WO2023009709A1

WO2023009709A1 - Pyrazolo piperazines as jak2 inhibitors

Info

Publication number: WO2023009709A1
Application number: PCT/US2022/038657
Authority: WO
Inventors: Craig E. Masse; Jeremy R. Greenwood; Jiayi Xu; Sayan Mondal; Phani GHANAKOTA; Fiona Michelle MCROBB
Original assignee: Ajax Therapeutics, Inc.
Priority date: 2021-07-29
Filing date: 2022-07-28
Publication date: 2023-02-02

Abstract

The present disclosure provides pyrazolo piperazine compounds and compositions thereof useful for inhibiting JAK2.

Description

PYRAZOLO PIPERAZINES AS JAK2 INHIBITORS RELATED APPLICATIONS [0001] This application claims priority to and benefit of U.S. Application No. 63/226,892, filed July 29, 2021, the entire contents of which are hereby incorporated by reference. BACKGROUND [0002] Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase involved in the JAK-STAT signaling pathway, which plays a role in cell processes such as immunity, cell division, and cell death. Dysfunction of the JAK-STAT pathway is implicated in various diseases, including cancer and other proliferative diseases, as well as diseases of the immune system. For example, essentially all BCR-ABL1-negative myeloproliferative neoplasms are associated with mutations that activate JAK2. In particular, JAK2V617F is the most prevalent mutation in myeloproliferative neoplasms, occurring in approx. 70% of all patients, and in up to 95% of patients with polycythemia vera. (Vainchenker, W., Kralovics, R. Blood 2017, 129(6):667-79). Even less common mutations, such as in MPL and CALR, have been shown to effect activation of JAK2, thereby initiating and/or driving disease progression. (Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev):82). Furthermore, polymorphisms in JAK2 have been linked to various autoimmune diseases and inflammatory conditions, such as psoriasis and inflammatory bowel disease. (O’Shea, J. J. et al., Ann. Rheum. Dis. 2013 Apr, 72:ii111-ii115). Increased signaling through JAK2, as well as other members of the JAK family, is also associated with atopic dermatitis. (Rodrigues, M. A. and Torres, T. J. Derm. Treat. 2019, 31(1):33-40). [0003] Inhibitors of JAKs (e.g., JAK2) are classified based on their binding mode. All currently approved JAK inhibitors are Type I inhibitors, which are those that bind the ATP- binding site in the active conformation of the kinase domain, thereby blocking catalysis (Vainchenker, W. et al.). However, increased phosphorylation of the JAK2 activation loop is observed with Type I inhibitors and may lead to acquired resistance in certain patients (Meyer S. C., Levine, R. L. Clin. Cancer Res. 2014, 20(8):2051-9). Type II inhibitors, on the other hand, bind the ATP-binding site of the kinase domain in the inactive conformation and, therefore, may avoid hyperphosphorylation observed with Type I inhibitors (Wu, S. C. et al. Cancer Cell 2015 Jul 13, 28(1):29-41). SUMMARY [0004] The present disclosure provides compounds useful for inhibiting JAK2. In some embodiments, provided compounds are useful for, among other things, treating and/or preventing diseases, disorders, or conditions associated with JAK2. [0005] In some embodiments, the present disclosure provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, R^a, R^x, R¹, R^1’, R², R^2’, R³, R^3’, R⁴, and R^4’ are as defined herein. DETAILED DESCRIPTION Compounds and Definitions [0006] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0007] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomic, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some case, Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and/or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure. [0008] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon, are within the scope of this disclosure. [0009] Aliphatic: The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C_1-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C_1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C_1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C_1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C_1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, and alkynyl groups and hybrids thereof. In some embodiments, “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation that has a single point of attachment to the rest of the molecule. [0010] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., 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. [0011] Carbocyclyl: The terms “carbocyclyl,” “carbocycle,” and “carbocyclic ring” as used herein, refer to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as described herein. Carbocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclyl” (or “cycloaliphatic”) refers to an optionally substituted monocyclic C₃-C₈ hydrocarbon, or an optionally substituted C₇-C₁₀ bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. The term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3–6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl. [0012] Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C_2-12, C_2-10, C_2-8, C_2-6, C_2-4, or C_2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. [0013] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., 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. [0014] Aryl: The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C6-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In some embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons. [0015] Heteroaryl: The terms “heteroaryl” and “heteroar–”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Exemplary heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2- a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H– quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)–one, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted. [0016] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. [0017] Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR⁺ (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3- dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). [0018] Partially Unsaturated: As used herein, the term “partially unsaturated”, when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined. [0019] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition. [0020] Substituted or optionally substituted: As described herein, compounds of this disclosure may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g.,

refers to at least

. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above. [0021] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH₂)_0-4Rº; –(CH₂)_0-4ORº; -O(CH₂)_0-4Rº, –O– (CH₂)_0-4C(O)OR°; –(CH₂)_0-4CH(ORº)₂; –(CH₂)_0-4SRº; –(CH₂)_0-4Ph, which may be substituted with R°; –(CH₂)_0-4O(CH₂)_0-1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH₂)_0-4O(CH₂)_0-1-pyridyl which may be substituted with R°; –NO₂; –CN; –N₃; -(CH₂)_0-4N(Rº)₂; –(CH₂)_0-4N(Rº)C(O)Rº; –N(Rº)C(S)Rº; –(CH₂)_0– ₄N(Rº)C(O)NRº₂; -N(Rº)C(S)NRº₂; –(CH₂)_0-4N(Rº)C(O)ORº; - N(Rº)N(Rº)C(O)Rº; -N(Rº)N(Rº)C(O)NRº₂; -N(Rº)N(Rº)C(O)ORº; –(CH₂)_0-4C(O)Rº; – C(S)Rº; –(CH₂)_0-4C(O)ORº; –(CH₂)_0-4C(O)SRº; -(CH₂)_0-4C(O)OSiRº₃; –(CH₂)_0-4OC(O)Rº; – OC(O)(CH₂)_0-4SR°; –(CH₂)_0-4SC(O)Rº; –(CH₂)_0-4C(O)NRº₂; –C(S)NRº₂; –C(S)SR°; – SC(S)SR°, -(CH₂)_0-4OC(O)NRº₂; -C(O)N(ORº)Rº; –C(O)C(O)Rº; –C(O)CH₂C(O)Rº; – C(NORº)Rº; -(CH₂)_0-4SSRº; –(CH₂)_0-4S(O)₂Rº; –(CH₂)_0-4S(O)₂ORº; –(CH₂)_0-4OS(O)₂Rº; – S(O)₂NRº₂; -(CH₂)_0-4S(O)(NH)R°; -(CH₂)_0-4S(O)Rº; -N(Rº)S(O)₂NRº₂; –N(Rº)S(O)₂Rº; – N(ORº)Rº; –C(NH)NRº₂; –P(O)₂Rº; -P(O)Rº₂; -OP(O)Rº₂; –OP(O)(ORº)₂; –SiRº₃; –(C_1-4 straight or branched alkylene)O–N(Rº)₂; or –(C_1–4 straight or branched alkylene)C(O)O–N(Rº)₂, wherein each Rº may be substituted as defined below and is independently hydrogen, C_1– ₆ aliphatic, –CH₂Ph, –O(CH₂)_0-1Ph, -CH₂-(5- to 6-membered heteroaryl ring), or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of Rº, taken together with their intervening atom(s), form a 3- to 12- membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. [0022] Suitable monovalent substituents on Rº (or the ring formed by taking two independent occurrences of Rº together with their intervening atoms), are independently halogen, –(CH₂)_0-2R^●, –(haloR^●), –(CH₂)_0-2OH, –(CH₂)_0-2OR^●, –(CH₂)0– ₂CH(OR^●)₂, -O(haloR^●), –CN, –N₃, –(CH₂)_0–2C(O)R^●, –(CH₂)_0-2C(O)OH, –(CH₂)_0–2C(O)OR^●, – (CH₂)_0-2SR^●, –(CH₂)_0-2SH, –(CH₂)_0-2NH₂, –(CH₂)_0-2NHR^●, –(CH₂)_0-2NR^● ₂, –NO₂, –SiR^● ₃, – OSiR^● ₃, -C(O)SR^●, –(C_1-4 straight or branched alkylene)C(O)OR^●, or –SSR^● wherein each R^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C_1–4 aliphatic, –CH₂Ph, –O(CH₂)_0-1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of Rº include =O and =S. [0023] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O (“oxo”), =S, =NNR^* ₂, =NNHC(O)R^*, =NNHC(O)OR^*, =NNHS(O)₂R^*, =NR^*, =NOR^*, –O(C(R^* ₂))_2-3O–, or –S(C(R^* ₂))_2-3S–, wherein each independent occurrence of R^* is selected from hydrogen, C_1–6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR^* ₂)_2-3O–, wherein each independent occurrence of R^* is selected from hydrogen, 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. [0024] Suitable substituents on the aliphatic group of R^* include halogen, –R^●, -(haloR^●), -OH, –OR^●, –O(haloR^●), –CN, –C(O)OH, –C(O)OR^●, –NH₂, –NHR^●, –NR^●2, or –NO₂, wherein each R^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1–4 aliphatic, –CH₂Ph, –O(CH₂)_0-1Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0025] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R^†, –NR^† ₂, –C(O)R^†, –C(O)OR^†, –C(O)C(O)R^†, – C(O)CH₂C(O)R^†, -S(O)₂R^†, -S(O)₂NR^† ₂, –C(S)NR^† ₂, –C(NH)NR^† ₂, or –N(R^†)S(O)₂R^†; wherein each R^† is independently hydrogen, C_1–6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0026] Suitable substituents on the aliphatic group of R^† are independently halogen, – R^●, -(haloR^●), –OH, –OR^●, –O(haloR^●), –CN, –C(O)OH, –C(O)OR^●, –NH₂, –NHR^●, –NR^● ₂, or -NO₂, wherein each R^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1-4 aliphatic, –CH₂Ph, –O(CH₂)_0-1Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0027] Treat: As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. Provided Compounds [0028] The present disclosure provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Z is –O- or –NR^z-; R^x is hydrogen, halogen, -OR⁵, -N(R⁵)₂, -SR⁵, optionally substituted C_1-6 aliphatic, or –CN; R^z is hydrogen or optionally substituted C_1-6 aliphatic; R¹, R^1’, R², R^2’, R³, and R^3’are each independently hydrogen or optionally substituted C_1-6 aliphatic; R⁴ and R^4’ are each independently hydrogen or optionally substituted C_1-6 aliphatic, or R⁴ and R^4’ are taken together to form an oxo; each R⁵ is independently hydrogen or optionally substituted C_1-6 aliphatic; Ring A is optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is optionally substituted phenyl, optionally substituted 9- to 16-membered bicyclic or tricyclic aryl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 7- to 16-membered saturated or partially unsaturated bicyclic or tricyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent C1-3 straight or branched hydrocarbon chain; and 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 carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0029] In some embodiments, the present disclosure provides a compound of Formula IA:

or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, R^a, and R¹ are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0030] In some embodiments, the present disclosure provides a compound of Formula IB:

or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, R^a, and R¹ are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0031] In some embodiments, the present disclosure provides a compound of Formula IC:

