 14 (S)-N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3- methoxypyrrolidine-1-carboxamide [0323] Synthesis of I-14. Compound I-14 was prepared from 6.1 and (S)-3- methoxypyrrolidine, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.9% methanol in DCM).
  • Example 15 2-Morpholinoethyl (4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)- 1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate [0324] Synthesis of I-15. Compound I-15 was prepared from 6.1 and 2-morpholinoethan-1- ol, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in DCM).
  • Example 16 Oxetan-3-yl (4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate [0325] Synthesis of I-16. Compound I-16 was prepared from 6.1 and oxetan-3-ol, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.7% methanol in DCM).
  • Example 18 (R)-Tetrahydrofuran-3-yl (4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5- (trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate [0327] Synthesis of I-18. Compound I-18 was prepared from 6.1 and (R)-tetrahydrofuran-3- ol, following the procedure described in the synthesis of I-17. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.2% methanol in DCM).
  • Example 20 2-Hydroxyethyl (4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)- 1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate [0333] Synthesis of compound 20.1. To a solution of 2-(benzyloxy)ethan-1-ol (0.063 g, 0.416 mmol, 1.0 equiv) in DMF (5 mL) was sodium hydride (0.049 g, 1.248 mmol, 3.0 equiv) at 0 °C and stirred for 30 min.
  • Example 21 3-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1-dimethylurea [0335] Synthesis of compound 21.1.
  • the reaction mixture was degassed by bubbling through a stream of argon for 10 min. Tris(dibenzylideneacetone)dipalladium(0) (0.030 g, 0.032 mmol, 0.07 equiv) and 1,1′-bis(diphenylphosphino)ferrocene (0.039 g, 0.070 mmol, 0.15 equiv) were added, and degassed for 5 min.
  • the reaction mixture was stirred at 210 °C in a microwave reactor for 1 h. It was cooled to room temperature, transferred into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Example 22 Methyl (4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate [0343] Synthesis of I-22.
  • Example 25 N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)morpholine-4-carboxamide [0347] Synthesis of I-25. Compound I-25 was prepared from 24.1 and morpholine, following the procedure of the synthesis of I-24. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM). MS(ES): m/z: 551.3 [M+H] + .
  • Example 26 N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxyazetidine-1- carboxamide [0348] Synthesis of I-26. Compound I-26 was prepared from 24.1 and 3-methoxyazetidine hydrochloride, following the procedure of the synthesis of I-24. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.2% methanol in DCM).
  • Example 27 1-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methylurea
  • Synthesis of I-27 Compound I-27 was prepared from 21.7 and methylamine, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol in DCM).
  • Example 28 (R)-N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-hydroxypyrrolidine-1- carboxamide [0350] Synthesis of I-28. Compound I-28 was prepared from 21.7 and (R)-pyrrolidin-3-ol, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.4% methanol in DCM).
  • Example 29 (S)-N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-hydroxypyrrolidine-1- carboxamide [0351] Synthesis of I-29. Compound I-29 was prepared from 21.7 and (S)-pyrrolidin-3-ol, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM).
  • Example 30 6-((2-Aminopyridin-4-yl)oxy)-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridine-7-carbonitrile [0352] Synthesis of I-30. Compound I-30 was prepared from 21.7 and azetidine, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol in DCM). MS(ES): m/z: 521.4 [M+H] + .
  • Example 31 Methyl (4-((2-((1-(2-oxaspiro[3.3]heptan-6-yl)-5-(trifluoromethyl)-1H-pyrazol-3- yl)amino)-7-cyano-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate [0353] Synthesis of compound 31.1 To a solution of 4-bromopyridin-2-amine (100 g, 577.9 mmol, 1.0 equiv) in DMF (1300 mL) was added sodium hydride (111 g, 2773.9 mmol, 4.8 equiv) at 0 °C in portions and stirred for 2 h.
  • Example 32 2-Methoxyethyl (4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate [0363] Synthesis of I-32. Compound I-32 was prepared from 21.7 and 2-methoxyethan-1-ol, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM).
  • Example 33 (R)-N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxypyrrolidine-1- carboxamide [0364] Synthesis of I-33. Compound I-33 was prepared from 21.7 and (R)-3- methoxypyrrolidine hydrochloride, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.3% methanol in DCM).
  • Example 34 (S)-N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxypyrrolidine-1- carboxamide [0365] Synthesis of I-34. Compound I-34 was prepared from 21.7 and (S)-3- methoxypyrrolidine hydrochloride, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.3% methanol in DCM).
  • Example 35 N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-hydroxyazetidine-1- carboxamide
  • Synthesis of I-35 Compound I-35 was prepared from 21.7 and azetidin-3-ol hydrochloride, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.2% methanol in DCM).
  • Example 36 (S)-tetrahydrofuran-3-yl (4-((7-cyano-2-((4,4-difluoro-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6- yl)oxy)pyridin-2-yl)carbamate [0367] Synthesis of I-36. Compound I-36 was prepared from 21.7 and (S)-tetrahydrofuran- 3-ol, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.2% methanol in DCM).
