6-hetero aryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors

Abstract

The present disclosure provides 6-heteroaryloxy benzimidazole and azabenzimidazole compounds and compositions thereof useful for inhibiting JAK2.

Description

6-HETEROARYLOXY BENZIMIDAZOLES AND AZABENZIMIDAZOLES AS JAK2INHIBITORSRELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Application No. 63 / 277,343, filed November 9, 2021, and U.S. Application No. 63 / 354,403, filed June 22, 2022, the entire contents of each 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., FlOOOResearch 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:iil 11-iil 15). 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(l):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 Ior a pharmaceutically acceptable salt thereof, wherein Ring A, n, L, W, X, Y, Z, R1, R2, Ra, and Rcare as defined herein.

[0006] In some embodiments, the present disclosure provides a compound of Formula IIor a pharmaceutically acceptable salt thereof, wherein Ring A, n, W, X, Y, Z, R1, R2, and Rcare as defined herein.

[0007] In some embodiments, the present disclosure provides a compound of Formula IIIor a pharmaceutically acceptable salt thereof, wherein Ring A, L, Z, R2, R4, Ra, and Rxare as defined herein.

[0008] In some embodiments, the present disclosure provides a compound of Formula IVor a pharmaceutically acceptable salt thereof, wherein Ring A, L, Z, R’, R2, Ra, and Rxare as defined herein.DETAILED DESCRIPTIONCompounds and Definitions

[0009] 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, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0010] 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.

[0011] 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 by13C- or14C-enriched carbon are within the scope of this disclosure.

[0012] Aliphatic: The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C1-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, 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.

[0013] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, C1 -4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0014] 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-C8hydrocarbon, or an optionally substituted C7-C10bicyclic 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.

[0015] Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0016] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g.,C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0017] 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.

[0018] 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 71 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[l,2- a]pyrimidinyl, imidazo[l,2-a]pyridinyl, thienopyrimidinyl, triazol opyridinyl, 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]-l,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.

[0019] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen.

[0020] 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)).

[0021] 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.

[0022] 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.

[0023] 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 (i.e., as described below for optionally substituted groups). “Substituted” applies to one or more hydrogens that are either explicit oran “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.

[0024] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)0-4R°; -(CH2)0-4OR°; -O(CH2)0-4R°, -O- (CH2)0-4C(O)OR°; -(CH2)0-4CH (OR°)2; -(CH2)0-4SR°; -(CH2)0-4Ph, which may be substituted with R°; -(CH2)0-4O(CH2)0-1Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)0-4O(CH2)0-1-pyridyl which may be substituted with R°; -NO2; -CN; -N3; (CH2)0-4N(R°)2; -(CH2)0-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)O-4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)0-4N(R°)C(O)0R°;N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°; - C(S)R°; -(CH2)0-4C(O)0R°; -(CH2)0-4C(O)SR°; -(CH2)0-4C(O)OSiRo3; -(CH2)0-40C(0)R°; - OC(O)(CH2)0-4SR°; -(CH2)0-4SC(O)R°; -(CH2)0-4C(0)NR°2; -C(S)NR°2; -C(S)SR°; - SC(S)SR°, -(CH2)0-4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; - C(NOR°)R°; -(CH2)0-4SSR°; -(CH2)0-4S(O)2R°; -(CH2)0-4S(O)2OR°; -(CH2)0-4OS(O)2R°; - S(O)2NR°2; -(CH2)0-4S(0)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; - P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; -SiR°3; -(C1-4straight or branched alkylene)0-N(R°)2; or -(C1-4straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2Ph, -O(CH2)0-iPh, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0025] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)0-2R●, -(haloR●), -(CH2)0-20H, -(CH2)0-20Re, -(CH2)o-2CH(OR●)2, -O(haloR●), -CN, -N3, -(CH2)0-2C(0)R●, -(CH2)0-2C(0)OH, -(CH2)0-2C(0)OR●, - (CH2X-2SR●, -(CH2)0-2SH, -(CH2)0N-2H2, -(CH2)0-2NHR●, -(CH2)0-2NR●2, -NO2, -SiR●3, - OSiRe3, -C(O)SRe, -(C1-4straight or branched alkylene)C(O)ORe, or -SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4aliphatic, -CH2Ph, -0(CH2)0-1Ph, or a 3- to 6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0026] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0 (“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, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6aliphatic 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.

[0027] Suitable substituents on the aliphatic group of R* include halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, -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.

[0028] 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, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] Suitable substituents on the aliphatic group of R†are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2,or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –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.

[0030] Treat: As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. 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

[0031] In some embodiments, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: W is CRwor N; X is CRxor N; Y is CRyor N; Z is –O- or –NRz-; Rw, Rx, and Ryare each independently hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6aliphatic, or –CN; Rzis hydrogen or optionally substituted C1-6aliphatic;R1is –N(R)2, –N(R)C(O)R’, -C(O)N(R)2, –N(R)C(O)N(R)2, or –N(R)C(O)OR; each Rcis independently selected from halogen, -CN, -CO2R, -C(O)N(R)2, -NO2, -N(R)2, -OR, - SR, or optionally substituted C1-6aliphatic; n is 0, 1, 2, or 3, provided that when R1is –N(R)2, –N(R)C(O)R’ or -C(O)N(R)2, then n is 1, 2, or 3; R2is optionally substituted C1-6aliphatic; R3is hydrogen or optionally substituted C1-6aliphatic; 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; L is a covalent bond or a bivalent C1-3straight or branched hydrocarbon chain; Rais hydrogen, halogen, optionally substituted C1-6aliphatic, 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; each R is independently hydrogen, optionally substituted C1-6aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently optionally substituted C1-6aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl.

[0032] In some embodiments, the present disclosure provides a compound of Formula I-A:or a pharmaceutically acceptable salt thereof, wherein Ring A, n, L, Z, R1, R2, Ra, Rc, Rx, and Ryare as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0033] In some embodiments, the present disclosure provides a compound of Formula I-B:or a pharmaceutically acceptable salt thereof, wherein Ring A, n, L, Z, R1, R2, Ra, Rc, and Ryare as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0034] In some embodiments, the present disclosure provides a compound of Formula I-C:or a pharmaceutically acceptable salt thereof, wherein Ring A, n, L, Z, R1, R2, Ra, Rc, and Rxare as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0035] In some embodiments, the present disclosure provides a compound of Formula I-D:or a pharmaceutically acceptable salt thereof, wherein Ring A, n, L, W, X, Y, Z, R1, R2, Ra, and Rcare as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and Rbis hydrogen, halogen, -CN, -OR, -O(CH2)mR, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, - C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, - N(R)SO2R’, -SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 1, 2, or 3.

[0036] In some embodiments, the present disclosure provides a compound of Formula I-E:or a pharmaceutically acceptable salt thereof, wherein Ring A, L, W, X, Y, Z, R1, R2, and Raare as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0037] In some embodiments, the present disclosure provides a compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein: W is CRwor N; X is CRxor N; Y is CRyor N; Z is –O- or –NRz-; Rw, Rx, and Ryare each independently hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6aliphatic, or –CN; Rzis hydrogen or optionally substituted C1-6aliphatic; R1is –N(R)2, –N(R)C(O)R’, -C(O)N(R)2, –N(R)C(O)N(R)2, or –N(R)C(O)OR; each Rcis independently selected from halogen, -CN, -CO2R, -C(O)N(R)2, -NO2, -N(R)2, -OR, - SR, or optionally substituted C1-6aliphatic; n is 0, 1, 2, or 3; R2is optionally substituted C1-6aliphatic; R3is hydrogen or optionally substituted C1-6aliphatic; Ring A 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 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionallysubstituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, optionally substituted C1-6aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently optionally substituted C1-6aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl.

[0038] In some embodiments, the present disclosure provides a compound of Formula II-A:or a pharmaceutically acceptable salt thereof, wherein Ring A, n, Z, R1, R2, Rc, Rx, and Ryare as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.

[0039] In some embodiments, the present disclosure provides a compound of Formula II-B:or a pharmaceutically acceptable salt thereof, wherein Ring A, n, Z, R1, R2, Rc, and Ryare as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.

[0040] In some embodiments, the present disclosure provides a compound of Formula II-C:or a pharmaceutically acceptable salt thereof, wherein Ring A, n, Z, R1, R2, Rc, and Rxare as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.

[0041] In some embodiments, the present disclosure provides a compound of Formula II-D:or a pharmaceutically acceptable salt thereof, wherein Ring A, W, X, Y, Z, R1, and R2are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.

[0042] In some embodiments, the present disclosure provides a compound of Formula II-E:or a pharmaceutically acceptable salt thereof, wherein n, W, X, Y, Z, R1, R2, and Rcare as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and Ring A1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring A1 is fused to Ring A2; Ring A2 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring A2 is optionally (i) further fused to Ring A3, or (ii) Ring A2 and Ring A3 combine to form a spirocycle; and Ring A3, 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.

[0043] In some embodiments, the present disclosure provides a compound of Formula II-F:or a pharmaceutically acceptable salt thereof, wherein Ring A2, n, W, X, Y, Z, R1, R2, and Rcare as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.

[0044] In some embodiments, the present disclosure provides a compound of Formula III:or a pharmaceutically acceptable salt thereof, wherein: Z is –O- or –NRz-; Rxis hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6aliphatic, or –CN; Rzis hydrogen or optionally substituted C1-6aliphatic; R2is optionally substituted C1-6aliphatic; R3is hydrogen or optionally substituted C1-6aliphatic; R4is halogen, –OR, -N(R)2, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A is optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 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; L is a covalent bond or a bivalent C1-3straight or branched hydrocarbon chain; Rais hydrogen, halogen, optionally substituted C1-6aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatomsindependently 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; and each R is independently hydrogen, optionally substituted C1-6aliphatic, 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.

[0045] In some embodiments, the present disclosure provides a compound of Formula IV:or a pharmaceutically acceptable salt thereof, wherein: Z is –O- or –NRz-; Rxis hydrogen, halogen, -OR3, or –CN; Rzis hydrogen or optionally substituted C1-6aliphatic; R2is optionally substituted C1-6aliphatic; R3is hydrogen or optionally substituted C1-6aliphatic;selected from (i) or (ii):wherein Ring A is further substituted at least once, andat least one substituent on Ring A is C1-6haloalkyl; L is a covalent bond or a bivalent C1-3straight or branched hydrocarbon chain; Rais hydrogen, halogen, optionally substituted C1-6aliphatic, 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; and R’ is C1-6aliphatic or 3- to 7-membered saturated or partially unsaturated carbocyclyl.

[0046] In some embodiments of any of Formulae I, I-D, I-E, II, II-D, II-E, and II-F, W is CRw. In some embodiments, W is N.

[0047] In some embodiments of any of Formulae I, I-D, I-E, II, II-D, II-E, and II-F, X is CRx. In some embodiments, X is N.

[0048] In some embodiments of any of Formulae I, I-D, I-E, II, II-D, II-E, and II-F, Y is CRy. In some embodiments, Y is N.

[0049] In some embodiments of any of Formulae I, I-D, I-E, II, II-D, II-E, and II-F, W is CRwor N, X is CRxor N, and Y is CRyor N, and no more than one of W, X, and Y is N. In some embodiments of any of Formulae I, I-D, I-E, II, II-D, II-E, and II-F, W is CRwor N, X is CRxor N, and Y is CRyor N, and no more than two of W, X, and Y is N.

[0050] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II- C, II-D, II-E, II-F, III, and IV, Z is –O-. In some embodiments, Z is –NRz-. In some embodiments, Z is –NH-.

[0051] In some embodiments of any of Formulae I, I-D, I-E, II, II-D, II-E, and II-F, Rwis hydrogen, halogen, or optionally substituted C1-6aliphatic. In some embodiments, Rwis hydrogen. In some embodiments, Rwis halogen. In some embodiments, Rwis fluoro. In some embodiments, Rwis chloro. In some embodiments, Rwis –OR2. In some embodiments, Rwis – OR2, wherein R2is optionally substituted C1-6aliphatic. In some embodiments, Y is N, W is CRw, and Rwis –OR2wherein R2is optionally substituted C1-6aliphatic. In some embodiments, Rwis –N(R2)2. In some embodiments, Rwis –SR2. In some embodiments, Rwis –SR2, wherein R2is optionally substituted C1-6aliphatic. In some embodiments, Y is N, W is CRw, and Rwis – SR2wherein R2is optionally substituted C1-6aliphatic. In some embodiments, Rwis optionally substituted C1-6aliphatic. In some embodiments, Rwis optionally substituted straight-chain or branched C1-6aliphatic (i.e., optionally substituted acyclic C1-6aliphatic). In some embodiments, Rwis optionally substituted C1-6alkyl. In some embodiments, Rwis optionally substituted C1-4alkyl. In some embodiments, Rwis optionally substituted C1-2alkyl. In some embodiments, Rwis optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, Rwis –CN.

[0052] In some embodiments of any of Formulae I, I-A, I-C, I-D, I-E, II, II-A, II-C, II-D, II- E, II-F, III, and IV, Rxis hydrogen, halogen, -CN, -OR2, or optionally substituted C1-6aliphatic. In some embodiments, Rxis hydrogen, halogen, -CN, -O(C1-4alkyl), or C1-4alkyl optionally substituted with one or more halogen. In some embodiments, Rxis hydrogen, halogen, -OR2, or optionally substituted C1-6aliphatic. In some embodiments, Rxis hydrogen, halogen, -O(C1-4alkyl), or C1-4alkyl optionally substituted with one or more halogen. In some embodiments, Rxis hydrogen, halogen, or optionally substituted C1-6aliphatic. In some embodiments, Rxis hydrogen, halogen, -CN, or OR2. In some embodiments, Rxis hydrogen, halogen, -CN, or O(C1-4 alkyl). In some embodiments, Rxis halogen or –CN. In some embodiments, Rxis hydrogen. In some embodiments, Rxis halogen. In some embodiments, Rxis fluoro. In some embodiments, Rxis chloro. In some embodiments, Rxis –OR2. In some embodiments, Rxis – OR2, wherein R2is optionally substituted C1-6aliphatic (e.g., optionally substituted C1-6alkyl). In some embodiments, Rxis -O(C1-4alkyl). In some embodiments, Rxis –OCH3. In some embodiments, Rxis –N(R2)2. In some embodiments, Rxis –SR2. In some embodiments, Rxis – SR2, wherein R2is optionally substituted C1-6aliphatic. In some embodiments, Rxis optionally substituted C1-6aliphatic. In some embodiments, Rxis optionally substituted straight-chain orbranched C1-6aliphatic (i.e., optionally substituted acyclic C1-6aliphatic). In some embodiments, Rxis optionally substituted C1-6alkyl (e.g., C1-6alkyl optionally substituted with one or more fluoro). In some embodiments, Rxis optionally substituted C1-4alkyl (e.g., C1-4alkyl optionally substituted with one or more fluoro). In some embodiments, Rxis optionally substituted C1-2alkyl (e.g., C1-2alkyl optionally substituted with one or more fluoro). In some embodiments, Rxis optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro, e.g., -CHF2). In some embodiments, Rxis –CN.

[0053] In some embodiments of any of Formulae I, I-A, I-B, I-D, I-E, II, II-A, II-B, II-D, II- E, II-F, Ryis hydrogen, halogen, or optionally substituted C1-6aliphatic. In some embodiments, Ryis hydrogen. In some embodiments, Ryis halogen. In some embodiments, Ryis fluoro. In some embodiments, Ryis chloro. In some embodiments, Ryis –OR2. In some embodiments, Ryis –OR2, wherein R2is optionally substituted C1-6aliphatic. In some embodiments, W is N, Y is CRy, and Ryis –OR2wherein R2is optionally substituted C1-6aliphatic. In some embodiments, Ryis –N(R2)2. In some embodiments, Ryis –SR2. In some embodiments, Ryis –SR2, wherein R2is optionally substituted C1-6aliphatic. In some embodiments, W is N, Y is CRy, and Ryis –SR2wherein R2is optionally substituted C1-6aliphatic. In some embodiments, Ryis optionally substituted C1-6aliphatic. In some embodiments, Ryis optionally substituted straight-chain or branched C1-6aliphatic (i.e., optionally substituted acyclic C1-6aliphatic). In some embodiments, Ryis optionally substituted C1-6alkyl. In some embodiments, Ryis optionally substituted C1-4alkyl. In some embodiments, Ryis optionally substituted C1-2alkyl. In some embodiments, Ryis optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, Ryis –CN.

[0054] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II- C, II-D, II-E, II-F, III, and IV, Rzis hydrogen. In some embodiments, Rzis optionally substituted C1-6aliphatic. In some embodiments, Rzis optionally substituted straight-chain or branched C1-6aliphatic (i.e., optionally substituted acyclic C1-6aliphatic). In some embodiments, Rzis optionally substituted C1-6alkyl. In some embodiments, Rzis optionally substituted C1-4alkyl. In some embodiments, Rzis unsubstituted C1-4alkyl. In some embodiments, Rzis optionally substituted C1-2alkyl. In some embodiments, Rzis unsubstituted C1-2alkyl.

[0055] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II- C, II-D, II-E, and II-F, R1is –N(R)C(O)N(R)2or –N(R)C(O)OR. In some embodiments, R1is –N(R)2, –N(R)C(O)R’, or -C(O)N(R)2. In some embodiments, R1is –N(R)C(O)R’ or - C(O)N(R)2. In some embodiments, R1is –N(R)C(O)R’, -C(O)N(R)2, –N(R)C(O)N(R)2, or – N(R)C(O)OR.

[0056] In some embodiments, when R1is –N(R)2, –N(R)C(O)R’, or -C(O)N(R)2, then n is 1, 2, or 3. In some embodiments, when n is 0, then R1is –N(R)C(O)N(R)2or –N(R)C(O)OR.

[0057] In some embodiments, R1is –N(R)2. In some embodiments, R1is –N(H)(R). In some embodiments, R1is –NH2. In some embodiments, when R1is –N(R)2, then n is 1, 2, or 3.

[0058] In some embodiments, R1is –N(R)C(O)R’. In some embodiments, R1is – N(H)C(O)R’. In some embodiments, R1is –N(R)C(O)(optionally substituted C1-6aliphatic). In some embodiments, R1is –N(H)C(O)(optionally substituted C1-6aliphatic). In some embodiments, R1is –N(R)C(O)(C1-6aliphatic). In some embodiments, R1is –N(H)C(O)(C1-6aliphatic). In some embodiments, R1is –N(R)C(O)(straight-chain or branched C1-6aliphatic). In some embodiments, R1is –N(H)C(O)(straight-chain or branched C1-6aliphatic). In some embodiments, R1is –N(R)C(O)(optionally substituted C1-6alkyl). In some embodiments, R1is – N(H)C(O)(optionally substituted C1-6alkyl). In some embodiments, R1is –N(R)C(O)R’, wherein R’ of R1is C1-6alkyl optionally substituted with halogen, -OH, –O(C1-6alkyl), - NH(CH2)2O(C1-6alkyl), -NH(C1-4haloalkyl), or an optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1is –N(H)C(O)R’, wherein R’ of R1is C1-6alkyl optionally substituted with halogen, -OH, –O(C1-6alkyl), -NH(CH2)2O(C1-6alkyl), -NH(C1-4haloalkyl), or an optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1is –N(R)C(O)(C1-6alkyl). In some embodiments, R1is –N(H)C(O)(C1-6alkyl). In some embodiments, R1is –N(R)C(O)(optionally substituted C1-4alkyl). In some embodiments, R1is –N(H)C(O)(optionally substituted C1-4alkyl). In some embodiments, R1is – N(R)C(O)R’, wherein R’ of R1is C1-4alkyl optionally substituted with halogen, -OH, –O(C1-6alkyl), -NH(CH2)2O(C1-6alkyl), -NH(C1-4haloalkyl), or an optionally substituted 3- to 7- membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1is –N(H)C(O)R’, wherein R’ of R1is C1-4alkyl optionally substituted with halogen, -OH, –O(C1-6alkyl), -NH(CH2)2O(C1-6alkyl), - NH(C1-4haloalkyl), or an optionally substituted 3- to 7-membered saturated monocyclicheterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1is –N(R)C(O)(C1-4alkyl). In some embodiments, R1is – N(H)C(O)(C1-4alkyl). In some embodiments, R1is –N(R)C(O)(C1-2alkyl). In some embodiments, R1is –N(H)C(O)(C1-2alkyl). In some embodiments, R1is –N(R)C(O)CH3. In some embodiments, R1is –N(H)C(O)CH3. In some embodiments, R1is –N(R)C(O)(optionally substituted C3-7cycloalkyl). In some embodiments, R1is –N(H)C(O)(optionally substituted C3-7cycloalkyl). In some embodiments, R1is –N(R)C(O)(optionally substituted cyclopropyl). In some embodiments, R1is –N(H)C(O)(optionally substituted cyclopropyl). In some embodiments, when R1is –N(R)C(O)R’, then n is 1, 2, or 3.

[0059] In some embodiments, R1is -C(O)N(R)2. In some embodiments, R1is – C(O)N(R)(C1-6aliphatic). In some embodiments, R1is –C(O)N(H)(C1-6aliphatic). In some embodiments, R1is –C(O)N(R)(straight-chain or branched C1-6aliphatic). In some embodiments, R1is –C(O)N(H)(straight-chain or branched C1-6aliphatic). In some embodiments, R1is –C(O)N(R)(C1-6alkyl). In some embodiments, R1is –C(O)N(H)(C1-6alkyl). In some embodiments, R1is –C(O)N(R)(C1-4alkyl). In some embodiments, R1is – C(O)N(H)(C1-4alkyl). In some embodiments, R1is –C(O)N(R)(C1-2alkyl). In some embodiments, R1is –C(O)N(H)( C1-2alkyl). In some embodiments, R1is –C(O)N(R)CH3. In some embodiments, R1is –C(O)N(H)(R). In some embodiments, when R1is -C(O)N(R)2, then n is 1, 2, or 3.

[0060] In some embodiments, R1is –N(R)C(O)N(R)2. In some embodiments, R1is – N(H)C(O)N(R)2. In some embodiments, R1is –N(H)C(O)N(optionally substituted C1-6aliphatic)2. In some embodiments, R1is –N(H)C(O)N(optionally substituted C1-6alkyl)2. In some embodiments, R1is –N(H)C(O)N(optionally substituted C1-4alkyl)2. In some embodiments, R1is –N(H)C(O)N(optionally substituted C1-2alkyl)2. In some embodiments, R1is –N(R)C(O)NH(R). In some embodiments, R1is –N(H)C(O)NH(R). In some embodiments, R1is –N(H)C(O)NH(optionally substituted C1-6aliphatic). In some embodiments, R1is – N(H)C(O)NH(optionally substituted C1-6alkyl). In some embodiments, R1is – N(H)C(O)NH(optionally substituted C1-4alkyl). In some embodiments, R1is – N(H)C(O)NH(optionally substituted C1-2alkyl). In some embodiments, R1is – N(H)C(O)NH(optionally substituted C3-7cycloaliphatic). In some embodiments, R1is – N(H)C(O)NH(optionally substituted C3-7cycloalkyl). In some embodiments, R1is –N(H)C(O)NH(optionally substituted cyclopropyl). In some embodiments, R1is – N(H)C(O)NH(optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R1is –N(H)C(O)NH(optionally substituted 4- to 6- membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R1is –N(H)C(O)NH(optionally substituted oxetanyl). In some embodiments, R1is –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, R1is –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, R1is –N(H)C(O)N(R)2, wherein the two R groups attached to the same nitrogen are taken together to form a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, C1-6alkyl, -OH, and –O(C1-6alkyl). In some embodiments, R1is –N(H)C(O)N(R)2, wherein the two R groups attached to the same nitrogen are taken together to form an optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1is –N(H)C(O)N(R)2, wherein the two R groups attached to the same nitrogen are taken together to form a 4- to 6- membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, C1-6alkyl, -OH, and –O(C1-6alkyl). In some embodiments, R1is selected from:In some embodiments, R1is notIn some embodiments, when X is CH, then R1is not

[0061] In some embodiments, R1is –N(R)C(O)OR. In some embodiments, R1is – N(H)C(O)OR. In some embodiments, R1is –N(H)C(O)OR, wherein R of R1is optionally substituted C1-6aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1is –N(H)C(O)OR, wherein R of R1is optionally substituted C1-6alkyl or optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1is –N(H)C(O)OR, wherein R of R1is C1-6alkyl optionally substituted with one or more –OH, –O(C1-6alkyl), -N(C1-6alkyl)2, or 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1is –N(H)C(O)OR, wherein R of R1is 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C1-6alkyl. In some embodiments, R1is selected from:

[0062] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II- C, II-D, II-E, II-F, III, and IV, R2is optionally substituted straight-chain or branched C1-6aliphatic (i.e., optionally substituted acyclic C1-6aliphatic). In some embodiments, R2is optionally substituted C1-6alkyl. In some embodiments, R2is optionally substituted C1-4alkyl.In some embodiments, R2is unsubstituted C1-4alkyl. In some embodiments, R2is optionally substituted C1-2alkyl. In some embodiments, R2is unsubstituted C1-2alkyl. In some embodiments, R2is methyl.