or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, R^a, and R¹ are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. [0032] In some embodiments, the present disclosure provides a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, Z, R^a, R^x, R¹, R^1’, R², R^2’, R³, R^3’, R⁴, and R^4’ are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and: R^b is hydrogen, halogen, -CN, -OR, -SR, -N(R)₂, -NO₂, -C(O)R’, -C(O)OR, -C(O)N(R)₂, - OC(O)R’, -OC(O)N(R)₂, -OC(O)OR, -OSO₂R, -OSO₂N(R)₂, -N(R)C(O)R’, -N(R)SO₂R’, - SO₂R’, -SO₂N(R)₂, -SO₃R’, optionally substituted C_1-6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, optionally substituted C_1-6 aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently optionally substituted C_1-6 aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl. [0033] In some embodiments, the present disclosure provides a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, Z, R^a, R^x, R¹, R^1’, R², R^2’, R³, R^3’, R⁴, and R^4’ are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and: R⁶ is –N(R)₂, –N(R)C(O)R’, –C(O)N(R)₂, or –N(R)C(O)N(R)₂; each R is independently hydrogen, optionally substituted C_1-6 aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently optionally substituted C_1-6 aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl. [0034] In some embodiments, the present disclosure provides a compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, Z, R^a, R^x, R¹, R^1’, R², R^2’, R³, R^3’, R⁴, and R^4’ are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and: Ring B1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring B1 is fused to Ring B2; Ring B2 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring B2 is optionally (i) further fused to Ring B3, or (ii) Ring B2 and Ring B3 combine to form a spirocycle; and Ring B3, when present, is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0035] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV, Z is –O-. In some embodiments, Z is –NR^z-. In some embodiments, Z is –NH-. [0036] In some embodiments of any of Formulae I, II, III, and IV, R^x is hydrogen, halogen, or optionally substituted C_1-6 aliphatic. In some embodiments, R^x is hydrogen or optionally substituted C_1-6 aliphatic. In some embodiments, R^x is hydrogen or C_1-6 alkyl. In some embodiments, R^x is hydrogen. In some embodiments, R^x is halogen. In some embodiments, R^x is fluoro. In some embodiments, R^x is chloro. In some embodiments, R^x is –OR¹. In some embodiments, R^x is –OR¹, wherein R¹ is optionally substituted C_1-6 aliphatic. In some embodiments, R^x is –N(R¹)₂. In some embodiments, R^x is –SR¹. In some embodiments, R^x is – SR¹, wherein R¹ 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. In some embodiments, R^x is optionally substituted C_1-4 alkyl. In some embodiments, R^x is optionally substituted C_1-2 alkyl. In some embodiments, R^x is –CN. [0037] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV, R^z is hydrogen. In some embodiments, R^z is optionally substituted C_1-6 aliphatic. In some embodiments, R^z is optionally substituted straight-chain or branched C_1-6 aliphatic (i.e., optionally substituted acyclic C_1-6 aliphatic). In some embodiments, R^z is optionally substituted C_1-6 alkyl. In some embodiments, R^z is optionally substituted C_1-4 alkyl. In some embodiments, R^z is unsubstituted C_1-4 alkyl. In some embodiments, R^z is optionally substituted C_1-2 alkyl. In some embodiments, R^z is unsubstituted C_1-2 alkyl. [0038] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV, R¹ is hydrogen or optionally substituted C_1-6 alkyl. In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is optionally substituted C_1-6 aliphatic. In some embodiments, R¹ is optionally substituted C_1-6 alkyl. In some embodiments, R¹ is optionally substituted C_1-4 alkyl. In some embodiments, R¹ is optionally substituted C_1-2 alkyl. In some embodiments, R¹ is methyl. [0039] In some embodiments of any of Formulae I, II, III, and IV, R^1’ is hydrogen or optionally substituted C_1-6 alkyl. In some embodiments, R^1’ is hydrogen. In some embodiments, R^1’ is optionally substituted C_1-6 aliphatic. In some embodiments, R^1’ is optionally substituted C_1-6 alkyl. In some embodiments, R^1’ is optionally substituted C_1-4 alkyl. In some embodiments, R^1’ is optionally substituted C_1-2 alkyl. In some embodiments, R^1’ is methyl. [0040] In some embodiments of any of Formulae I, II, III, and IV, R² is hydrogen or optionally substituted C_1-6 alkyl. In some embodiments, R² is hydrogen. In some embodiments, R² is optionally substituted C_1-6 aliphatic. In some embodiments, R² is optionally substituted C_1-6 alkyl. In some embodiments, R² is optionally substituted C_1-4 alkyl. In some embodiments, R² is optionally substituted C_1-2 alkyl. In some embodiments, R² is methyl. [0041] In some embodiments of any of Formulae I, II, III, and IV, R^2’ is hydrogen or optionally substituted C_1-6 alkyl. In some embodiments, R^2’ is hydrogen. In some embodiments, R^2’ is optionally substituted C_1-6 aliphatic. In some embodiments, R^2’ is optionally substituted C_1-6 alkyl. In some embodiments, R^2’ is optionally substituted C_1-4 alkyl. In some embodiments, R^2’ is optionally substituted C_1-2 alkyl. In some embodiments, R^2’ is methyl. [0042] In some embodiments of any of Formulae I, II, III, and IV, R³ is hydrogen or optionally substituted C_1-6 alkyl. In some embodiments, R³ is hydrogen. In some embodiments, R³ is optionally substituted C_1-6 aliphatic. In some embodiments, R³ is optionally substituted C_1-6 alkyl. In some embodiments, R³ is optionally substituted C_1-4 alkyl. In some embodiments, R³ is optionally substituted C_1-2 alkyl. In some embodiments, R³ is methyl. [0043] In some embodiments of any of Formulae I, II, III, and IV, R^3’ is hydrogen or optionally substituted C_1-6 alkyl. In some embodiments, R^3’ is hydrogen. In some embodiments, R^3’ is optionally substituted C_1-6 aliphatic. In some embodiments, R^3’ is optionally substituted C_1-6 alkyl. In some embodiments, R^3’ is optionally substituted C_1-4 alkyl. In some embodiments, R^3’ is optionally substituted C_1-2 alkyl. In some embodiments, R^3’ is methyl. [0044] In some embodiments of any of Formulae I, II, III, and IV, R⁴ is hydrogen or optionally substituted C_1-6 alkyl. In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is optionally substituted C_1-6 aliphatic. In some embodiments, R⁴ is optionally substituted C_1-6 alkyl. In some embodiments, R⁴ is optionally substituted C_1-4 alkyl. In some embodiments, R⁴ is optionally substituted C_1-2 alkyl. In some embodiments, R⁴ is methyl. [0045] In some embodiments of any of Formulae I, II, III, and IV, R^4’ is hydrogen or optionally substituted C_1-6 alkyl. In some embodiments, R^4’ is hydrogen. In some embodiments, R^4’ is optionally substituted C_1-6 aliphatic. In some embodiments, R^4’ is optionally substituted C_1-6 alkyl. In some embodiments, R^4’ is optionally substituted C_1-4 alkyl. In some embodiments, R^4’ is optionally substituted C_1-2 alkyl. In some embodiments, R^4’ is methyl. [0046] In some embodiments, R⁴ and R^4’ are taken together to form an oxo. In some embodiments, both R⁴ and R^4’ are hydrogen. [0047] In some embodiments, all of R¹, R^1’, R², R^2’, R³, and R^3’ are hydrogen. In some embodiments, R¹ is optionally substituted C_1-6 alkyl, and R^1’, R², R^2’, R³, and R^3’ are hydrogen. In some embodiments, R¹ is methyl, and R^1’, R², R^2’, R³, and R^3’ are hydrogen. [0048] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV, each R⁵ is independently hydrogen or optionally substituted C_1-4 aliphatic. In some embodiments, each R⁵ is independently hydrogen or optionally substituted C_1-2 aliphatic. In some embodiments, each R⁵ is hydrogen. In some embodiments, each R⁵ is independently optionally substituted C_1-6 aliphatic. In some embodiments, each R⁵ is independently optionally substituted straight-chain or branched C_1-6 aliphatic (i.e., optionally substituted acyclic C_1-6 aliphatic). In some embodiments, each R⁵ is independently optionally substituted C_1-4 aliphatic. In some embodiments, each R⁵ 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 R⁵ is independently optionally substituted C_1-2 aliphatic. In some embodiments, each R⁵ is independently hydrogen or C_1-6 alkyl. In some embodiments, each R⁵ is independently hydrogen or C_1-4 alkyl. In some embodiments, each R⁵ is independently hydrogen or C_1-2 alkyl. [0049] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV, Ring A is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, -Rº, -CN, -ORº, -SRº, -N(Rº)₂, -NO₂, -C(O)Rº, -C(O)OR°, - C(O)NRº₂, -OC(O)Rº, -OC(O)NRº₂, –OC(O)OR°, -OS(O)₂Rº, -OS(O)₂NRº₂, -N(Rº)C(O)Rº, - N(Rº)S(O)₂Rº, -S(O)₂Rº, -SO₂NRº₂, and -S(O)₂ORº, and (ii) optionally substituted on a substitutable nitrogen atom with one or more groups selected from –R^†, –NR^† ₂, –C(O)R^†, – C(O)OR^†, -S(O)₂R^†, and -S(O)₂NR^† ₂. In some embodiments, Ring A is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, and Rº, and (ii) optionally substituted on a substitutable nitrogen atom with one or more groups selected from –R^†. In some embodiments, Ring A is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from halogen and Rº, and (ii) optionally substituted on a substitutable nitrogen atom with one or more groups selected from –R^†. In some embodiments, Ring A is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from Rº, and (ii) optionally substituted on a substitutable nitrogen atom with one or more groups selected from –R^†. [0050] In some embodiments, Ring A is optionally substituted with one or more R^b (i.e., in addition to being substituted with –L-R^a), wherein R^b is as defined in Formula II above and described in classes and subclasses herein. In some embodiments, Ring A is substituted with zero, one, two, three, four, or five R^b, as valency allows. [0051] In some embodiments, Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0052] In some embodiments, Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0053] In some embodiments, Ring A is optionally substituted phenyl.

[0054] In some embodiments, Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted pyrazolyl. In some embodiments, Ring A is optionally substituted 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted pyridonyl.

[0055] In some embodiments, Ring A is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 8-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted tetrahydropyrazolo[1,5-a]pyridinyl. In some embodiments, Ring A is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0056] In some embodiments, Ring A is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted C_3-7 cycloalkyl. In some embodiments, Ring A is optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted 6- membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted 7-membered saturated or partially unsaturated monocyclic carbocyclyl. [0057] In some embodiments, Ring A is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 3- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0058] In some embodiments, Ring A is optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 7- membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 9-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0059] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV, L is a covalent bond. In some embodiments, L is a bivalent C_1-3 straight or branched hydrocarbon chain. In some embodiments, L is a bivalent C_1-2 straight or branched hydrocarbon chain. In some embodiments, L is methylene (i.e., -CH₂-). In some embodiments, L is –CH₂CH₂-. In some embodiments, L is –CH₂CH₂CH₂-. In some embodiments, L is a covalent bond or –CH₂-. [0060] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV, 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. In some embodiments, R^a is optionally substituted C_1-6 aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^a is optionally substituted C_1-6 alkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted 3- to 6-membered saturated monocyclic heterocyclyl having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 8-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0061] In some embodiments, R^a is hydrogen. In some embodiments, R^a is not hydrogen. [0062] In some embodiments, R^a is halogen. In some embodiments, R^a is fluoro, chloro, bromo, or iodo. In some embodiments, R^a is fluoro. In some embodiments, R^a is chloro. [0063] In some embodiments, R^a is optionally substituted C_1-6 aliphatic. In some embodiments, R^a is optionally substituted straight-chain or branched C_1-6 aliphatic (i.e., optionally substituted acyclic C_1-6 aliphatic). In some embodiments, R^a is optionally substituted C_1-6 alkyl. In some embodiments, R^a is optionally substituted C_1-4 alkyl. In some embodiments, R^a is –CH₃. [0064] In some embodiments, R^a is optionally substituted phenyl. [0065] In some embodiments, R^a is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0066] In some embodiments, R^a is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R^a is optionally substituted C_3-6 cycloalkyl. In some embodiments, R^a is optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R^a is optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R^a is optionally substituted cyclobutyl (e.g., cyclobutyl optionally substituted with –OH). In some embodiments, R^a is optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R^a is optionally substituted 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R^a is optionally substituted 7-membered saturated or partially unsaturated monocyclic carbocyclyl. [0067] In some embodiments, R^a is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^a is optionally substituted 4- to 6- membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^a is optionally substituted 3- membered saturated monocyclic heterocyclyl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^a is optionally substituted 4-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^a is optionally substituted 5-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^a is tetrahydrofuranyl. In some embodiments, R^a is optionally substituted 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^a is optionally substituted 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0068] In some embodiments, R^a is optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^a is optionally substituted 7- to 10- membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^a is optionally substituted 7- to 8-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^a is optionally substituted 2-oxaspiro[3.3]heptanyl. [0069] In some embodiments, R^a is selected from the group consisting of:

[0070] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV,

s –R^a (i.e., L is a covalent bond). In some embodiments,

is –(C_1-3 alkylene)-R^a (i.e., L is a C_1- ₃ straight or branched hydrocarbon chain). In some embodiments,

is –(C_1-2 alkylene)-R^a (i.e., L is a C_1-2 straight or branched hydrocarbon chain). In some embodiments,

is – CH₂-R^a (i.e., L is a C₁ hydrocarbon chain). In some embodiments,

is –CH₂CH₂-R^a (i.e., L is a C₂ straight hydrocarbon chain). In some embodiments,

is –CH₂CH₂CH₂-R^a (i.e., L is a C3 straight hydrocarbon chain). [0071] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV, up to five occurrences of R^b may be present, as allowed by valency rules, and is each independently halogen, -CN, -OR, -SR, -N(R)₂, -NO₂, -C(O)R’, -C(O)OR, -C(O)N(R)₂, -OC(O)R’, - OC(O)N(R)₂, -OC(O)OR, -OSO₂R, -OSO₂N(R)₂, -N(R)C(O)R’, -N(R)SO₂R’, -SO₂R’, - SO₂N(R)₂, -SO₃R’, optionally substituted C_1-6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each occurrence of R^b is independently optionally substituted C_1-6 aliphatic or optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, each occurrence of R^b is independently optionally substituted C_1-4 alkyl or optionally substituted C₃-C₄ cycloalkyl. In some embodiments, each occurrence of R^b is independently C_3-4 cycloalkyl or C_1-4 alkyl optionally substituted with one or more halogen. In some embodiments, each occurrence of R^b is independently C_1-4 alkyl or C_3-4 cycloalkyl. [0072] In some embodiments, R^b is hydrogen. [0073] In some embodiments, R^b is halogen. In some embodiments, R^b is fluoro, chloro, bromo, or iodo. In some embodiments, R^b is fluoro. In some embodiments, R^b is chloro. [0074] In some embodiments, R^b is -CN, -OR, -SR, -N(R)₂, -NO₂, -C(O)R’, -C(O)OR, - C(O)N(R)₂, -OC(O)R’, -OC(O)N(R)₂, -OC(O)OR, -OSO₂R, -OSO₂N(R)₂, -N(R)C(O)R’, - N(R)SO₂R’, -SO₂R, -SO₂N(R)₂, or -SO₃R’. [0075] In some embodiments, R^b is optionally substituted C_1-6 aliphatic. In some embodiments, R^b is optionally substituted straight-chain or branched C_1-6 aliphatic (i.e., optionally substituted acyclic C_1-6 aliphatic). In some embodiments, R^b is optionally substituted C_1-6 alkyl. In some embodiments, R^b is optionally substituted C_1-4 alkyl. In some embodiments, R^b is C_1-4 alkyl optionally substituted with one or more halogen. In some embodiments, R^b is C_1- ₄ alkyl. In some embodiments, R^b is selected from the group consisting of –CH₃ and –C(CH₃)₃. [0076] In some embodiments, R^b is optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R^b is optionally substituted C₃-C₆ cycloalkyl. In some embodiments, R^b is optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R^b is cyclopropyl. In some embodiments, R^b is optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R^b is optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R^b is optionally substituted 6-membered saturated or partially unsaturated monocyclic carbocyclyl. [0077] In some embodiments, R^b is optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0078] In some embodiments, R^b is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0079] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV, optionally substituted

In some embodiments, optionally substituted

[0080] In some embodiments,

s , , or

[0081] In some embodiments,

[0082] In some embodiments,

is selected from the group consisting of:

, , , , [0083] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV, Ring B (including Ring B1 and/or Ring B2 and/or, when present, Ring B3) is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, -Rº, -CN, -ORº, -SRº, -N(Rº)₂, -NO₂, -C(O)Rº, -C(O)OR°, -C(O)NRº₂, -OC(O)Rº, - OC(O)NRº₂, –OC(O)OR°, -OS(O)₂Rº, -OS(O)₂NRº₂, -N(Rº)C(O)Rº, -N(Rº)C(O)NRº₂, - N(Rº)S(O)₂Rº, -S(O)₂Rº, -SO₂NRº₂, and -S(O)₂ORº, and (ii) optionally substituted on a substitutable nitrogen atom with one or more groups selected from –R^†, –NR^† ₂, –C(O)R^†, – C(O)OR^†, -S(O)₂R^†, and -S(O)₂NR^† ₂. In some embodiments, Ring B is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, -Rº, -CN, -ORº, -N(Rº)₂, -C(O)NRº₂, -N(Rº)C(O)Rº, and -N(Rº)C(O)NRº₂, and (ii) optionally substituted on a substitutable nitrogen with –R^†. In some embodiments, Ring B is optionally substituted on a substitutable carbon atom with one or more groups independently selected from -N(Rº)₂, -C(O)NRº₂, -N(Rº)C(O)Rº, and -N(Rº)C(O)NRº₂. [0084] In some embodiments, Ring B is optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 9- to 16-membered bicyclic or tricyclic aryl, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 7- to 16- membered saturated or partially unsaturated bicyclic or tricyclic carbocyclyl, optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0085] In some embodiments, Ring B is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 10- to 16- membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 8- to 10- membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0086] In some embodiments, Ring B is monocyclic. In some embodiments, Ring B is polycyclic (e.g., bicyclic or tricyclic). In some embodiments, Ring B is bicyclic. In some embodiments, each ring in a bicyclic ring system of Ring B contains at least one heteroatom. In some embodiments, one and only one ring of a bicyclic ring system of Ring B contains no heteroatoms. In some embodiments, each ring in a bicyclic ring system of Ring B is aromatic. In some embodiments, one and only one ring of a bicyclic ring system of Ring B is aromatic. In some embodiments, no ring in a bicyclic ring system of Ring B is aromatic. [0087] In some embodiments, Ring B is optionally substituted phenyl. [0088] In some embodiments, Ring B is optionally substituted 9- to 16-membered bicyclic or tricyclic aryl. In some embodiments, Ring B is optionally substituted 9- to 10-membered bicyclic aryl. In some embodiments, Ring B is optionally substituted 9-membered bicyclic aryl (e.g., a 5-membered carbocycle fused to a phenyl ring). In some embodiments, Ring B is optionally substituted 10-membered bicyclic aryl (e.g., naphthyl or a 6-membered carbocycle fused to a phenyl ring). [0089] In some embodiments, Ring B is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted pyridyl. [0090] In some embodiments, Ring B is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 8-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0091] In some embodiments, Ring B is optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0092] In some embodiments, Ring B is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring B is optionally substituted C_3-7 cycloalkyl. In some embodiments, Ring B is optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring B is optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring B is optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring B is optionally substituted 6- membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring B is optionally substituted 7-membered saturated or partially unsaturated monocyclic carbocyclyl. [0093] In some embodiments, Ring B is optionally substituted 7- to 16-membered saturated or partially unsaturated bicyclic or tricyclic carbocyclyl. [0094] In some embodiments, Ring B is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 3- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0095] In some embodiments, Ring B is optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 7- to 10-membered fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 7-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 8-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 9-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is optionally substituted 10-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0096] In some embodiments, Ring B is optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0097] In some embodiments, Ring B is

, wherein R⁶ is as defined in Formula III and described in classes and subclasses herein, both singly and in combination. [0098] In some embodiments, Ring B is

. In some embodiments, Ring B is

. [0099] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV, R⁶ is – N(R)C(O)R’, –C(O)N(R)₂, or –N(R)C(O)N(R)₂, wherein R and R’ are as defined in Formula III and described in classes and subclasses herein, both singly and in combination. In some embodiments, R⁶ is –N(R)C(O)R’ or –C(O)N(R)₂. [0100] In some embodiments, R⁶ is –N(R)C(O)R’. In some embodiments, R⁶ is – N(H)C(O)R’. In some embodiments, R⁶ is –N(R)C(O)(optionally substituted C_1-6 aliphatic). In some embodiments, R⁶ is –N(H)C(O)(optionally substituted C_1-6 aliphatic). In some embodiments, R⁶ is –N(R)C(O)(C_1-6 aliphatic). In some embodiments, R⁶ is –N(H)C(O)(C_1-6 aliphatic). In some embodiments, R⁶ is –N(R)C(O)(straight-chain or branched C_1-6 aliphatic). In some embodiments, R⁶ is –N(H)C(O)(straight-chain or branched C_1-6 aliphatic). In some embodiments, R⁶ is –N(R)C(O)(optionally substituted C_1-6 alkyl). In some embodiments, R⁶ is – N(H)C(O)(optionally substituted C_1-6 alkyl). In some embodiments, R⁶ is –N(R)C(O)(C_1-6 alkyl). In some embodiments, R⁶ is –N(H)C(O)(C_1-6 alkyl). In some embodiments, R⁶ is – N(R)C(O)(optionally substituted C_1-4 alkyl). In some embodiments, R⁶ is –N(H)C(O)(optionally substituted C_1-4 alkyl). In some embodiments, R⁶ is –N(R)C(O)(C_1-4 alkyl). In some embodiments, R⁶ is –N(H)C(O)(C_1-4 alkyl). In some embodiments, R⁶ is –N(R)C(O)(optionally substituted C_1-2 alkyl). In some embodiments, R⁶ is –N(H)C(O)(optionally substituted C_1-2 alkyl). In some embodiments, R⁶ is –N(R)C(O)(C_1-2 alkyl). In some embodiments, R⁶ is – N(H)C(O)(C_1-2 alkyl). In some embodiments, R⁶ is –N(R)C(O)CH₃. In some embodiments, R⁶ is –N(H)C(O)CH₃. In some embodiments, R⁶ is –N(R)C(O)(optionally substituted C_3-7 carbocyclyl). In some embodiments, R⁶ is –N(H)C(O)(optionally substituted C_3-7 carbocyclyl). In some embodiments, R⁶ is –N(R)C(O)(optionally substituted C_3-7 cycloalkyl). In some embodiments, R⁶ is –N(H)C(O)(optionally substituted C_3-7 cycloalkyl). In some embodiments, R⁶ is –N(R)C(O)(C_3-6 cycloalkyl). In some embodiments, R⁶ is –N(H)C(O)(C_3-6 cycloalkyl). In some embodiments, R⁶ is –N(R)C(O)(cyclopropyl). In some embodiments, R⁶ is – N(H)C(O)(cyclopropyl). [0101] In some embodiments, R⁶ is –C(O)N(R)₂. In some embodiments, R⁶ is – C(O)N(R)(C_1-6 aliphatic). In some embodiments, R⁶ is –C(O)N(H)(C_1-6 aliphatic). In some embodiments, R⁶ is –C(O)N(R)(straight-chain or branched C_1-6 aliphatic). In some embodiments, R⁶ is –C(O)N(H)(straight-chain or branched C_1-6 aliphatic). In some embodiments, R⁶ is –C(O)N(R)(C_1-6 alkyl). In some embodiments, R⁶ is –C(O)N(H)(C_1-6 alkyl). In some embodiments, R⁶ is –C(O)N(R)(C_1-4 alkyl). In some embodiments, R⁶ is – C(O)N(H)(C_1-4 alkyl). In some embodiments, R⁶ is –C(O)N(R)(C_1-2 alkyl). In some embodiments, R⁶ is –C(O)N(H)(C_1-2 alkyl). [0102] In some embodiments, R⁶ is –N(R)₂. In some embodiments, R⁶ is –N(H)(R). [0103] In some embodiments, R⁶ is –N(R)C(O)N(R)₂. In some embodiments, R⁶ is – N(R)C(O)N(R)₂, wherein the two R groups attached to the same nitrogen are taken together to form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R⁶ is –N(R)C(O)N(R)₂, wherein the two R groups attached to the same nitrogen are taken together to form an optionally substituted 3- to 5-membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R⁶ is –N(H)C(O)N(R)₂. In some embodiments, R⁶ is –N(H)C(O)N(R)₂, wherein the two R groups attached to the same nitrogen are taken together to form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R⁶ is –N(H)C(O)N(R)₂, wherein the two R groups attached to the same nitrogen are taken together to form an optionally substituted 3- to 5-membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0104] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV, each R is independently hydrogen or optionally substituted C_1-6 aliphatic. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C_1-6 aliphatic. In some embodiments, R is optionally substituted straight-chain or branched C_1-6 aliphatic (i.e., optionally substituted acyclic C_1-6 aliphatic). In some embodiments, R is optionally substituted C_1-6 alkyl. In some embodiments, R is optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R when attached to the same nitrogen atom are taken together form a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0105] In some embodiments of any of Formulae I, IA, IB, IC, II, III, and IV, R’ is optionally substituted C_1-6 aliphatic. In some embodiments, R’ is optionally substituted straight- chain or branched C_1-6 aliphatic (i.e., optionally substituted acyclic C_1-6 aliphatic). In some embodiments, R’ is optionally substituted C_1-6 alkyl. In some embodiments, R’ is optionally substituted C_1-4 alkyl. In some embodiments, R’ is unsubstituted C_1-4 alkyl. In some embodiments, R’ is optionally substituted C_1-2 alkyl. In some embodiments, R’ is unsubstituted C_1-2 alkyl. In some embodiments, R’ is methyl. In some embodiments, R’ is 3- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R’ is optionally substituted C_3-6 cycloalkyl. In some embodiments, R’ is cyclopropyl. [0106] In some embodiments, Ring B is

wherein Ring B1 and Ring B2 are defined as in Formula IV and described in classes and subclasses herein, both singly and in combination; and Ring B1 is fused to Ring B2; and Ring B2 is optionally (i) further fused to Ring B3 or (ii) Ring B2 and Ring B3 combine to form a spirocycle.