  • Example 37 (R)-tetrahydrofuran-3-yl (4-((7-cyano-2-((4,4-difluoro-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6- yl)oxy)pyridin-2-yl)carbamate [0368] Synthesis of I-37. Compound I-37 was prepared from 21.7 and (R)-tetrahydrofuran- 3-ol, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.2% methanol in DCM).
  • Example 38 2-(Dimethylamino)ethyl (4-((7-cyano-2-((4,4-difluoro-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6- yl)oxy)pyridin-2-yl)carbamate [0369] Synthesis of I-38. Compound I-38 was prepared from 21.7 and 2- (dimethylamino)ethan-1-ol, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.5% methanol in DCM).
  • Example 39 1-Methylazetidin-3-yl (4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5- (trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate [0370] Synthesis of I-39.
  • Example 40 Methyl (4-((7-chloro-1-methyl-2-((5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate [0371] Synthesis of compound 40.1.
  • Example 41 Methyl (4-((7-cyano-1-methyl-2-((5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate [0374] Synthesis of compound 41.1. Compound 41.1 was prepared from 31.5 and Int-8, following the procedure described in the synthesis of 40.1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.5% methanol in DCM). MS(ES): m/z: 671.5 [M+H] + .
  • Example 42 1-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-cyclopropylurea [0377] Synthesis of I-42. Compound I-42 was prepared from 6.1 and cyclopropanamine, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol in DCM).
  • Example 44 3-(4-((7-cyano-2-((4,4-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1-dimethylurea [0381] Synthesis of I-44. Compound I-44 was prepared from 43.2 and dimethylamine, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM).
  • Example 45 N-(4-((7-cyano-2-((4,4-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide
  • Synthesis of I-45 Compound I-45 was prepared from 43.2 and pyrrolidine, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol in DCM).
  • Example 46 3-(4-((7-chloro-1-methyl-2-((5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1-dimethylurea [0383] Synthesis of I-46. Compound I-46 was prepared from 40.2 and dimethylamine, following the procedure of the synthesis of I-23. The product further purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM).
  • Example 47 N-(4-((7-cyano-2-((4,4-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)azetidine-1-carboxamide
  • Compound I-47 was prepared from 43.2 and azetidine, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol in DCM).
  • Example 48 (R)-Tetrahydrofuran-3-yl (4-((7-cyano-2-((4,4-dimethyl-6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate [0385] Synthesis of I-48. Compound I-48 was prepared from 43.2 and (R)-tetrahydrofuran- 3-ol, following the procedure of the synthesis of I-23.
  • Example 51 N-(4-((7-chloro-1-methyl-2-((1-(methyl-d3)-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide
  • Synthesis of compound 51.1 To a solution of 21.5 (0.150 g, 0.487 mmol, 1.0 equiv) in THF (2 mL) was added 1,1'-thiocarbonyldiimidazole (0.433 g, 2.43 mmol, 5.0 equiv). The reaction mixture was stirred at 80 °C for 1 h.
  • Example 52 3-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1-bis(methyl- d 3 )urea
  • Compound I-52 was prepared from 6.1 and dimethylamine hydrochloride (d 6 ), following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol in DCM).
  • Compound I-54 was prepared from 40.2 and oxetan-3-ol, following the procedure described in the synthesis of I-53. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM).
  • Example 55 (S)-tetrahydrofuran-3-yl (4-((7-chloro-1-methyl-2-((5-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate [0393] Synthesis of I-55. Compound I-55 was prepared from 40.2 and (S)-tetrahydrofuran- 3-ol, following the procedure described in the synthesis of I-53. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM).
  • Example 56 3-(4-((7-cyano-2-((5',6'-dihydrospiro[cyclobutane-1,4'-pyrrolo[1,2-b]pyrazol]-2'- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1-dimethylurea
  • Synthesis of compound 56.1 Compound 56.1 was prepared from 31.5 and Int-10, following the procedure described in the synthesis of I-19. The product was purified by flash column chromatography on silica gel (CombiFlash®, DCM). MS(ES): m/z 668 [M+H] + .
  • Example 57 methyl (4-((7-cyano-2-((5',6'-dihydrospiro[cyclobutane-1,4'-pyrrolo[1,2- b]pyrazol]-2'-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate [0397] Synthesis of I-57. Compound I-57 was prepared from 56.2 following the procedure described in the synthesis of I-22. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2% DCM: methanol). MS(ES): m/z 486.35 [M+H] + .
  • Example 58 1-(4-((7-cyano-2-((5',6'-dihydrospiro[cyclobutane-1,4'-pyrrolo[1,2-b]pyrazol]-2'- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methylurea [0398] Synthesis of I-58. Compound I-58 was prepared from 56.2 and methylamine, following the procedure described in the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM).
  • Example 59 (S)-N-(4-((7-cyano-2-((5',6'-dihydrospiro[cyclobutane-1,4'-pyrrolo[1,2-b]pyrazol]- 2'-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxypyrrolidine- 1-carboxamide [0399] Synthesis of I-59. Compound I-59 was prepared from 56.2 and (S)-3- methoxypyrrolidine, following the procedure described in the synthesis of I-23.