[0063] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II- C, II-D, II-E, II-F, III, and IV, each R3is independently hydrogen or optionally substituted C1-4aliphatic. In some embodiments, each R3is independently hydrogen or optionally substituted C1-2 aliphatic. In some embodiments, each R3is hydrogen. In some embodiments, each R3is independently optionally substituted C1-6aliphatic. In some embodiments, each R3is independently optionally substituted straight-chain or branched C1-6aliphatic (i.e., optionally substituted acyclic C1-6aliphatic). In some embodiments, each R3is independently optionally substituted C1-4aliphatic. In some embodiments, each R3is independently optionally substituted straight-chain or branched C1-4aliphatic (i.e., optionally substituted acyclic C1-4aliphatic). In some embodiments, each R3is independently optionally substituted C1-2aliphatic. In some embodiments, each R3is independently hydrogen or C1-6alkyl. In some embodiments, each R3is independently hydrogen or C1-4alkyl. In some embodiments, each R3is independently hydrogen or C1-2alkyl.

[0064] In some embodiments of Formula III, R4is halogen. In some embodiments, R4is fluoro. In some embodiments, R4is chloro. In some embodiments, R4is –OR. In some embodiments, R4is –OH or –O(optionally substituted C1-6alkyl). In some embodiments, R4is – OH or –O(C1-6alkyl). In some embodiments, R4is –OH or –OCH3. In some embodiments, R4is –N(R)2. In some embodiments, R4is –NH(R). In some embodiments, R4is –NH(optionally substituted C1-6alkyl). In some embodiments, R4is –NH(R), wherein R of R4is C1-6alkyl optionally substituted with one or more halogen or –O(C1-6alkyl). In some embodiments, R4is – NH(CH2)2F or –NH(CH2)2OCH3. In some embodiments, R4is 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, R4is optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4is 4- to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C1-6alkyl. Insome embodiments, R4is tetrahydropyranyl or morpholinyl optionally substituted with one or more C1-6alkyl.

[0065] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, II, II-A, II-B, II-C, II- E, and II-F, each Rcis independently selected from halogen, -CN, -CO2R, -C(O)N(R)2, -NO2, - N(R)2, -OR, -SR, or optionally substituted C1-6alkyl, wherein each R of Rcis independently hydrogen or C1-6alkyl. In some embodiments, Rcis halogen (e.g., fluoro). In some embodiments, Rcis -CN, -CO2R, -C(O)N(R)2, or -NO2. In some embodiments, Rcis -N(R)2, - OR, or –SR. In some embodiments, Rcis optionally substituted C1-6aliphatic (e.g., C1-6alkyl).

[0066] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, II, II-A, II-B, II-C, II- E, and II-F, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0067] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, and III, 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. 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. 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 or optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0068] In some embodiments, Ring A is optionally substituted phenyl. In some embodiments, Ring A is not optionally substituted phenyl.

[0069] In some embodiments, Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 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 pyrazolyl. In some embodiments, Ring A is optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted pyridonyl.

[0070] 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]pyridyl or dihydro-4H-pyrazolo[5,1- c][1,4]oxazinyl. In some embodiments, Ring A is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0071] In some embodiments, Ring A is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A is not optionally substituted 6-membered saturated or partiallyunsaturated monocyclic carbocyclyl. In some embodiments, Ring A is optionally substituted 7- membered saturated or partially unsaturated monocyclic carbocyclyl.

[0072] In some embodiments, Ring A is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 3- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 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.

[0073] 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.

[0074] In some embodiments, Ring A isor

[0075] In some embodiments of any of Formulae II, II-A, II-B, II-C, II-D, II-E, and II-F, Ring A is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 10- to 16- membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 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 or optionally substituted 10- to 16-membered polycyclic heteroaryl having 1- 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or optionally substituted 10- to 16- membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0076] In some embodiments, each ring in a bicyclic or polycyclic ring system of Ring A contains at least one heteroatom. In some embodiments, one and only one ring of a bicyclic or polycyclic ring system of Ring A contains no heteroatoms.

[0077] In some embodiments, each ring in a bicyclic or polycyclic ring system of Ring A is aromatic. In some embodiments, one and only one ring of a bicyclic or polycyclic ring system of Ring A is aromatic. In some embodiments, no ring in a bicyclic or polycyclic ring system of Ring A is aromatic.

[0078] In some embodiments, Ring A is optionally substituted 9- to 16-membered bicyclic or tricyclic aryl. In some embodiments, Ring A is optionally substituted 9- to 10-memberedbicyclic aryl. In some embodiments, Ring A is optionally substituted 9-membered bicyclic aryl (e.g., a 5-membered carbocycle fused to a phenyl ring). In some embodiments, Ring A is not substituted indanyl (e.g., indanyl substituted with one or more halogens). In some embodiments, Ring A is optionally substituted 10-membered bicyclic aryl (e.g., naphthyl or a 6-membered carbocycle fused to a phenyl ring).

[0079] In some embodiments, Ring A is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more oxo, halogen, or C1-6alkyl. In some embodiments, Ring A is optionally substituted 8-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted dihydro-1H-imidazo[1,2- b]pyrazolyl, In some embodiments, Ring A is optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more oxo, halogen, or C1-6alkyl. In some embodiments, Ring A is optionally substituted tetrahydropyrazolo[1,5-a]pyridyl, dihydropyrazolo[1,5-a]pyrazin-4(5H)-onyl, tetrahydropyrazolo[1,5-a]pyrimidinyl, or dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl. In some embodiments, Ring A is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C1-6alkyl. In some embodiments, Ring A is optionally substituted tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepinyl, tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepinyl, tetrahydropyrazolo[1,5-d][1,4]oxazepinyl, or tetrahydro-4H-pyrazolo[1,5-a]azepinyl.

[0080] In some embodiments, Ring A is optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 11-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted dihydrospiro[cyclobutane-1,4’-pyrrolo[1,2-b]pyrazolyl], dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyridyl], dihydro-5'H- spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine], or dihydro-4'H-spiro[cyclopropane-1,5'- pyrazolo[1,5-a]pyrimidinyl].

[0081] In some embodiments, Ring A is optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 7- to 10-membered fused bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 7-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 8-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 9-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionally substituted 10-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0082] In some embodiments, Ring A is optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0083] In some embodiments, Ring A is selected from:

[0084] In some embodiments, Ring A is, wherein Ring A1 and Ring A2 are defined as in Formula II-E and described in classes and subclasses herein, both singly and in combination; and Ring A1 is fused to Ring A2; and Ring A2 is optionally (i) further fused to Ring A3 or (ii) Ring A2 and Ring A3 combine to form a spirocycle.

[0085] In some embodiments, Ring A1 is an optionally substituted ring selected from 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0086] In some embodiments, Ring A1 is optionally substituted phenyl. In some embodiments, when Ring A1 is phenyl, Ring A2 contains at least one heteroatom.

[0087] In some embodiments, Ring A1 is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A1 is unsubstituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A1 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A1 is optionally substituted pyrazole. In some embodiments, Ring A1 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0088] In some embodiments, Ring A1 is optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, when Ring A1 is optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, Ring A2 contains at least one heteroatom. In some embodiments, when Ring A2 is not aromatic, Ring A1 is optionally substituted 5- to 7-membered saturated monocyclic carbocyclyl. In some embodiments, Ring A1 is optionally substituted 5- to 7-membered partially saturated monocyclic carbocyclyl.

[0089] In some embodiments, Ring A1 is optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, when Ring A2 is not aromatic, Ring A1 is optionally substituted 5- to 7-membered saturated monocyclic heterocyclyl having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A1 is optionally substituted 5- to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0090] In some embodiments, optionally substituted Ring A1 fused to Ring A2 is

[0091] In some embodiments, Ring A2 is an optionally substituted ring selected from 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0092] In some embodiments, Ring A2 is optionally substituted phenyl. In some embodiments, when Ring A2 is phenyl, Ring A1 contains at least one heteroatom.

[0093] In some embodiments, Ring A2 is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A2 is optionally substituted 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A2 is optionally substituted 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0094] In some embodiments, Ring A2 is optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, when Ring A2 is optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, Ring A1 contains at least one heteroatom. In some embodiments, when Ring A1 is not aromatic, Ring A2 is optionally substituted 5- to 7-membered saturated monocyclic carbocyclyl. In some embodiments, Ring A2 is optionally substituted 5- to 7-membered partially saturated monocyclic carbocyclyl.

[0095] In some embodiments, Ring A2 is optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, when Ring A1 (and Ring A3, if present) is not aromatic, Ring A2 is optionally substituted 5- to 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen,and sulfur. In some embodiments, Ring A2 is optionally substituted 5- to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A2 is optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A2 is 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C1-6alkyl. In some embodiments, Ring A2 is optionally substituted pyrrolidine or imidazolidine. In some embodiments, Ring A2 is optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A2 is 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more oxo, halogen, and C1-6alkyl. In some embodiments, Ring A2 is optionally substituted piperidine, hexahydropyrimidine, morpholine, or piperazinone. In some embodiments, Ring A2 is optionally substituted 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A2 is 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C1-6alkyl. In some embodiments, Ring A2 is azepane, diazepane, or oxazepane.

[0096] In some embodiments, optionally substituted Ring A2 fused to Ring A1 is selected from the group consisting of:

[0097] In some embodiments, Ring A1 is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring A2 is an optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, Ring A1 is an optionally substituted 5- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring A2 is an optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A1 is an optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring A2 is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A1 is an optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring A2 is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A1 is an optionally substituted 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring A2 is an optionally substituted 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0098] In some embodiments, Ring A2 is further fused to Ring A3. In some embodiments, Ring A2 and Ring A3 combine to form a spirocycle. In some embodiments, when Ring A2 and Ring A3 combine to form a spirocycle, Ring A3 is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl or optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0099] In some embodiments, Ring A3, when present, is optionally substituted phenyl. In some embodiments, Ring A3, when present, is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A3, when present, is optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring A3, when not fused to an aromatic Ring A2, is 3- to 7-membered saturated monocyclic carbocyclyl. In some embodiments, Ring A3 is 3- to 7-membered partially saturated monocyclic carbocyclyl. In some embodiments, Ring A3 is optionally substituted C3-C7 cycloalkyl (e.g.,cyclopropyl or cyclobutyl). In some embodiments, Ring A3 is 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A3, when not fused to an aromatic Ring A2, is 3- to 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A3 is 3- to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0100] In some embodiments, optionally substituted Ring A2 fused to Ring A1 and combined to form a spirocycle with Ring A3 is selected from:

[0101] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II- C, II-D, II-E, II-F, III, and IV, Ring A is optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, R ^, -CN, -OR ^, -O(CH2)1-4Ro, -SR ^, -N(R ^)2, -NO2, -C(O)R ^, -C(O)OR°, -C(O)NR ^2, -OC(O)R ^, -OC(O)NR ^2, – OC(O)OR°, -OS(O)2R ^, -OS(O)2NR ^2, -N(R ^)C(O)R ^, -N(R ^)S(O)2R ^, -S(O)2R ^, -SO2NR ^2, and -S(O)2OR ^, and (ii) optionally substituted on a substitutable nitrogen atom with one or more groups selected from –R†, –NR†2, –C(O)R†, –C(O)OR†, -S(O)2R†, and -S(O)2NR†2. In some embodiments, Ring A is (i) optionally substituted on a substitutable carbon atom with one or more groups independently selected from oxo, halogen, R ^, -OR ^, and -O(CH2)1-4Ro, 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 oxo, halogen, and R ^, and (ii) optionally substituted on a substitutable nitrogen atom with one or more groups selected from –R†.

[0102] In some embodiments, Ring A is optionally substituted with one or more Rb(e.g., in addition to being substituted with –L-Ra, when present), wherein Rbis as defined in Formula I-D above and described in classes and subclasses herein. In some embodiments, Ring A is substituted with zero, one, two, three, four, or five Rb, as valency allows.

[0103] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, III, and IV, L is a covalent bond. In some embodiments, L is a bivalent C1-3 straight or branched hydrocarbonchain. In some embodiments, L is a bivalent C1-2straight 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 –C(CH3)2-. In some embodiments, L is a covalent bond or –CH2-.

[0104] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, III, and IV, Rais halogen, optionally substituted C1-6aliphatic, 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, Rais optionally substituted C1-6aliphatic, 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, Rais hydrogen, halogen, optionally substituted C1-6aliphatic, 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.

[0105] In some embodiments, Rais hydrogen. In some embodiments, Rais not hydrogen.

[0106] In some embodiments, Rais halogen. In some embodiments, Rais fluoro, chloro, bromo, or iodo. In some embodiments, Rais fluoro. In some embodiments, Rais chloro.

[0107] In some embodiments, Rais optionally substituted C1-6aliphatic. In some embodiments, Rais optionally substituted straight-chain or branched C1-6aliphatic (i.e., optionally substituted acyclic C1-6aliphatic). In some embodiments, Rais C1-6aliphatic optionally substituted with one or more halogen, -N(C1-6alkyl)2, –OH, or -O(optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl). In some embodiments, Rais optionally substituted C1-6alkyl. In some embodiments, Rais C1-6alkyl optionally substituted with one or more halogen, -N(C1-6alkyl)2, –OH, or -O(optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl). In some embodiments, Rais optionally substituted C1-4alkyl. In some embodiments, Rais C1-4alkyl optionally substituted with one or more halogen, -N(C1-6alkyl)2, –OH, or -O(optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl). In some embodiments,

[0108] In some embodiments, Rais optionally substituted phenyl.

[0109] In some embodiments, Rais optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0110] In some embodiments, Rais optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Rais optionally substituted 3- to 6-membered saturated monocyclic carbocyclyl. In some embodiments, Rais optionally substituted 3-membered saturated monocyclic carbocyclyl. In some embodiments, Rais optionally substituted 4-membered saturated monocyclic carbocyclyl. In some embodiments, Rais optionally substituted 5-membered saturated monocyclic carbocyclyl. In some embodiments, Rais optionally substituted 6-membered saturated monocyclic carbocyclyl. In some embodiments, Rais optionally substituted 7-membered saturated monocyclic carbocyclyl.

[0111] In some embodiments, Rais 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, Rais optionally substituted 4- to 7- membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais optionally substituted 3- membered saturated monocyclic heterocyclyl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais optionally substituted 4-memberedsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais optionally substituted 5-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais optionally substituted pyrrolidinyl or tetrahydrofuranyl. In some embodiments, Rais optionally substituted 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais optionally substituted 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0112] In some embodiments, Rais 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, Rais optionally substituted 7- to 10- membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais optionally substituted 7- to 9-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais optionally substituted 7-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais optionally substituted 2-oxaspiro[3.3]heptanyl. In some embodiments, Rais optionally substituted 8-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais optionally substituted 9-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais optionally substituted 7-oxaspiro[3.5]nonanyl. In some embodiments, Rais optionally substituted 10-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0113] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, III, and IV, is –Ra(i.e., L is a covalent bond). In some embodiments, is –(C1-alkylene)-Ra3(i.e., L is a C1-3straight or branched hydrocarbon chain). In some embodiments,is –(C1-2 alkylene)-Ra(i.e., L is a C1-2straight or branched hydrocarbon chain). In some embodiments, is –CH2-Ra(i.e., L is a C1 hydrocarbon chain). In some embodiments, is –CH2CH2-Ra(i.e., L is a C2straight hydrocarbon chain). In some embodiments,is – CH2CH2CH2-Ra(i.e., L is a C3straight hydrocarbon chain). In some embodiments,is – C(CH3)2-Ra(i.e., L is a C3 branched hydrocarbon chain).

[0114] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II- C, II-D, II-E, II-F, III, and IV, up to five occurrences of Rbmay be present, as allowed by valency rules, and is each independently halogen, -CN, -OR, -O(CH2)mR, -SR, -N(R)2, -NO2, - C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, - N(R)C(O)R’, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 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 Rbis independently halogen, optionally substituted C1-6aliphatic, -OR, or -O(CH2)mR. In some embodiments, each occurrence of Rbis independently halogen, optionally substituted C1-6alkyl, -OR, or –OCH2R, wherein R of Rbis optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each occurrence of Rbis halogen or C1-6alkyl optionally substituted with one or more halogen.

[0115] In some embodiments, one occurrence of Rbis present. In some embodiments, two occurrences of Rbare present. In some embodiments, three occurrences of Rbare present. In some embodiments, four occurrences of Rbare present. In some embodiments, five occurrences of Rbare present. In some embodiments, Rbis not present. In some embodiments, 1-4 occurrences of Rbare present. In some embodiments, one or two occurrences of Rbare present.

[0116] In some embodiments, Rbis hydrogen.

[0117] In some embodiments, Rbis halogen. In some embodiments, Rbis fluoro, chloro, bromo, or iodo. In some embodiments, Rbis fluoro. In some embodiments, Rbis chloro.

[0118] In some embodiments, Rbis -CN, -OR, -O(CH2)mR, -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’. In some embodiments, Rbis –CN. In some embodiments, Rbis -N(R)2. In some embodiments, Rbis -C(O)N(R)2.

[0119] In some embodiments, Rbis –OR. In some embodiments, Rbis -OR, wherein R is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis –OR, wherein R is optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis –OR, wherein R is 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted with one or more C1-6alkyl (e.g., methyl). In some embodiments, Rbis –OR, wherein R is optionally substituted azetidinyl or pyrrolidinyl. In some embodiments, Rbis –OR, wherein R is azetidinyl or pyrrolidinyl optionally substituted with one or more C1-6alkyl (e.g., methyl). In some embodiments, Rbis.

[0120] In some embodiments, Rbis -O(CH2)mR. In some embodiments, Rbis -OCH2R. In some embodiments, Rbis -O(CH2)mR, wherein R is optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis -O(CH2)mR, wherein R is optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis -O(CH2)mR, wherein R is 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted with one or more C1-6alkyl (e.g., methyl). In some embodiments, Rbis -O(CH2)mR, wherein R is optionally substituted pyrrolidinyl. In some embodiments, Rbis -O(CH2)mR, wherein R is pyrrolidinyl optionally substituted with one or more C1-6alkyl (e.g., methyl). In some embodiments,

[0121] In some embodiments, Rbis optionally substituted C1-6aliphatic. In some embodiments, Rbis optionally substituted straight-chain or branched C1-6aliphatic (i.e., optionally substituted acyclic C1-6aliphatic). In some embodiments, Rbis optionally substitutedC1-6alkyl. In some embodiments, Rbis optionally substituted C1-4alkyl. In some embodiments, Rbis C1-4alkyl optionally substituted with one or more of halogen. In some embodiments, Rbis –CH3, –CF3, or –C(CH3)3.

[0122] In some embodiments, Rbis optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Rbis optionally substituted C3-C6cycloalkyl.

[0123] In some embodiments, Rbis optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis optionally substituted 3- to 6- membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0124] In some embodiments, Rbis optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0125] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II- C, II-D, II-E, II-F, III, and IV, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0126] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, and III, optionallyIn some embodiments, optionally substitutedis selected from the group consisting of:

[0127] In some embodiments of Formula IV,selected from the groupsome embodiments,is selected from the group consisting of:In some embodiments, whenthen –L-Rais C1-6haloalkyl. In some embodiments, orwherein Ring A is further substituted at least once, and at least one substituenton Ring A is C1-6haloalkyl (e.g., -CF3). In some embodiments, whenisthen Ring A is further substituted with Rbas defined and described in classes and subclasses herein, and at least one substituent on Ring A (i.e., either Rbor –L-Ra) is C1-6haloalkyl (e.g., -CF3). In some embodiments,is selected from the group consisting of:

[0128] In some embodiments of any of Formulae II, II-A, II-B, II-C, II-D, II-E, and II-F, optionally substitutedIn some embodiments, optionally substituted. In some embodiments, optionally substitutedis selected from the group consisting of:, , , , , ,

[0129] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II- C, II-D, II-E, II-F, III, and IV, each R is independently hydrogen, optionally substituted C1-6aliphatic, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently hydrogen or optionally substituted C1-6aliphatic. In some embodiments, each R is independently hydrogen, optionally substituted C1-6aliphatic, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur. In some embodiments, each R is independently optionally substituted C1-6aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently is hydrogen, optionally substituted C1-6alkyl or optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0130] In some embodiments, R is hydrogen.

[0131] In some embodiments, R is optionally substituted C1-6aliphatic. In some embodiments, R is optionally substituted straight-chain or branched C1-6aliphatic (i.e., optionally substituted acyclic C1-6aliphatic). In some embodiments, R is optionally substituted C1-6alkyl. In some embodiments, R is C1-6alkyl optionally substituted with one or more –OH, –O(C1-6alkyl), -N(C1-6alkyl)2, or 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted C1-4alkyl. In some embodiments, R is optionally substituted C1-2alkyl.

[0132] In some embodiments, R is optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R is optionally substituted C3-7cycloalkyl.

[0133] 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, R is optionally substituted 4- to 6- membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is 4- to 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more C1-6alkyl. In some embodiments, R is optionally substituted oxetanyl.

[0134] In some embodiments, 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. In some embodiments, two R groups attached to the same nitrogen are taken together to form a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen,and sulfur and optionally substituted with one or more halogen, C1-6alkyl, -OH, or –O(C1-6alkyl). In some embodiments, two R groups attached to the same nitrogen are taken together to form an optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups attached to the same nitrogen are taken together to form a 4- to 6- membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more halogen, C1-6alkyl, -OH, and –O(C1-6alkyl).

[0135] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II- C, II-D, II-E, II-F, III, and IV, each R’ is independently optionally substituted C1-6alkyl or optionally substituted C3-7cycloalkyl. In some embodiments, R’ is optionally substituted C1-6aliphatic. In some embodiments, R’ is optionally substituted straight-chain or branched C1-6aliphatic (i.e., optionally substituted acyclic C1-6aliphatic). In some embodiments, R’ is optionally substituted C1-6alkyl. In some embodiments, R’ is C1-6alkyl optionally substituted with halogen, -OH, –O(C1-6alkyl), -NH(CH2)2O(C1-6alkyl), -NH(C1-4haloalkyl), or an optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R’ is optionally substituted C1-4alkyl. In some embodiments, R’ is optionally substituted C1-2alkyl. In some embodiments, R’ is methyl. In some embodiments, R’ is optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R’ is optionally substituted C3-7cycloalkyl. In some embodiments, R’ is optionally substituted cyclopropyl. In some embodiments, R’ is cyclopropyl.

[0136] In some embodiments of any of Formulae described herein, the compound is not:.

[0137] In some embodiments, the compound is not:

[0138] In some embodiments, the compound is not:

[0139] In some embodiments, the compound is not:

[0140] In some embodiments of any of Formulae I, I-A, I-B, I-C, I-D, and I-E, when R1isand Y is N, then Rxis not hydrogen. In some embodiments, when R1is , then Ring A is not pyrazolyl. In some embodiments, when Ring A ispyrazolyl, then R1is not –N(R)C(O)N(R)2. In some embodiments, when Ring A is pyrazolyl and Y is N, then Rxis not hydrogen.

[0141] In some embodiments of any of Formulae II, II-A, II-B, II-C, II-D, II-E, and II-F, Ring A is not. In some embodiments, when Ring, then R1is not –N(H)C(O)CH3. In some embodiments, when Ring, then X is not N and Rxis not –CN.

[0142] In some embodiments of Formula III, R4is not tetrahydropyranyl. In some embodiments, when R4is tetrahydropyranyl and Y is N, then Rxis not chloro.

[0143] In some embodiments of Formula IV, when Y is N and Rxis not hydrogen, then –L-

[0144] In some embodiments, the present disclosure provides compounds selected from Table 1:or a pharmaceutically acceptable salt thereof.

[0145] 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, SET2-pSTAT5 Cellular Assay, hPBMC-GMCSF-STAT5 Assay, hPBMC-IL12-STAT4 Assay, or hPBMC-IL2-STAT5 Assay described herein) and / or have one or more other characteristics that make them more suitable for drug development, such as better selectivity over other kinases and / or better ADME (absorption, distribution, metabolism, and excretion) properties including but not limited to better permeability, cytotoxicity, hepatocyte stability, solubility, and / or plasma protein binding profiles (e.g., based on assays described in the ensuing examples), than other known compounds. In some embodiments, provided compounds display certain desirable characteristics in one or more assays described herein, e.g., compared to other known compounds. Without wishing to be bound by any particular theory, the present disclosure encompasses the recognition that 6- heteroaryloxy benzimidazoles and azabenzimidazoles (e.g., compounds described herein) display certain more desirable characteristics (such as better properties in one or more assays described herein) than corresponding 5-heteroaryloxy benzimidazoles and azabenzimidazoles.

[0146] 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).

[0147] 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 I, I-A, I-B, I-C, I-D, and I-E and compound species of such formulas disclosed herein; reference to a compound of Formula II is intended to also include Formulae II, II-A, II-B, II-C, II-D, II-E, andII-F and compound species of such formulas disclosed herein; reference to a compound of Formula III is intended to also include compound species of such formulas disclosed herein; and reference to a compound of Formula IV is intended to also include compound species of such formulas disclosed herein. Preparing Provided Compounds

[0148] Provided compounds may generally be made by the processes described in the ensuing schemes and examples. In some embodiments, provided compounds are prepared according to the following Scheme:wherein PG is a suitable protecting group (e.g., p-methoxybenzyl, acetyl, methyl carbamate, etc.), and Ring A, n, L, W, X, Y, R, R2, Ra, and Rcare 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 coupling agent and / or a suitable base (e.g., potassium tert-butoxide). In some embodiments, a process for preparing intermediate A.3 further comprises a deprotection step and / or a functionalization step (e.g., cyanation) under suitable conditions. In some embodiments, intermediate A.4 is prepared by a process comprising contacting intermediate A.3 with phenyl chloroformate in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound A-1 is prepared by a process comprising contacting intermediate A.4 with RO-H, optionally in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound A-1 is prepared by aprocess comprising contacting intermediate A.3 with RO-C(O)-Cl in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound A-2 is prepared by a process comprising contacting intermediate A.4 with R2N-H, optionally in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound A-2 is prepared by a process comprising contacting intermediate A.3 with R2N-C(O)-Cl in the presence of a suitable base (e.g., triethylamine).