[0107] In some embodiments, Ring B1 is an optionally substituted ring selected from 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0108] In some embodiments, Ring B1 is optionally substituted phenyl. In some embodiments, when Ring B1 is phenyl, Ring B2 contains at least one heteroatom.

[0109] In some embodiments, Ring B1 is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is unsubstituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0110] In some embodiments, Ring B1 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, when Ring B1 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, Ring B2 contains at least one heteroatom. In some embodiments, when Ring B2 is not aromatic, Ring B1 is optionally substituted 5- to 6-membered saturated monocyclic carbocyclyl. In some embodiments, Ring B1 is optionally substituted 5- to 6-membered partially saturated monocyclic carbocyclyl.

[0111] In some embodiments, Ring B1 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, when Ring B2 is not aromatic, Ring B1 is optionally substituted 5- to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is optionally substituted 5- to 6-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0112] In some embodiments, Ring B2 is an optionally substituted ring selected from 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0113] In some embodiments, Ring B2 is optionally substituted phenyl. In some embodiments, when Ring B2 is phenyl, Ring B1 contains at least one heteroatom.

[0114] In some embodiments, Ring B2 is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B2 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B2 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0115] In some embodiments, Ring B2 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, when Ring B2 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, Ring B1 contains at least one heteroatom. In some embodiments, when Ring B1 (and Ring B3, if present) is not aromatic, Ring B2 is optionally substituted 5- to 6-membered saturated monocyclic carbocyclyl. In some embodiments, Ring B2 is optionally substituted 5- to 6-membered partially saturated monocyclic carbocyclyl.

[0116] In some embodiments, Ring B2 is optionally substituted 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, when Ring B1 (and Ring B3, if present) is not aromatic, Ring B2 is optionally substituted 5- to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B2 is optionally substituted 5- to 6-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0117] In some embodiments, Ring B1 and Ring B2 are both optionally substituted 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring B2 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring B2 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0118] In some embodiments, Ring B2 is further fused to Ring B3. In some embodiments, Ring B2 and Ring B3 combine to form a spirocycle. [0119] In some embodiments, Ring B3, when present, is optionally substituted phenyl. In some embodiments, Ring B3 is 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B3 is 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring B3, when not fused to an aromatic Ring B2, is 3- to 7-membered saturated monocyclic carbocyclyl. In some embodiments, Ring B3 is 3- to 7-membered partially saturated monocyclic carbocyclyl. In some embodiments, Ring B3 is 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B3, when not fused to an aromatic Ring B2, is 3- to 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B3 is 3- to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0120] In some embodiments, the present disclosure provides compounds selected from Table 1:

or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the present disclosure encompasses the recognition that provided compounds display certain desirable characteristics, e.g., as compared to other known compounds. For example, in some embodiments, provided compounds are more potent in one or more biochemical or cellular assays (e.g., the JAK2 Binding Assay or SET2-pSTAT5 Cellular Assay described herein) and/or have one or more other characteristics that make them more suitable for drug development, such as better selectivity over other kinases and/or better ADME (absorption, distribution, metabolism, and excretion) properties including but not limited to better permeability, cytotoxicity, hepatocyte stability, solubility, and/or plasma protein binding profiles (e.g., based on assays described in the ensuing examples), than other known compounds. In some embodiments, provided compounds display certain desirable characteristics in one or more assays described herein, e.g., compared to other known compounds.

[0122] In some embodiments, provided compounds are provided and/or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated. Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19(1977).

[0123] It will be appreciated that throughout the present disclosure, unless otherwise indicated, reference to a compound of Formula I is intended to also include Formulae IA, IB, IC, II, III, and IV, and compound species of such formulas disclosed herein. Preparing Provided Compounds [0124] Provided compounds may generally be made by the processes described in the ensuing schemes and examples. [0125] In some embodiments, provided compounds (e.g., compounds of Formula I) are prepared according to the following Scheme:

wherein PG is a suitable protecting group (e.g., Cbz); LG¹ is a first suitable leaving group (e.g., halogen, e.g., chloro or bromo); LG² is a second suitable leaving group (e.g., halogen, e.g., chloro or bromo); and Ring A, Ring B, L, Z, R¹, R^1’, R², R^2’, R³, R^3’, R⁴, R^4’, R^x, and R^a are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. Accordingly, in some embodiments, intermediate A.3 is prepared by a process comprising contacting intermediate A.1 with intermediate A.2 in the presence of a suitable base (e.g., K3PO4). In some embodiments, intermediate A.3 is prepared by a process comprising contacting intermediate A.2 in the presence of a suitable base (e.g., K3PO4), a suitable metal complex (e.g., a palladium complex such as methanesulfonato (di-tert-butyl)phenylphosphino(2′- amino-1,1′-biphenyl-2-yl)palladium(II)), and, optionally, a suitable ligand. In some embodiments, a compound of Formula I is prepared by a process comprising subjecting intermediate A.3 to suitable deprotection conditions, followed by contacting the resulting compound with intermediate A.4, optionally in the presence of a suitable base (e.g., K₂CO₃). Suitable deprotection conditions are known in the art; for example, when PG is Cbz, suitable deprotection conditions may comprise H₂ and a metal compound (e.g., Pd/C or Pd(OH₂)₂). [0126] In some embodiments, provided compounds (e.g., compounds of Formula I) are prepared according to the following Scheme:

wherein PG is a suitable protecting group (e.g., Cbz); LG¹ is a first suitable leaving group (e.g., halogen, e.g., chloro or bromo); LG² is a second suitable leaving group (e.g., halogen, e.g., chloro or bromo); and Ring A, Ring B, L, Z, R¹, R^1’, R², R^2’, R³, R^3’, R⁴, R^4’, R^x, and R^a are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. Accordingly, in some embodiments, intermediate B.3 is prepared by a process comprising contacting intermediate B.1 with intermediate B.2 in the presence of a suitable base. In some embodiments, intermediate B.3 is prepared by a process comprising contacting intermediate B.2 in the presence of a suitable base, a suitable metal complex (e.g., a palladium complex), and, optionally, a suitable ligand. In some embodiments, a compound of Formula I is prepared by a process comprising subjecting intermediate B.3 to suitable deprotection conditions, followed by contacting the resulting compound with intermediate B.4, optionally in the presence of a suitable base. Suitable deprotection conditions are known in the art; for example, when PG is Cbz, suitable deprotection conditions may comprise H₂ and a metal compound (e.g., Pd/C or Pd(OH₂)₂). [0127] In some embodiments, provided compounds (e.g., compounds of Formula I wherein R⁴ and R^4’ are taken together to form an oxo) are prepared according to the following Scheme:

wherein PG is a suitable protecting group (e.g., Cbz); and Ring A, Ring B, L, Z, R¹, R^1’, R², R^2’, R³, R^3’, R^x, and R^a are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. Accordingly, in some embodiments, compound C is prepared by a process comprising subjecting intermediate C.1 to suitable deprotection conditions, followed by contacting the resulting compound with intermediate C.2 under suitable amide coupling conditions (e.g., in the presence of a suitable base and/or suitable coupling agent). Suitable deprotection conditions are known in the art; for example, when PG is Cbz, suitable deprotection conditions may comprise H₂ and a metal compound (e.g., Pd/C or Pd(OH₂)₂). [0128] In some embodiments, a provided compound is obtained by a process comprising a purification method described in the Examples section. In some such embodiments, a compound is the 1^st eluting isomer. In some such embodiments, a compound is the 2^nd eluting isomer. In some embodiments, a compound is the 3^rd eluting isomer. In some embodiments, a compound is the 4^th eluting isomer. In some embodiments, a compound is the 5^th, 6^th, 7^th, 8^th, or more eluting isomer. Compositions [0129] The present disclosure also provides compositions comprising a compound provided herein with one or more other components. In some embodiments, provided compositions comprise and/or deliver a compound described herein (e.g., compounds of Formulae I, IA, IB, IC, II, III, and IV). [0130] In some embodiments, a provided composition is a pharmaceutical composition that comprises and/or delivers a compound provided herein (e.g., compounds of Formulae I, IA, IB, IC, II, III, and IV) and further comprises a pharmaceutically acceptable carrier. Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and/or anti-statics, etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and/or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions. Methods of preparing pharmaceutical compositions are well known in the art. [0131] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.

[0132] Provided compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of any disease or disorder described herein.

Uses

[0133] The present disclosure provides uses for compounds and compositions described herein. In some embodiments, provided compounds and compositions are useful in medicine (e.g., as therapy). In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and/or control compounds in biological assays.

[0134] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with JAK2. [0135] In some embodiments, provided compounds are useful as JAK2 inhibitors. In some embodiments, provided compounds are useful as Type II JAK2 inhibitors. In some embodiments, the present disclosure provides methods of inhibiting JAK2 in a subject comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods of inhibiting JAK2 in a biological sample comprising contacting the sample with a provided compound or composition.

[0136] JAK (e.g., JAK2) has been implicated in various diseases, disorders, and conditions, such as myeloproliferative neoplasms (Vainchenker, W. et al., FlOOOResearch 2018, 7(F1000 Faculty Rev):82), atopic dermatitis (Rodrigues, M. A. and Torres, T. J. Derm. Treat. 2019, 31(1), 33-40.) and acute respiratory syndrome, hyperinflammation, and/or cytokine storm syndrome (The Lancet. doi:10.1016/S0140-6736(20)30628-0). Accordingly, in some embodiments, the present disclosure provides methods of treating a disease, disorder or condition associated with JAK2 in a subject in need thereof comprising administering to the subject a provided compound or composition. In some embodiments, a disease, disorder or condition is associated with overexpression of JAK2.

[0137] In some embodiments, the present disclosure provides methods of treating cancer, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating proliferative diseases, comprising administering a provided compound or composition to a subject in need thereof. [0138] In some embodiments, the present disclosure provides methods of treating a hematological malignancy, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, a hematological malignancy is leukemia (e.g., chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, or acute monocytic leukemia). In some embodiments, a hematological malignancy is lymphoma (e.g., Burkitt’s lymphoma, Hodgkin’s lymphoma, or non-Hodgkin’s lymphoma). In some embodiments, a non- Hodgkin’s lymphoma is a B-cell lymphoma. In some embodiments, a non-Hodgkin’s lymphoma is a NK/T-cell lymphoma (e.g., cutaneous T-cell lymphoma). In some embodiments, a hematological malignancy is myeloma (e.g., multiple myeloma). In some embodiments, a hematological malignancy is myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or myelofibrosis). In some embodiments, a hematological malignancy is myelodysplastic syndrome.

[0139] In some embodiments, the present disclosure provides methods of treating an inflammatory disease, disorder, or condition (e.g., acute respiratory syndrome, hyperinflammation, and/or cytokine storm syndrome (including those associated with COVID- 19) or atopic dermatitis), comprising administering a provided compound or composition to a subject in need thereof.

[0140] In some embodiments, a provided compound or composition is administered as part of a combination therapy. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.

[0141] For example, in some embodiments, a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapies (e.g., an anti-cancer therapy and/or therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care). Exemplary additional therapies include, but are not limited to, BCL2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mivebresib), proteasome inhibitors (e.g., bortezomib), LSD1 inhibitors (e.g., IMG-7289), and CXCR2 inhibitors. Useful combinations of a JAK2 inhibitor with BCL2, HDAC, BET, and proteasome inhibitors have been demonstrated in cells derived from cutaneous T-cell lymphoma patients (Yumeen, S., et al., Blood Adv. 2020, 4(10), 2213-2226). A combination of a JAK2 inhibitor with a LSD1 inhibitor demonstrated good efficacy in a mouse model of myeloproliferative neoplasms (Jutzi, J.S., et al., HemaSphere 2018, 2(3), dx.doi.org/10.1097/HS9.0000000000000054). CXCR2 activity has been shown to modulate signaling pathways involved in tumor growth, angiogenesis, and/or metastasis, including the JAK-STAT3 pathway (Jaffer, T., Ma, D. Transl. Cancer Res. 2016, 5(Suppl. 4), S616-S628).