  • Example 60 (R)-N-(4-((7-cyano-2-((5',6'-dihydrospiro[cyclobutane-1,4'-pyrrolo[1,2-b]pyrazol]- 2'-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxypyrrolidine- 1-carboxamide [0400] Synthesis of I-60. Compound I-60 was prepared from 56.2 and (R)-3- methoxypyrrolidine, following the procedure described in the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM).
  • Example 61 N-(4-((7-cyano-2-((5',6'-dihydrospiro[cyclobutane-1,4'-pyrrolo[1,2-b]pyrazol]-2'- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxyazetidine-1- carboxamide [0401] Synthesis of I-61. Compound I-61 was prepared from 56.2 and 3-methoxyazetidine, following the procedure described in the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM).
  • Example 62 2-methoxyethyl (4-((7-cyano-2-((5',6'-dihydrospiro[cyclobutane-1,4'-pyrrolo[1,2- b]pyrazol]-2'-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate [0402] Synthesis of I-62. Compound I-62 was prepared from 56.2 and 2-methoxyethan-1-ol, following the procedure described in the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM).
  • Example 63 methyl (4-((7-cyano-2-((6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5- a]pyridin]-2'-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate [0403] Synthesis of compound 63.1. Compound 63.1 was prepared from 31.5 and Int-11, following the procedure described in the synthesis of 40.1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2% methanol in DCM).
  • Example 64 1-(4-((7-cyano-2-((6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5- a]pyridin]-2'-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methylurea
  • Synthesis of I-64 Compound I-64 was prepared from 63.2 and methylamine, following the procedure described in the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM).
  • Example 65 3-(4-((7-cyano-2-((6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5- a]pyridin]-2'-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1- dimethylurea
  • Synthesis of I-65 Compound I-65 was prepared from 63.2 and dimethyl carbonyl chloride, following the procedure described in the synthesis of I-21. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM).
  • Example 66 oxetan-3-yl (4-((7-cyano-2-((5',6'-dihydrospiro[cyclobutane-1,4'-pyrrolo[1,2- b]pyrazol]-2'-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate [0408] Synthesis of I-66. Compound I-66 was prepared from 63.2 and oxetan-3-ol, following the procedure described in the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM) followed by HPLC.
  • Example 68 methyl (4-((7-cyano-2-((4,4-dimethyl-4,5,7,8-tetrahydropyrazolo[1,5- d][1,4]oxazepin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate [0412] Synthesis of I-68. Compound I-68 was prepared from 67.2, following the procedure described in the synthesis of I-22. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.9% methanol in DCM).
  • Example 69 1-(4-((7-cyano-2-((4,4-dimethyl-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxazepin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methylurea [0413] Synthesis of I-69. Compound I-69 was prepared from 67.2 and methylamine, following the procedure described in the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.4% methanol in DCM).
  • Example 70 3-(4-((2-((1-(tert-butyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-6-yl)amino)-7- cyano-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1-dimethylurea
  • Synthesis of compound 70.1 Compound 70.1 was prepared from 31.5 and Int-13, following the procedure described in the synthesis of 40.1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.0% methanol in DCM. MS(ES): m/z 685.83 [M+H] + .
  • Example 71 methyl (4-((2-((1-(tert-butyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-6-yl)amino)- 7-cyano-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate [0417] Synthesis of I-71. To a solution of 70.2 (0.050 g, 0.112 mmol, 1.0 equiv) in THF (5 mL) was added lithium bis(trimethylsilyl)amide (0.33 mL, 0.336 mmol, 3.0 equiv) at 0 °C and stirred for 10 min.
  • Example 72 1-(4-((2-((1-(tert-butyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-6-yl)amino)-7- cyano-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methylurea
  • Synthesis of I-72 Compound I-72 was prepared from 70.2 and methylamine, following the procedure described in the synthesis of I-23. The product was purified by preparative HPLC.
  • Example 73 3-(4-((7-cyano-2-((6,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1-dimethylurea [0419] Synthesis of compound 73.1. Compound 73.1 was prepared from 31.5 and methylamine following the procedure described in the synthesis of 3.7 The product was purified by flash column chromatography on silica gel (CombiFlash®, 5.2% methanol in DCM).
  • Example 74 (S)-N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-(tetrahydro-2H- pyran-2-yl)acetamide and (R)-N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)- 1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-(tetrahydro- 2H-pyran-2-yl)acetamide [0422] Synthesis of compound ( ⁇ )-I-74.
  • Tris(dibenzylideneacetone)dipalladium(0) (0.030 g, 0.032 mmol, 0.15 equiv) and 1,1′- bis(diphenylphosphino)ferrocene (0.035 g, 0.065 mmol, 0.3 equiv) were added and degassed for 5 min.
  • the reaction mixture was stirred at 170 °C in a microwave reactor for 2 h. It was cooled to room temperature, transferred into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Example 75 N-(4-((7-chloro-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2- methoxyacetamide
  • Synthesis of compound 75.1 A mixture of 1.1 (1.0 g, 7.78 mmol, 1.0 equiv) and 2- methoxyacetic acid (3.5 g, 38.89 mmol, 5 equiv) was stirred at in a microwave reactor at 190 °C for 2 h.