[0149] In some embodiments, provided compounds are prepared according to the following Scheme:wherein PG is a suitable protecting group (e.g., p-methoxybenzyl, acetyl, methyl carbamate, etc.), and Ring A, n, W, X, Y, R, R2, and Rcare as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. Accordingly, in some embodiments, intermediate A.6 is prepared by a process comprising contacting intermediate A.5 with intermediate A.2 in the presence of a suitable coupling agent and / or a suitable base (e.g., potassium tert-butoxide). In some embodiments, a process for preparing intermediate A.6 further comprises a deprotection step and / or a functionalization step (e.g., cyanation) under suitable conditions. In some embodiments, intermediate A.7 is prepared by a process comprising contacting intermediate A.6 with phenyl chloroformate in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound A-3 is prepared by a process comprising contacting intermediate A.7 with RO-H, optionally in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound A-3 is prepared by a process comprising contacting intermediate A.6 with RO-C(O)-Cl in the presence of a suitable base (e.g.,triethylamine). In some embodiments, compound A-4 is prepared by a process comprising contacting intermediate A.7 with R2N-H, optionally in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound A-4 is prepared by a process comprising contacting intermediate A.6 with R2N-C(O)-Cl in the presence of a suitable base (e.g., triethylamine).

[0150] In some embodiments, provided compounds are prepared according to the following Scheme:wherein LG is a suitable leaving group (e.g., halogen, e.g., chloro or bromo), and Ring A, n, L, W, X, Y, Z, R1, R2, Ra, and Rcare as defined above for Formulae I and / or II and described in classes and subclasses herein, both singly and in combination. Accordingly, in some embodiments, compound B-1 is prepared by a process comprising contacting intermediate B.1 with intermediate B.2 in the presence of a suitable base (e.g., K3PO4, K2CO3, or Cs2CO3), and optionally in the presence of a suitable metal complex (e.g., a palladium complex such as tris(dibenzylideneacetone)dipalladium(0)) and / or a suitable ligand (e.g., 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene). In some embodiments, compound B-2 is prepared by a process comprising contacting intermediate B.1 with intermediate B.3 in the presence of a suitable base (e.g., K3PO4, K2CO3, or Cs2CO3), and optionally in the presence of a suitable metal complex (e.g., a palladium complex such as tris(dibenzylideneacetone)dipalladium(0)) and / or a suitable ligand (e.g., 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene). In some embodiments, a process for preparing compound B-1 or B-2 further comprises a deprotection step under suitable conditions. In someembodiments, a process for preparing compound B-1 or B-2 further comprises a funtionalization step (e.g., cyanation) under suitable conditions.

[0151] In some embodiments, provided compounds are prepared according to the following Scheme:wherein Ring A, n, L, W, X, Y, R1, R2, Ra, and Rcare as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. Accordingly, in some embodiments, compound C-1 is prepared by a process comprising contacting intermediate C.1 with intermediate C.2 in the presence of a suitable coupling agent and / or a suitable base (e.g., potassium tert-butoxide). In some embodiments, a process for preparing compound C-1 further comprises a deprotection and / or functionalization (e.g., cyanation) step under suitable conditions.

[0152] In some embodiments, provided compounds are prepared according to the following Scheme:wherein Ring A, n, W, X, Y, R1, R2, and Rcare as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. Accordingly, in some embodiments, compound C-2 is prepared by a process comprising contacting intermediate C.3 with intermediate C.2 in the presence of a suitable coupling agent and / or a suitable base (e.g., potassium tert-butoxide). In some embodiments, a process for preparing compound C-2 further comprises a deprotection and / or functionalization (e.g., cyanation) step under suitable conditions.Compositions

[0153] 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, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV).

[0154] 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, I-A, I-B, I-C, I-D, I-E, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV) and further comprises a pharmaceutically acceptable carrier. 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.

[0155] 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.

[0156] 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

[0157] 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.

[0158] 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.

[0159] 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.

[0160] JAK (e.g., JAK2) has been implicated in various diseases, disorders, and conditions, such as myeloproliferative neoplasms (Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev):82), atopic dermatitis (Rodrigues, M. A. and Torres, T. J. Derm. Treat.2019, 31(1), 33-40) and acute respiratory syndrome, hyperinflammation, and / or cytokine storm syndrome (The Lancet. 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.

[0161] In some embodiments, the present disclosure provides methods of treating cancer, comprising administering a provided compound or composition to a subject in need thereof. Insome embodiments, the present disclosure provides methods of treating proliferative diseases, comprising administering a provided compound or composition to a subject in need thereof.

[0162] 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.

[0163] 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.

[0164] 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 beadministered 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.

[0165] 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 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), http: / / 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). Exemplary Embodiments

[0166] The following numbered embodiments, while non-limiting, are exemplary of certain aspects of the present disclosure: 1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: W is CRwor N;X is CRxor N; Y is CRyor N; Z is –O- or –NRz-; Rw, Rx, and Ryare each independently hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6aliphatic, or –CN; Rzis hydrogen or optionally substituted C1-6aliphatic; R1is –N(R)2, –N(R)C(O)R’, -C(O)N(R)2, –N(R)C(O)N(R)2, or –N(R)C(O)OR; each Rcis independently selected from halogen, -CN, -CO2R, -C(O)N(R)2, -NO2, -N(R)2, -OR, - SR, or optionally substituted C1-6aliphatic; n is 0, 1, 2, or 3, provided that when R1is –N(R)2, –N(R)C(O)R’ or -C(O)N(R)2, then n is 1, 2, or 3; R2is optionally substituted C1-6aliphatic; R3is hydrogen or optionally substituted C1-6aliphatic; 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; L is a covalent bond or a bivalent C1-3straight or branched hydrocarbon chain; Rais hydrogen, halogen, optionally substituted C1-6aliphatic, 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;each R is independently hydrogen, optionally substituted C1-6aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently optionally substituted C1-6aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl. 2. The compound of embodiment 1, wherein the compound is not:3. The compound of embodiment 1 or embodiment 2, wherein Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4. The compound of any one of the preceding embodiments, wherein Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 5. The compound of any one of the preceding embodiments, wherein Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.6. The compound of any one of the preceding embodiments, wherein Rais halogen, optionally substituted C1-6aliphatic, optionally substituted phenyl, optionally substituted 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7. The compound of any one of the preceding embodiments, wherein Rais optionally substituted C1-6aliphatic, 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. 8. The compound of any one of the preceding embodiments, wherein Rais optionally substituted C1-6aliphatic or optionally substituted 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 9. The compound of any one of the preceding embodiments, wherein:is substituted with 1-5 Rb, as valency allows; and each Rbis independently hydrogen, halogen, -CN, -OR, -O(CH2)mR, -SR, -N(R)2, -NO2, - C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, - OSO2N(R)2, -N(R)C(O)R’, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 1, 2, or 3.10. The compound of embodiment 9, wherein each Rbis independently halogen, -CN, -OR, - O(CH2)mR, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, - OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 11. The compound of embodiment 9 or 10, wherein each Rbis independently halogen or optionally substituted C1-6aliphatic. 12. The compound of any one of embodiments 9-11, wherein13. The compound of any one of the preceding embodiments, wherein L is a covalent bond. 14. The compound of any one of embodiments 1-12, wherein L is –CH2-. 15. The compound of any one of the preceding embodiments, wherein the compound is of Formula I-C:or a pharmaceutically acceptable salt thereof. 16. The compound of any one of the preceding embodiments, wherein the compound is of Formula I-D:or a pharmaceutically acceptable salt thereof, wherein: Rbis hydrogen, halogen, -CN, -OR, -O(CH2)mR, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, - C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, - N(R)SO2R’, -SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 1, 2, or 3. 17. The compound of any one of the preceding embodiments, wherein the compound is of Formula I-E:or a pharmaceutically acceptable salt thereof. 18. A compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein: W is CRwor N; X is CRxor N; Y is CRyor N; Z is –O- or –NRz-; Rw, Rx, and Ryare each independently hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6aliphatic, or –CN; Rzis hydrogen or optionally substituted C1-6aliphatic; R1is –N(R)2, –N(R)C(O)R’, -C(O)N(R)2, –N(R)C(O)N(R)2, or –N(R)C(O)OR; each Rcis independently selected from halogen, -CN, -CO2R, -C(O)N(R)2, -NO2, -N(R)2, -OR, - SR, or optionally substituted C1-6aliphatic; n is 0, 1, 2, or 3; R2is optionally substituted C1-6aliphatic; R3is hydrogen or optionally substituted C1-6aliphatic; Ring A 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 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, optionally substituted C1-6aliphatic, 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 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently optionally substituted C1-6aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl. 19. The compound of embodiment 18, wherein the compound is not:. 20. The compound of embodiment 18 or 19, wherein Ring A is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 21. The compound of any one of embodiments 18-20, wherein Ring A is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 22. The compound of any one of embodiments 18-21, wherein Ring A is 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with one or more oxo, halogen, or C1-6alkyl. 23. The compound of any one of embodiments 18-22, wherein Ring A is optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 24. The compound of any one of embodiments 18-23, wherein: RingRing A1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein Ring A1 is fused to Ring A2; Ring A2 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring A2 is optionally (i) further fused to Ring A3, or (ii) Ring A2 and Ring A3 combine to form a spirocycle; and Ring A3, 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. 25. The compound of embodiment 24, wherein Ring A1 is optionally substituted 5- to 6- membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 26. The compound of embodiment 24 or 25, wherein optionally substituted Ring A is27. The compound of any one of embodiments 24-26, wherein Ring A2 is optionally substituted 5- to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 28. The compound of any one of embodiments 24-27, wherein optionally substituted Ring A is selected from the group consisting of:29. The compound of any one of embodiments 24-27, wherein optionally substituted Ring A is selected from the group consisting of:30. The compound of any one of embodiments 18-29, wherein:is substituted with 1-5 Rb, as valency allows; and each Rbis independently hydrogen, halogen, -CN, -OR, -O(CH2)mR, -SR, -N(R)2, -NO2, - C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, - OSO2N(R)2, -N(R)C(O)R’, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 1, 2, or 3. 31. The compound of embodiment 30, wherein each Rbis independently halogen, -CN, -OR, -O(CH2)mR, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, - OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 32. The compound of embodiment 30 or embodiment 31, wherein each Rbis independently halogen, optionally substituted C1-6aliphatic, -OR, or -O(CH2)mR.33. The compound of any one of embodiments 30-32, whereinis selected from the group consisting of:34. The compound of any one of embodiments 30-32, whereinis selected from the group consisting of:35. The compound of any one of embodiments 18-34, wherein the compound is of Formula II-C:or a pharmaceutically acceptable salt thereof. 36. The compound of any one of embodiments 18-35, wherein the compound is of Formula II-D:or a pharmaceutically acceptable salt thereof. 37. The compound of any one of embodiments 18-36, wherein the compound is of Formula II-E:or a pharmaceutically acceptable salt thereof, wherein: Ring A1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein Ring A1 is fused to Ring A2; Ring A2 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring A2 is optionally (i) further fused to Ring A3, or (ii) Ring A2 and Ring A3 combine to form a spirocycle; and Ring A3, 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. 38. The compound of any one of the preceding embodiments, wherein W is CRw. 39. The compound of embodiment 38, wherein Rwis hydrogen. 40. The compound of any one of embodiments 1-37, wherein W is N. 41. The compound of any one of the preceding embodiments, wherein X is CRx. 42. The compound of any one of the preceding embodiments, wherein Rxis hydrogen, halogen, -CN, -OR3, or optionally substituted C1-6aliphatic. 43. The compound of any one of embodiments 1-40, wherein X is N. 44. The compound of any one of the preceding embodiments, wherein Y is CRy. 45. The compound of embodiment 44, wherein Ryis hydrogen. 46. The compound of any one of embodiments 1-43, wherein Y is N. 47. The compound of any one of the preceding embodiments, wherein R1is – N(R)C(O)N(R)2, or –N(R)C(O)OR. 48. The compound of any one of the preceding embodiments, wherein R1is – N(R)C(O)N(R)2. 49. The compound of any one of the preceding embodiments, wherein R1is – N(H)C(O)N(R)2, and each R of R1is independently hydrogen, optionally substituted C1-6aliphatic, or optionally substituted 3- to 7-membered saturated or partially unsaturatedcarbocyclyl, or the two R groups attached to the same nitrogen are taken together to form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. 50. The compound of any one of embodiments 1-47, wherein R1is –N(R)C(O)OR. 51. The compound of any one of embodiments 1-47, wherein R1is –N(H)C(O)OR, and R of R1is optionally substituted C1-6aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 52. The compound of any one of embodiments 1-46, wherein R1is –N(R)C(O)R’. 53. The compound of any one of embodiments 1-46, wherein R1is –N(H)C(O)(optionally substituted C1-6aliphatic). 54. The compound of any one of the preceding embodiments, wherein each Rcis independently halogen. 55. The compound of any one of the preceding embodiments, wherein n is 0. 56. A compound of Formula III:or a pharmaceutically acceptable salt thereof, wherein: Z is –O- or –NRz-; Rxis hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6aliphatic, or –CN; Rzis hydrogen or optionally substituted C1-6aliphatic; R2is optionally substituted C1-6aliphatic; R3is hydrogen or optionally substituted C1-6aliphatic; R4is halogen, –OR, -N(R)2, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring A is optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 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; L is a covalent bond or a bivalent C1-3straight or branched hydrocarbon chain; Rais hydrogen, halogen, optionally substituted C1-6aliphatic, 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; and each R is independently hydrogen, optionally substituted C1-6aliphatic, 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. 57. The compound of embodiment 56, wherein the compound is not:58. The compound of embodiment 56 or embodiment 57, wherein R4is halogen, –OR, - N(R)2, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and each R of R4is independently hydrogen or optionally substituted C1-6aliphatic. 59. The compound of any one of embodiments 56-58, 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. 60. The compound of any one of embodiments 56-59, wherein Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 61. The compound of any one of embodiments 56-60, wherein Ring A is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 62. The compound of any one of embodiments 56-61, wherein Rais halogen, optionally substituted C1-6aliphatic, 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. 63. The compound of any one of embodiments 56-62, wherein Rais optionally substituted C1-6aliphatic.64. The compound of any one of embodiments 56-63, wherein:is substituted with 1-5 Rb, as valency allows; and each Rbis independently hydrogen, halogen, -CN, -OR, -O(CH2)mR, -SR, -N(R)2, -NO2, - C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, - OSO2N(R)2, -N(R)C(O)R’, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 1, 2, or 3. 65. The compound of embodiment 64, wherein each Rbis independently halogen, -CN, -OR, -O(CH2)mR, -SR, -N(R)2, -NO2, -C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, - OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R’, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 66. The compound of embodiment 64 or 65, wherein each Rbis independently optionally substituted C1-6aliphatic. 67. The compound of any one of embodiments 64-66, wherein68. The compound of any one of embodiments 56-67, wherein L is a covalent bond. 69. The compound of any one of embodiments 56-67, wherein L is –CH2-.70. The compound of any one of the preceding embodiments, wherein each R is independently hydrogen, optionally substituted C1-6aliphatic, or optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. 71. The compound of any one of the preceding embodiments, wherein each R is independently hydrogen or optionally substituted C1-6aliphatic. 72. The compound of any one of the preceding embodiments, wherein each R’ is independently optionally substituted C1-6alkyl or optionally substituted C3-7cycloalkyl. 73. The compound of any one of the preceding embodiments, wherein each R’ is independently optionally substituted C1-6aliphatic. 74. A compound of Formula IV:or a pharmaceutically acceptable salt thereof, wherein: Z is –O- or –NRz-; Rxis hydrogen, halogen, -OR3, or –CN; Rzis hydrogen or optionally substituted C1-6aliphatic; R2is optionally substituted C1-6aliphatic; R3is hydrogen or optionally substituted C1-6aliphatic;selected from (i) or (ii):wherein Ring A is further substituted at least once,and at least one substituent on Ring A is C1-6haloalkyl; L is a covalent bond or a bivalent C1-3straight or branched hydrocarbon chain; Rais hydrogen, halogen, optionally substituted C1-6aliphatic, 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; and R’ is C1-6aliphatic or 3- to 7-membered saturated or partially unsaturated carbocyclyl. 75. The compound of embodiment 74, wherein the compound is not:76. The compound of embodiment 74 or 75, wherein Rais halogen, optionally substituted C1- 6 aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7- to 10- membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 77. The compound of any one of embodiments 74-76, wherein Rais optionally substituted C1-6aliphatic, 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. 78. The compound of any one of embodiments 74-77, wherein L is a covalent bond. 79. The compound of any one of embodiments 74-77, wherein L is –CH2-. 80. The compound of any one of embodiments 74-79, wherein R’ is methyl or cyclopropyl. 81. The compound of any one of embodiments 56-80, wherein Rxis hydrogen, halogen, -CN, -OR3, or optionally substituted C1-6aliphatic. 82. The compound of any one of embodiments 56-81, wherein Rxis hydrogen, halogen, - OR3, or –CN.83. The compound of any one of embodiments 56-82, wherein Rxis halogen or –CN. 84. The compound of any one of the preceding embodiments, wherein R2is C1-4alkyl. 85. The compound of any one of the preceding embodiments, wherein Z is –O-. 86. The compound of any one of embodiments 1-84, wherein Z is –NRz-. 87. The compound of embodiment 86, wherein Rzis hydrogen. 88. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof. 89. A pharmaceutical composition comprising a compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 90. A method of inhibiting JAK2 in a subject comprising administering the compound of any one of embodiments 1-88 or the composition of embodiment 89. 91. 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 embodiments 1-88 or the composition of embodiment 89. 92. A method of treating cancer, comprising administering to a subject in need thereof the compound of any one of embodiments 1-88 or the composition of embodiment 89. 93. A method of treating a hematological malignancy, comprising administering to a subject in need thereof the compound of any one of embodiments 1-88 or the composition of embodiment 89. 94. The method of embodiment 93, wherein the hematological malignancy is leukemia or lymphoma. 95. A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof the compound of any one of embodiments 1-88 or the composition of embodiment 89. 96. The method of embodiment 95, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia or myelofibrosis. EXAMPLES

[0167] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, thefollowing 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 Intermediates Preparation of Intermediate Int-1: 5-fluoro-N-methyl-2-nitropyridin-3-amine

[0168] Synthesis of compound Int-1.1 Hydrogen peroxide (30 wt%, 31 mL) was added dropwise to concentrated sulfuric acid (60 mL) at 0 °C. To the solution was added a solution of 3,5-difluoropyridin-2-amine (5.0 g, 38.43 mmol, 1.0 equiv) in concentrated sulfuric acid (60 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 48 h. It was carefully poured over crushed ice and stirred. The aqueous mixture was basified with saturated aqueous sodium bicarbonate. Precipitates were removed by filtration and the filtrate was 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-1.1.1H NMR (CDCl3, 400 MHz): δ 8.35 (bs, 1H), 7.62-7.58 (m, 1H).

[0169] Synthesis of compound Int-1. To a solution of Int-1.1 (2.3 g, 14.37 mmol, 1.0 equiv) in acetonitrile (20 mL) was added aqueous methylamine solution (40%, 1.1 mL, 14.37 mmol, 1.0 equiv) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 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 to afford Int-1.1H NMR (CDCl3, 400 MHz): δ 7.93 (bs, 1H), 7.78-7.75 (d, 1H), 7.02- 6.99 (m, 1H), 3.06 (s, 3H). Preparation of Intermediate Int-2: 4-chloro-5-fluoro-N-methyl-2-nitropyridin-3-amine

[0170] Synthesis of compound Int-2.1. To a solution of 3,5-difluoropyridin-2-amine (10 g, 76.87 mmol, 1.0 equiv) in THF (200 mL), was added n-butyllithium (2.5 M in hexane, 61.4 mL,153.7 mmol, 2.0 equiv). The reaction mixture was stirred at -78 °C for 40 min. Hexachloroethane (36.3 g, 153.7 mmol, 2.0 equiv) was added and the reaction mixture was stirred at -78 °C for 30-40 min. A saturated ammonium chloride solution was added carefully to quenched the reaction. The mixture was warmed to room temperature 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®, 12% ethyl acetate in hexane) to afford Int- 2.1.1H NMR (DMSO-d6, 400 MHz): δ 7.98-7.94 (m, 1H), 6.48 (bs, 2H).

[0171] Synthesis of compound Int-2.2. Concentrated sulfuric acid (3 mL, 6 vol) was added dropwise to potassium persulfate (2.05 g, 7.6 mmol, 2.5 equiv) at room temperature and stirred for 15 min. To the mixture was added Int-2.1 (0.5 g, 3.04 mmol, 1.0 equiv) in small portions maintaining temperature at 30-40 °C. The reaction mixture was stirred at room temperature for 3-4 h. It was poured over crushed ice, stirred, 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®, 2-3% ethyl acetate in hexane) to afford Int-2.2.1H NMR (DMSO-d6, 400MHz): δ 8.78 (s, 1H).

[0172] Synthesis of compound Int-2. To a solution of Int-2.2 (0.970 g, 4.99 mmol, 1.0 equiv) in acetonitrile (10 mL) was added aqueous methylamine solution (40%, 0.8 mL, 9.98 mmol, 2.0 equiv) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 10- 20 min. 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) to afford Int-2.1H NMR (DMSO-d6, 400 MHz): δ 7.98 (s, 1H), 7.05 (bs, 1H), 2.79 (d, 3H). Preparation of Intermediate Int-3: (S)-5-(tert-butyl)-3-isothiocyanato-1-(tetrahydrofuran-3- yl)-1H-pyrazole

[0173] Synthesis of compound Int-3.1. A round-bottom flask equipped with a Dean-Stark apparatus and a condenser was charged with 5-(tert-butyl)-1H-pyrazol-3-amine (5.0 g, 35.92 mmol, 1.0 equiv), 2,5-hexanedione (4.09 g, 35.92 mmol, 1.0 equiv), toluene (100 mL) and a few drops of acetic acid. The reaction mixture was heated to reflux for 3 hours. It was cooled rt and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 12% ethyl acetate in hexane as eluant) to afford Int-3.1. MS (ES): m / z 218.3 [M+H]+.

[0174] Synthesis of compound Int-3.2 and Int-3.3. A mixture of Int-3.1 (2.5 g, 11.50 mmol, 1.0 equiv), (R)-tetrahydrofuran-3-yl methanesulfonate (1.91 g, 11.50 mmol, 1.0 equiv) and cesium carbonate (7.49 g, 23 mmol, 2.0 equiv) in DMF (15 mL) was stirred at 70 °C for 12 h under nitrogen. It was poured into ice-water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2% ethyl acetate in hexane as eluant) to afford Int- 3.2. MS (ES): m / z 287.4 [M+H]+and Int-3.3. MS (ES): m / z 248.3 [M+H]+.

[0175] Synthesis of compound Int-3.4. To a solution of Int-3.3 (0.120 g, 0.417 mmol, 1.0 equiv) in ethanol-water (2:1, 2 mL) was added hydroxylamine hydrochloride (0.287 g, 4.17 mmol, 10 equiv). The reaction mixture was stirred at 120 °C in a microwave reactor for 1 h. It was poured over ice-water, basified by 2 N sodium hydroxide and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford Int-3.4. MS (ES): m / z 210.3 [M+H]+.

[0176] Synthesis of compound Int-3. To a solution of Int-3.4 (0.070 g, 0.334 mmol, 1.0 equiv) in dichloromethane (2 mL) was added a solution of sodium bicarbonate (0.140 g, 1.67 mmol, 5.0 equiv) in water (1 mL) followed by thiophosgene (0.096 g, 0.835 mmol, 2.5 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. It was poured over ice-water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford Int-3. MS (ES): m / z 252.3 [M+H]+. Preparation of Intermediate Int-4: (R)-5-(tert-butyl)-3-isothiocyanato-1-(tetrahydrofuran-3- yl)-1H-pyrazole

[0177] Synthesis of compound Int-4. Compound Int-4 was prepared from Int-3.2, following the procedures described in the synthesis of Int-3. MS (ES): m / z 252.3 [M+H]+. Preparation of Intermediate Int-5: 3-isothiocyanato-1-methyl-5-(trifluoromethyl)pyridin- 2(1H)-one

[0178] Synthesis of compound Int-5.1. A mixture of 3-nitro-5-(trifluoromethyl)pyridin- 2(1H)-one (1.0 g, 4.81 mmol, 1.0 equiv) and potassium carbonate (1.3 g, 9.62 mmol, 2.0 equiv) in DMF (15 mL) was stirred for 15 min before the addition of methyl iodide (1.0 g, 7.21 mmol, 1.5 equiv). The reaction mixture was stirred at 70 °C for 2 h. It was transferred into ice-water and product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel (CombiFlash®, 40% ethyl acetate in hexane) to afford Int-5.1. MS(ES): m / z 223.12 [M+H]+.

[0179] Synthesis of compound Int-5.2. A mixture of compound Int-5.1 (0.57 g, 2.57 mmol, 1.0 equiv) and 10% palladium on carbon (0.3 g) in methanol (18 mL) was stirred under hydrogen (1 atm) for 1 h. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to obtain Int-5.2. MS(ES): m / z 193.14 [M+H]+.