EXAMPLES

[0142] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Preparation of Provided Compounds Example 1: N-(4-(((R)-2-((5-(tert-butyl)-1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)- 4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)pyridin-2-yl)acetamide and N-(4- (((S)-2-((5-(tert-butyl)-1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-4-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)pyridin-2-yl)acetamide

[0143] Synthesis of compound 1.1. To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (30 g, 190.9 mmol, 1.0 equiv) in dichloromethane (600 mL) was added N,O- dimethylhydroxylamine hydrochloride (37.2 g, 381.8 mmol, 2.0 equiv) followed by addition of HATU (145 g, 381.8 mmol, 2.0 equiv) and triethylamine (106 mL, 763.6 mmol, 4.0 equiv). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture concentrated under reduced pressure to afford a residue. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1% methanol in dichloromethane) to afford 1.1. MS(ES): m/z 201.1 [M+H]⁺. [0144] Synthesis of compound 1.2. A mixture of compound 1.1 (30 g, 149.8 mmol, 1.0 equiv) and 10% palladium on carbon (15 g) in methanol (300 mL) was stirred under hydrogen (1 atm) for 5 h. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford 1.2. MS(ES): m/z 171.0 [M+H]⁺. [0145] Synthesis of compound 1.3. A solution of 1.2 (23.4 g, 137.5 mmol, 1.0 equiv), hexane-2,5-dione (23.5 g, 206.2 mmol, 1.5 equiv) and p-toluenesulphonic acid (1.18 g, 6.87 mmol, 0.05 equiv) in toluene (250 mL) was heated to reflux with a Dean-Stark trap for 5 h. It was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford 1.3. MS (ES): m/z 249.1 [M+H]⁺. [0146] Synthesis of compound 1.4. A mixture of 1.3 (25 g, 100.6 mmol, 1.0 equiv), tert- butyl (2-chloroethyl)carbamate (90.44 g, 503.4 mmol, 5.0 equiv) and sodium carbonate (53.3 g, 503.4 mmol, 5.0 equiv) in DMF (250 mL) was stirred at 110 °C for 6 h. The reaction mixture was cooled to room temperature, poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1.6% methanol in dichloromethane) to afford 1.4. MS(ES): m/z 392.2 [M+H]⁺. [0147] Synthesis of compound 1.5. To a solution of 1.4 (14.7 g, 37.55 mmol, 1.0 equiv) in THF (150 mL) was added methyl magnesium bromide (3 M in diethyl ether, 31.3 mL, 93.87 mmol, 2.5 equiv) at -78 °C. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was transferred into saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford 1.5. MS (ES): m/z 347.3 [M+H]⁺. [0148] Synthesis of compound 1.6. To a solution of 1.5 (12.1 g, 34.93 mmol, 1.0 equiv) in dichloromethane was added trifluoroacetic acid (22 mL, 1.8 equiv) at 0 °C and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (100 mL) and sodium borohydride (6.6 g, 174.65 mmol, 5.0 equiv) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 2 h. It was poured over ice-cold water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (3% methanol in dichloromethane) to afford 1.6. MS (ES): m/z 231.1 [M+H]⁺. [0149] Synthesis of compound 1.7. To a solution of 1.6 (2.0 g, 8.68 mmol, 1.0 equiv) in THF (20 mL) was added sodium bicarbonate (2.18 g, 26.04 mmol, 3.0 equiv) and cooled to 0 °C followed by addition of benzylchloroformate (2.21 g, 13.02 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 2 h. It was poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford 1.7. MS(ES): m/z 365.1 [M+H]⁺. [0150] Synthesis of compound 1.8. A solution of 1.7 (2.0 g, 5.49 mmol, 1.0 equiv) and hydroxylamine hydrochloride (26.7 g, 384.3 mmol, 70 equiv) in ethanol:water (2:1, 20 mL) was stirred at 120 °C for 6 h. The reaction mixture was poured over ice-cold water, followed by 2 N sodium hydroxide and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1.9% methanol in dichloromethane) to afford 1.8. MS(ES): m/z 287.3 [M+H]⁺. [0151] Synthesis of compound 1.9. A solution of 5-(tert-butyl)-1H-pyrazol-3-amine (5.0 g, 35.92 mmol, 1.0 equiv), 2,5-hexanedione (4.09 g, 35.92 mmol, 1.0 equiv) and acetic acid (catalytic) in toluene (100 mL) was heated to reflux with a Dean-Stark trap to remove water. After completion of reaction, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 12% ethyl acetate in hexane) to afford 1.9. MS (ES): m/z 218.3 [M+H]⁺. [0152] Synthesis of compound 1.11. A mixture of 1.9 (2.5 g, 11.50 mmol, 1.0 equiv), (S)- tetrahydrofuran-3-yl methanesulfonate (1.91 g, 11.50 mmol, 1.0 equiv) and cesium carbonate (7.49 g, 23 mmol, 2.0 equiv) in DMF (15 mL) was stirred at 80-90 °C for 12 h. The reaction mixture was transferred into ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2% ethyl acetate in hexane) to afford 1.10 and 1.11, MS (ES): m/z 248.3 [M+H]⁺. [0153] Synthesis of compound 1.12. A solution of 1.11 (0.200 g, 0.695 mmol, 1.0 equiv) and hydroxylamine hydrochloride (0.479 g, 6.95 mmol, 10 equiv) in ethanol:water (2:1, 3 mL) was stirred at 120 °C in a microwave reactor for 1 h. The reaction mixture was transferred into ice-water, followed by addition of a solution of sodium hydroxide (2 N), and the product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 1.12. MS(ES): m/z 210.3 [M+H]⁺. [0154] Synthesis of compound 1.13. To a solution of 1.12 (1.0 g, 4.78 mmol, 1.0 equiv) in acetonitrile (15 mL) was added p-toluenesulfonic acid (1.08 g, 5.73 mmol, 1.2 equiv) followed by copper(II) bromide (0.010 g, 0.047 mmol, 0.01 equiv). The reaction mixture was cooled to 0 °C and tert-butyl nitrite (0.738 g, 7.17 mmol, 1.5 equiv) was added followed by tetrabutylammonium bromide (3.08 g, 9.56 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 5 min. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 1.13. MS(ES): m/z : 274.1 [M+H]⁺. [0155] Synthesis of compound 1.14. To a solution of (2-aminopyridin-4-yl)methanol (2.0 g, 16.11 mmol, 1.0 equiv) in toluene (10 mL) was added thionyl chloride (11.7 mL, 161.1 mmol, 10.0 equiv) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. It was concentrated under reduced pressure. The residue was purified by trituration in diethyl ether to afford 1.14. ¹H NMR (DMSO-d₆, 400 MHz): δ 14.04 (bs, 1H), 8.32 (bs, 2H), 7.97-7.95 (d, J = 6.8Hz, 1H), 7.06 (s, 1H), 6.85-6.84 (d, J = 6.0Hz, 1H), 4.82 (s, 2H). [0156] Synthesis of compound 1.15. To a solution of 1.14 (1.8 g, 10.05 mmol, 1.0 equiv) and diisopropylethyl amine (3.8 mL, 22.11 mmol, 2.2 equiv) in dichloromethane (20 mL) at 0 °C was added acetyl chloride (0.8 mL, 11.05 mmol, 1.1 equiv). The reaction mixture was stirred for 15 min. It was transferred into ice-water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 1.15. MS(ES): m/z 185.2 [M+H]⁺. [0157] Synthesis of compound 1.16. A mixture of 1.8 (0.250 g, 0.873 mmol, 1.0 equiv), 1.13 (0.357 g, 1.31 mmol, 1.5 equiv) and potassium phosphate (1.3 g, 6.11 mmol, 7.0 equiv) in DMF (6 mL) was degassed by bubbling through a stream of argon for 10 min. Under argon atmosphere, methanesulfonato (di-tert-butyl)phenylphosphino(2′-amino-1,1′-biphenyl-2- yl)palladium(II) (0.277 g, 0.349 mmol, 0.4 equiv) was added, again degassed for 5 min. The reaction mixture was stirred at room temperature for 12 h. It was poured over ice cold water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1.8% methanol in dichloromethane) to afford 1.16. MS(ES): m/z 479.2 [M+H]⁺. [0158] Synthesis of compound 1.17. A mixture of compound 1.16 (0.240 g, 0.501 mmol, 1.0 equiv) and 20% palladium hydroxide (0.120 g) in methanol:THF (10 mL, 8:2) was stirred under hydrogen (1 atm) for 1 h. The reaction mixture was filtered through a pad of Celite® and rinsed with 20% methanol in dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.0% methanol in dichloromethane) to afford 1.17. MS(ES): m/z: 345.4 [M+H]⁺. [0159] Synthesis of compound I-1-a and I-1-b. A mixture of 1.17 (0.150 g, 0.435 mmol, 1.0 equiv), 1.15 (0.088 g, 0.479 mmol, 1.1 equiv) and potassium carbonate (0.180 g, 1.305 mmol, 3.0 equiv) in DMF (5 mL) was stirred at 90 °C for 48 h. The reaction mixture was poured over ice cold water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in dichloromethane). The mixture of diastereomers were separated using HPLC (column: CHIRALPAK IBN-5 (250 mm x 4.6 mm, 5 µm); mobile phase: (A) 0.1% DEA in n- hexane, (B) 0.1% DEA in propane-2-ol:methanol (50:50); flow rate: 20 mL/min) to afford first eluting fraction (I-1-a) and second eluting fraction (I-1-b). *Absolute stereochemistry not determined. [0160] I-1-a: MS(ES): m/z: 493.7 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 10.46 (s, 1H), 8.39 (s, 1H), 8.24-8.23 (d, J = 4.8 Hz, 1H), 8.13 (s, 1H), 7.09-7.08 (d, d, J = 4.8 Hz, 1H), 5.84 (s, 1H), 5.74 (s, 1H), 5.10 (bs, 1H), 4.06-3.98 (m, 3H), 3.86-3.73 (m, 5H), 3.54-3.50 (m, 1H), 3.07- 3.04 (m, 1H), 2.71-2.67 (m, 1H), 2.24-2.17 (m, 2H), 2.08 (s, 3H), 1.34 (s, 9H), 1.31 (s, 3H). [0161] I-1-b: MS(ES): m/z: 493.3 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 10.46 (s, 1H), 8.39 (s, 1H), 8.24-8.23 (d, J = 4.8 Hz, 1H), 8.13 (s, 1H), 7.09-7.08 (d, d, J = 4.8 Hz, 1H), 5.84 (s, 1H), 5.74 (s, 1H), 5.10 (bs, 1H), 4.06-3.98 (m, 3H), 3.86-3.73 (m, 5H), 3.54-3.50 (m, 1H), 3.07- 3.04 (m, 1H), 2.71-2.67 (m, 1H), 2.24-2.17 (m, 2H), 2.08 (s, 3H), 1.34 (s, 9H), 1.31 (s, 3H). Example 2: N-(4-(((S)-2-((5-(tert-butyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-4- methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)pyridin-2-yl)acetamide and N-(4- (((R)-2-((5-(tert-butyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-4-methyl-6,7- dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)pyridin-2-yl)acetamide