  • Example 76 N-(4-((7-chloro-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-fluoroacetamide [0430] Synthesis of compound 76.1.
  • Example 78 (R)-N-(4-((7-chloro-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-(4- methylmorpholin-2-yl)acetamide and (S)-N-(4-((7-chloro-1-methyl-2-((1-methyl-2-oxo-5- (trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)-2-(4-methylmorpholin-2-yl)acetamide [0442] Synthesis of compound ( ⁇ )-78.1.
  • Example 79 N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2- methoxyacetamide [0452] Synthesis of compound 79.1.
  • Example 80 N-(4-((2-((1-(2-hydroxyethyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3- yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0454] Synthesis of compound 80.1.
  • Example 81 (N-(4-((7-cyano-2-((1-(2-hydroxyethyl)-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)acetamide
  • 81.1 To a solution of 80.3 (30.5 g, 87.19 mmol, 1.0 equiv) in DCM (600 mL) was added sulphuryl chloride (435.5 g, 3226 mmol, 37 equiv) at 0 °C and stirred for 15 min.
  • Example 82 N-(4-((7-chloro-1-methyl-2-((1-(methyl-d 3 )-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide
  • 4-bromopyridin-2-amine 100 g, 577.9 mmol, 1.0 equiv
  • DMF 1300 mL
  • sodium hydride 111 g, 2773.9 mmol, 4.8 equiv
  • Example 83 N-(4-((7-cyano-1-methyl-2-((1-(methyl-d 3 )-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0473] Synthesis of I-83. Compound I-83 was prepared from I-82, following the procedure described in the synthesis of ( ⁇ )-I-74. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in DCM) t.
  • Example 84 N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-fluoroacetamide [0474] Synthesis of I-84. To a solution of 3.8 (0.070 g, 0.153 mmol, 1.0 equiv) in THF (5 mL) was added HATU (0.088 g, 0.229 mmol, 1.5 equiv) and stirred for 30 min.
  • Example 85 N-(4-((7-chloro-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-((2- methoxyethyl)amino)acetamide
  • Synthesis of compound 85.1 To a solution of 1.2 (5.00 g, 25.0 mmol, 1.0 equiv) and trimethylamine (7.575 g, 75.0 mmol, 3.0 equiv) in THF (50 mL) at 0 °C was added chloroacetyl chloride (4.235 g, 37.5 mmol, 1.5 equiv).
  • Example 87 N-(4-((7-chloro-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-((2- fluoroethyl)amino)acetamide
  • Example 88 N-(4-((7-chloro-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)-5-fluoropyridin-2-yl)acetamide [0495] Synthesis of compound 88.1.
  • the reaction mixture was purged with argon for another 5 min and stirred at 100 °C for 2 h. It was poured in water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM). The product was dissolved in methanol and an aqueous solution of sodium hydroxide (2.0 g, 5.00 mmol, 10 equiv) was added. The reaction mixture was stirred at 80 °C for 4 h. It was poured in water and extracted with ethyl acetate.
  • Example 90 (R)-N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-(4- methylmorpholin-2-yl)acetamide and (S)-N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5- (trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)-2-(4-methylmorpholin-2-yl)acetamide [0509] Synthesis of compound ( ⁇ )-90.1.
  • Example 92 N-(4-((7-chloro-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0519] Synthesis of compound I-92. Compound I-92 was prepared from 80.2 and Int-7, following the procedure described in the synthesis of I-19. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM) to afford I-92.
  • Example 93 N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0520] Synthesis of compound I-93. Compound I-93 was prepared from I-92, following the procedure described in the synthesis of 31.5. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.5% methanol in DCM).
  • Example 94 N-(4-((7-chloro-2-((4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)amino)- 1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0521] Synthesis of I-94. Compound I-94 was prepared from 80.2 and Int-18, following the procedure described in the synthesis of 3.7. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.9% methanol in DCM.
  • Example 96 (S)-N-(4-((7-chloro-1-methyl-2-((3-((1-methylpyrrolidin-2-yl)methoxy)-5- (trifluoromethyl)phenyl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0526] Synthesis of I-96. Compound I-96 was prepared from 81.1 and Int-19.3, following the procedure described in the synthesis of I-10. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5.6% methanol in DCM).
  • Example 97 (R)-N-(4-((7-chloro-1-methyl-2-((3-((1-methylpyrrolidin-2-yl)methoxy)-5- (trifluoromethyl)phenyl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0527] Synthesis of I-97. Compound I-97 was prepared from 81.1 and Int-20.1, following the procedure described in the synthesis of I-10. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5.6% methanol in DCM).
  • Example 98 N-(4-((2-((1-(2-oxaspiro[3.3]heptan-6-yl)-5-(trifluoromethyl)-1H-pyrazol-3- yl)amino)-7-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0528] Synthesis of compound I-98. Compound I-98 was prepared from 80.2 and Int-6, following the procedure described in the synthesis of 3.7. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5.0% methanol in DCM).