[0180] Synthesis of compound Int-5. To a solution of Int-5.2 (0.200 g, 1.04 mmol, 1.0 equiv) and triethylamine (0.4 mL, 2.49 mmol, 2.4 equiv) in THF (6mL) was added thiophosgene (0.143 g, 1.25 mmol, 1.2 eq) at 0 °C. The reaction mixture was stirred at room temperature for 30 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 to afford Int-5. MS(ES): m / z 192.15 [M+H]+. Preparation of Intermediate Int-6: 1-(2-oxaspiro[3.3]heptan-6-yl)-5-(trifluoromethyl)-1H- pyrazol-3-amine

[0181] Synthesis of compound Int-6.1. To a solution of 2-oxaspiro[3.3]heptan-6-one (0.600 g, 5.35 mmol, 1.0 equiv) in methanol (10 mL), was added sodium borohydride (0.203 g, 5.35 mmol, 1.0 equiv) in portions at 0 °C. The reaction mixture was stirred for 2 h. It was transferred into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Int-6.1. MS (ES): m / z 115.2 [M+H]+.

[0182] Synthesis of compound Int-6.2. To a solution of Int-6.1 (0.540 g, 4.73 mmol, 1.0 equiv) in dichloromethane (10 mL) was added triethylamine (1.64 mL, 11.82 mmol, 2.5 equiv) at 0 °C followed by addition of methanesulfonyl chloride (0.71 mL, 9.46 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 12 h. It was transferred into 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®, 40% ethyl acetate in hexane) to afford Int-6.2. MS (ES): m / z 193.2 [M+H]+.

[0183] Synthesis of compound Int-6. To a solution of Int-6.2 (0.4 g, 2.08 mmol, 1.0 equiv) and 5-(trifluoromethyl)-1H-pyrazol-3-amine (0.314 g, 2.08 mmol, 1.0 equiv) in DMF (7 mL) was added cesium carbonate (1.352 g, 4.16 mmol, 2.0 equiv). The reaction mixture was heated at 80 °C for 5 h. It was transferred into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain Int-6. MS (ES): m / z 248.2 [M+H]+. Preparation of Intermediate Int-7: 4,4-difluoro-2-isothiocyanato-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridine

[0184] Synthesis of compound Int-7.1. To a solution of diethyl 1H-pyrazole-3,5- dicarboxylate (100 g, 471 mmol, 1.0 equiv) and ethyl 4-bromobutanoate (91.92 g, 471 mmol, 1.0 equiv) in acetonitrile (1000 mL) was added potassium carbonate (64.99 g, 471 mmol, 1.0 equiv) and the reaction mixture was stirred at 80 °C for 4 h. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to afford Int-7.1. MS(ES): m / z 327.2 [M+H]+.

[0185] Synthesis of compound Int-7.2. To a solution of Int-7.1 (120 g, 367 mmol, 1.0 equiv) in toluene (1000 mL) was added potassium tert-butoxide (1M in THF) (403 mL, 403.7 mmol, 1.1 equiv) at room temperature. The reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was poured into ice-water, and product extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to afford Int-7.2. m / z: 281.2 [M+H]+.

[0186] Synthesis of compound Int-7.3. To Int-7.2 (65 g, 231 mmol 1.0 equiv) was added hydrochloric acid:water (2:1, 600 mL) and the reaction mixture heated 100 °C for 6 h. It was concentrated under reduced pressure. The residue was dissolved in acetonitrile-THF (1:4, 250 mL) and the solution was concentrated under reduced pressure to afford Int-7.3. MS(ES): m / z 181.1 [M+H]+.

[0187] Synthesis of compound Int-7.4. To a solution of Int-7.3 (38 g, 210 mmol, 1.0 equiv) in DMF (4000 mL) was added potassium carbonate (57.96 g, 420 mmol, 2.0 equiv) followed by methyl iodide (15.7 mL, 252 mmol, 1.2 equiv) and reaction mixture was stirred at room temperature for 4 h. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, 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 Int-7.4. MS(ES): m / z 195.0 [M+H]+.

[0188] Synthesis of compound Int-7.5. To a solution of Int-7.4 (22 g, 113.29 mmol, 1.0 equiv) in 1,2-dichloroethane (130 mL) was added diethylaminosulfur trifluoride (150 mL, 1132.9 mmol, 10.0 equiv) and the reaction mixture was stirred at room temperature for 5 days. It was transferred into ice-cold saturated sodium bicarbonate solution 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-7.5. MS(ES): m / z 217.1 [M+H]+.

[0189] Synthesis of compound Int-7.6. To a solution of Int-7.5 (11.2 g, 51.81 mmol, 1.0 equiv) in THF (110 mL) was added lithium hydroxide (4.35 g, 103.62 mmol, 2.0 equiv) and water (11 mL). The reaction mixture was stirred at room temperature for 16 h. It was poured intoice-water, and adjusted pH to 5 by adding 2 M hydrochloric acid. Product was 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-7.6. MS(ES): m / z 203.0 [M+H]+.

[0190] Synthesis of compound Int-7.7. To a suspension of Int-7.6 (8.0 g, 39.57 mmol, 1.0 equiv) in toluene (100 mL) was added triethylamine (11 mL, 79.14 mmol, 2.0 equiv), followed by benzyl alcohol (21.4 g, 197.85 mmol, 5.0 equiv) and diphenylphosphoryl azide (21.77 g, 79.14 mmol, 2.0 equiv). The reaction mixture was stirred at 90 °C for 16 h. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford to afford crude material. This was further purified by flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate in hexane) to afford Int-7.7. MS(ES): m / z 308.2 [M+H]+.

[0191] Synthesis of compound Int-7.8. A mixture of Int-7.7 (5.4 g, 17.57 mmol, 1.0 equiv) and 10% palladium on charcoal (2.0 g) in methanol (100 mL) was stirred under hydrogen (1 atm) for 2 h. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford Int-7.8. MS(ES): m / z 174.1 [M+H]+.

[0192] Synthesis of compound Int-7. Compound Int-7 was prepared from Int-7.8 following the procedure described in the synthesis of Int-3. It was used without purification. MS(ES): m / z 216.2 [M+H]+. Preparation of Intermediate Int-8: 2-isothiocyanato-5-methyl-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one

[0193] Synthesis of compound Int-8.1. To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (2.0 g, 12.73 mmol, 1.0 equiv) and 2-(methylamino)ethan-1-ol (1.43 g, 19.10 mmol, 1.5equiv) in DCM (20 mL) were added dropwise thionyl chloride (4.6 mL, 63.65 mmol, 5.0 equiv) and a drop of DMF at -5 °C. The reaction mixture was stirred for 10 and it was heated at 50 °C for 16 h. It was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DMF (20 mL) and was added triethylamine (5.3 mL, 38.19 mmol, 3.0 equiv) stirred for 16 h. It was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 1.0% methanol in DCM) to afford Int-8.1. MS (ES): m / z 197.1 [M+H]+.

[0194] Synthesis of compound Int-8.2. A mixture of Int-8.1 (1.3 g, 6.63 mmol, 1.0 equiv), ammonium chloride (1.79 g, 33.15 mmol, 5.0 equiv) and iron powder (1.85 g, 33.15 mmol 5.0 equiv) in ethanol (20 mL) and water (7 mL) was stirred at 80 °C for 4 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was poured into ice-water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol in DCM) to afford Int-8.2. MS(ES): m / z 167.0 [M+H]+.

[0195] Synthesis of compound Int-8. Compound Int-8 was prepared from Int-8.2 following the procedure described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, 0.5% methanol in DCM). MS(ES): m / z 209.1 [M+H]+. Preparation of Intermediate Int-9: 2-isothiocyanato-4,4-dimethyl-6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazine

[0196] Synthesis of compound Int-9.1. To a solution of ethyl 5-amino-1H-pyrazole-3- carboxylate (15.0 g, 96.68 mmol, 1.0 equiv) and hexane-2,5-dione (16.55 g, 145.01 mmol, 1.5 equiv) in toluene (150 mL) was added p-toluenesulfonic acid (0.919 g, 4.83 mmol, 0.05 equiv). The reaction mixture was heated to reflux with a Dean-Stark trap to remove water for 2 h. It was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane) to afford Int-9.1. MS (ES): m / z 234.2 [M+H]+.

[0197] Synthesis of compound Int-9.2. To a mixture of Int-9.1 (10 g, 42.87 mmol, 1.0 equiv), (2-bromoethoxy)(tert-butyl)dimethylsilane (15.38 g, 64.30 mmol, 1.0 equiv) and potassium carbonate (17.74 g, 128.61 mmol, 3.0 equiv) in acetonitrile (100 mL) was stirred at 80 °C for 1 h. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate in hexane) to afford Int-9.2. MS(ES): m / z 392.2 [M+H]+.

[0198] Synthesis of compound Int-9.3. To a solution of Int-9.2 (7.2 g, 18.39 mmol, 1.0 equiv) in THF (70 mL) was added methyl magnesium bromide (3 M in diethyl ether, 18.4 mL, 55.17 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice-water, and product 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®, 18% ethyl acetate in hexane) to afford Int-9.3. m / z: 378.5 [M+H]+.

[0199] Synthesis of compound Int-9.4. To a solution of Int-9.3 (5.3 g, 14.04 mmol, 1.0 equiv) in THF (50 mL) was added tetrabutylammonium fluoride solution (1 M in THF, 35 mL, 35.1 mmol, 2.5 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. It was poured into ice-water, and product 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 Int-9.4. m / z: 264.2 [M+H]+.

[0200] Synthesis of compound Int-9.5. To a solution of Int-9.4 (2.3 g, 8.73 mmol, 1.0 equiv) and 4-dimethylaminopyridine (0.010 g, 0.087 mmol, 0.01 equiv) in DCM (25 mL) was added a solution of 4-toluenesulfonyl chloride (2.16 g, 11.34 mmol, 1.3 equiv) in DCM (5 mL) and triethylamine (3.7 mL, 26.19 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. It was poured into ice-water, and product extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford material. To the solution of this crude material in THF (50 mL) was added sodium hydride (1.05 g, 26.19 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 30 min. It was poured into ice-water, and product 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-9.5. m / z: 246.2 [M+H]+.

[0201] Synthesis of compound Int-9.6. To a solution of Int-9.5 (0.900 g, 3.67 mmol, 1.0 equiv) in ethanol-water (2:1, 20 mL) was added hydroxylamine hydrochloride (12.75 g, 183.5 mmol, 50 equiv). The reaction mixture was stirred at 120 °C for 1 h. It was poured into ice-water and neutralized by 2 N sodium hydroxide. The mixture was 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®, 2% methanol in DCM) to afford Int-9.6. MS(ES): m / z 168.1 [M+H]+.

[0202] Synthesis of compound Int-9. Compound Int-9 was prepared from Int-9.6 following the procedure described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, DCM). MS(ES): m / z 210.1 [M+H]+.Preparation of Intermediate Int-10: 2'-isothiocyanato-5',6'-dihydrospiro[cyclobutane-1,4'- pyrrolo[1,2-b]pyrazole]

[0203] Synthesis of compound Int-10.1. To a solution of lithium bis(trimethylsilyl)amide (1 M in THF, 17.4 mL, 17.44 mmol, 2.2 equiv) in anhydrous tetrahydrofuran (25 mL) at -78 °C was added a solution of 6-oxaspiro[3.4]octan-5-one (1.0 g, 7.93 mmol, 1.0 equiv) and acetonitrile (0.83 mL, 15.86 mmol, 2.0 equiv) in tetrahydrofuran (8 mL). The reaction mixture was stirred at -78 °C for 30 min and it was allowed to warm to room temperature stirring for 2 h. It was transferred into saturated aqueous ammonium chloride solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain residue which was purified by flash column chromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexane) to afford Int-10.1.1H NMR (DMSO-d6, 400MHz): δ 4.01 (s, 1H), 3.76 (m, 1H), 3.66- 3.62 (m, 1H), 2.84 (bs, 2H), 2.10 (bs, 2H), 1.99 (bs, 2H), 1.87-1.82 (m, 2H), 1.67 (bs, 2H).

[0204] Synthesis of compound Int-10.2. To a solution of Int-10.1 (0.800 g, 4.78 mmol, 1.0 equiv) in ethanol (10 mL) was added hydrazine monohydrate (0.358 g, 7.17 mmol, 1.5 equiv). The reaction mixture was heated at 60 °C for 72 h. The reaction mixture was cooled to room temperature and carbon dioxide was bubbled through it for 1 h. It was concentrated under reduced pressure. To the residue was added methanol (15 mL) and stirred for a while. The precipitated solids were removed by filtration. The filtration was concentrated under reduced pressure to obtain Int-10.2. MS(ES): m / z 182.1 [M+H]+.

[0205] Synthesis of compound Int-10.3. To a solution of Int-10.2 (0.610 g, 3.37 mmol, 1.0 equiv) in THF (10 mL) was added thionyl chloride (1.22 mL, 16.85 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 3 h. It was slowly transferred into (1:1) mixture of aqueous ammonium hydroxide and ice, stirred and extracted with dichloromethane.The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain residue which was purified by flash column chromatography on silica gel (CombiFlash®, 2% methanol in dichloromethane) to afford Int-10.3. MS(ES): m / z 164.1 [M+H]+.

[0206] Synthesis of compound Int-10. Compound Int-10 was prepared from Int-10.3 following the procedure described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, dichloromethane). MS(ES): m / z 205.9 [M+H]+. Preparation of Intermediate Int-11: 2'-isothiocyanato-6',7'-dihydro-5'H-spiro[cyclopropane- 1,4'-pyrazolo[1,5-a]pyridine]

[0207] Synthesis of compound Int-11.1. To a solution of LiHMDS (35 mL, 35 mmol, 2.2 equiv) in THF (40 mL) at -78 °C was added acetonitrile (1.3 g, 32 mmol, 2 equiv) dropwise. The resulting solution was stirred for 1 h, and a solution of 5-oxaspiro[2.5]octan-4-one (2 g, 15.85 mmol, 1 equiv) in THF (10 mL) was added dropwise. The reaction mixture was stirred at -78 °C for another 2 h. It was allowed to warm to room temperature and quenched by a saturated ammonium chloride solution and extracted by DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Int-11.1. MS(ES): m / z: 167.21 [M+H]+.

[0208] Synthesis of compound Int-11.2. To a solution of Int-11.1 (1.7 g, 10.17 mmol, 1 equiv) in methanol (50 mL) was added hydrazine hydrate (1.52 g, 30.51 mmol, 3 equiv). The reaction mixture was stirred at in an autoclave at 120 °C for 16 h. The reaction mixture was cooled to room temperature and dry ice was added slowly over a period of 15 min. The solution was decanted, and solvent removed under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 6.0% methanol in DCM) to afford Int- 11.2. MS(ES): m / z 181.24 [M+H]+.

[0209] Synthesis of compound Int-11.3. To a stirred solution of Int-11.2 (1.2 g, 6.62 mmol, 1 equiv) in dichloroethane (24 mL) was added thionyl chloride (0.937 g, 7.94 mmol, 1.2 equiv) at room temperature. The reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was cooled to room temperature, quenched by a saturated aqueous potassium carbonate solution and extracted by DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Int- 11.3. MS(ES): m / z: 199.68 [M+H]+.

[0210] Synthesis of compound Int-11.4. A mixture of Int-11.3 (1 g, 5.01 mmol, 1 equiv) and K2CO3 (1.38 g, 10.02 mmol, 2 equiv) in acetonitrile (20 mL) was stirred at 80 °C for 16 h. It was cooled to room temperature, poured into water and extracted by 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®, 5.0% methanol in DCM) to afford Int-11.4. MS(ES): m / z: 163.22 [M+H]+.

[0211] Synthesis of compound Int-11. Compound Int-11 was prepared from Int-11.4, following the procedures described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, 40% ethyl acetate in hexane). MS(ES): m / z 205.28 [M+H]+. Preparation of Intermediate Int-12: 2-isothiocyanato-4,4-dimethyl-4,5,7,8- tetrahydropyrazolo[1,5-d][1,4]oxazepane

[0212] Synthesis of compound Int-12.1. A mixture of Int-9.1 (40 g, 171.67 mmol, 1.0 equiv), ((2-bromoethoxy)methyl)benzene (46.13 g, 214.59 mmol, 1.25 equiv) and potassium carbonate (71.07 g, 515.02 mmol, 3.0 equiv) in acetonitrile (100 mL) was stirred at 80 °C for 1 h. 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 flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate in hexane) to afford Int-12.1. MS(ES): m / z 369.2 [M+H]+.

[0213] Synthesis of compound Int-12.2. To a solution of Int-12.1 (34.8 g, 94.56 mmol, 1.0 equiv) in THF (350 mL) was added lithium aluminum hydride (1 M in THF, 60.0 mL, 94.56 mmol, 1.0 equiv) at 0 °C and was stirred for 30 min. It was poured into ethyl acetate and the precipitates were removed by filtering through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford Int-12.2. MS(ES): m / z 326.1 [M+H]+.

[0214] Synthesis of compound Int-12.3. To a solution of Int-12.2 (30.6 g, 94.15 mmol, 1.0 equiv) and triethylamine (23.77 g, 235.38 mmol, 2.5 equiv) in DCM (300 mL) was added methanesulfonyl chloride (16.1 g, 141.23 mmol, 1.5 equiv) at 0 °C and was stirred for 20 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. To the residue was added acetonitrile, followed by tetrabutylammoniumcyanide (55.59 g, 207.38 mmol, 2.0 equiv). The mixture was stirred at 80 °C for 1 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 28% ethyl acetate in hexane) to afford Int-12.3. MS(ES): m / z: 335.3 [M+H]+.

[0215] Synthesis of compound Int-12.4. To a solution of Int-12.3 (20.8 g, 62.27 mmol, 1.0 equiv) in DMF (220 mL) was added sodium hydride (60%, 7.47 g, 186.82 mmol, 3.0 equiv) followed by methyl iodide (44.21 g, 311.37 mmol, 5.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. 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 flash column chromatography on silica gel (CombiFlash®, 17% ethyl acetate in hexane) to afford Int- 12.4. MS(ES): m / z: 363.61 [M+H]+.

[0216] Synthesis of compound Int-12.5. To a solution of Int-12.4 (2.0 g, 5.52 mmol, 1.0 equiv) in DCM (25 mL) was added diisobutylaluminum hydride (1.0 M in hexane, 10.0 mL) at - 78 °C and was stirred for 30 min. The reaction mixture was poured into a saturated aqueous solution of sodium potassium tartrate and was stirred for 1 h. It was filtered through a pad of Celite® and the filtrate was 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 Int-12.5. MS(ES): m / z: 366.61 [M+H]+.

[0217] Synthesis of compound Int-12.6. To a solution of Int-12.5 (11.4 g, 31.23 mmol, 1.0 equiv) in methanol (125 mL) was added sodium borohydride (11.4 g, 62.46 mmol, 2.0 equiv) at 0 °C and was stirred for 1 h. It was poured into dilute hydrochloric acid (30 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 40% ethyl acetate in hexane) to afford Int-12.6. MS(ES): m / z: 368.41 [M+H]+.

[0218] Synthesis of compound Int-12.7. To a solution of Int-12.6 (9.75 g, 26.56 mmol, 1.0 equiv) and triethylamine (10.7 g, 106.26 mmol, 4.0 equiv) in DCM (130 mL) was added methanesulfonyl chloride (6.05 g, 53.13 mmol, 2.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 30 min, transferred into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 28% ethyl acetate in hexane) to afford Int-12.7. MS(ES): m / z: 446.81 [M+H]+.

[0219] Synthesis of compound Int-12.8. To a solution of Int-12.7 (7.8 g, 17.52 mmol, 1.0 equiv) in DCM (150 mL) was added trifluoromethanesulfonic acid (20.0 mL) at 0 °C and was stirred for 15 min. It was poured into a saturated aqueous solution of sodium bicarbonate 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®, 2% methanol in DCM) to afford Int-12.8. MS(ES): m / z: 356.36 [M+H]+.

[0220] Synthesis of compound Int-12.9. To a solution of Int-12.8 (4.1 g, 11.54 mmol, 1.0 equiv) in dimethyl sulfoxide (60 mL) was added sodium hydride (60%, 2.30 g, 57.74 mmol, 5.0 equiv) at room temperature and was stirred for 2 h. 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 flash column chromatography on silica gel (CombiFlash®, 25% ethyl acetate in hexane) to afford Int-12.9. MS(ES): m / z: 260.26 [M+H]+.

[0221] Synthesis of compound Int-12.10. To a solution of Int-12.9 (1.9 g, 7.33 mmol, 1.0 equiv) in ethanol and water (1:1, 25 mL) was added hydroxylamine hydrochloride (20.24 g, 293.43 mmol, 40.0 equiv) at room temperature. The reaction mixture was stirred at 120 °C for 4 h. It was poured into a saturated aqueous solution of sodium bicarbonate 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®, 4.2% methanol in DCM) to afford Int- 12.10. MS(ES): m / z: 182.27 [M+H]+.

[0222] Synthesis of compound Int-12. Compound Int-12 was prepared from Int-12.10, following the procedures described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, DCM). MS(ES): m / z 224.1 [M+H]+. Preparation of Intermediate Int-13: 1-(tert-butyl)-6-isothiocyanato-2,3-dihydro-1H- imidazo[1,2-b]pyrazole

[0223] Synthesis of compound Int-13.1. A mixture of dimethyl 1H-pyrazole-3,5- dicarboxylate (25 g, 135.76 mmol, 1.0 equiv), potassium carbonate (28.10 g, 203.64 mmol, 1.5 equiv) and ((2-bromoethoxy)methyl)benzene (37.96 g, 176.49 mmol, 1.3 equiv) in acetonitrile (250 mL) was stirred at 80 °C for 4 h. It was cooled to room temperature, 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 to afford Int-13.1. MS(ES): m / z 319.1 [M+H]+.

[0224] Synthesis of compound Int-13.2. To a solution of Int-13.1 (32.5 g, 102.10 mmol, 1.0 equiv) and potassium hydroxide (5.61 g, 102.10 mmol, 1.0 equiv) in methanol (200 mL) was stirred at room temperature under nitrogen atmosphere for 16 h. It was concentrated under reduced pressure. The residue was added to water, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Int-13.2 MS(ES): m / z 305.2 [M+H]+.

[0225] Synthesis of compound Int-13.3. To a solution of compound Int-13.2 (28.50 g, 93.66 mmol, 1.0 equiv) and triethylamine (16.2 mL, 112.39 mmol, 1.2 equiv) in tert-butanol (40 mL) was added diphenyl phosphoryl azide (30.9 g, 112.39 mmol, 1.2 equiv) under nitrogen at room temperature. The reaction mixture was stirred at 80 °C for 3 h. 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 flash column chromatography on silica gel (CombiFlash®, 25-30% ethyl acetate in hexane) to afford Int-13.3. MS(ES): m / z: 376.7 [M+H]+.

[0226] Synthesis of compound Int-13.4. A mixture of compound Int-13.3 (21.0 g, 55.94 mmol, 1.0 equiv) and 20% palladium on hydroxide (5.25 g) in methanol (210 mL) was stirred under hydrogen for 8 h. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford Int-13.4. MS(ES): m / z: 286 [M+H]+.

[0227] Synthesis of compound Int-13.5. To a solution of compound Int-13.4 (15 g, 52.58 mmol, 1.0 equiv) in THF (300 mL) was added tri-tert-butyl phosphine (15.93, 78.87 mmol, 1.5 equiv) followed by diethyl azodicarboxylate (19.87 g, 78.87 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. 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 flash column chromatography on silica gel (CombiFlash®, 50-55% ethyl acetate in hexane) to afford Int-13.5. MS(ES): m / z: 268.7 [M+H]+.

[0228] Synthesis of compound Int-13.6. To a solution of Int-13.5 (13.0 g, 48.64 mmol, 1.0 equiv) in a mixture of THF and methanol (100 mL, 5:1) was added lithium hydroxide (6.1 g, 145.92 mmol, 3.0 equiv) solution in water, and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. To the residue was added water and pH adjusted to 3-4 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Int-13.6. MS(ES): m / z 254.5 [M+H]+.

[0229] Synthesis of compound Int-13.7. To a suspension of compound Int-13.6 (9.5 g, 37.51 mmol, 1.0 equiv) in toluene (20 mL) was added benzyl alcohol (4.8 g, 45.01 mmol, 1.2 equiv), diphenyl phosphoryl azide (12.33 g, 45.01 mmol, 1.2 equiv) and triethylamine (6.8 mL, 48.76 mmol, 1.3 equiv) at room temperature. The reaction mixture was stirred at 100 °C for 6 h. 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 trituration in a mixture of ethyl acetate:methanol (1:1) to afford Int-13.7. MS(ES): m / z: 359.7 [M+H]+.

[0230] Synthesis of compound Int-13.8. To a solution of Int-13.7 (8.2 g, 22.88 mmol, 1.0 equiv) in DCM (5 mL) was added trifluoroacetic acid (82 mL) at room temperature. The reaction mixture was stirred for 3 h. It was transferred into a mixture of ice and saturated aqueous solution of sodium bicarbonate and extracted with 10% methanol in DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Int-13.8. MS(ES): m / z 259 [M+H]+.