[0162] Synthesis of compound 2.1. Compound 2.1 was prepared from compound 1.9 and (R)-tetrahydrofuran-3-yl methanesulfonate, following the procedure described in the synthesis of 1.11. The product was purified by flash column chromatography on silica gel (Combiflash®, 2% ethyl acetate in hexane). MS (ES): m/z 248.3 [M+H]⁺. [0163] Synthesis of compound 2.2. Compound 2.2 was prepared from compound 2.1, following the procedure described in the synthesis of 1.12. The product was used without purification. MS(ES): m/z 210.3 [M+H]⁺. [0164] Synthesis of compound 2.3. Compound 2.3 was prepared from compound 2.2, following the procedure described in the synthesis of 1.13. The product was purified by flash column chromatography on silica gel (10% ethyl acetate in hexane). MS(ES): m/z: 274.1 [M+H]⁺. [0165] Synthesis of compound 2.4. Compound 2.4 was prepared from compound 2.3, following the procedure described in the synthesis of 1.16. The product was purified by flash column chromatography on silica gel (Combiflash®, 1.8% methanol in dichloromethane). MS(ES): m/z 479.2 [M+H]⁺. [0166] Synthesis of compound 2.5. Compound 2.5 was prepared from compound 2.4, following the procedure described in the synthesis of 1.17. The product was purified by flash column chromatography on silica gel (Combiflash®, 3% methanol in dichloromethane). MS(ES): m/z: 345.3 [M+H]⁺. [0167] Synthesis of compounds I-2-a and I-2-b. Compounds I-2-a and I-2-b were prepared from compound 2.5, following the procedure described in the synthesis of I-1-a and I-1-b. The diastereomers were separated by HPLC (column: CHIRALPAK IBN-5 (250 mm x 4.6 mm, 5 µm), mobile phase: (A) 0.1% DEA in n-hexane. (B) 0.1% DEA in propan-2-ol:methanol (50:50); flow rate: 20 mL/min) to afford first eluting fraction (I-2-a) and second eluting fraction (I-2-b). *Absolute stereochemistry not determined. [0168] I-2-a: MS(ES): m/z: 493.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 10.48 (s, 1H), 8.41 (s, 1H), 8.25-8.24 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.10-7.09 (d, d, J = 4.4 Hz, 1H), 5.84 (s, 1H), 5.75 (s, 1H), 5.12-5.07 (m, 2H), 4.06-3.98 (m, 3H), 3.86-3.73 (m, 5H), 3.55-3.51 (m, 1H), 3.08-3.05 (m, 1H), 2.75-2.68 (m, 1H), 2.25-2.15 (m, 2H), 2.09 (s, 3H), 1.32 (s, 9H), 1.24 (s, 3H). [0169] I-2-b. MS(ES): m/z: 493.3 [M+H]⁺ ; ¹H NMR (DMSO-d₆, 400 MHz): δ 10.48 (s, 1H), 8.41 (s, 1H), 8.25-8.24 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.10-7.09 (d, d, J = 4.4 Hz, 1H), 5.84 (s, 1H), 5.75 (s, 1H), 5.12-5.07 (m, 2H), 4.06-3.98 (m, 3H), 3.86-3.73 (m, 5H), 3.55-3.51 (m, 1H), 3.08-3.05 (m, 1H), 2.75-2.68 (m, 1H), 2.25-2.15 (m, 2H), 2.09 (s, 3H), 1.32 (s, 9H), 1.24 (s, 3H). [0170] Example 3: N-(4-(((R)-2-((5-(tert-butyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-3- yl)amino)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)pyridin-2- yl)cyclopropanecarboxamide and N-(4-(((S)-2-((5-(tert-butyl)-1-((S)-tetrahydrofuran-3-yl)-1H- pyrazol-3-yl)amino)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)methyl)pyridin-2- yl)cyclopropanecarboxamide

[0171] Synthesis of compound 3.1. To a solution of 4-(chloromethyl)pyridin-2-amine (5 g, 35.07 mmol, 1.0 equiv) and N,N-diisopropylethylamine (9.08 g, 70.14 mmol, 2.0 equiv) in dichloromethane (75 mL) was added cyclopropanecarbonyl chloride (5.50 g, 52.6 mmol, 1.5 equiv) 0 °C and stirred for 2.5 h. The reaction mixture was poured over ice-water, stirred and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane) to afford 3.1. MS (ES): m/z 211.3 [M+H]⁺. [0172] Synthesis of compound I-3-a and I-3-b. Compounds I-3-a and I-3-b were prepared from compound 3.1, following the procedure described in the synthesis of I-1-a and I-1-b. The diastereomers were separated by HPLC (column: CHIRALPAK IC (250 mm x 4.6 mm, 5 µm); mobile phase: (A) 0.1% DEA in n-hexane, (B) 0.1% DEA in propane-2-ol:acetonitrile (70:30); flow rate: 20 mL/min) to afford first eluting fraction (I-3-a) and second eluting fraction (I-3-b). *Absolute stereochemistry not determined. [0173] I-3-a: MS(ES): m/z: 519.5 [M+H]⁺ ; ¹H NMR (DMSO-d₆, 400 MHz): δ 10.76 (s, 1H), 8.37 (s, 1H), 8.24-8.23 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.08-7.07 (d, d, J = 4.4 Hz, 1H), 5.82 (s, 1H), 5.76 (s, 1H), 5.10 (bs, 1H), 4.04-3.88 (m, 3H), 3.85-3.71 (m, 5H), 3.52-3.48 (m, 1H), 3.06- 3.03 (m, 1H), 2.23-2.16 (m, 2H), 2.01-2.00 (m, 2H), 1.34 (s, 9H), 1.24 (bs, 3H), 0.85-0.78 (m, 4H). [0174] I-3-b: MS(ES): m/z: 519.5 [M+H]⁺ ; ¹H NMR (DMSO-d₆, 400 MHz): δ 10.77 (s, 1H), 8.39 (s, 1H), 8.24-8.23 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.08-7.07 (d, d, J = 4.4 Hz, 1H), 5.82 (s, 1H), 5.76 (s, 1H), 5.10 (bs, 1H), 3.99-3.88 (m, 3H), 3.85-3.71 (m, 5H), 3.52-3.48 (m, 1H), 3.06-3.03 (m, 1H), 2.23-2.16 (m, 2H), 2.01-1.99 (m, 2H), 1.34 (s, 9H), 1.23 (bs, 3H), 0.85- 0.78 (m, 4H). Preparation of Intermediate Int-1: 3-amino-5-cyclopropyl-1-methylpyridin-2(1H)-one

[0175] Synthesis of compound Int-1.1. A mixture of 5-bromo-3-nitropyridin-2(1H)-one (5.0 g, 22.83 mmol, 1.0 equiv) and potassium carbonate (6.6 g, 47.94 mmol, 2.1 equiv) in DMF (50 mL) was stirred for 15 min before the addition of methyl iodide (3.56 g, 25.11 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 1 h. It was poured into ice- water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford Int-1.1. MS(ES): m/z 234.02 [M+H]⁺. [0176] Synthesis of compound Int-1.2. A mixture of Int-1.1 (0.7 g, 3.0 mmol, 1.0 equiv), cyclopropylboronic acid (0.774 g, 9.0 mmol, 3.0 equiv), potassium phosphate (1.9 g, 9.0 mmol, 3.0 equiv) and tricyclohexylphosphine (0.168 g, 0.6 mmol, 0.2 equiv) in toluene (10 mL) and water (1 mL) was degassed by bubbling through a stream of argon for 10 min. Under argon atmosphere palladium(II) acetate (0.336 g, 1.5 mmol, 0.5 equiv) was added, and the mixture was degassed for additional 5 min. The reaction mixture was stirred at 100 °C for 2 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate in hexane) to afford Int-1.2. MS(ES): m/z 195.2 [M+H]⁺. [0177] Synthesis of compound Int-1. A mixture of compound Int-1.2 (0.182 g, 0.93 mmol, 1.0 equiv) and 10% palladium on carbon (0.1 g) in methanol (5 mL) was stirred under hydrogen atmosphere (1 atm) at rt for 2 h. The mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford Int-1. MS(ES): m/z 165.21 [M+H]⁺. [0178] Int-1 can be used to prepare compounds I-4-i and I-4-ii using methods described herein. Preparation of Intermediate Int-2: 4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- amine

[0179] Synthesis of compound Int-2.2. To a solution of Int-2.1 (10 g, 99.88 mmol, 1.0 equiv) and methyl iodide (24.8 mL, 399.52 mmol, 4.0 equiv) in THF (200 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 219 mL, 219.7 mmol, 2.2 equiv) at -78 °C. The reaction mixture was stirred at room temperature for 16 h. It was poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane as eluant) to afford Int-2.2. MS (ES): m/z 129.2 [M+H]⁺. [0180] Synthesis of compound Int-2.3. To a solution of diisopropylamine (4.88 g, 48.37 mmol, 1.0 equiv) in THF (100 mL) at -78°C was slowly added a solution of n-butyl lithium (2.5M in hexane, 24.2 mL, 60.46 mmol, 1.25 equiv). The reaction mixture was stirred for 5 min followed by addition of acetonitrile (2.5 mL, 48.37 mmol, 1.0 equiv). The reaction mixture stirred for 10 min and compound Int-2.3 (6.20 g, 48.37 mmol, 1.0 equiv) in THF (30 mL) was added to it. The reaction mixture was stirred at 5 °C for 6 h. It was poured over cold saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexane as eluant) to afford Int-2.3. MS (ES): m/z 170.2 [M+H]⁺. [0181] Synthesis of compound Int-2.4. To a solution of Int-2.3 (3.9 g, 23.05 mmol, 1.0 equiv) in ethanol (40 mL) was added hydrazine hydrochloride (2.35 g, 34.57 mmol, 1.5 equiv) followed by addition of potassium carbonate (4.77 g, 34.57 mmol, 1.5 equiv). The reaction mixture was heated to reflux for 16 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3-4% methanol in dichloromethane as eluant) to afford Int-2.4. MS (ES): m/z 184.26 [M+H]⁺. [0182] Synthesis of compound Int-2. To a solution of Int-2.4 (1.1 g, 6.0 mmol, 1.0 equiv) in THF (20 mL) was added thionyl chloride (2.15 mL, 30 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 2 h. It was poured over saturated sodium bicarbonate solution, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2% methanol in dichloromethane as eluant) to afford Int-2. MS (ES): m/z 166.24 [M+H]⁺. [0183] Int-2 can be used to prepare compounds I-5-i and I-5-ii using methods described herein. Preparation of Intermediate Int-3: 1-((1r,3r)-3-(benzyloxy)cyclobutyl)-5-(tert-butyl)-1H- pyrazol-3-amine

[0184] Synthesis of compound Int-3.1. To a solution of 3-(benzyloxy)cyclobutan-1-one (10 g, 56.75 mmol, 1.0 equiv) in methanol (100 mL) was added sodium borohydride (6.4 g, 170.2 mmol, 3.0 equiv) in small portions at 0 °C. The reaction mixture was stirred at room temperature for 3 h. It was poured over ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford Int-3.1. MS (ES): m/z 179.3 [M+H]⁺. [0185] Synthesis of compound Int-3.2 To a solution of Int-3.1 (3.0 g, 16.83 mmol, 1.0 equiv) in DCM (30 mL) was added triethylamine (3.0 mL, 21.87 mmol, 1.3 equiv) at 0 °C followed by addition of methanesulfonyl chloride (1.7 mL, 21.87 mmol, 1.3 equiv). The reaction mixture was stirred at room temperature for 12 h. It was poured into ice-water, stirred and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexane) to afford Int-3.2. MS (ES): m/z 257.3 [M+H]⁺. [0186] Synthesis of compound Int-3.3. A mixture of 1.9 (3.2 g, 12.48 mmol, 1.0 equiv), Int-3.2 (2.71 g, 12.48 mmol, 1.0 equiv) and cesium carbonate (8.13 g, 24.96 mmol, 2.0 equiv) in DMF (30 mL) was stirred at 80-90 °C for 12 h. It was poured into ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 8-12% ethyl acetate in hexane) to afford Int-3.3. MS (ES): m/z 378.5 [M+H]⁺. [0187] Synthesis of compound Int-3. Compound Int-3 was prepared from Int-3.3 following the procedure described in the synthesis of compound 1.12. The product was purified by flash column chromatography on silica gel (CombiFlash®, 24-28% ethyl acetate in hexane). MS(ES): m/z 300.4 [M+H]⁺. [0188] Int-3 can be used to prepare compounds I-6-i and I-6-ii, after deprotection using standard conditions, using methods described herein. Preparation of Intermediate Int-4: 5-(tert-butyl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrazol-3- amine