  • Example 99 (S)-N-(4-((7-chloro-1-methyl-2-((3-((1-methylpyrrolidin-3-yl)oxy)-5- (trifluoromethyl)phenyl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0529] Synthesis of I-99. Compound I-99 was prepared from 80.2 and Int-21, following the procedure described in the synthesis of I-19. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.2% methanol in DCM).
  • Example 100 (R)-N-(4-((7-chloro-1-methyl-2-((3-((1-methylpyrrolidin-3-yl)oxy)-5- (trifluoromethyl)phenyl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide
  • Compound I-100 was prepared from 80.2 and Int-22, following the procedure described in the synthesis of I-19. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.2% methanol in DCM) to afford I-100 (0.025 g, Yield: 19.08%).
  • Example 101 N-(4-((7-chloro-1-methyl-2-((3-(((1-methylazetidin-3-yl)oxy)methyl)-5- (trifluoromethyl)phenyl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide
  • Compound 101.1 was prepared from 81.1 and Int-23, following the procedure described in the synthesis of I-10. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5.0% methanol in DCM. MS (ES): m/z 663.43 [M-H] + .
  • Example 102 (R)-N-(4-((7-chloro-1-methyl-2-((3-(1-methylpyrrolidin-2-yl)-5- (trifluoromethyl)phenyl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide and (S)-N-(4-((7-chloro-1-methyl-2-((3-(1-methylpyrrolidin-2-yl)-5-(trifluoromethyl)phenyl)amino)- 1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide
  • Example 104 N-(4-((7-cyano-1-methyl-2-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3- yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0539] Synthesis of compound 104.1.
  • the reaction mixture was stirred at 190 °C in a microwave reactor for 3 h. It was cooled to room temperature, transferred into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.2% methanol in DCM) to afford I-104.
  • Example 105 N-(4-((7-cyano-2-((4-((dimethylamino)methyl)-3- (trifluoromethyl)phenyl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)acetamide
  • Compound 105.1 was prepared from 31.5 and Int-18, following the procedure described in the synthesis of 40.1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.9% methanol in DCM). MS(ES): m/z 723.77 [M+H] + .
  • Synthesis of compound 105.2 was prepared from 31.5 and Int-18, following the procedure described in the synthesis of 40.1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.9% methanol in DCM). MS(ES): m/z 723.77 [M+H] + . [0543] Synthesis of compound
  • Example 106 N-(4-((2-((1-(2-oxaspiro[3.3]heptan-6-yl)-5-(trifluoromethyl)-1H-pyrazol-3- yl)amino)-7-cyano-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide
  • Compound 106.1 was prepared from 31.8, following the procedure described in the synthesis of I-105. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.8% methanol in DCM). MS(ES): m/z: 343.74 [M+H] + .
  • Example 107 N-(4-((2-((1-(7-oxaspiro[3.5]nonan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3- yl)amino)-7-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2- methoxyacetamide
  • Example 108 (R)-N-(4-((7-chloro-1-methyl-2-((4-(1-methylpyrrolidin-2-yl)-3- (trifluoromethyl)phenyl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide and (S)-N-(4-((7-chloro-1-methyl-2-((4-(1-methylpyrrolidin-2-yl)-3-(trifluoromethyl)phenyl)amino)- 1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0548] Synthesis of I-108-a.
  • Compound I-108-a was prepared from 80.2 and Int-27-a, following the procedure described in the synthesis of 3.7. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.8% methanol in DCM).
  • Compound I-108-b was prepared from 80.2 and Int-27-b, following the procedure described in the synthesis of 3.7. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.9% methanol in DCM).
  • Example 109 (R)-N-(4-((7-cyano-1-methyl-2-((4-(1-methylpyrrolidin-2-yl)-3- (trifluoromethyl)phenyl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide and (S)-N-(4-((7-cyano-1-methyl-2-((4-(1-methylpyrrolidin-2-yl)-3-(trifluoromethyl)phenyl)amino)- 1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0550] Synthesis of I-109-a Compound I-109-a was prepared from I-108-a, following the procedure described in the synthesis of ( ⁇ )-I-74.
  • Example 110 N-(4-((2-((1-(7-oxaspiro[3.5]nonan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3- yl)amino)-7-cyano-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2- methoxyacetamide
  • Compound 110.1 was prepared from 31.5 and Int-26, following the procedure described in the synthesis of I-19. The product was purified by flash column chromatography on silica gel (CombiFlash®, 38-48% ethyl acetate in hexane).
  • Example 111 N-(4-((7-chloro-1-methyl-2-((2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-4- yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0555] Synthesis of compound I-111. Compound I-111 was prepared from 80.2 and Int-28, following the procedure described in the synthesis of I-19. The product was purified by flash column chromatography on silica gel (CombiFlash®, 85-90% ethyl acetate in hexane.
  • Example 112 N-(4-((7-cyano-2-((4,4-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0556] Synthesis of I-112.
  • Example 113 N-(4-((7-cyano-2-((5',6'-dihydrospiro[cyclobutane-1,4'-pyrrolo[1,2-b]pyrazol]-2'- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide
  • Synthesis of compound 113.1 Compound 113.1 was prepared from 31.5 and Int-29, following the procedure described in the synthesis of I-19. The product was purified by flash column chromatography on silica gel (CombiFlash®, dichloromethane) to afford 113.1. MS(ES): m/z 668 [M+H] + .