[0231] Synthesis of compound Int-13.9. To a solution of Int-13.8 (7.0 g, 27.10 mmol, 1.0 equiv) in a mixture of DCM:toluene (1:1, 350 mL) was added boron trifluoride etherate (7 mL) followed by tert-butyl 2,2,2-trichloroacetimidate (11.84 g, 54.20 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred for 16 h. It was transferred into an aqueous solution of sodium bicarbonate 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®, 2.3-2.5% methanol in DCM) to afford Int-13.9. MS(ES): m / z 315.2 [M+H]+.

[0232] Synthesis of compound Int-13.10. A mixture of compound Int-13.9 (2.8 g, 8.91 mmol, 1.0 equiv) and 20% palladium on hydroxide (0.700 g) in methanol (42 mL) was stirred under hydrogen (1 atm) for 3 h. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3-3.5% methanol in DCM) to afford Int-13.10. MS(ES): m / z: 181.6 [M+H]+.

[0233] Synthesis of compound Int-13. To a solution of Int-13.10 (1.0 g, 5.55 mmol, 1.0 equiv) in acetonitrile (15 mL) was added imidazole (0.096 g, 1.66 mmol, 0.3 equiv) followed by thiocarbonyldiimidazole (1.9 g, 11.1 mmol, 2.0 equiv) and was stirred at room temperature for 1 h. 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 flash column chromatography on silica gel (CombiFlash®, 100% DCM) to afford Int-13. MS(ES): m / z: 223 [M+H]+. Preparation of Intermediate Int-14: 2-isothiocyanato-6,6-dimethyl-6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazine

[0234] Synthesis of compound Int-14.1. To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (5.0 g, 8.51 mmol, 1.0 equiv) in THF (100 mL) was added DMF (0.1 mL) and oxalyl chloride (3.58 mL, 9.50 mmol, 1.3 equiv) dropwise at 0 °C and stirred at room temperature for 2 h. Most solvent was removed under reduced pressure, and the residue was dissolved in THF and added lithium borohydride (24 mL, 4.70 mmol, 1.3 equiv). The mixture was stirred at room temperature for 16 h. It was transferred into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in DCM) to afford Int-14.1. MS (ES): m / z 143.10 [M+H]+.

[0235] Synthesis of compound Int-14.2. A mixture of Int-14.1 (1.7 g, 11.77 mmol, 1.0 equiv) and cesium carbonate (0.772 g, 2.377 mmol, 0.2 equiv) in 2,2-dimethyloxirane (30 mL) was stir at 70 °C for 3 h. It was transferred into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 1.2% methanol in DCM) to afford Int- 14.2. MS (ES): m / z 216.81 [M+H]+.

[0236] Synthesis of compound Int-14.3. A solution of Int-14.2 (0.5 g, 2.32 mmol, 1.0 equiv) in sulfuric acid (10 mL) was stirred at 45 °C for 16 h. It was transferred into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 0.5% methanol in DCM) to afford Int-14.3. MS (ES): m / z 198.19 [M+H]+.

[0237] Synthesis of compound Int-14.4. A mixture of palladium on carbon (10%; 0.200 g) and compound Int-14.3 (350 g, 5.72 mmol, 1.0 equiv) in methanol (5 mL) was stirred under hydrogen for 2 h. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford Int-14.4. MS(ES): m / z 168.21 [M+H]+.

[0238] Synthesis of compound Int-14. Compound Int-14 was prepared from Int-14.4, following the procedures described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol in DCM). MS (ES): m / z 210.27 [M+H]+. Preparation of Intermediate Int-15: 1-(2-(benzyloxy)ethyl)-3-isothiocyanato-5- (trifluoromethyl)pyridin-2(1H)-one

[0239] Synthesis of compound Int-15.1. To a solution of 5-(trifluoromethyl)pyridin-2(1H)- one (5.0 g, 30.66 mmol, 1.0 equiv) in concentrated sulfuric acid (25 mL) was added fuming nitric acid (8 mL) at 0 °C. The reaction mixture was stirred at 65 °C for 6 h. It was transferred into crushed ice, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in DCM) to afford Int-15.1. MS(ES): m / z 209.10 [M+H]+.

[0240] Synthesis of compound Int-15.2. A mixture of Int-15.1 (0.5 g, 2.4 mmol, 1.0 equiv) and potassium carbonate (0.662 g, 4.8 mmol, 2.0 equiv) in DMF (7 mL) was stirred for 15 min. To the mixture was added ((2-bromoethoxy)methyl)benzene (0.775 g, 3.6 mmol, 1.5 equiv) and stirred at 110 °C for 2 h. 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 flash columnchromatography on silica gel (CombiFlash®, 30% ethyl acetate in hexane) to afford Int-15.2. MS(ES): m / z 343.2 [M+H]+.

[0241] Synthesis of compound Int-15.3. A mixture of Int-15.2 (0.322 g, 0.940 mmol, 1.0 equiv), iron powder (0.263 g, 4.7 mmol, 5.0 equiv) and ammonium chloride (0.253 g, 4.7 mmol, 5.0 equiv) in ethanol:water (2:1, 10 mL) was stirred at 80 °C for 2 h. It was transferred into 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. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in DCM) to afford Int-15.3. MS(ES): m / z 313.3 [M+H]+.

[0242] Synthesis of compound Int-15. Compound Int-15 was prepared from Int-15.3, following the procedures described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol in DCM). MS(ES): m / z 355.3 [M+H]+. Preparation of Intermediate Int-16: 3-isothiocyanato-1-(methyl-d3)-5- (trifluoromethyl)pyridin-2(1H)-one

[0243] Synthesis of compound Int-16.1. A mixture of Int-15.1 (12 g, 57.67 mmol, 1.0 equiv) and potassium carbonate (23.87 g, 173.01 mmol, 3.0 equiv) in DMF (140 mL) was stirred for 15 min before the addition of iodomethane-d3(10.03 g, 69.20 mmol, 1.2 equiv). The reaction mixture was stirred at 70 °C for 1 h. It was transferred into 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-16.1. MS(ES): m / z 226.1 [M+H]+.

[0244] Synthesis of compound Int-16.2. A mixture of Int-16.1 (10 g, 44.42 mmol, 1.0 equiv), iron powder (12.43 g, 222.1 mmol, 5.0 equiv), acetic acid (17.76 g, 222.1 mmol, 5.0 equiv) in ethanol (100 mL) and water (20 mL) was stirred at 80 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was transferred into 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®, 2.5% methanol in DCM) to afford Int-16.2. MS(ES): m / z 196.2 [M+H]+.

[0245] Synthesis of compound Int-16. Compound Int-16 was prepared from Int-16.2, following the procedures described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate in hexane). MS(ES): m / z 238.1 [M+H]+. Preparation of Intermediate (±)-Int-17: 2-(tetrahydrofuran-3-yl)-6-(trifluoromethyl)pyridin-4- amine

[0246] Synthesis of compound Int-17.1. A mixture of 2-chloro-6-(trifluoromethyl)pyridin- 4-amine (0.600 g, 3.05 mmol, 1.0 equiv), 2-(4,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (0.898 g, 4.58 mmol, 1.5 equiv) and potassium carbonate (1.26 g, 9.15 mmol, 3.0 equiv) in 1,4-dioxane (10 mL) and water (1 mL) was degassed by bubbling through a stream of argon for 10 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM complex (0.125 g, 0.152 mmol, 0.05 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 120 °C for 3 h. It was cooled to room temperature, 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®, 1% methanol in DCM) to afford Int-17.1. MS(ES): m / z 231.19 [M+H]+.

[0247] Synthesis of compound (±)-Int-17. A mixture of palladium on carbon (10%, 0.2 g) and compound Int-17.1 (0.308 g, 1.34 mmol, 1.0 equiv) in methanol (5 mL) was stirred under hydrogen (1 atm) for 12 h. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford (±)-Int-17. MS(ES): m / z 233.21 [M+H]+. Preparation of Intermediate Int-18: 1-(4-isothiocyanato-2-(trifluoromethyl)phenyl)-N,N- dimethylmethanamine

[0248] Synthesis of compound Int-18.1. A solution of 4-nitro-2-(trifluoromethyl)benzoic acid (2.0 g, 8.51 mmol, 1.0 equiv), HATU (1.2 g, 2.92 mmol, 1.1 equiv) and triethylamine (3.5 g, 2.92 mmol, 3.0 equiv) in DCM (30 mL) was stirred at room temperature for 30 min. Dimethyl amine (4.1 mL, 2.9 mmol, 2.5 equiv) and was added and stirred for 16 h. It was transferred into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.4 methanol in DCM to afford Int-18.1. MS (ES): m / z 262.19 [M+H]+.

[0249] Synthesis of compound Int-18.2. A mixture of palladium on carbon (10%, 0.800 g) and compound Int-18.1 (1.5 g, 5.72 mmol, 1.0 equiv) in methanol (5 mL) was stirred under hydrogen (1 atm) for 2 h. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford Int-18.2. MS(ES): m / z 233.21 [M+H]+.

[0250] Synthesis of compound Int-18.3. To a solution of Int-18.2 (0.900 g, 4.58 mmol, 1.0 equiv) in THF (15 mL) was added lithium aluminum hydride (1.088 g, 13.76 mmol, 5.0 equiv). The mixture was heated to reflux for 1 h. It was cooled to rt and quenched by stirring with sodium sulfate hydrate powder. It was filtered and washed with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.8% methanol in DCM) to afford Int-18.3. MS(ES): m / z 219.22 M+H]+.

[0251] Synthesis of compound Int-18. Compound Int-18 was prepared from Int-18.3, following the procedure described in the synthesis of Int-13. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.4% methanol in DCM). MS(ES): m / z 261.28 [M+H]+.Preparation of Intermediate Int-19: (S)-2-((3-isothiocyanato-5- (trifluoromethyl)phenoxy)methyl)-1-methylpyrrolidine

[0252] Synthesis of compound Int-19.1. To solution of 1-fluoro-3-nitro-5- (trifluoromethyl)benzene (0.7 g, 3.35 mmol, 1.0 equiv) and tert-butyl (S)-2- (hydroxymethyl)pyrrolidine-1-carboxylate (0.808 g, 4.02 mmol, 1.2 equiv) in DMF (12 mL) was added sodium hydride (0.201 g, 5.025 mmol, 1.5 equiv) at 0 °C and reaction mixture was stirred at room temperature for 30 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 The residue was purified by flash column chromatography on silica gel (CombiFlash®, 15-17% ethyl acetate in hexane) to afford Int-19.1 MS(ES): m / z 391.0 [M+H]+.

[0253] Synthesis of compound Int-19.2. A mixture of compound Int-19.1 (0.420 g, 1.08 mmol, 1.0 equiv) and 10% palladium on carbon (0.200 g) in methanol (10 mL) was stirred under hydrogen (1 atm) for 2 h. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 20-23% ethyl acetate in hexane) to afford Int-19.2. MS(ES): m / z 361.2 [M+H]+.

[0254] Synthesis of compound Int-19.3. To a solution of Int-19.2 (0.270 g, 0.749 mmol, 1.0 equiv) in THF (5 mL) was added lithium aluminum hydride (1 M in THF, 5.2 mL, 5.243 mmol, 7.0 equiv) at 0 °C. The reaction mixture was heated to reflux for 30 min. It was cooled to room temperature, transferred into ice, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 60-65% ethyl acetate in hexane) to afford Int-19.3. MS(ES): m / z 275.1 [M+H]+.

[0255] Synthesis of compound Int-19. Compound Int-19 was prepared from Int-19.3, following the procedure described in the synthesis of Int-13. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol in DCM). MS(ES): m / z 317.2 [M+H]+. Preparation of Intermediate Int-20: (R)-2-((3-isothiocyanato-5- (trifluoromethyl)phenoxy)methyl)-1-methylpyrrolidine

[0256] Synthesis of compound Int-20. Compound Int-20 was prepared by following the procedures described in the synthesis of Int-19. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol in DCM). MS(ES): m / z 317.3 [M+H]+. Preparation of Intermediate Int-21: (S)-3-(3-isothiocyanato-5-(trifluoromethyl)phenoxy)-1- methylpyrrolidine

[0257] Synthesis of compound Int-21.1. To solution of 1-fluoro-3-nitro-5- (trifluoromethyl)benzene (1.0 g, 4.78 mmol, 1.0 equiv) and (S)-1-methylpyrrolidin-3-ol (0.580 g, 5.74 mmol, 1.2 equiv) in DMF (10 mL) was added sodium hydride (0.382 g, 9.56 mmol, 2.0 equiv) at 0 °C and stirred at room temperature for 30 min. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM) to afford Int-21.1. MS(ES): m / z 291.2 [M+H]+.

[0258] Synthesis of compound Int-21.2. A mixture of compound Int-21.1 (0.670 g, 2.31 mmol, 1.0 equiv) and 10% palladium on carbon (0.350 g) in methanol (5 mL) was stirred under hydrogen (1 atm) for 1 h. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford Int-21.1. MS(ES): m / z 261.1 [M+H]+.

[0259] Synthesis of compound Int-21. Compound Int-21 was prepared from Int-21.2, following the procedure described in the synthesis of Int-13. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.0% methanol in DCM). MS(ES): m / z 303.2 [M+H]+. Preparation of compound Int-22: (S)-3-(3-isothiocyanato-5-(trifluoromethyl)phenoxy)-1- methylpyrrolidine

[0260] Synthesis of compound Int-22. Compound Int-22 was prepared by following the procedures described in the synthesis of Int-21. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.0% methanol in DCM). MS(ES): m / z 303.2 [M+H]+. Preparation of Intermediate Int-23: tert-butyl 3-((3-amino-5- (trifluoromethyl)benzyl)oxy)azetidine-1-carboxylate

[0261] Synthesis of compound Int-23.1. To a solution of (3-nitro-5- (trifluoromethyl)phenyl)methanol (2.0 g, 9.04 mmol, 1.0 equiv) in THF (30 mL) was added triphenylphosphine (4.74 g, 18.09 mmol, 2.0 equiv) followed by N-bromosuccinimide (3.22 g, 18.09 mmol, 2.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. It was transferred into a saturated aqueous solution of 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- 23.1. MS(ES): m / z 285.32 [M+H]+.

[0262] Synthesis of compound Int-23.2. To a solution of Int-23.1 (0.800 g, 4.62 mmol, 1.0 equiv) in THF (10 mL) was added NaH (60%, 0.277 g, 6.93 mmol, 1.5 equiv) in portions at 0 °C stirred for 20 min. A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.6 g, 5.54 mmol, 1.2 equiv) in THF (5 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 16 h. 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 flash column chromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexane) to afford Int-23.2. MS(ES): m / z 377.62 [M+H]+.

[0263] Synthesis of compound Int-23. A mixture of Int-23.2 (0.850 g, 2.26 mmol, 1.0 equiv) and 10% palladium on carbon (0.450 g) in methanol (15 mL) was stirred under hydrogen (1 atm) for 2 h. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford Int-23. MS(ES): m / z 347.51 [M+H]+. Preparation of Intermediate Int-24-a and I-24-b: (R)- 2-(3-isothiocyanato-5- (trifluoromethyl)phenyl)-1-methylpyrrolidine and (S)- 2-(3-isothiocyanato-5- (trifluoromethyl)phenyl)-1-methylpyrrolidine

[0264] Synthesis of compound Int-24.1. A mixture of 3-bromo-5-(trifluoromethyl)aniline (2.5 g, 10.42 mmol, 1.0 equiv), (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (4.4 g, 20.83 mmol, 2.0 equiv) and sodium carbonate (3.31 g, 31.26 mmol, 3.0 equiv) in dimethoxyethane (25 mL) was degassed by bubbling through a stream of argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.042 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 80 °C for 5 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in DCM) to afford Int-24.1. MS(ES): m / z 327.2 [M+H]+.

[0265] Synthesis of compound (±)-Int-24.2. A mixture of compound Int-24.1 (2.1 g, 6.44 mmol, 1.0 equiv) and 20% palladium hydroxide (1.0 g) in methanol (20 mL) was stirred under hydrogen (1 atm) for 1 h. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford (±)-Int-24.2. MS(ES): m / z 331.1 [M+H]+.

[0266] Synthesis of compound (±)-Int-24.3. To a solution of (±)-Int-24.2 (1.37 g, 4.15 mmol, 1.0 equiv) in THF (10 mL) was added lithium aluminum hydride (1 M in THF, 29 mL, 29.05 mmol, 7.0 equiv) at 0 °C. The reaction mixture was heated to reflux for 30 min. It was cooled to room temperature, transferred into ice, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-Int-24.3. MS(ES): m / z 245.1 [M+H]+. The racemate was subjected to chiral HPLC separation (column CHIRALPAK AD-H (250 mm * 21 mm, 5 μm); mobile phases: (A) 0.1% DEA in n-hexane (B) 0.1% DEA in isopropanol; flow rate = 30 mL / min) to afford first eluting fraction (Int-24.3-a) and second eluting fraction (Int-24.3- b). MS(ES): m / z: 245.1 [M+H]+.

[0267] Synthesis of compound Int-24-a and Int-24-b. Compound Int-24-a and Int-24-b were prepared from Int-24.3-a and Int-24.4-b respectively, following the procedure described in the synthesis of Int-13. The products were purified by flash column chromatography on silica gel (CombiFlash®, 12% ethyl acetate in hexane). MS(ES): m / z 287.2 [M+H]+. Preparation of Intermediate Int-25: tert-butyl 3-(3-amino-5- (trifluoromethyl)phenoxy)azetidine-1-carboxylate

[0268] Synthesis of compound Int-25.1. To a solution of 1-fluoro-3-nitro-5- (trifluoromethyl)benzene (1.0 g, 4.78 mmol, 1.0 equiv) in DMF (10 mL) was added sodium hydride (0.313 g, 7.17 mmol, 1.5 equiv) at 0 °C and stirred for 1 h. To the mixture was added tert-butyl 3-hydroxyazetidine-1-carboxylate (1.24 g, 7.17 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 2 h. It was transferred into ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 38% ethyl acetate in hexane) to afford Int-25.1. MS(ES): m / z: 363.31 [M+H]+.

[0269] Synthesis of compound Int-25. A mixture of Int-25.1 (0.700 g, 1.93 mmol, 1.0 equiv), iron powder (0.541 g, 9.66 mmol, 5.0 equiv) and ammonium chloride (0.512 g, 9.66mmol, 5.0 equiv) in ethanol:water (8:2, 6 mL) was stirred at 80 °C for 2 h. The reaction mixture was filtered through a pad of Celite® and rinsed with ethanol. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 63% ethyl acetate in hexane) to afford Int-25. MS(ES): m / z 333.32 [M+H]+. Preparation of Intermediate Int-26: 3-isothiocyanato-1-(7-oxaspiro[3.5]nonan-2-yl)-5- (trifluoromethyl)-1H-pyrazole

[0270] Synthesis of compound Int-26.1. To a solution of 4-methylenetetrahydro-2H-pyran (5.0 g, 50.95 mmol, 1.0 equiv) in tert-butyl methyl ether (100 mL) was added zinc-copper couple (71.73 g, 560.45 mmol, 11.0 equiv) followed by a solution of diphosgene (37.10 g, 204.08 mmol, 4.0 equiv) in dimethoxyethane (40 mL) at 0 °C. The mixture was stirred at room temperature for 18 h. It was filtered through a pad of Celite®, and the filtrate was washed with solution of sodium bicarbonate and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Int-26.1. MS(ES): m / z: 210.0 [M+H]+.

[0271] Synthesis of compound Int-26.2. A mixture of Int-26.1 (8.9 g, 42.58 mmol, 1.0 equiv), saturated aqueous ammonium chloride and zinc (27.67 g, 425.8 mmol, 10.0 equiv) in methanol (200 mL) was stirred at room temperature for 16 h. The reaction mixture was filtered through a pad of Celite®, rinsed with diethyl ether and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate in hexane) to afford Int-26.2. MS(ES): m / z: 141.1 [M+H]+.

[0272] Synthesis of compound Int-26.3. To a solution of Int-26.2 (3.9 g, 27.82 mmol, 1.0 equiv) in methanol (40 mL) was added sodium borohydride (0.308 g, 8.34 mmol, 0.3 equiv) at 0 °C and stirred at room temperature for 16 h. 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 to afford Int-26.3. MS(ES): m / z: 143.1 [M+H]+.

[0273] Synthesis of compound Int-26.4. To a solution of Int-26.3 (3.0 g, 21.1 mmol, 1.0 equiv) and triethylamine (8.8 mL, 63.3 mmol, 3.0 equiv) in DCM (30 mL) at 0 °C was added methanesulfonyl chloride (2.4 mL, 31.65 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 30 min. It was transferred into ice-water, stirred, and extracted with DCM. The combined organic layers were washed with saturated sodium bicarbonate followed by brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Int-26.4. MS(ES): m / z: 221.0 [M+H]+.

[0274] Synthesis of compound Int-26.5. A mixture of Int-26.4 (2.8 g, 12.22 mmol, 1.0 equiv), 3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl)-1H-pyrazole (4.04 g, 18.32 mmol, 1.3 equiv) and cesium carbonate (7.94 g, 24.44 mmol, 2.0 equiv) in DMF (15 mL) was stirred at 90 °C for 4 h. It was transferred into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% ethyl acetate in hexane) to afford Int-26.5. MS (ES): m / z 354.2 [M+H]+.

[0275] Synthesis of compound Int-26.6. A solution of Int-26.5 (1.5 g, 4.24 mmol, 1.0 equiv) and hydroxylamine hydrochloride (11.4 g, 169.6 mmol, 40 equiv) in ethanol:water (2:1, 50 mL) was heated to reflux for 3 h. It was transferred into ice-water and 2 N sodium hydroxide was added to adjust pH to 10. The mixture was 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®, 2.5% methanol in DCM) to afford Int-26.6. MS(ES): m / z 276.0 [M+H]+.

[0276] Synthesis of compound Int-26. Compound Int-26 was prepared from Int-26.6, following the procedures described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, DCM). MS(ES): m / z 318.2 [M+H]+. Preparation of Intermediate Int-27-a and Int-27-b: (R)-2-(4-isothiocyanato-2- (trifluoromethyl)phenyl)-1-methylpyrrolidine and (S)-2-(4-isothiocyanato-2- (trifluoromethyl)phenyl)-1-methylpyrrolidine

[0277] Synthesis of compound Int-27.1. To mixture of 4-bromo-3-(trifluoromethyl)aniline (3.0 g, 12.5 mmol, 1.0 equiv), (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (3.9 g, 18.7 mmol, 1.5 equiv) and sodium carbonate (5.2 g, 50.02 mmol, 4.0 equiv) in dimethoxyethane (40 mL) was degassed by bubbling argon through for 10 min. Tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.3 mmol, 0.9 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 80 °C for 5 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 8.0% methanol in DCM) to afford Int-27.1. MS(ES): m / z 327.32 [M+H]+.

[0278] Synthesis of compound (±)-Int-27.2. A mixture of compound Int-27.1 (1.4 g, 4.29 mmol, 1.0 equiv) and 20% palladium hydroxide (1.0 g) in methanol (38 mL) was stirred underhydrogen (1 atm) for 7 h. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford (±)-Int-27.2. MS(ES): m / z 331.35 [M+H]+. The racemate was subjected to chiral SFC separation: (column CHIRALPAK AD-H (250 mm * 4.6 mm, 5 μm); mobile phases: (A) CO2(B) 0.1% diethylamine in isopropanol:acetonitrile (50:50); flow rate = 75 mL / min) to afford first eluting faction (Int- 27.2-a) and second eluting fraction (Int-27.2-b).

[0279] Synthesis of compound Int-27.3-a and Int-27.3-b. To a solution of Int-27.2-a (0.410 g, 1.24 mmol, 1.0 equiv) in THF (10 mL) was added lithium aluminum hydride (1 M in THF, 8.6 mL, 8.69 mmol, 7.0 equiv) at 0 °C. The reaction mixture was heated to reflux for 30 min. It was cooled to room temperature and stirred with sodium sulfate decahydrate. The solids were removed by filtration and rinsed with ethyl acetate. The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Int-27.2-a. MS(ES): m / z 245.26[M+H]+. Int-27.3-b was prepared from Int-27.2-b, following the same procedure.

[0280] Synthesis of compound Int-27-a and Int-27-b. Compound Int-27-a was prepared from Int-27.3-a, following the procedure described in the synthesis of Int-13. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.1% methanol in DCM). MS(ES): m / z 287.32[M+H]+. Int-27-b was prepared from Int-27.3-b in the same manner. Preparation of Intermediate Int-28: 4-isothiocyanato-2-(pyrrolidin-1-yl)-6- (trifluoromethyl)pyridine

[0281] Synthesis of compound Int-28.1. A mixture of 2-chloro-6-(trifluoromethyl)pyridin- 4-amine (0.500 g, 2.54 mmol, 1.0 equiv), pyrrolidine (0.271 g, 3.82 mmol, 1.5 equiv) and potassium carbonate (1.05 g, 7.62 mmol, 3.0 equiv) in DMF (5 mL) was stirred at 150 °C for 18 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 20-30% ethyl acetate in hexane) to afford Int-28.1. MS(ES): m / z 232.5 [M+H]+.