[0189] Synthesis of compound Int-4.1. Concentrated sulfuric acid (60 mL, 6 vol) was added dropwise to potassium persulfate (54.31 g, 201.15 mmol, 2.8 equiv) at room temperature and stirred for 15 min. To the mixture was added 5-(tert-butyl)-1H-pyrazol-3-amine (10 g, 71.84 mmol, 1.0 equiv) in small portions maintaining temperature at 30-40 °C. The reaction mixture was stirred at room temperature for 30 min. It was poured over crushed ice, stirred and basified with saturated sodium bicarbonate 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®, 15% ethyl acetate in hexane) to afford Int-4.1.¹H NMR (DMSO-d₆, 400 MHz): δ 11.20 (s, 1H), 6.26 (s, 1H), 1.29 (s, 9H). [0190] Synthesis of compound Int-4.2. To a solution of Int-4.1 (1.2 g, 7.09 mmol, 1.0 equiv) and 2-oxaspiro[3.3]heptan-6-yl methanesulfonate (2.05 g, 10.64 mmol, 1.5 equiv) in DMF (10 mL) was added cesium carbonate (6.91 g, 21.27 mmol, 3.0 equiv) and the reaction mixture was stirred at 80-90 °C for 12 h. It was poured over ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 15-20% ethyl acetate in hexane) to afford Int-4.2. MS (ES): m/z 266.3 [M+H]⁺. [0191] Synthesis of compound Int-4. To a solution of Int-4.2 (0.200 g, 0.753 mmol, 1.0 equiv) in ethanol-water (2:1, 5 mL) was added iron powder (0.210 g, 3.765 mmol, 5 equiv) followed by ammonium chloride (0.203 g, 3.765 mmol, 5 equiv). The reaction mixture was stirred at 50 °C for 30 min. It was poured over ice-water, filtered and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford Int-4.3. MS (ES): m/z 236.3 [M+H]⁺. [0192] Int-4 can be used to prepare compounds I-7-i and I-7-ii using methods described herein. JAK2 Binding Assay [0193] JAK2 (JH1domain-catalytic, Y1007F,Y1008F) kinase was expressed as N-terminal fusion to the DNA binding domain of NFkB in transiently transfected HEK293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mmol/L DTT) to remove unbound ligand and to reduce nonspecific phage binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (1x PBS, 0.05% Tween 20, 0.1% BSA, 1 mmol/L DTT). Test compound was prepared as 111x stocks in 100% DMSO and directly diluted into the assay wells. All reactions were performed in polypropylene 384-well plates in a final volume of 0.02 mL. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05 % Tween 20). The beads were then re-suspended in elution buffer (1x PBS, 0.05 % Tween 20, 0.5 μmol/L non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluate was measured by qPCR. [0194] Results of the JAK2 JH1 Domain Binding Assay described above are presented in Table 2. Compounds denoted as “A” had a Kd < 10 nM; compounds denoted as “B” had a Kd ≥ 10 nM and < 50 nM; compounds denoted as “C” had a K_d ≥ 50 nM and < 1 µM; compounds denoted as “D” had a K_d ≥ 1 µM and < 5 µM; and compounds denoted as “E” had a K_d ≥ 5 µM. Table 2. Results of JAK2 Binding Assay

JAK Family Selectivity Assays

[0195] Provided compounds are evaluated for selectivity by comparing their JAK2 binding affinity (Kd) in the above JAK2 Binding Assay with their binding affinity (Kd) for one or more other kinases. Binding affinity for other kinases is determined as follows: Kinase-tagged T7 phage strains are prepared in an E. coli host derived from the BL21 strain. E. coli are grown to log-phase and infected with T7 phage and incubated with shaking at 32 °C until lysis. The lysates are centrifuged and filtered to remove cell debris. The remaining kinases are produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads are treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads are blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding. Binding reactions are assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds are prepared as 11 IX stocks in 100% DMSO. Kds are determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds are then diluted directly into the assays such that the final concentration of DMSO is 0.9%. All reactions are performed in polypropylene 384-well plate. Each has a final volume of 0.02 ml. The assay plates are incubated at room temperature with shaking for 1 hour and the affinity beads are washed with wash buffer (lx PBS, 0.05% Tween 20). The beads are then re-suspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 mM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates is measured by qPCR. Compounds that exhibit a better binding affinity for JAK2 compared to one or more other kinases are considered to be JAK2-selective compounds. In some embodiments, provided compounds may be JAK2-selective over one or more of the following kinases: JAK1, JAK3, and Tyk2. SET2-pSTAT5 Cellular Assay [0196] This assay measures inhibition of JAK2-mediated pSTAT5 signaling in constitutively active essential thrombocytopenia cells carrying the V617F mutation. Cells are harvested from a flask into cell culture medium, and the number of cells is counted. The cells are diluted with culture medium and 100 µL of cell suspension (50000/well) is added into each well of a 96-well cell culture plate. A solution of test compound is added to the assay plate. The plates are covered with a lid and placed in a 37 °C 5% CO₂ incubator for 4 hours. After 4 hours, the cells are spun, and the cell pellets are re-suspended with 100 µL cold PBS. Then, the cells are spun again at 4 °C and 4000 rpm for 5 min. PBS is aspirated, and 25 µL lysis buffer (with protease and phosphatase inhibitor cocktail) is added to each cell pellet. The cell lysate is shaken at 4 °C for 20 min to fully lyse the cells. The cell lysate is spun at 4 °C and 4000 rpm for 15 min, and then the supernatant is transferred into a new plate and stored at -80 °C. Meso-scale discovery (MSD) is used to analyze plates as follows: a standard MSD plate is coated with capture antibody in PBS (40 µL/well) and is incubated at 4 °C overnight with shaking. The MSD plate is washed three times with 150 µL/well of 1x MSD Wash Buffer (Tris-buffered saline with 0.1% Tween® 20 detergent, TBST). The MSD plates are then blocked with 150 µL of blocking buffer (5% BSA in TBST) and shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 µL/well of 1x MSD Wash Buffer (TBST). Sample lysates are then added to MSD plates (25 µL/well) and shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 µL/well of 1x MSD Wash Buffer (TBST). Detection antibody (prepared in Antibody Detection buffer, 1% BSA in 1xTBST) is then added to the MSD plates, and they are shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 µL/well of 1x MSD Wash Buffer (TBST). A secondary detection antibody (prepared in Antibody Detection buffer, 1% BSA in 1xTBST) is then added to the MSD plates, and they are shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 µL/well of 1x MSD Wash Buffer (TBST). MSD reading buffer (1x) is added to the plates (150 µL/well), and they are diluted from 4x with water. The plates are imaged using an MSD imaging instrument according to the manufacturer’s instructions. Caco2 Permeability Assay [0197] Preparation of Caco-2 Cells: 50 μL and 25 mL of cell culture medium are added to each well of a Transwell® insert and reservoir, respectively. Then, the HTS Transwell® plates are incubated at 37 °C, 5% CO₂ for 1 hour before cell seeding. Caco-2 cell cells are diluted to 6.86х105 cells/mL with culture medium, and 50 μL of cell suspension are dispensed into the filter well of the 96-well HTS Transwell® plate. Cells are cultivated for 14-18 days in a cell culture incubator at 37 °C, 5% CO₂, 95% relative humidity. Cell culture medium is replaced every other day, beginning no later than 24 hours after initial plating. [0198] Preparation of Stock Solutions: 10 mM stock solutions of test compounds are prepared in DMSO. The stock solutions of positive controls are prepared in DMSO at the concentration of 10 mM. Digoxin and propranolol are used as control compounds in this assay. [0199] Assessment of Cell Monolayer Integrity: Medium is removed from the reservoir and each Transwell® insert and is replaced with prewarmed fresh cuture medium. Transepithelial electrical resistance (TEER) across the monolayer is measured using Millicell Epithelial Volt- Ohm measuring system (Millipore, USA). The Plate is returned to the incubator once the measurement is done. The TEER value isss calucated according to the following equation: TEER measurement (ohms) x Area of membrane (cm²) = TEER value (ohm•cm²). A TEER value greater than 230 ohm•cm² indicates a well-qualified Caco-2 monolayer. [0200] Assay Procedure: The Caco-2 plate is removed from the incubator and washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4), and then incubated at 37 °C for 30 minutes. The stock solutions of control compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) to get 5 μM working solutions. The stock solutions of the test compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES and 4% BSA, pH 7.4) to get 5 μM working solutions. The final concentration of DMSO in the incubation system is 0.5%. To determine the rate of drug transport in the apical to basolateral direction. 75 μL of 5 μM working solutions of test compounds are added to the Transwell® insert (apical compartment) and the wells in the receiver plate (basolateral compartment) are filled with 235 μL of HBSS (10 mM HEPES and 4% BSA, pH 7.4). To determine the rate of drug transport in the basolateral to apical direction, 235 μL of 5 μM working solutions of test compounds are added to the receiver plate wells (basolateral compartment) and then the Transwell® inserts (apical compartment) are filled with 75 μL of HBSS (10 mM HEPES and 4% BSA, pH 7.4). Time 0 samples are prepared by transferring 50 μL of 5 μM working solution to wells of the 96-deepwell plate, followed by the addition of 200 μL cold methanol containing appropriate internal standards (IS). The plates are incuabted at 37 °C for 2 hours. At the end of the incubation, 50 μL samples from donor sides (apical compartment for Ap→Bl flux, and basolateral compartment for Bl→Ap) and receiver sides (basolateral compartment for Ap→Bl flux, and apical compartment for Bl→Ap) are transferred to wells of a new 96-well plate, followed by the addition of 4 volume of cold acetonitrile or methanol containing appropriate internal standards (IS). Samples are vortexed for 5 minutes and then centrifuged at 3,220 g for 40 minutes. An aliquot of 100 µL of the supernatant is mixed with an appropriate volume of ultra-pure water before LC-MS/MS analysis. To determine the Lucifer Yellow leakage after 2 hour transport period, stock solution of Lucifer yellow is prepared in ultra-pure water and diluted with HBSS (10 mM HEPES, pH 7.4) to reach the final concentration of 100 μM. 100 μL of the Lucifer yellow solution is added to each Transwell® insert (apical compartment), followed by filling the wells in the receiver plate (basolateral compartment) with 300 μL of HBSS (10 mM HEPES, pH 7.4). The plates are incubated at 37 °C for 30 minutes.80 μL samples are removed directly from the apical and basolateral wells (using the basolateral access holes) and transferred to wells of new 96 wells plates. The Lucifer Yellow fluorescence (to monitor monolayer integrity) signal is measured in a fluorescence plate reader at 485 nM excitation and 530 nM emission. Cytotoxicity Assay [0201] HEK293T cells are harvested from flask into cell culture medium, and then the cells are counted. The cells are diluted with culture medium to the desired density, and 40 μL of cell suspension is added into each well of a 384-well cell culture plate. The plates are covered with a lid and spun at room temperature at 1,000 RPM for 1 minute and then transferred into 37 °C 5% CO₂ incubator overnight. Test compounds are dissolved at 10 mM DMSO stock solution.45 μL of stock solution is then transferred to a 384 PP-plate. A 3-fold, 10-point dilution is performed via transferring 15 μL compound into 30 μL DMSO by using TECAN (EVO200) liquid handler. The plates are spun at room temperature at 1,000 RPM for 1 minute and shaken on a plate shaker for 2 minutes. 40 nL of diluted compound is transferred from compound source plate into the cell plate by using liquid handler Echo550. After compound treatment for 48 hours, CTG detection is performed for compound treatment plates: the plates are removed from incubators and equilibrated at room temperature for 15 minutes. 30 μL of CellTiter-Glo reagent is added into each well to be detected. The plates are then placed at room temperature for 30 min followed by reading on EnVision. Inhibition activity is calculated with the following formula: %Inhibition = 100 x (LumHC – LumSample) / (LumHC –LumLC), wherein HC is reading obtained from cells treated with 0.1% DMSO only and LC is reading from cells treated with 10 μL staurosporine. IC50 values are calculated using XLFit (equation 201). Hepatocyte Stability Assay [0202] 10 mM stock solutions of test compound and positive control are prepared in DMSO. Stock solutions are diluted to 100 μM by combining 198 μL of 50% acetonitrile/50% water and 2 μL of 10 mM stock solution. Verapamil is used as positive control in the assay. Vials of cryopreserved hepatocytes are thawed in a 37 °C water bath with gently shaking. The contents are poured into the 50 mL thawing medium conical tube. Vials are centrifuged at 100 g for 10 minutes at room temperature. Thawing medium is aspirated and hepatocytes are re-suspended with serum-free incubation medium to yield ~1.5 × 106 cells/mL. Cell viability and density are counted using a Trypan Blue exclusion, and then cells are diluted with serum-free incubation medium to a working cell density of 0.5×106 viable cells/mL. A portion of the hepatocytes at 0.5×106 viable cells/mL are boiled for 5 min prior to adding to the plate as negative control to eliminate the enzymatic activity so that little or no substrate turnover should be observed. Aliquots of 198 μL hepatocytes are dispensed into each well of a 96-well non-coated plate. The plate is placed in the incubator for approximately 10 minutes. Aliquots of 2 μL of the 100 μM test compound and 2 μL positive control are added into respective wells of a non-coated 96-well plate to start the reaction. The final concentration of test compound is 1 μM. This assay is performed in duplicate. The plate is incubated in the incubator for the designed time points. 25 μL of contents are transferred and mixed with 6 volumes (150 μL) of cold acetonitrile with internal standard (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine and 200 nM diclofenac) to terminate the reaction at time points of 0, 15, 30, 60, 90 and 120 minutes. Samples are centrifuged for 25 minutes at 3,220 g and aliquots of 150 μL of the supernatants are used for LC-MS/MS analysis. Kinetic Solubility Assay [0203] Stock solutions of test compounds are prepared in DMSO at the concentration of 10 mM, and a stock solution of control compound is prepared in DMSO at the concentration of 30 mM. Diclofenac is used as positive control in the assay. 30 µL stock solution of each compound is placed into their a 96-well rack, followed by adding 970 µL of PBS at pH 4.0 and pH 7.4 into each vial of the cap-less solubility sample plate. This study is performed in duplicate. One stir stick is added to each vial and then vials are sealed using a molded PTDE/SIL 96-Well Plate Cover. The solubility sample plate is transferred to the Thermomixer comfort plate shaker and incubated at RT for 2 hours with shaking at 1100 rpm. After 2 hours incubation, stir sticks are removed using a big magnet and all samples from the solubility sample plate are transferred into the filter plate. All the samples are filtered by vacuum manifold. The filtered samples are diluted with methanol. Samples are analyzed by LC-MS/MS and quantified against a standard of known concentration in DMSO using LC coupled with Mass spectral peak identification and quantitation. The solubility values of the test compounds are calculated as follows, wherein INJ VOL is injection volume, DF is dilution factor, and STD is standard:

Plasma Protein Binding Assay [0204] Working solutions of test compounds and control compound are prepared in DMSO at the concentration of 200 μM, and then the working solutions are spiked into plasma. The final concentration of compound is 1 μM. The final concentration of DMSO is 0.5%. Ketoconazole is used as positive control in the assay. Dialysis membranes are soaked in ultrapure water for 60 minutes to separate strips, then in 20% ethanol for 20 minutes, finally in dialysis buffer for 20 minutes. The dialysis set up is assembled according to the manufacturer’s instruction. Each Cell is with 150 μL of plasma sample and dialyzed against equal volume of dialysis buffer (PBS). The assay is performed in duplicate. The dialysis plate is sealed and incubated in an incubator at 37 °C with 5% CO₂ at 100 rpm for 6 hours. At the end of incubation, 50 μL of samples from both buffer and plasma chambers are transferred to wells of a 96-well plate. 50 μL of plasma is added to each buffer samples and an equal volume of PBS is supplemented to the collected plasma sample. 400 μL of precipitation buffer acetonitrile containing internal standards (IS, 100 nM alprazolam, 200 nM labetalol, 200 nM imipramine and 2 μM ketoplofen) is added to precipitate protein and release compounds. Samples are vortexed for 2 minutes and centrifuged for 30 minutes at 3,220 g. Aliquot of 50 µL of the supernatant is diluted by 150 µL acetonitrile containing internal standards : ultra-pure H2O = 1 : 1, and the mixture is used for LC-MS/MS analysis. [0205] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMS 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Z is –O- or –NR^z-; R^x is hydrogen, halogen, -OR⁵, -N(R⁵)₂, -SR⁵, optionally substituted C_1-6 aliphatic, or –CN; R^z is hydrogen or optionally substituted C_1-6 aliphatic; R¹, R^1’, R², R^2’, R³, and R^3’are each independently hydrogen or optionally substituted C_1-6 aliphatic; R⁴ and R^4’ are each independently hydrogen or optionally substituted C_1-6 aliphatic, or R⁴ and R^4’ are taken together to form an oxo; each R⁵ is independently hydrogen or optionally substituted C_1-6 aliphatic; Ring A is optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is optionally substituted phenyl, optionally substituted 9- to 16-membered bicyclic or tricyclic aryl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 7- to 16-membered saturated or partially unsaturated bicyclic or tricyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent C_1-3 straight or branched hydrocarbon chain; and 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 carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

2. The compound of claim 1, wherein 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.

3. The compound of any one of the preceding claims, wherein Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

4. The compound of any one of the preceding claims, wherein Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

5. The compound of any one of the preceding claims, wherein 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.

6. The compound of any one of the preceding claims, wherein R^a is optionally substituted C_1-6 aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

7. The compound of any one of the preceding claims, wherein R^a is optionally substituted C_1-6 alkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted 3- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 8-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

8. The compound of any one of the preceding claims, wherein:

R^b is hydrogen, halogen, -CN, -OR, -SR, -N(R)₂, -NO₂, -C(O)R’, -C(O)OR, -C(O)N(R)₂, - OC(O)R’, -OC(O)N(R)₂, -OC(O)OR, -OSO₂R, -OSO₂N(R)₂, -N(R)C(O)R’, -N(R)SO₂R’, - SO₂R’, -SO₂N(R)₂, -SO₃R’, optionally substituted C_1-6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, optionally substituted C_1-6 aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently optionally substituted C_1-6 aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl.

9. The compound of claim 8, wherein R^b is halogen, -CN, -OR, -SR, -N(R)₂, -NO₂, - C(O)R’, -C(O)OR, -C(O)N(R)₂, -OC(O)R’, -OC(O)N(R)₂, -OC(O)OR, -OSO₂R, -OSO₂N(R)₂, - N(R)C(O)R’, -N(R)SO₂R’, -SO₂R’, -SO₂N(R)₂, -SO₃R’, optionally substituted C_1-6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

10. The compound of claim 8 or 9, wherein R^b is optionally substituted C_1-6 aliphatic or optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl.

11. The compound of any one of claims 8-10, wherein R^b is C_1-4 alkyl or C₃-C₄ cycloalkyl.

12. The compound of any one of claims 8-11, wherein

,

13. The compound of any one of claims 8-12, wherein

14. The compound of any one of claims 8-12, wherein

15. The compound of any one of the preceding claims, wherein L is a covalent bond.

16. The compound of any one of the preceding claims, wherein L is –CH₂-.

17. The compound of any one of the preceding claims, wherein Ring B is optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

18. The compound of any one of the preceding claims, wherein Ring B is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

19. The compound of any one of the preceding claims, wherein Ring B is

, wherein: R⁶ is –N(R)₂, –N(R)C(O)R’, –C(O)N(R)₂, or –N(R)C(O)N(R)₂; each R is independently hydrogen, optionally substituted C_1-6 aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently optionally substituted C_1-6 aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl.

20. The compound of claim 19, wherein R⁶ is –N(R)C(O)R’ or –C(O)N(R)₂.

21. The compound of claim 19 or 20, wherein R⁶ is –N(R)C(O)R’.

22. The compound of any one of claims 19-21, wherein R⁶ is –N(H)C(O)(optionally substituted C_1-6 alkyl) or –N(H)C(O)(optionally substituted C_3-7 cycloalkyl).

23. The compound of any one of claims 19-22, wherein R⁶ is -N(H)C(O)CH₃ or - N (H)C (O)(cy cl opropyl) .

24. The compound of any one of claims 1-16, wherein Ring B is optionally substituted 9- to 16-membered bicyclic or tricyclic aryl, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 7- to 16- membered saturated or partially unsaturated bicyclic or tricyclic carbocyclyl, optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

25. The compound of claim 24, wherein Ring B is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 7- to 10- membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

26. The compound of claim 24 or 25, wherein Ring B is optionally substituted 8- to 10- membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or optionally substituted 10- to 16-membered polycyclic heteroaryl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

27. The compound of any one of claims 24-26, wherein Ring B is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

28. The compound of any one of the preceding claims, wherein: Ring B is

; Ring B1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring B1 is fused to Ring B2; Ring B2 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring B2 is optionally (i) further fused to Ring B3, or (ii) Ring B2 and Ring B3 combine to form a spirocycle; and Ring B3, when present, is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

29. The compound of claim 28, wherein Ring B1 is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

30. The compound of claim 28 or 29, wherein Ring B2 is optionally substituted 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

31. The compound of any one of the preceding claims, wherein each R is independently hydrogen or optionally substituted C_1-6 aliphatic.

32. The compound of any one of the preceding claims, wherein each R is hydrogen.

33. The compound of any one of the preceding claims, wherein R’ is optionally substituted C_1-6 aliphatic.

34. The compound of any one of the preceding claims, wherein R’ is optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl.

35. The compound of any one of the preceding claims, wherein R’ is methyl or cyclopropyl.

36. The compound of any one of the preceding claims, wherein R¹ is hydrogen or optionally substituted C_1-6 alkyl.

37. The compound of any one of the preceding claims, wherein R¹ is optionally substituted C_1-6 alkyl.

38. The compound of any one of the preceding claims, wherein R¹ is methyl.

39. The compound of any one of the preceding claims, wherein R^1’, R², R^2’, R³, and R^3’ are each hydrogen.

40. The compound of any one of the preceding claims, wherein R⁴ and R^4’ are each hydrogen.

41. The compound of any one of claim 1-39, wherein R⁴ and R^4’ are taken together to form an oxo.

42. The compound of any one of the preceding claims, wherein R^x is hydrogen.

43. The compound of any one of the preceding claims, wherein Z is –O-.

44. The compound of any one of claims 1-43, wherein Z is –NR^z-.

45. The compound of claim 44, wherein R^z is hydrogen.

46. The compound of any one of the preceding claims, wherein the compound is of Formula IA:

or a pharmaceutically acceptable salt thereof.

47. The compound of any one of the preceding claims, wherein the compound is of Formula IB:

or a pharmaceutically acceptable salt thereof.

48. The compound of any one of the preceding claims, wherein the compound is of Formula IC:

or a pharmaceutically acceptable salt thereof.

49. The compound of any one of the preceding claims, wherein the compound is of Formula II:

or a pharmaceutically acceptable salt thereof, wherein: R^b is hydrogen, halogen, -CN, -OR, -SR, -N(R)₂, -NO₂, -C(O)R’, -C(O)OR, -C(O)N(R)₂, - OC(O)R’, -OC(O)N(R)₂, -OC(O)OR, -OSO₂R, -OSO₂N(R)₂, -N(R)C(O)R’, -N(R)SO₂R’, - SO₂R’, -SO₂N(R)₂, -SO₃R’, optionally substituted C_1-6 aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, optionally substituted C_1-6 aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently optionally substituted C_1-6 aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl.

50. The compound of any one of the preceding claims, wherein the compound is of Formula III:

or a pharmaceutically acceptable salt thereof, wherein: R⁶ is –N(R)₂, –N(R)C(O)R’, –C(O)N(R)₂, or –N(R)C(O)N(R)₂; each R is independently hydrogen, optionally substituted C_1-6 aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently optionally substituted C_1-6 aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl.

51. The compound of any one of the preceding claims, wherein the compound is of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

Ring B1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring B1 is fused to Ring B2;

Ring B2 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 6- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring B2 is optionally (i) further fused to Ring B3, or (ii) Ring B2 and Ring B3 combine to form a spirocycle; and Ring B3, when present, is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

52. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

53. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

54. A method of inhibiting JAK2 in a subject comprising administering the compound of any one of claims 1-52 or the composition of claim 53.

55. A method of treating a disease, disorder, or condition associated with JAK2, comprising administering to a subject in need thereof the compound of any one of claims 1-52 or the composition of claim 53.

56. A method of treating cancer, comprising administering to a subject in need thereof the compound of any one of claims 1-52 or the composition of claim 53.

57. A method of treating a hematological malignancy, comprising administering to a subject in need thereof the compound of any one of claims 1-52 or the composition of claim 53.

58. The method of claim 57, wherein the hematological malignancy is leukemia or lymphoma.

59. A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof the compound of any one of claims 1-52 or the composition of claim 53.

60. The method of claim 59, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia or myelofibrosis.