  • Example 114 N-(4-((7-cyano-2-((6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5- a]pyridin]-2'-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0560] Synthesis of I-114. Compound I-114 was prepared from 63.2, following the procedure described in the synthesis of I-112. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM).
  • Example 115 N-(4-((2-((1-(tert-butyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-6-yl)amino)-7- cyano-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0561] Synthesis of I-115. Compound I-115 was prepared from 70.2, following the procedure described in the synthesis of I-112. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.1-3.7% methanol in DCM).
  • Example 118 N-(4-((7-cyano-2-((4,4-dimethyl-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxazepin- 2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide [0562] Synthesis of compound I-118. Compound I-118 was prepared from 67.2, following the procedure described in the synthesis of I-112.
  • Example 119 N-(4-((7-cyano-1-methyl-2-((5'-methyl-6',7'-dihydro-5'H-spiro[cyclopropane- 1,4'-pyrazolo[1,5-a]pyrazin]-2'-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)acetamide [0563] Synthesis of compound 119.1. Compound 119.1 was prepared from 31.5 and Int-30, following the procedure described in the synthesis of I-19. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM).
  • Example 120 (S)-tetrahydrofuran-3-yl (4-((7-cyano-2-((5',6'-dihydrospiro[cyclobutane-1,4'- pyrrolo[1,2-b]pyrazol]-2'-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate [0566] Synthesis of compound I-120.
  • Example 121 (R)-tetrahydrofuran-3-yl (4-((7-cyano-2-((5',6'-dihydrospiro[cyclobutane-1,4'- pyrrolo[1,2-b]pyrazol]-2'-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate [0567] Synthesis of compound I-121. Compound I-121 was prepared from 56.2 and (R)- tetrahydrofuran-3-ol, following the procedure described in the synthesis of I-120.
  • Example 122 N-(4-((7-cyano-2-((5',6'-dihydrospiro[cyclobutane-1,4'-pyrrolo[1,2-b]pyrazol]-2'- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide [0568] Synthesis of I-122.
  • Example 123 1-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-(oxetan-3- yl)urea [0569] Synthesis of I-123. Compound I-123 was prepared from 6.1 and oxetan-3-amine, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (7.0% methanol in DCM) to afford I-123.
  • JAK2 Binding Assay [0571] JAK2 (JH1domain-catalytic, Y1007F,Y1008F) kinase was expressed as N-terminal fusion to the DNA binding domain of NFkB in transiently transfected HEK293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (1x PBS, 0.05% Tween 20, 0.1% BSA, 1 mmol/L DTT). Test compound was prepared as 111x stocks in 100% DMSO and directly diluted into the assay wells. All reactions were performed in polypropylene 384-well plates in a final volume of 0.02 mL.
  • JAK Family Selectivity Assays Provided compounds are evaluated for selectivity by comparing their JAK2 binding affinity (K d ) in the above JAK2 Binding Assay with their binding affinity (K d ) for one or more other kinases. Binding affinity for other kinases is determined as follows: Kinase-tagged T7 phage strains are prepared in an E. coli host derived from the BL21 strain. E. coli are grown to log-phase and infected with T7 phage and incubated with shaking at 32 °C until lysis. The lysates are centrifuged and filtered to remove cell debris.
  • the remaining kinases are produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection.
  • Streptavidin-coated magnetic beads are treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • the liganded beads are blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding.
  • blocking buffer SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT
  • Binding reactions are assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT).
  • Test compounds are prepared as 111X stocks in 100% DMSO. Kds are determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds are then diluted directly into the assays such that the final concentration of DMSO is 0.9%. All reactions are performed in polypropylene 384-well plate. Each has a final volume of 0.02 ml.
  • the assay plates are incubated at room temperature with shaking for 1 hour and the affinity beads are washed with wash buffer (1x PBS, 0.05% Tween 20). The beads are then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 ⁇ M non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes.
  • the kinase concentration in the eluates is measured by qPCR. Compounds that exhibit a better binding affinity for JAK2 compared to one or more other kinases are considered to be JAK2-selective compounds.
  • provided compounds may be JAK2-selective over one or more of the following kinases: JAK1, JAK3, and Tyk2.
  • Results of the JAK2 Selectivity Assay described above are presented in Table 3. Compounds denoted as “A” had a Kd/Kd ratio ⁇ 1000; compounds denoted as “B” had a Kd/Kd ratio ⁇ 1000 and ⁇ 300; compounds denoted as “C” had a Kd/Kd ratio ⁇ 300 and ⁇ 100; compounds denoted as “D” had a K d /K d ratio ⁇ 100.
  • Table 3 SET2-pSTAT5 Cellular Assay [0575] 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.
  • Results of the SET2-pSTAT5 Cellular Assay described above are presented in Table 4. Compounds denoted as “A” had a IC50 ⁇ 125 nM; compounds denoted as “B” had a IC50 ⁇ 125 nM and ⁇ 200 nM; compounds denoted as “C” had a IC 50 ⁇ 200 nM and ⁇ 1 ⁇ M; compounds denoted as “D” had a IC50 ⁇ 1 ⁇ M and ⁇ 5 ⁇ M. Table 4.