[0282] Synthesis of compound Int-28. Compound Int-28 was prepared from Int-28.1, following the procedures described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5-10% ethyl acetate in hexane). MS(ES): m / z 274.5 [M+H]+. Preparation of Intermediate Int-29: 2'-isothiocyanato-5',6'-dihydrospiro[cyclobutane-1,4'- pyrrolo[1,2-b]pyrazole]

[0283] Synthesis of compound Int-29.1. To a solution of lithium bis(trimethylsilyl)amide (1 M in THF, 17.4 mL, 17.44 mmol, 2.2 equiv) in anhydrous THF (25 mL) at -78 °C was added solution of 6-oxaspiro[3.4]octan-5-one (1.0 g, 7.93 mmol, 1.0 equiv) and acetonitrile (0.83 mL, 15.86 mmol, 2.0 equiv) in THF (8 mL). The reaction mixture was stirred at -78 °C for 30 min and it was allowed to warm to room temperature, stirring for 2 h. It was transferred into saturated aqueous ammonium chloride solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford residue which was purified by flash column chromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexane) to afford Int-29.1.

[0284] Synthesis of compound Int-29.2. To a solution of Int-29.1 (0.800 g, 4.78 mmol, 1.0 equiv) in ethanol (10 mL) was added hydrazine monohydrate (0.358 g, 7.17 mmol, 1.5 equiv). The reaction mixture was stirred at 60 °C for 72 h. The reaction mixture was cooled to room temperature and carbon dioxide was bubbled through it for 1 h. The reaction mixture was concentrated under reduced pressure. To the residue was added methanol (15 mL), stirred, and the precipitated solids were removed by filtration. The filtrate was concentrated under reduced pressure to afford Int-29.2. MS(ES): m / z 182.1 [M+H]+.

[0285] Synthesis of compound Int-29.3. To a solution of Int-29.2 (0.610 g, 3.37 mmol, 1.0 equiv) in THF (10 mL) was added thionyl chloride (1.22 mL, 16.85 mmol, 5.0 equiv). Thereaction mixture was stirred at room temperature for 3 h. It was slowly was transferred into a mixture of aqueous ammonium hydroxide and ice, stirred, and extracted DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford residue which was purified by flash column chromatography on silica gel (CombiFlash®, 2% methanol in DCM) to afford Int-29.3. MS(ES): m / z 164.1 [M+H]+.

[0286] Synthesis of compound Int-29. Compound Int-29 was prepared from Int-29.3, following the procedures described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, DCM). MS(ES): m / z 205.9 [M+H]+. Preparation of Intermediate Int-30: 2'-isothiocyanato-5'-methyl-6',7'-dihydro-5'H- spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine]

[0287] Synthesis of compound Int-30.1. To a solution of Int-8.2 (0.600 g, 4.81 mmol, 1.0 equiv) in toluene (6 mL) was added hexane-2,5-dione (0.618 g, 5.41 mmol, 1.5 equiv) followed by acetic acid (catalytic) at room temperature. The reaction mixture was stirred at 130 °C for 3 hr. It was cooled to rt and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 0.5% methanol in DCM) to afford Int- 30.1. MS(ES): m / z 245 [M+H]+.

[0288] Synthesis of compound Int-30.2. To a solution of Int-30.2 (0.500 g, 2.55 mmol, 1.0 equiv) in THF (10 mL) was added titanium isopropoxide (1.45 g, 5.102 mmol, 2.0 equiv) followed by ethyl magnesium bromide (1 M in THF, 3.4 mL, 10.2 mmol, 4.0 equiv) at 80 °C. The reaction mixture was stirred for 30 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 to afford material. The residuewas purified by flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate in hexane) to afford Int-30.2. MS(ES): m / z: 257[M+H]+.

[0289] Synthesis of compound Int-30.3. To solution of Int-30.3 (0.450 g, 1.75 mmol, 1.0 equiv) in ethanol (8 mL) and water (2 mL) was added hydroxylamine hydrochloride (3.65 g, 52.5 mmol, 30.0 equiv). The reaction mixture was stirred at 60 °C for 1 h. It was transferred into ice- cold saturated aqueous solution of sodium bicarbonate 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 trituration with diethyl ether to afford Int-30.3. MS(ES): m / z: 179 [M+H]+.

[0290] Synthesis of compound Int-30. Compound Int-30 was prepared from Int-30.3, following the procedures described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, 0.5% methanol in DCM). MS(ES): m / z 221 [M+H]+. Preparation of Provided Compounds Example 1: (R)-N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1- methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxyazetidine-1-carboxamide

[0291] Synthesis of compound 1.1. To a solution of benzyl alcohol (17.05 g, 157.69 mmol, 1.0 equiv) in THF (250 mL) at 0 °C was added sodium hydride (12.61 g, 315.38 mmol, 2.0 equiv) in small portions. The mixture was stirred for 1 h and 2-chloro-4-nitropyridine (25 g, 157.69 mmol, 1.0 equiv) was added in portions. The reaction mixture was stirred at 0 °C for 2 h. It was poured over ice, stirred, and extracted with ethyl acetate three times. 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 1.1. MS (ES): m / z 220.13 [M+H]+.

[0292] Synthesis of compound 1.2. A solution of compound 1.1 (20 g, 91.05 mmol, 1.0 equiv) in THF (200 mL) was degassed by bubbling argon through for 10 min.2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (4.34 g, 9.105 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium (4.17 g, 4.55 mmol, 0.05 equiv) were added under argon atmosphere and degassed by bubbling through a stream of argon for 5 min. To the mixture was added a solution of lithium bis(trimethylsilyl)amide (1 M in THF, 182 mL, 182.1 mmol, 2.0 equiv) and it was stirred at 60 °C for 1 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®, 3% methanol in DCM as eluant) to afford 1.2. MS (ES): m / z 201.2 [M+H]+.

[0293] Synthesis of compound 1.3. To a solution of 1.2 (2.0 g, 9.99 mmol, 1.0 equiv) and triethylamine (4.2 mL, 29.97 mmol, 3.0 equiv) in THF (20 mL) was added phenyl chloroformate(4.67 g, 29.97 mmol, 3.0 equiv) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 3 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1.1. MS (ES): m / z 321.3 [M+H]+. It was used in the next step without further purification.

[0294] Synthesis of compound 1.4. To a solution of 1.3 (3.0 g, 9.36 mmol, 1.0 equiv) and triethylamine (12.5 mL, 84.24 mmol, 9.0 equiv) in DMF (20 mL) was added 3-methoxyazetidine (1.06 g, 12.17 mmol, 1.3 equiv) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 16 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in DCM) to afford 1.4. MS (ES): m / z 314.3 [M+H]+.

[0295] Synthesis of compound 1.5. A mixture of compound 1.4 (1.1 g, 3.51 mmol, 1.0 equiv) and 10% palladium on carbon (0.5 g) in methanol (10 mL) was stirred under hydrogen (1 atm) for 3 h. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford 1.5. MS(ES): m / z 224.2 [M+H]+.

[0296] Synthesis of compound 1.6. A mixture of 1.5 (0.760 g, 3.4 mmol, 1.0 equiv) in DMF (10 mL), Int-1 (0.699 g, 4.09 mmol, 1.2 equiv) and sodium carbonate (0.720 g, 6.8 mmol, 2.0 equiv) was stirred at 90 °C for 12 h. It was cooled to room temperature, poured into ice-water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.8% methanol in DCM) to afford 1.6. MS(ES): m / z 375.3 [M+H]+.

[0297] Synthesis of compound 1.7. To a solution of 1.6 (0.700 g, 1.87 mmol, 1.0 equiv) in ethanol-water (2:1, 10 mL) was added iron powder (0.733 g, 13.09 mmol, 7.0 equiv) followed by ammonium chloride (0.706 g, 13.09 mmol, 7.0 equiv). The reaction mixture was stirred at 90 °C for 3 h. It was poured into 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. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM) to afford 1.6. MS(ES): m / z 345.5 [M+H]+.

[0298] Synthesis of compound 1.8. To a solution of 1.7 (0.400 g, 1.16 mmol, 1.0 equiv) in THF (5 mL) was added 1,1'-thiocarbonyldiimidazole (1.03 g, 5.8 mmol, 5.0 equiv). The reaction mixture was stirred at 70 °C for 1 h. It was cooled to room temperature and poured into ice- water. The solids precipitated were collected by filtration and triturated with hexane to afford 1.8. MS(ES): m / z: 387.4 [M+H]+.

[0299] Synthesis of compound 1.9. To a solution of 1.8 (0.350 g, 0.905 mmol, 1.0 equiv) in DCM (5 mL) was added sulfuryl chloride (2.7 mL, 33.48 mmol, 37 equiv) at 0 °C and stirred for 10 min. It was transferred into a saturated sodium bicarbonate solution, 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®, 2.4% methanol in DCM) to afford 1.9. MS (ES): m / z 389.8 [M+H]+.

[0300] Synthesis of compound 1. A mixture of 1.9 (0.080 g, 0.205 mmol, 1.0 equiv), Int-3 (0.052 g, 0.246 mmol, 1.2 equiv) and potassium carbonate (0.070 g, 0.512 mmol, 2.5 equiv) in 1,4-dioxane (2 mL) was degassed by bubbling through a stream of argon for 10 min.4,5- Bis(diphenylphosphino)-9,9-dimethylxanthene (0.023 g, 0.041 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (0.01 g, 0.021 mmol, 0.1 equiv) were added, and degassed for another 5 min. The reaction mixture was stirred at 80 °C for 3 h. It was cooled to room temperature, transferred into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM) to afford compound 1. MS(ES): m / z: 562.6 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 9.89 (s, 1H), 9.20 (s, 1H), 8.11-8.10 (d, J = 5.6Hz, 1H), 7.96-7.95 (d, J = 2.4Hz, 1H), 7.63-7.62 (d, J = 2.4Hz, 1H), 7.47 (bs, 1H), 6.60-6.58 (m, 2H), 5.77(s, 1H), 5.26 (bs, 1H), 4.13-4.07 (m, 5H), 3.88-3.83 (m, 2H), 3.75-3.73 (m, 2H), 3.68 (s, 3H), 3.19 (s, 3H), 2.27-2.24 (m, 1H), 1.41 (s, 9H). Example 3: Methyl (4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate

[0301] Synthesis of compound 3.1. A mixture of benzyl alcohol (102.3 g, 946.13 mmol, 1.0 equiv) and cesium carbonate (768.7 g, 2365.3 mmol, 2.5 equiv) in DMF (1000 mL) was stirred at room temperature for 2 h. A solution of 2-chloro-4-nitropyridine (150 g, 946.13 mmol, 1.0 equiv) in DMF (500 mL) was added and stirred for 16 h. It was poured into ice-water, stirred, and precipitated solids were collected by filtration and dried under vacuum to afford 3.1. MS (ES): m / z 220.5 [M+H]+.

[0302] Synthesis of compound 3.2. A solution of 3.1 (150 g, 682.85 mmol, 1.0 equiv) in THF (1500 mL) was degassed by bubbling through a stream of argon for 10 min. To the solution was added 2-dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′-biphenyl]-2-yl]phosphane (32.55 g, 68.28 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (31.26 g, 34.14 mmol, 0.05 equiv) and degassed for another 10 min. Lithium bis(trimethylsilyl)amide solution (1 M in THF, 1365 mL, 1365.7 mmol, 2.0 equiv) was added and the reaction mixture was stirred at 60 °C for 1 h. It was concentrated under reduced pressure. The residue was added to ice and 6 N hydrochloric acid (1500 mL) slowly and extracted with ethyl acetate. The aqueous layer was separated and neutralized with solid sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to afford 3.2. MS(ES): m / z 201.2 [M+H]+. It was used in the next step without purification.

[0303] Synthesis of compound 3.3. To a solution of 3.2 (100 g, 499 mmol, 1.0 equiv) in methanol (1000 mL) was added di-tert-butyl dicarbonate (130.5 g, 598.8 mmol, 1.2 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. After completion of reaction, precipitated solid was filtered out and rinsed with methanol, dried under vacuum to afford 3.3. MS(ES): m / z 259.2 [M+H]+.

[0304] Synthesis of compound 3.4. A mixture of 3.3 (106 g, 410.4 mmol, 1.0 equiv) and 10% palladium on carbon (100 g) in methanol (1000 mL) was stirred under hydrogen (1 atm) for 1 h. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford 3.4. MS(ES): m / z 169.1 [M+H]+.

[0305] Synthesis of compound 3.5. To a solution of 3.4 (66 g, 392.5 mmol, 1.0 equiv) in DMF (660 mL) was added Int-2 (64.55 g, 314 mmol, 0.8 equiv) followed by sodium carbonate (124.8 g, 1177.5 mmol, 3.0 equiv). The reaction mixture was stirred at 60 °C for 3 h. It was poured into ice-water, and precipitated solids were collected by filtration, dried under vacuum to afford 3.5. MS(ES): m / z 354.5 [M+H]+.

[0306] Synthesis of compound 3.6. Compound 3.6 was prepared from compound 3.5 following the procedure described in the synthesis of compound 1.7. The product was purified by flash column chromatography on silica gel (CombiFlash®, 7.0% methanol in DCM) to afford 3.6. MS(ES): m / z 324.5 [M+H]+.

[0307] Synthesis of compound 3.7. To a solution of 3.6 (38 g, 117.38 mmol, 1.0 equiv) and Int-5 (41.23 g, 176 mmol, 1.5 equiv) in THF (1300 mL) was added potassium tert-butoxide (1 M in THF, 704 mL, 704.28 mmol, 6.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. It was poured into ice-water, and product 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®, 12% methanol in DCM) to afford 3.7. MS(ES): m / z: 524.2 [M+H]+.

[0308] Synthesis of compound 3.8. To a solution of 3.7 (0.500 g, 0.954 mmol, 1.0 equiv) in DMA (11 mL) were added zinc (0.012 g, 0.190 mmol, 0.2 equiv) and zinc cyanide (0.056 g, 0.477 mmol, 0.5 equiv). The reaction mixture was degassed by bubbling through a stream ofargon for 10 min. Tris(dibenzylideneacetone)dipalladium(0) (0.131 g, 0.143 mmol, 0.15 equiv) and 1,1′-bis(diphenylphosphino)ferrocene (0.158 g, 0.286 mmol, 0.3 equiv) were added, and degassed for 5 min. The reaction mixture was stirred at 190 °C in a microwave reactor for 2 h. It was cooled to room temperature, transferred into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford material.

[0309] Synthesis of I-3. To a solution of 3.8 (9.6 g, 21.03 mmol, 1.0 equiv) in THF (200 mL) was added triethylamine (5.9 mL, 42.06 mmol, 2.0 equiv) at 0 °C followed by methyl chloroformate (1.8 mL, 23.13 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 4 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®, 2.4% methanol in DCM) to afford I-3. MS(ES): m / z: 515.2 [M+H]+.1H NMR (DMSO-d6, 400MHz): δ 10.41 (s, 1H), 9.07 (s, 1H), 8.66 (s, 1H), 8.34 (s, 1H), 8.23-8.21 (d, J = 6.8Hz 2H), 7.49 (s, 1H), 6.76-6.75 (d, J = 5.2Hz 1H), 3.98 (s, 3H), 3.68 (s, 3H), 3.64 (s, 3H). Example 4: 3-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1-dimethylurea

[0310] Synthesis of I-4. To a solution of 3.8 (0.040 g, 0.087 mmol, 1.0 equiv) and dimethylcarbamic chloride (0.010 g, 0.096 mmol, 1.1 equiv) in THF (2 mL) was added potassium tert-butoxide (1M in THF) (0.52 mL, 0.522 mmol, 6.0 equiv) at 0 °C and stirred at same temperature for 15 min. The reaction mixture was poured into ice-water, and product 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®, 2.5% methanol in DCM) to afford I-4. MS(ES): m / z: 528.3 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 9.04-9.03 (d, J =6.8Hz 2H), 8.66 (s, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.48 (s, 1H), 6.69 (bs, 1H), 3.97 (s, 3H), 3.67 (s, 3H), 2.90 (s, 6H). Example 5: 1-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methylurea

[0311] Synthesis of I-5. To a solution of 3.8 (0.040 g, 0.087 mmol, 1.0 equiv) and methylcarbamic chloride (0.009 g, 0.105 mmol, 1.2 equiv) in THF (2 mL) was added potassium tert-butoxide (1M in THF) (0.35 mL, 0.348 mmol, 4.0 equiv) at 0 °C and stirred at same temperature for 15 min. The reaction mixture was poured into ice-water, and product 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®, 4.5% methanol in DCM) to afford I- 5. MS(ES): m / z: 514.2 [M+H]+.1H NMR (DMSO-d6, 400MHz): δ 9.21 (s, 1H), 9.07 (s, 1H), 8.66-8.65 (d, J = 1.6Hz, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 8.14-8.13 (d, J = 6.0Hz, 1H), 7.80 (bs, 1H), 7.09-7.07 (d, J = 7.2Hz, 1H), 7.04 (s, 1H), 3.98 (s, 3H), 3.67 (s, 3H), 2.70-2.69 (d, 3H). Example 6: N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-4- methylpiperazine-1-carboxamide

[0312] Synthesis of compound 6.1 To a solution of 3.8 (0.025 g, 0.054 mmol, 1.0 equiv) and triethylamine (0.016 g, 0.162 mmol, 3.0 equiv) in THF (3 mL) was added phenyl chloroformate (0.012 g, 0.081 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min. 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 to afford 6.1. MS(ES): m / z: 577.4 [M+H]+.

[0313] Synthesis of I-6. To a solution of 6.1 (0.030 g, 0.052 mmol, 1.0 equiv) and triethylamine (0.015 g, 0.156 mmol, 3.0 equiv) in dimethyl sulfoxide (3 mL) was added 1- methylpiperazine (0.008 g, 0.078 mmol, 1.5 equiv). The reaction mixture was stirred at 80 °C for 15 min. It was transferred into 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®, 7.0% methanol in DCM) to afford I-6. MS(ES): m / z: 583.3 [M+H]+, 1H NMR (DMSO-d6, 400MHz): δ 9.37 (s, 1H), 9.06 (s, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 8.20 (bs, 2H), 7.47 (s, 1H), 6.70 (s, 1H), 3.98 (s, 3H), 3.68 (s, 3H), 3.43 (bs, 4H), 2.45 (bs, 4H), 2.29 (s, 3H). Example 7: N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)azetidine-1- carboxamide

[0314] Synthesis of I-7. Compound I-7 was prepared from 6.1 and azetidine hydrochloride, following the procedure described in the synthesis of I-6. The product was purified by preparative HPLC. MS(ES): m / z: 540.4 [M+H]+.1H NMR (DMSO-d6, 400MHz): δ 9.23 (s, 1H), 9.06 (s, 1H), 8.66 (s, 1H), 8.31 (s, 1H), 8.20 (bs, 1H), 8.18-8.17 (d, J = 6Hz, 1H), 7.58 (s, 1H), 6.68 (s, 1H), 3.98 (s, 3H), 3.95 (bs, 4H), 3.67 (s, 3H), 2.16-2.12 (m, 2H). Example 8: N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3- hydroxyazetidine-1-carboxamide

[0315] Synthesis of I-8. Compound I-8 was prepared from 6.1 and azetidin-3-ol hydrochloride, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM). MS(ES): m / z: 556.3 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 9.29 (s, 1H), 9.05 (s, 1H), 8.66 (s, 1H), 8.31 (s, 1H), 8.20 (bs, 1H), 8.18-8.17 (d, J = 5.6Hz, 1H), 7.58 (bs, 1H), 6.69-6.67 (m, 1H), 5.63-5.62 (d, J = 6.4Hz, 1H), 4.40-4.38 (m, 1H), 4.14-4.11 (m, 2H), 3.97 (s, 3H), 3.67 (s, 3H), 3.19-3.17 (m, 2H). Example 9: N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3- methoxyazetidine-1-carboxamide

[0316] Synthesis of I-9. Compound I-9 was prepared from 6.1 and 3-methoxyazetidine hydrochloride, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM). MS(ES): m / z: 570.3 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 9.38 (s, 1H), 9.05 (s, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 8.19-8.18 (m, 2H), 7.57 (bs, 1H), 6.69 (bs, 1H), 4.14 (bs, 4H), 3.98 (s, 3H), 3.76 (bs, 1H), 3.68 (s, 3H), 3.20 (s, 3H). Example 10: Methyl (4-((2-((1-(2-oxaspiro[3.3]heptan-6-yl)-5-(trifluoromethyl)-1H-pyrazol-3- yl)amino)-7-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate

[0317] Synthesis of compound 10.1. To a solution of 3.6 (8.0 g, 24.71 mmol, 1.0 equiv) in THF (80 mL) was added 1,1'-thiocarbonyldiimidazole (21.99 g, 123.5 mmol, 5.0 equiv). The reaction mixture was stirred at 70 °C for 1 h. It was cooled to room temperature and poured into ice-water. The solids precipitated were collected by filtration and triturated with hexane to afford 10.1. MS(ES): m / z: 332.2 [M+H]+.

[0318] Synthesis of compound 10.2. To a solution of 10.1 (2.0 g, 5.47 mmol, 1.0 equiv) in DCM (20 mL) was added sulfuryl chloride (16.4 mL, 202.39 mmol, 37 equiv) at 0 °C and the reaction mixture was stirred for 10 min. It was transferred into saturated sodium bicarbonate solution, 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®, 2.3% methanol in DCM) to afford 10.2. MS (ES): m / z 369.1 [M+H]+.

[0319] Synthesis of I-10. A mixture of 10.2 (0.050 g, 0.135 mmol, 1.0 equiv) and Int-6 (0.043 g, 0.176 mmol, 1.3 equiv) and cesium carbonate (0.131 g, 0.405 mmol, 3.0 equiv) in 1,4- dioxane (2 mL) was degassed by bubbling through a stream of argon for 10 min. 4,5- Bis(diphenylphosphino)-9,9-dimethylxanthene (0.015 g, 0.027 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (0.012 g, 0.013 mmol, 0.1 equiv) were added, and degassed for 5 min. The reaction mixture was stirred at 110 °C for 2 h. It was cooled to room temperature, transferred into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM) to afford I-10. MS(ES): m / z: 579.4 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.58 (s, 1H), 10.32 (s, 1H), 8.15 (bs, 2H), 7.36 (s, 1H), 7.31 (s, 1H), 6.65-6.64 (d, J = 3.6Hz, 1H), 4.88-4.82 (m, 1H), 4.70 (bs, 2H), 4.58 (bs, 2H), 3.96 (s, 3H), 3.60 (s, 3H), 2.81 (bs, 4H).Example 11: N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)pyrrolidine-1- carboxamide

[0320] Synthesis of I-11. Compound I-11 was prepared from 6.1 and pyrrolidine, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.2% methanol in DCM). MS(ES): m / z: 554.3 [M+H]+.1H NMR (DMSO-d6, 400MHz): δ 9.05 (s, 1H), 8.85 (s, 1H), 8.67-8.66 (d, J = 2.0Hz, 1H), 8.32 (s, 1H), 8.20-8.18 (m, 2H), 7.57 (bs, 1H), 6.70-6.69 (d, J = 3.2Hz, 1H), 3.98 (s, 3H), 3.68 (s, 3H), 2.47 (bs, 4H), 1.82 (bs, 4H). Example 12: 2-methoxyethyl (4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)- 1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate

[0321] Synthesis of I-12. A solution of 6.1 (0.110 g, 0.190 mmol, 1.0 equiv), 2- methoxyethan-1-ol (0.022 g, 0.286 mmol, 1.5 equiv) and triethylamine (0.115 g, 1.14 mmol, 6.0 equiv) in dimethyl sulfoxide (5 mL) was stirred at 100 °C for 16 h. It was transferred into 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®, 3.5% methanol in DCM) to afford I-12. MS(ES): m / z: 559.2 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.41 (s, 1H), 9.06 (s, 1H), 8.66 (s, 1H), 8.34 (s, 1H), 8.22-8.21 (m, 2H), 7.47 (bs, 1H), 6.76- 6.75 (d, J = 2.8Hz, 1H), 4.19 (bs, 2H), 3.98 (s, 3H), 3.68 (s, 3H), 3.53 (bs, 2H), 3.27 (s, 3H). Example 13: (R)-N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3- methoxypyrrolidine-1-carboxamide

[0322] Synthesis of I-13. Compound I-13 was prepared from 6.1 and (R)-3- methoxypyrrolidine, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.7% methanol in DCM). MS(ES): m / z: 584.3 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 9.04 (s, 1H), 8.94 (s, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 8.19-8.17 (m, 2H), 7.55-7.54 (d, J = 2.0Hz, 1H), 6.70-6.68 (m, 1H), 3.96 (s, 3H), 3.66 (s, 3H), 3.46 (bs, 2H), 3.38 (bs, 1H), 3.21 (s, 3H), 2.54 (bs, 2H), 1.93 (bs, 2H). Example 14: (S)-N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3- methoxypyrrolidine-1-carboxamide

[0323] Synthesis of I-14. Compound I-14 was prepared from 6.1 and (S)-3- methoxypyrrolidine, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.9% methanol in DCM). MS(ES): m / z: 584.3 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 9.04 (s, 1H), 8.94 (s, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 8.18-8.17 (m, 2H), 7.54 (z, 1H), 6.69-6.68 (m, 1H), 3.96 (s, 3H), 3.66 (s, 3H), 3.46 (bs, 2H), 3.39 (bs, 1H), 3.21 (s, 3H), 2.54 (bs, 2H), 1.93 (bs, 2H). Example 15: 2-Morpholinoethyl (4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)- 1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate

[0324] Synthesis of I-15. Compound I-15 was prepared from 6.1 and 2-morpholinoethan-1- ol, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in DCM). MS(ES): m / z: 614.3 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.37 (s, 1H), 9.06 (s, 1H), 8.65 (s, 1H), 8.33 (s, 1H), 8.19 (bs, 2H), 7.45 (s, 1H), 6.74 (s, 1H), 4.16 (bs, 2H), 3.96 (s, 3H), 3.66 (s, 3H), 3.53 (bs, 4H), 2.40 (bs, 6H). Example 16: Oxetan-3-yl (4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate

[0325] Synthesis of I-16. Compound I-16 was prepared from 6.1 and oxetan-3-ol, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.7% methanol in DCM). MS(ES): m / z: 557.2 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.63 (s, 1H), 9.05 (s, 1H), 8.65 (s, 1H), 8.32 (s, 1H), 8.23-8.22 (d, J = 5.6Hz, 1H), 8.19 (s, 1H), 7.40 (s, 1H), 6.78 (bs, 1H), 5.36 (bs, 1H), 4.77-4.75 (m, 2H), 4.50 (bs, 2H), 3.96 (s, 3H), 3.66 (s, 3H). Example 17: (S)-Tetrahydrofuran-3-yl (4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5- (trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate

[0326] Synthesis of I-17. Compound 6.1 (0.110 g, 0.190 mmol, 1.0 equiv) and (S)- tetrahydrofuran-3-ol (0.084 g, 0.954 mmol, 5.0 equiv) in triethylamine (1.0 mL) was stirred at 110 °C for 6 h. It was transferred into 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 columnchromatography on silica gel (CombiFlash®, 3.2% methanol in DCM) to afford I-17. MS(ES): m / z: 571.3 [M+H]+.1H NMR (DMSO-d6, 400MHz): δ 10.37 (s, 1H), 9.06 (s, 1H), 8.65 (s, 1H), 8.33 (s, 1H), 8.21-8.20 (m, 2H), 7.43 (s, 1H), 6.76-6.75 (d, J = 4.0Hz, 1H), 5.20 (bs, 1H), 3.96 (s, 3H), 3.78-3.72 (m, 4H), 3.66 (s, 3H), 2.16-2.10 (m, 1H), 1.92-1.89 (m, 1H). Example 18: (R)-Tetrahydrofuran-3-yl (4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5- (trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate

[0327] Synthesis of I-18. Compound I-18 was prepared from 6.1 and (R)-tetrahydrofuran-3- ol, following the procedure described in the synthesis of I-17. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.2% methanol in DCM). MS(ES): m / z: 571.3 [M+H]+.1H NMR (DMSO-d6, 400MHz): δ 10.38 (s, 1H), 9.07 (s, 1H), 8.67 (s, 1H), 8.34 (s, 1H), 8.22-8.21 (m, 2H), 7.45 (s, 1H), 6.77 (bs, 1H), 5.21 (bs, 1H), 3.98 (s, 3H), 3.79-3.70 (m, 4H), 3.68 (s, 3H), 2.15-2.11 (m, 1H), 1.92 (bs, 1H). Example 19: 2-(Dimethylamino)ethyl (4-((7-chloro-1-methyl-2-((1-methyl-2-oxo-5- (trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate

[0328] Synthesis of compound 19.1. A solution of 1.3 (0.400 g, 1.25 mmol, 1.0 equiv), triethylamine (0.87 mL, 6.25 mmol, 5.0 equiv) and 2-(dimethylamino)ethan-1-ol (0.166 g, 1.87 mmol, 1.5 equiv) was stirred at 70 °C for 30 min. It was transferred into 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®, 3.0% methanol in DCM) to afford 19.1. MS(ES): m / z: 316.3 [M+H]+.