  • hPBMC-GMCSF-STAT5 Assay measures inhibition of JAK2-homodimeric-mediated STAT5 signaling in human peripheral blood mononuclear cells.
  • PBMCs are thawed with assay media comprising: Then, cells are counted. The cells are diluted with culture medium and 120 ⁇ L of cell suspension (500000/well) is added into each well of a 96-well cell culture plate. The test compound is diluted to 10X in assay media, and 15 ⁇ L of the solution is added to the assay plates. The plates are covered with a lid and placed in a 37 °C, 5% CO 2 incubator for 4 hours.
  • GM- CSF stock solution (100 ⁇ g/mL) is diluted to 50 ng/mL in assay media, and 15 ⁇ L of the solution is added to the assay plates, such that the final concentration in the assay is 5 ng/mL.
  • the plates are covered with a lid and placed in a 37 °C, 5% CO 2 incubator for 5 min. After 5 min, the cells are spun and culture medium aspirated. Then, 50 ⁇ L lysis buffer (with protease and phosphatase inhibitor cocktail) is added to each cell pallet, and the cell lysate is shaken at 4 °C for 20 min.
  • the cell lysate is then spun at 4 °C, 4000 rpm for 5 min, and the supernatant is transferred into a new plate and stored at -80 °C until further use.
  • An MSD standard plate is coated with capture antibody in PBS (40 ⁇ L/well) and incubated at 4 °C overnight with shaking. The MSD plate is then washed three times with 150 ⁇ L/well of TBST. Sample lysates (50 ⁇ L/well) are added to the MSD plates and shaken for 1 h at RT, 600 rpm. The MSD plates are then washed three times with 150 ⁇ L/well of TBST.
  • Detection antibody is added (25 ⁇ L/well) and shaken for 1 h at RT, 600 rpm.
  • the detection antibody is prepared in Antibody Detection buffer (1% Blocker A in TBST).
  • the MSD plates are then washed three times with 150 ⁇ L/well of TBST.
  • the second detection antibody is added (25 ⁇ L/well), shaken for 1 h at RT, 600 rpm.
  • the second detection antibody is prepared in Antibody Detection buffer (1% Blocker A in TBST).
  • the MSD plates are then washed three times with 150 ⁇ L/well of TBST.
  • MSD reading buffer (2x) is added (150 ⁇ L/well) and diluted from 4x with water.
  • hPBMC-IL12-STAT4 Assay measures inhibition of Tyk2/JAK2-mediated STAT4 signaling in human peripheral blood mononuclear cells.
  • PBMCs are thawed with assay media comprising: Then, cells are counted. The cells are diluted with culture medium and 120 ⁇ L of cell suspension (200000/well) is added into each well of a 96-well cell culture plate. The test compound is diluted to 10X in assay media, and 15 ⁇ L of the solution is added to the assay plates. The plates are covered with a lid and placed in a 37 °C, 5% CO 2 incubator for 1 hour.
  • IL12 stock solution 50 ng/mL
  • assay media 50 ng/mL
  • 15 ⁇ L of the solution is added to the assay plates, such that the final concentration in the assay is 1.7 ng/mL.
  • the plates are covered with a lid and placed in a 37 °C, 5% CO 2 incubator for 25 min. After 25 min, the cells are spun and culture medium aspirated. Then, 65 ⁇ L lysis buffer (with protease and phosphatase inhibitor cocktail) is added to each cell pallet, and the cell lysate is shaken at 4 °C for 30 min.
  • the cell lysate is then spun at 4 °C, 4000 rpm for 5 min, and the supernatant is transferred into a new plate and stored at -80 °C until further use.
  • An MSD standard plate is blocked with blocking buffer (3% Blocker A in Wash buffer) and shaken for 1 h at RT, 600 rpm.
  • the MSD plate is then washed three times with 150 ⁇ L/well of Wash buffer.
  • Sample lysates 25 ⁇ L/well
  • the MSD plates are then washed three times with 150 ⁇ L/well of Wash buffer.
  • Detection antibody is added (25 ⁇ L/well) and shaken for 1 h at RT, 600 rpm.
  • the detection antibody is prepared in Antibody Detection buffer (for one plate, 150 ⁇ L 2% Blocker D-M, 30 ⁇ L 10% Blocker D-R, 1 mL of Blocker A solution, 1.82 mL of 1x Wash buffer).
  • the MSD plates are then washed three times with 150 ⁇ L/well of TBST. Then, MSD reading buffer (1x) is added (150 ⁇ L/well) and diluted from 4x with water.
  • the plates are imaged using an MSD imaging instrument according to the manufacturer’s instructions.
  • hPBMC-IL2-STAT5 Assay measures inhibition of JAK1/JAK3-mediated STAT5 signaling in human peripheral blood mononuclear cells.