[0329] Synthesis of compound 19.2. A mixture of compound 19.1 (0.230 g, 0.729 mmol, 1.0 equiv) and 10% palladium on carbon (0.200 g) in methanol (5 mL) was stirred under hydrogen (1 atm) for 30 min. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford 19.2. MS(ES): m / z 226.1 [M+H]+.

[0330] Synthesis of compound 19.3. A mixture of 19.2 (0.150 g, 0.665 mmol, 1.0 equiv), Int-2 (0.109 g, 0.532 mmol, 0.8 equiv) and potassium carbonate (0.275 g, 1.995 mmol, 3.0 equiv) ) in DMF (5 mL) was stirred at room temperature for 1.5 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®, 7.0% methanol in DCM) to afford 19.3. MS(ES): m / z 411.5 [M+H]+.

[0331] Synthesis of compound 19.4. Compound 19.4 was prepared from 19.3 following the procedure described in the synthesis of compound 3.6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 9.0% methanol in DCM). MS(ES): m / z 381.5 [M+H]+.

[0332] Synthesis of I-19. To a solution of 19.4 (0.080 g, 0.210 mmol, 1.0 equiv) in THF (3.0 mL) was added Int-5 (0.098 g, 0.420 mmol, 2.0 equiv) followed by addition of potassium tert- butoxide (1 M in THF, 0.63 mL, 0.630 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was poured into ice-water, and product extractedwith ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in THF (3.0 mL) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.120 g, 0.630 mmol, 3.0 equiv) was added. The reaction mixture was stirred at 70 °C for 1.5 h. It was transferred into water and product extracted with ethyl acetate. This was further purified by flash column chromatography on silica gel (CombiFlash®, 10% methanol in DCM) to afford I-19. MS(ES): m / z: 581.2 [M+H]+.1H NMR (DMSO-d6, 400MHz): δ 10.31 (s, 1H), 8.87 (s, 1H), 8.63 (s, 1H), 8.25 (s, 1H), 8.16 (bs, 2H), 7.36 (s, 1H), 6.67 (bs, 1H), 4.17 (bs, 2H), 3.99 (s, 3H), 3.66 (s, 3H), 3.52-3.45 (m, 2H), 2.30 (bs, 6H). Example 20: 2-Hydroxyethyl (4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)- 1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate

[0333] Synthesis of compound 20.1. To a solution of 2-(benzyloxy)ethan-1-ol (0.063 g, 0.416 mmol, 1.0 equiv) in DMF (5 mL) was sodium hydride (0.049 g, 1.248 mmol, 3.0 equiv) at 0 °C and stirred for 30 min. To the mixture was added 6.1 (0.200 g, 0.346 mmol, 1.0 equiv) and stirred at room temperature for 30 min. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford material This was further purified by flash column chromatography on silica gel (CombiFlash®, 2.2% methanol in DCM) to afford 20.1. MS(ES): m / z: 635.4 [M+H]+.

[0334] Synthesis of I-20. To solution of 20.1 (0.040 g, 0.063 mmol, 1.0 equiv) in DCM (3 mL) was added triflic acid (1 mL) at 0 °C and stirred for 10 min. It was transferred into ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM) to afford I-20. MS(ES): m / z: 545.2 [M+H]+.1H NMR (DMSO-d6, 400MHz): δ 10.63 (s, 1H), 8.99 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 8.14 (bs, 2H), 7.41 (s, 1H), 6.68 (bs, 1H), 4.74 (s, 1H), 4.02 (bs, 2H), 3.91 (s, 3H), 3.61 (s, 3H), 3.51 (bs, 2H). Example 21: 3-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1-dimethylurea

[0335] Synthesis of compound 21.1. To a solution of 3,5-difluoropyridin-2-amine (10 g, 76.87 mmol, 1.0 equiv) in THF (200 mL), was added n-butyl lithium (2.5M in hexane) (61.4 mL, 153.7 mmol, 2.0 equiv) at -78 °C and stirred for 40 min. Hexachloroethane (36.3 g, 153.7 mmol, 2.0 equiv) was added and the reaction mixture was stirred at -78 °C for 40 min. A saturated aqueous ammonium chloride solution was added carefully to quench the reaction. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue by flash column chromatography on silica gel (CombiFlash®, 12% ethyl acetate in hexane) to afford 21.1.1H NMR (DMSO-d6, 400 MHz): δ 7.98-7.94 (m, 1H), 6.48 (bs, 2H).

[0336] Synthesis of compound 21.2. Concentrated sulfuric acid (3 mL) was added dropwise to potassium persulfate (2.05 g, 7.6 mmol, 2.5 equiv) at room temperature and stirred for 15 min. To the mixture was added 21.1 (0.5 g, 3.04 mmol, 1.0 equiv) in small portions while maintaining temperature in the range of 30-40 °C. After the addition the reaction mixture was stirred at room temperature for 3-4 h. 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 solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2-3% ethyl acetate in hexane) to afford 21.2.1H NMR (DMSO-d6, 400 MHz): δ 8.78 (s, 1H).

[0337] Synthesis of compound 21.3. To a solution of 21.2 (0.970 g, 4.99 mmol, 1.0 equiv) in acetonitrile (10 mL) was added aqueous methylamine solution (40%) (0.8 mL, 9.98 mmol, 2.0 equiv) dropwise at 0 °C. The reaction mixture was allowed to warm to at room temperature and stirred for 20 min. It was poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane) to afford 21.3.1H NMR (DMSO-d6, 400 MHz): δ 7.98 (s, 1H), 7.05 (bs, 1H), 2.79 (d, 3H).

[0338] Synthesis of compound 21.4. A mixture of 21.3 (0.930 g, 4.52 mmol, 1.0 equiv), N- (4-hydroxypyridin-2-yl)acetamide (0.895 g, 5.88 mmol, 1.3 equiv) and sodium carbonate (0.958 g, 9.04 mmol, 2.0 equiv) in DMF (10 mL) was stirred at 50 °C for 6 h. The reaction mixture was cooled to room temperature, poured over ice-water. The precipitated solids were collected by filtration, rinsed with water and dried under vacuum to afford 21.4. MS (ES): m / z 338.7 [M+H]+.

[0339] Synthesis of compound 21.5. To a solution of compound 21.4 (0.850 g, 2.52 mmol, 1.0 equiv) in ethanol-water (8:2, 10 mL) was added iron powder (0.705 g, 12.6 mmol, 5.0 equiv) followed by ammonium chloride (0.673 g, 12.6 mmol, 5.0 equiv). The reaction mixture was stirred at 80 °C for 2 h. It was filtered through a pad of Celite® and rinsed with ethanol. The filtrate was concentrated under reduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 2.4% methanol in dichloromethane) to afford 21.5. MS (ES): m / z 308.5 [M+H]+.

[0340] Synthesis of compound 21.6. Compound 21.6 was prepared from 21.5 and Int-7, following the procedure described in the synthesis of I-19. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM). MS(ES): m / z: 489.6 [M+H]+.

[0341] Synthesis of compound 21.7. To a solution of 21.6 (0.230 g, 0.470 mmol, 1.0 equiv) in DMA (5 mL) was added zinc (0.006 g, 0.094 mmol, 0.2 equiv) and zinc cyanide (0.275 g, 2.35 mmol, 5.0 equiv). The reaction mixture was degassed by bubbling through a stream of argon for 10 min. Tris(dibenzylideneacetone)dipalladium(0) (0.030 g, 0.032 mmol, 0.07 equiv) and 1,1′-bis(diphenylphosphino)ferrocene (0.039 g, 0.070 mmol, 0.15 equiv) were added, and degassed for 5 min. The reaction mixture was stirred at 210 °C in a microwave reactor for 1 h. It was cooled to room temperature, transferred into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 4.5% methanol in DCM as eluent to afford to afford 21.7. MS (ES): m / z 438.2 [M+H]+.

[0342] Synthesis of I-21. To a solution of 21.7 (0.050 g, 0.114 mmol, 1.0 equiv) in THF (2 mL) was added dimethylcarbamic chloride (0.013 g, 0.125 mmol, 1.1 equiv) followed by addition of potassium tert-butoxide (1M in THF) (0.57 mL, 0.57 mmol, 5.0 equiv) at 0 °C and stirred at same temperature for 15 min. The reaction mixture was poured into ice-water, and product extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford I-21. MS(ES): m / z: 509.3 [M+H]+.1H NMR (DMSO-d6, 400MHz): δ 10.69 (s, 1H), 9.01 (s, 1H), 8.19 (s, 1H), 8.16-8.15 (d, J = 6.0Hz, 1H), 7.45 (s, 1H), 7.10 (s, 1H), 6.66-6.65 (d, J = 3.6Hz, 1H), 4.16 (bs, 2H), 3.92 (s, 3H), 2.89 (s, 6H), 2.69-2.67 (m, 2H), 2.19 (bs, 2H). Example 22: Methyl (4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate

[0343] Synthesis of I-22. To a solution of 21.7 (0.050 g, 0.114 mmol, 1.0 equiv) and triethylamine (0.023 g, 0.228 mmol, 2.0 equiv) in THF (2 mL) was added methyl chloroformate (0.011 g, 0.125 mmol, 1.1 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 4 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 preparative HPLC to afford I- 22. MS(ES): m / z: 496.2 [M+H]+.1H NMR (DMSO-d6, 400MHz): δ 10.72 (s, 1H), 10.43 (s, 1H), 8.22-8.21 (d, J = 2.4Hz, 1H), 8.19 (s, 1H), 7.43 (s, 1H), 7.08 (s, 1H), 6.74-6.73 (m, 1H), 4.16 (bs, 2H), 3.92 (s, 3H), 3.63 (s, 3H), 2.45 (bs, 2H), 2.19 (bs, 2H). Example 23: N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide

[0344] Synthesis of I-23. To a solution of 21.7 (0.050 g, 0.114 mmol, 1.0 equiv) and triethylamine (0.034 g, 0.342 mmol, 3.0 equiv) in THF (3 mL) was added phenyl chloroformate (0.027 g, 0.171 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred for 15 min before added pyrrolidine (0.040 g, 0.57 mmol, 5.0 equiv). The reaction mixture was stirred at 50 °C for 15 min. It was transferred into 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®, 4.5% methanol in DCM) to afford I-23. MS(ES): m / z: 535.4 [M+H]+.1H NMR (DMSO-d6, 400MHz): δ 10.67 (s, 1H), 8.80 (s, 1H), 8.19 (s, 1H), 8.16-8.15 (d, J = 5.6Hz, 1H), 7.54 (s, 1H), 7.09 (s, 1H), 6.83-6.81 (d, J = 7.2Hz, 1H), 4.16 (bs, 2H), 3.93 (s, 3H), 3.39-3.33 (m, 4H), 1.92-1.84 (m, 4H), 1.80-1.76 (m, 4H).Example 24: N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-4-methylpiperazine-1- carboxamide

[0345] Synthesis of compound 24.1. To a solution of 21.7 (0.080 g, 0.182 mmol, 1.0 equiv) and triethylamine (0.055 g, 0.546 mmol, 3.0 equiv) in THF (3 mL) was added phenyl chloroformate (0.042 g, 0.274 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred for 15 min. 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 to afford 24.1. MS(ES): m / z: 558.4 [M+H]+.

[0346] Synthesis of I-24. To a solution of 24.1 (0.090 g, 0.161 mmol, 1.0 equiv) and triethylamine (0.097 g, 0.966 mmol, 6.0 equiv) in dimethyl sulfoxide (3 mL) was added N- methylpiperazine (0.024 g, 0.242 mmol, 1.5 equiv). The reaction mixture was stirred at 90 °C for 15 min. It was transferred into 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®, 7.5% methanol in DCM) to afford I-24. MS(ES): m / z: 562.5 [M- H]+.1H NMR (DMSO-d6, 400MHz): δ 10.67 (s, 1H), 9.33 (s, 1H), 8.19-8.18 (d, J = 4.0Hz, 1H), 8.17 (s, 1H), 7.45 (s, 1H), 7.10 (s, 1H), 6.84 (bs, 1H), 4.17 (bs, 2H), 3.93 (s, 3H), 3.43 (bs, 4H), 2.31 (bs, 4H), 2.20 (s, 3H), 1.56 (bs, 2H), 1.25 (bs, 2H). Example 25: N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)morpholine-4-carboxamide

[0347] Synthesis of I-25. Compound I-25 was prepared from 24.1 and morpholine, following the procedure of the synthesis of I-24. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM). MS(ES): m / z: 551.3 [M+H]+.1H NMR (DMSO-d6, 400MHz): δ 10.68 (s, 1H), 9.36 (s, 1H), 8.19-8.18 (d, J = 4.0Hz, 1H), 8.16 (s, 1H), 7.09 (s, 1H), 7.06 (s, 1H), 6.83 (bs, 1H), 4.16 (bs, 2H), 3.92 (s, 3H), 3.55 (bs, 4H), 3.40 (bs, 4H), 1.55 (bs, 2H), 1.23 (bs, 2H). Example 26: N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxyazetidine-1- carboxamide

[0348] Synthesis of I-26. Compound I-26 was prepared from 24.1 and 3-methoxyazetidine hydrochloride, following the procedure of the synthesis of I-24. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.2% methanol in DCM). MS(ES): m / z: 551.4 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.73 (s, 1H), 10.05 (s, 1H), 8.26 (bs, 1H), 7.32 (s, 1H), 7.08 (s, 1H), 6.96 (s, 1H), 6.84 (s, 1H), 4.18 (bs, 4H), 3.96 (bs, 2H), 3.94 (s, 3H), 3.82 (s, 3H), 3.74 (bs, 1H), 2.21 (bs, 2H), 1.56 (bs, 2H). Example 27: 1-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methylurea

[0349] Synthesis of I-27. Compound I-27 was prepared from 21.7 and methylamine, following the procedure of the synthesis of I-23. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 4.0% methanol in DCM). MS(ES): m / z: 495.3 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.67 (s, 1H), 8.80 (s, 1H), 8.19 (s, 1H), 8.16-8.15 (d, J = 5.6Hz, 1H), 7.54 (s, 1H), 7.09 (s, 1H), 6.83 (bs, 1H), 6.66-6.65 (d, J = 3.6Hz, 1H), 4.16 (bs, 2H), 3.93 (s, 3H), 3.38 (s, 3H), 2.19 (bs, 2H), 1.89-1.87 (m, 2H). Example 28: (R)-N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-hydroxypyrrolidine-1- carboxamide

[0350] Synthesis of I-28. Compound I-28 was prepared from 21.7 and (R)-pyrrolidin-3-ol, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.4% methanol in DCM). MS(ES): m / z: 551.4 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.68 (s, 1H), 8.86 (s, 1H), 8.20-8.16 (m, 2H), 7.54 (s, 1H), 7.10 (s, 1H), 6.84 (s, 1H), 5.36 (s, 1H), 4.95 (bs, 2H), 4.26 (bs, 1H), 4.11 (bs, 2H), 4.00 (bs, 2H), 3.94 (s, 3H), 2.20 (bs, 2H), 1.56 (bs, 4H). Example 29: (S)-N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-hydroxypyrrolidine-1- carboxamide

[0351] Synthesis of I-29. Compound I-29 was prepared from 21.7 and (S)-pyrrolidin-3-ol, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM). MS(ES): m / z: 551.4 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.69 (s, 1H), 8.86 (s, 1H), 8.20-8.16 (m, 2H), 7.54 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.36 (s, 1H), 4.95 (bs, 2H), 4.26 (s, 1H), 4.11 (bs, 2H), 4.00 (bs, 2H), 3.94 (s, 3H), 2.20 (bs, 2H), 1.56 (bs, 4H).Example 30: 6-((2-Aminopyridin-4-yl)oxy)-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridine-7-carbonitrile

[0352] Synthesis of I-30. Compound I-30 was prepared from 21.7 and azetidine, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol in DCM). MS(ES): m / z: 521.4 [M+H]+. LCMS purity: 98.49%, HPLC purity: 96.93%,1H NMR (DMSO-d6, 400MHz): δ 10.69 (s, 1H), 9.18 (s, 1H), 8.18 (s, 1H), 8.15 (bs, 1H), 7.55 (s, 1H), 7.09 (s, 1H), 6.23 (bs, 1H), 4.16 (bs, 2H), 3.95 (bs, 4H), 3.92 (s, 3H), 2.19-2.13 (m, 6H). Example 31: Methyl (4-((2-((1-(2-oxaspiro[3.3]heptan-6-yl)-5-(trifluoromethyl)-1H-pyrazol-3- yl)amino)-7-cyano-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate

[0353] Synthesis of compound 31.1 To a solution of 4-bromopyridin-2-amine (100 g, 577.9 mmol, 1.0 equiv) in DMF (1300 mL) was added sodium hydride (111 g, 2773.9 mmol, 4.8 equiv) at 0 °C in portions and stirred for 2 h. To the mixture was added 4- methoxybenzyl chloride (434 g, 2773.9 mmol, 4.8 equiv) and stirred at 0 °C for 30 min. It was transferred into ice-water, precipitated solid was filtered, and dried under vacuum to afford 1.1 (150 g, yield: 62.79%) MS(ES): m / z 414.2 [M+H]+.

[0354] Synthesis of compound 31.2. To a solution of 31.1 (60 g, 145 mmol, 1.0 equiv) in DMSO (1000 mL) was added copper(I) chloride (1.14 g, 11.6 mmol, 0.08 equiv) followed by addition of N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (3.8 g, 11.6 mmol, 0.08 equiv). The reaction mixture was stirred at room temperature for 10 min and was added an aqueous solution of sodium hydroxide (11.6 g, 290 mmol, 2.0 equiv). The mixture was stirred at 110 °C for 48 h. It was cooled to room temperature, transferred into ice cold water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to afford 31.2. MS(ES): m / z 351.2 [M+H]+.

[0355] Synthesis of compound 31.3. A mixture of 31.2 (39 g, 111.3 mmol, 1.0 equiv), sodium carbonate (23.59 g, 222.6 mmol, 2.0 equiv) and Int-2 (18.3 g, 89.04 mmol, 0.8eq ) in DMF (390 mL) stirred at 80 °C for 1 h. It was filtered, and the filtrate was transferred into 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®, 28% ethyl acetate in hexane) to afford 31.3. MS(ES): m / z 536.6 [M+H]+.

[0356] Synthesis of compound 31.4. Compound 31.4 was prepared from 31.3 following the procedure described in the synthesis of compound 3.6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 70% ethyl acetate in hexane). MS(ES): m / z 506.9 [M+H]+.

[0357] Synthesis of compound 31.5. Compound 31.5 was prepared from 31.4 following the procedure described in the synthesis of compound 21.7. The product further purified by flash column chromatography on silica gel (CombiFlash®, 1.8% methanol in DCM). MS (ES): m / z 497.5 [M+H]+.

[0358] Synthesis of compound 31.6. To a solution of 31.5 (1.0 g, 2.01 mmol, 1.0 equiv) in THF (10 mL) was added 1,1'-thiocarbonyldiimidazole (1.788 g, 10.05 mmol, 5.0 equiv). The reaction mixture was stirred at 80 °C for 6 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate in hexane) to afford 31.6. MS(ES): m / z: 539.5 [M+H]+.

[0359] Synthesis of compound 31.7. To a solution of 31.6 (0.510 g, 0.946 mmol, 1.0 equiv) in acetonitrile (7 mL) was added sulfuryl chloride (0.15 mL, 1.892 mmol, 2.0 equiv) at -40 °C and reaction mixture was stirred for 10 min. It was transferred into 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®, 40% ethyl acetate in hexane) to afford 31.7. MS (ES): m / z 541.9 [M+H]+.

[0360] Synthesis of compound 31.8. To solution of 31.7 (0.230 g, 0.425 mmol, 1.0 equiv) in DCM (8 mL) was added trifluoromethanesulfonic acid (0.2 mL) at 0 °C and stirred for 5 min. It was transferred into ice-cold saturated sodium bicarbonate solution 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®, 3.0% methanol in DCM) to afford 31.8. MS(ES): m / z: 301.5 [M+H]+.

[0361] Synthesis of compound 31.9. To a solution of 31.8 (0.070 g, 0.232 mmol, 1.0 equiv) in THF (3 mL) was added triethylamine (0.070 g, 0.696 mmol, 3.0 equiv) at 0 °C followed by addition of methyl chloroformate (0.033 g, 0.349 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 15 min. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.8% methanol in DCM) to afford 31.9. MS(ES): m / z: 359.5 [M+H]+.