  • PBMCs are thawed with assay media comprising: Then, cells are counted. The cells are diluted with culture medium and 120 ⁇ L of cell suspension (200000/well) is added into each well of a 96-well cell culture plate. The test compound is diluted to 10X in assay media, and 15 ⁇ L of the solution is added to the assay plates. The plates are covered with a lid and placed in a 37 °C, 5% CO 2 incubator for 1 hour.
  • IL2 stock solution 100 ⁇ g/mL is diluted to 250 ng/mL in assay media, and 15 ⁇ L of the solution is added to the assay plates, such that the final concentration in the assay is 25 ng/mL.
  • the plates are covered with a lid and placed in a 37 °C, 5% CO 2 incubator for 5 min. After 5 min, the cells are spun and culture medium aspirated. Then, 40 ⁇ L lysis buffer (with protease and phosphatase inhibitor cocktail) is added to each cell pallet, and the cell lysate is shaken at 4 °C for 20 min.
  • the cell lysate is then spun at 4 °C, 4000 rpm for 5 min, and the supernatant is transferred into a new plate and stored at -80 °C until further use.
  • An MSD standard plate is coated with capture antibody in PBS (40 ⁇ L/well) and incubated at 4 °C overnight with shaking. The MSD plate is then washed three times with 150 ⁇ L/well of TBST. The MSD plates are then blocked with blocking buffer (150 ⁇ L of 3% Blocker A in TBST) and shaken for 1 h at RT, 600 rpm. The MSD plate is then washed three times with 150 ⁇ L/well of TBST.
  • Sample lysates (40 ⁇ L/well) are added to the MSD plates and shaken for 1 h at RT, 600 rpm. The MSD plates are then washed three times with 150 ⁇ L/well of TBST. Detection antibody is added (25 ⁇ L/well) and shaken for 1 h at RT, 600 rpm. The detection antibody is prepared in Antibody Detection buffer (1% Blocker A in TBST). The MSD plates are then washed three times with 150 ⁇ L/well of TBST. The second detection antibody is added (25 ⁇ L/well), shaken for 1 h at RT, 600 rpm. The second detection antibody is prepared in Antibody Detection buffer (1% Blocker A in TBST).
  • substrate is prepared in freshly prepared Reaction Buffer (20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 0.02 mg/mL BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO). Any required cofactors are then added to the substrate solution. Then, the kinase is delivered into the substrate solution and is gently mixed. Test compounds in 100% DMSO are then added to the kinase reaction mixture using Acoustic technology (Echo550; nanoliter range) and incubated for 20 min at RT. 33 P-ATP is added to the reaction mixture and incubated for 2 h at RT.
  • Reaction Buffer 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 0.02 mg/mL BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO
  • Caco2 Permeability Assay 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.
  • Assay Procedure The Caco-2 plate is removed from the incubator and washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4), and then incubated at 37 °C for 30 minutes. The stock solutions of control compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) to get 5 ⁇ M working solutions.
  • the stock solutions of the test compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES and 4% BSA, pH 7.4) to get 5 ⁇ M working solutions.
  • the final concentration of DMSO in the incubation system is 0.5%.
  • 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 incubated at 37 °C for 2 hours.
  • Lucifer Yellow leakage after 2 hour transport period stock solution of Lucifer yellow is prepared in ultra-pure water and diluted with HBSS (10 mM HEPES, pH 7.4) to reach the final concentration of 100 ⁇ M. 100 ⁇ L of the Lucifer yellow solution is added to each Transwell® insert (apical compartment), followed by filling the wells in the receiver plate (basolateral compartment) with 300 ⁇ L of HBSS (10 mM HEPES, pH 7.4). The plates are incubated at 37 °C for 30 minutes.80 ⁇ L samples are removed directly from the apical and basolateral wells (using the basolateral access holes) and transferred to wells of new 96 wells plates.
  • HBSS mM HEPES, pH 7.4
  • the Lucifer Yellow fluorescence (to monitor monolayer integrity) signal is measured in a fluorescence plate reader at 485 nM excitation and 530 nM emission.
  • Results of the Caco-2 Permeability Assay described above are presented in Table 5. Compounds denoted as “A” had a ER ⁇ 2; compounds denoted as “B” had a ER > 2 and ⁇ 5; compounds denoted as “C” had a ER > 5 and ⁇ 10; compounds denoted as “D” had a ER > 10 and ⁇ 30.
  • Table 5 Cytotoxicity Assay [0586] 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 (EVO 2 00) 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.
  • %Inhibition 100 x (LumHC – LumSample) / (LumHC –LumLC), wherein HC is reading obtained from cells treated with 0.1% DMSO only and LC is reading from cells treated with 10 ⁇ L staurosporine.
  • IC50 values are calculated using XLFit (equation 201).
  • Hepatocyte Stability Assay [0587] 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.
  • Plasma Protein Binding Assay 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). The assay is performed in duplicate.
  • PBS dialysis buffer
  • 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.
  • 400 ⁇ L of precipitation buffer acetonitrile containing internal standards (IS, 100 nM alprazolam, 200 nM labetalol, 200 nM imipramine and 2 ⁇ M ketoplofen) is added to precipitate protein and release compounds.
  • Samples are vortexed for 2 minutes and centrifuged for 30 minutes at 3,220 g.

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