[0362] Synthesis of I-31. Compound I-31 was prepared from 31.9 and Int-6, following the procedure of the synthesis of I-10. The product was purified by flash column chromatography onsilica gel (CombiFlash®, 3.5% methanol in DCM). MS(ES): m / z: 570.3 [M+H]+,NMR (DMSO-d6, 400MHz): δ 10.59 (s, 1H), 10.32 (s, 1H), 8.17 (bs, 2H), 7.37 (s, 1H), 7.33 (s, 1H), 6.66-6.65 (d, J = 3.2Hz, 1H), 4.88-4.85 (m, 1H), 4.71 (bs, 2H), 4.61 (bs, 2H), 3.98 (s, 3H), 3.62 (s, 3H), 2.82 (bs, 4H). Example 32: 2-Methoxyethyl (4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate

[0363] Synthesis of I-32. Compound I-32 was prepared from 21.7 and 2-methoxyethan-1-ol, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM). MS(ES): m / z: 540.2 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.70 (s, 1H), 10.39 (s, 1H), 8.22-8.19 (m, 2H), 7.44 (s, 1H), 7.10 (s, 1H), 6.73-6.71 (m, 1H), 4.18 (bs, 3H), 3.93 (s, 3H), 3.53-3.51 (m, 2H), 3.26 (bs, 4H), 2.46 (bs, 2H), 2.20 (bs, 2H). Example 33: (R)-N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxypyrrolidine-1- carboxamide

[0364] Synthesis of I-33. Compound I-33 was prepared from 21.7 and (R)-3- methoxypyrrolidine hydrochloride, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.3% methanol in DCM). MS(ES): m / z: 565.4 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.69 (s, 1H), 8.92 (s, 1H), 8.19-8.17 (d, J = 7.2Hz, 1H), 7.52 (s, 1H), 7.08-7.07 (d, J = 7.6Hz, 1H), 6.83-6.81 (d, J = 7.2Hz, 1H), 6.68-6.67 (d, J = 3.6Hz, 1H), 5.36-5.35 (m, 1H), 4.16 (bs, 2H), 3.99 (bs, 2H), 3.92 (s, 3H), 3.50 (bs, 2H), 3.17 (s, 3H), 2.19 (bs, 2H), 1.93 (bs, 2H), 1.55 (bs, 2H).Example 34: (S)-N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxypyrrolidine-1- carboxamide

[0365] Synthesis of I-34. Compound I-34 was prepared from 21.7 and (S)-3- methoxypyrrolidine hydrochloride, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.3% methanol in DCM). MS(ES): m / z: 565.3 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.70 (s, 1H), 8.93 (s, 1H), 8.19-8.17 (d, J = 7.2Hz, 1H), 7.54 (s, 1H), 7.11 (bs, 1H), 6.85 (bs, 1H), 6.69 (bs, 1H), 5.37 (bs, 1H), 4.17 (bs, 2H), 4.01 (bs, 2H), 3.94 (s, 3H), 3.50 (bs, 2H), 3.23 (s, 3H), 2.21 (bs, 2H), 1.95 (bs, 2H), 1.57 (bs, 2H). Example 35: N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-hydroxyazetidine-1- carboxamide

[0366] Synthesis of I-35. Compound I-35 was prepared from 21.7 and azetidin-3-ol hydrochloride, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.2% methanol in DCM). MS(ES): m / z: 537.3 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.70 (s, 1H), 9.27 (s, 1H), 8.20 (s, 1H), 8.17-8.16 (d, J = 5.6Hz, 1H), 7.56 (s, 1H), 7.11 (bs, 1H), 6.85 (bs, 1H), 5.64-5.62 (m, 1H), 4.38 (bs, 1H), 4.17-4.14 (m, 4H), 3.94 (s, 3H), 3.70 (bs, 2H), 2.21 (bs, 2H), 1.57 (bs, 2H). Example 36: (S)-tetrahydrofuran-3-yl (4-((7-cyano-2-((4,4-difluoro-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6- yl)oxy)pyridin-2-yl)carbamate

[0367] Synthesis of I-36. Compound I-36 was prepared from 21.7 and (S)-tetrahydrofuran- 3-ol, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.2% methanol in DCM). MS(ES): m / z: 552.3 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.71 (s, 1H), 10.36 (s, 1H), 8.23 (bs, 2H), 7.42 (s, 1H), 7.11 (s, 1H), 6.75 (s, 1H), 5.21 (s, 1H), 4.17 (bs, 2H), 3.94 (s, 3H), 3.77-3.71 (m, 4H), 2.21 (bs, 4H), 1.94 (bs, 2H). Example 37: (R)-tetrahydrofuran-3-yl (4-((7-cyano-2-((4,4-difluoro-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6- yl)oxy)pyridin-2-yl)carbamate

[0368] Synthesis of I-37. Compound I-37 was prepared from 21.7 and (R)-tetrahydrofuran- 3-ol, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.2% methanol in DCM). MS(ES): m / z: 552.3 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.70 (s, 1H), 10.36 (s, 1H), 8.21-8.19 (m, 2H), 7.41 (s, 1H), 7.10 (s, 1H), 6.73 (s, 1H), 5.20 (s, 1H), 4.16 (bs, 2H), 3.93 (s, 3H), 3.75-3.70 (m, 4H), 2.20 (bs, 4H), 1.91 (bs, 2H). Example 38: 2-(Dimethylamino)ethyl (4-((7-cyano-2-((4,4-difluoro-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6- yl)oxy)pyridin-2-yl)carbamate

[0369] Synthesis of I-38. Compound I-38 was prepared from 21.7 and 2- (dimethylamino)ethan-1-ol, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.5% methanol in DCM). MS(ES): m / z: 553.4 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.71 (s, 1H), 10.35 (s, 1H), 8.22-8.20 (m, 2H), 7.46 (s, 1H), 7.09 (s, 1H), 6.73 (s, 1H), 4.16 (bs, 4H), 3.93 (s, 3H), 2.49 (bs, 2H), 2.20 (bs, 10H). Example 39: 1-Methylazetidin-3-yl (4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5- (trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate

[0370] Synthesis of I-39. To a solution of 6.1 (0.150 g, 0.260 mmol, 1.0 equiv), N,N- diisopropylethylamine (0.100 g, 0.780 mmol, 3.0 equiv) and 1-methylazetidin-3-ol (0.034 g, 0.390 mmol, 1.5 equiv) in dimethyl sulfoxide (3 mL) was stirred at 80 °C for 16 h. It was transferred into water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford I-39. MS(ES): m / z: 570.4 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 9.04 (s, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 8.26- 8.25 (d, J = 5.6Hz, 1H), 8.19 (s, 1H), 7.53 (s, 1H), 6.77 (bs, 1H), 5.30 (bs, 1H), 4.10 (bs, 1H), 3.97 (s, 3H), 3.87-3.84 (m, 2H), 3.67 (s, 3H), 3.52-3.50 (m, 2H), 2.83 (s, 3H). Example 40: Methyl (4-((7-chloro-1-methyl-2-((5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate

[0371] Synthesis of compound 40.1. To a solution of 31.4 (0.500 g, 0.988 mmol, 1.0 equiv) and Int-8 (0.308 g, 1.48 mmol, 1.5 equiv) in THF (5 mL) was added potassium tert-butoxide (1 M in THF, 2.96 mL, 2.964 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at same temperature for 30 min. The reaction mixture was poured into ice-water, and product 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 dissolved in methanol-THF (1:1, 10 mL) and ferric chloride (0.272 g, 1.68 mmol, 1.5 equiv) was added. The reaction mixture was stirred at 70 °C for 1 h. The reaction mixture was transferred into water and product extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM) to afford 40.1. MS(ES): m / z: 681.1 [M+H]+.

[0372] Synthesis of compound 40.2. To solution of 40.1 (0.300 g, 0.441 mmol, 1.0 equiv) in DCM (5 mL) was added trifluoromethanesulfonic acid (0.3 mL) at 0 °C and stirred for 5min. It was transferred into ice-cold saturated sodium bicarbonate solution 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 trituration with diethyl ether to afford 40.2. MS(ES): m / z: 440.5 [M+H]+.

[0373] Synthesis of compound I-40. To a solution of 40.2 (0.060 g, 0.136 mmol, 1.0 equiv) and triethylamine (0.041 g, 0.408 mmol, 3.0 equiv) in THF (2 mL) was added methyl chloroformate (0.015 g, 0.163 mmol, 1.2 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 5.0% methanol in DCM) to afford I-40. MS(ES): m / z: 498.3 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.28 (s, 1H), 8.12 (bs, 1H), 7.81 (s, 1H), 7.36 (s, 1H), 7.07 (bs, 1H), 6.83 (bs, 1H), 6.62 (bs, 1H), 3.87 (bs, 2H), 3.76 (s, 3H), 3.61-3.59 (m, 5H), 3.01 (s, 3H).Example 41: Methyl (4-((7-cyano-1-methyl-2-((5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate

[0374] Synthesis of compound 41.1. Compound 41.1 was prepared from 31.5 and Int-8, following the procedure described in the synthesis of 40.1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.5% methanol in DCM). MS(ES): m / z: 671.5 [M+H]+.

[0375] Synthesis of compound 41.2. Compound 41.2 was prepared from 41.1, following the procedure described in the synthesis of 40.2. The product was purified by trituration with diethyl ether. MS(ES): m / z: 431.2 [M+H]+.

[0376] Synthesis of compound I-41. Compound I-41 was prepared from 41.2, following the procedure described in the synthesis of I-40. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol in DCM). MS(ES): m / z: 489.3 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.72 (s, 1H), 10.39 (s, 1H), 8.23 (bs, 2H), 7.47 (s, 1H), 7.26 (s, 1H), 6.74 (bs, 1H), 4.35 (bs, 2H), 3.94 (s, 3H), 3.84 (bs, 2H), 3.64 (s, 3H), 3.05 (s, 3H). Example 42: 1-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-cyclopropylurea

[0377] Synthesis of I-42. Compound I-42 was prepared from 6.1 and cyclopropanamine, following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol in DCM). MS(ES): m / z : 540.3 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 9.06 (bs, 2H), 8.64 (s, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 8.13-8.11 (d, J=6.0Hz, 1H), 7.83 (s, 1H), 7.12 (s, 1H), 6.65-6.64 (d, J=3.6Hz, 1H), 3.96 (s, 3H), 3.66 (s, 3H), 1.23 (bs, 1H), 0.63-0.62 (m, 2H), 0.40 (bs, 2H). Example 43: Methyl (4-((7-cyano-2-((4,4-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin- 2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)carbamate

[0378] Synthesis of compound 43.1. Compound 43.1 was prepared from 31.5 and Int-9, following the procedure described in the synthesis of 40.1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.0% methanol in DCM). MS(ES): m / z: 672.5 [M+H]+.

[0379] Synthesis of compound 43.2. Compound 43.2 was prepared from 43.1, following the procedure described in the synthesis of 40.2. The product was purified by trituration with diethyl ether. MS(ES): m / z: 432.3 [M+H]+.

[0380] Synthesis of compound I-43. Compound I-43 was prepared from 43.2, following the procedure described in the synthesis of I-40. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM). MS(ES): m / z: 490.4 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.46 (s, 1H), 10.38 (s, 1H), 8.18 (bs, 2H), 7.44 (s, 1H), 6.72-6.71 (d, J = 4.0Hz, 1H), 6.64 (s, 1H), 4.09 (bs, 2H), 4.00 (bs, 2H), 3.91 (s, 3H), 3.62 (s, 3H), 1.53 (s, 6H).Example 44: 3-(4-((7-cyano-2-((4,4-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1-dimethylurea

[0381] Synthesis of I-44. Compound I-44 was prepared from 43.2 and dimethylamine, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol in DCM). MS(ES): m / z: 503.4 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.45 (s, 1H), 9.01 (s, 1H), 8.15 (bs, 2H), 7.44 (s, 1H), 6.66-6.64 (d, J = 5.6Hz, 2H), 4.09 (bs, 2H), 4.00 (bs, 2H), 3.90 (s, 3H), 2.89 (s, 6H), 1.53 (s, 6H). Example 45: N-(4-((7-cyano-2-((4,4-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide

[0382] Synthesis of I-45. Compound I-45 was prepared from 43.2 and pyrrolidine, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol in DCM). MS(ES): m / z: 529.4 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.45 (s, 1H), 8.82 (s, 1H), 8.16 (bs, 2H), 7.53-7.52 (d, J = 1.6Hz, 1H), 6.66-6.63 (m, 2H), 4.09 (bs, 2H), 4.00 (bs, 2H), 3.90 (s, 3H), 3.33 (bs, 4H), 1.80 (bs, 4H), 1.53 (bs, 6H). Example 46: 3-(4-((7-chloro-1-methyl-2-((5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1-dimethylurea

[0383] Synthesis of I-46. Compound I-46 was prepared from 40.2 and dimethylamine, following the procedure of the synthesis of I-23. The product further purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM). MS(ES): m / z: 511.4 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.39 (s, 1H), 8.93 (s, 1H), 8.11 (s, 1H), 7.36 (s, 1H), 7.23 (s, 1H), 7.07 (bs, 1H), 6.83 (bs, 1H), 4.32 (bs, 2H), 3.95 (s, 3H), 3.81 (bs, 2H), 3.03 (s, 3H), 2.88 (s, 6H). Example 47: N-(4-((7-cyano-2-((4,4-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2- yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)azetidine-1-carboxamide

[0384] Synthesis of I-47. Compound I-47 was prepared from 43.2 and azetidine, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol in DCM). MS(ES): m / z: 515.2 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.45 (s, 1H), 9.20 (s, 1H), 8.15 (bs, 2H), 7.54 (s, 1H), 7.07 (s, 1H), 6.83 (bs, 1H), 4.10 (bs, 2H), 4.00 (bs, 4H), 3.94 (bs, 2H), 3.91 (s, 3H), 2.14- 2.11 (m, 2H), 1.53 (s, 6H). Example 48: (R)-Tetrahydrofuran-3-yl (4-((7-cyano-2-((4,4-dimethyl-6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate

[0385] Synthesis of I-48. Compound I-48 was prepared from 43.2 and (R)-tetrahydrofuran- 3-ol, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.8% methanol in DCM). MS(ES): m / z: 546.5 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.42 (s, 1H), 10.33 (s, 1H), 8.21-8.18 (m, 2H), 7.38 (s, 1H), 6.76-6.75 (d, J = 3.6Hz, 1H), 6.62 (s, 1H), 5.21 (s, 1H), 4.09 (bs, 2H), 4.00 (bs, 2H), 3.90 (s, 3H), 3.78-3.70 (m, 4H), 2.16-2.11 (m, 1H), 1.93-1.89 (m, 1H), 1.53 (s, 6H).Example 49: (S)-Tetrahydrofuran-3-yl (4-((7-cyano-2-((4,4-dimethyl-6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate

[0386] Synthesis of I-49. Compound I-49 was prepared from 43.2 and (S)-tetrahydrofuran- 3-ol, following the procedure of the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol in DCM). MS(ES): m / z: 546.5 [M+H]+,1H NMR (DMSO-d6, 400MHz): δ 10.46 (s, 1H), 10.35 (s, 1H), 8.20-8.17 (m, 2H), 7.40 (s, 1H), 6.73-6.72 (d, J = 3.2Hz, 1H), 6.63 (s, 1H), 5.20 (bs, 1H), 4.09 (bs, 2H), 4.00 (bs, 2H), 3.90 (s, 3H), 3.77-3.69 (m, 4H), 2.15-2.10 (m, 1H), 1.92-1.88 (m, 1H), 1.53 (s, 6H). Example 51: N-(4-((7-chloro-1-methyl-2-((1-(methyl-d3)-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

[0387] Synthesis of compound 51.1. To a solution of 21.5 (0.150 g, 0.487 mmol, 1.0 equiv) in THF (2 mL) was added 1,1'-thiocarbonyldiimidazole (0.433 g, 2.43 mmol, 5.0 equiv). The reaction mixture was stirred at 80 °C for 1 h. It was cooled to room temperature and transferred into ice-water. The precipitated solids were collected by filtration and triturated with hexane to afford 51.1. MS(ES): m / z : 350.7 [M+H]+.

[0388] Synthesis of compound 51.2. To a solution of 51.1 (0.110 g, 0.314 mmol, 1.0 equiv) in acetic acid (5 mL) was added aqueous hydrobromic acid (0.037 g, 0.471 mmol, 1.5 equiv) at 0°C followed by bromine (0.200 g, 1.25 mmol, 4.0 equiv). The reaction mixture was stirred for 10 min. It was transferred into saturated sodium bicarbonate solution, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol in DCM) to afford 51.2. MS (ES): m / z 397.6 [M+H]+.

[0389] Synthesis of I-82. Compound I-82 was prepared from 51.2 and Int-16.2, following the procedure described in the synthesis of I-10. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.3% methanol in DCM) to afford I-82. MS(ES): m / z :511.2 [M]+,1H NMR (DMSO-d6, 400 MHz): δ 10.59 (s, 1H), 8.85 (s, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.25 (s, 1H), 8.20 (d, J = 6.0 Hz, 1H), 8.15 (s, 1H), 7.67 (s, 1H), 6.68-6.66 (m, 1H), 4.00 (s, 3H), 2.05 (s, 3H). Example 52: 3-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2- dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1-bis(methyl- d3)urea

[0390] Synthesis of I-52. Compound I-52 was prepared from 6.1 and dimethylamine hydrochloride (d6), following the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol in DCM). MS(ES): m / z: 540.3 [M+H]+;1H NMR (DMSO-d6, 400 MHz): δ 9.04 (d, J = 10.8 Hz, 2H), 8.67 (s, 1H), 8.32 (s, 1H), 7.50 (s, 1H), 7.10-7.09 (bs, 1H), 6.86-6.83 (bs, 1H), 6.71-6.696 (bs, 1H), 4.00 (s, 3H), 3.69 (s, 3H). Example 53: (R)-tetrahydrofuran-3-yl (4-((7-chloro-1-methyl-2-((5-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate

[0391] Synthesis of I-53. To a solution of 40.2 (0.080 g, 0.181 mmol, 1.0 equiv) in THF (3 mL) was added triethylamine (0.055 g, 0.545 mmol, 3.0 equiv) at 0 °C followed by phenyl chloroformate (0.042 g, 0.272 mmol, 1.5 equiv). The reaction mixture was stirred at 0 °C for 15 min. (R)-tetrahydrofuran-3-ol (0.080 g, 0.909 mmol, 5.0 equiv) was added and the mixture was stirred at 80 °C for 16 h. It was transferred into 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®, 3.5% methanol in DCM) to afford I-53. MS(ES): m / z: 554.4 [M+H]+;1H NMR (DMSO-d6, 400 MHz): δ 10.41(s, 1H), 10.28 (s,1H), 8.15 (d, J = 5 Hz, 2H), 7.32 (s, 1H), 7.23 (s, 1H), 6.66 (d, J = 5 Hz, 1H), 5.19 (bs, 1H), 4.34 (t, J = 7.5 Hz, 3H), 4.12-4.11 (m, 1H), 3.96 (s, 4H), 3.83-3.61 (m, 9H), 3.24 (m, 2H), 3.03 (s, 3H), 2.17-2.09 (m, 2H), 1.90-1.87 (m, 1H) Example 54: oxetan-3-yl (4-((7-chloro-1-methyl-2-((5-methyl-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2- yl)carbamate

[0392] Synthesis of I-54. Compound I-54 was prepared from 40.2 and oxetan-3-ol, following the procedure described in the synthesis of I-53. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol in DCM). MS(ES): m / z: 540.4 [M+H]+;1H NMR (DMSO-d6, 400 MHz): δ 10.54 (s, 1H), 10.41 (s,1H), 8.18-8.13 (m, 2H), 7.29-7.23 (m, 2H), 4.78-4.74 (m, 2H), 4.49 (bs, 2H), 4.33 (bs, 2H), 4.13-4.11 (bs, 2H), 3.952 (s, 4H), 3.821(bs, 2H), 3.18-3.16 (m, 4H), 3.03 (s, 4H), 2.17-2.09 (m, 2H), 1.55 (s, 1H).Exa...

Claims

CLAIMS 1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: W is CRwor N; X is CRxor N; Y is CRyor N; Z is –O- or –NRz-; Rw, Rx, and Ryare each independently hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6aliphatic, or –CN; Rzis hydrogen or optionally substituted C1-6aliphatic; R1is –N(R)2, –N(R)C(O)R’, -C(O)N(R)2, –N(R)C(O)N(R)2, or –N(R)C(O)OR; each Rcis independently selected from halogen, -CN, -CO2R, -C(O)N(R)2, -NO2, -N(R)2, -OR, - SR, or optionally substituted C1-6aliphatic; n is 0, 1, 2, or 3, provided that when R1is –N(R)2, –N(R)C(O)R’ or -C(O)N(R)2, then n is 1, 2, or 3; R2is optionally substituted C1-6aliphatic; R3is hydrogen or optionally substituted C1-6aliphatic; 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 optionallysubstituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a bivalent C1-3straight or branched hydrocarbon chain; Rais hydrogen, halogen, optionally substituted C1-6aliphatic, 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; each R is independently hydrogen, optionally substituted C1-6aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently optionally substituted C1-6aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl, wherein the compound is not:

2. The compound of claim 1, wherein R1is –N(R)C(O)N(R)2or –N(R)C(O)OR.

3. The compound of claim 2, wherein R1is –N(H)C(O)N(R)2.

4. The compound of claim 2, wherein R1is –N(H)C(O)OR.

5. The compound of claim 1, wherein R1is –N(H)C(O)R’.

6. 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 or optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

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

8. The compound of any one of the preceding claims, wherein Rais optionally substituted C1-6aliphatic, 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.

9. The compound of claim 8, wherein Rais optionally substituted C1-6aliphatic.

10. The compound of any one of the preceding claims, wherein:is substituted with 1-5 Rb, as valency allows; and each Rbis independently hydrogen, halogen, -CN, -OR, -O(CH2)mR, -SR, -N(R)2, -NO2, - C(O)R’, -C(O)OR, -C(O)N(R)2, -OC(O)R’, -OC(O)N(R)2, -OC(O)OR, -OSO2R, - OSO2N(R)2, -N(R)C(O)R’, -N(R)SO2R’, -SO2R’, -SO2N(R)2, -SO3R’, optionally substituted C1-6aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 1, 2, or 3.

11. The compound of claim 10, wherein each Rbis independently halogen or optionally substituted C1-6aliphatic.

12. The compound of claim 10 or 11, wherein13. The compound of any one of the preceding claims, wherein L is a covalent bond.

14. The compound of any one of the preceding claims, wherein R2is C1-4alkyl.

15. The compound of any one of the preceding claims, wherein each Rcis independently halogen.

16. The compound of any one of claims 1-14, wherein n is 0.

17. The compound of any one of the preceding claims, wherein W is CRw.

18. The compound of claim 17, wherein Rwis hydrogen.

19. The compound of any one of claims 1-16, wherein W is N.

20. The compound of any one of the preceding claims, wherein X is CRx.

21. The compound of claim 20, wherein Rxis hydrogen, halogen, -CN, -OR3, or optionally substituted C1-6aliphatic.

22. The compound of any one of claims 1-19, wherein X is N.

23. The compound of any one of the preceding claims, wherein Y is CRy.

24. The compound of claim 23, wherein Ryis hydrogen.

25. The compound of any one of claims 1-22, wherein Y is N.

26. The compound of any one of claims 1-25, wherein Z is –NRz-.

27. The compound of claim 26, wherein Rzis hydrogen.

28. The compound of any one of claims 1-25, wherein Z is –O-.

29. The compound of any one of the preceding claims, wherein each R is independently hydrogen or optionally substituted C1-6aliphatic.

30. The compound of any one of the preceding claims, wherein each R’ is independently optionally substituted C1-6alkyl or optionally substituted C3-7cycloalkyl.

31. The compound of any one of the preceding claims, wherein each R’ is independently optionally substituted C1-6aliphatic.

32. The compound of any one of the preceding claims, wherein the compound is of Formula I-C:or a pharmaceutically acceptable salt thereof.

33. A compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein: W is CRwor N; X is CRxor N; Y is CRyor N; Z is –O- or –NRz-; Rw, Rx, and Ryare each independently hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6aliphatic, or –CN; Rzis hydrogen or optionally substituted C1-6aliphatic; R1is –N(R)2, –N(R)C(O)R’, -C(O)N(R)2, –N(R)C(O)N(R)2, or –N(R)C(O)OR; each Rcis independently selected from halogen, -CN, -CO2R, -C(O)N(R)2, -NO2, -N(R)2, -OR, - SR, or optionally substituted C1-6aliphatic; n is 0, 1, 2, or 3; R2is optionally substituted C1-6aliphatic; R3is hydrogen or optionally substituted C1-6aliphatic;Ring A 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 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, optionally substituted C1-6aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R when attached to the same nitrogen atom are taken together form an optionally substituted 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently optionally substituted C1-6aliphatic or optionally substituted 3- to 7- membered saturated or partially unsaturated carbocyclyl, wherein the compound is not:

34. The compound of claim 33, wherein Ring A is optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

35. The compound of claim 33 or 34, wherein: RingRing A1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring A1 is fused to Ring A2;Ring A2 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 7- membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Ring A2 is optionally (i) further fused to Ring A3, or (ii) Ring A2 and Ring A3 combine to form a spirocycle; and Ring A3, 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.

36. The compound of claim 35, wherein Ring A1 is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

37. The compound of claim 35 or 36, wherein optionally substituted Ring.

38. The compound of any one of claims 35-37, wherein Ring A2 is optionally substituted 5- to 7-membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

39. The compound of any one of claims 35-38, wherein optionally substituted Ring A is selected from the group consisting of:

40. The compound of any one of claims 33-39, wherein the compound is of Formula II-C:or a pharmaceutically acceptable salt thereof.

41. A compound of Formula III:or a pharmaceutically acceptable salt thereof, wherein: Z is –O- or –NRz-; Rxis hydrogen, halogen, -OR3, -N(R3)2, -SR3, optionally substituted C1-6aliphatic, or –CN; Rzis hydrogen or optionally substituted C1-6aliphatic; R2is optionally substituted C1-6aliphatic; R3is hydrogen or optionally substituted C1-6aliphatic;R4is halogen, –OR, -N(R)2, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A is optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 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; L is a covalent bond or a bivalent C1-3straight or branched hydrocarbon chain; Rais hydrogen, halogen, optionally substituted C1-6aliphatic, 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; and each R is independently hydrogen, optionally substituted C1-6aliphatic, 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, wherein the compound is not:

42. A compound of Formula IV:or a pharmaceutically acceptable salt thereof, wherein: Z is –O- or –NRz-; Rxis hydrogen, halogen, -OR3, or –CN; Rzis hydrogen or optionally substituted C1-6aliphatic; R2is optionally substituted C1-6aliphatic; R3is hydrogen or optionally substituted C1-6aliphatic;is selected from (i) or (ii):wherein Ring A is further substituted at least once,and at least one substituent on Ring A is C1-6haloalkyl; L is a covalent bond or a bivalent C1-3straight or branched hydrocarbon chain;Rais hydrogen, halogen, optionally substituted C1-6aliphatic, 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; and R’ is C1-6aliphatic or 3- to 7-membered saturated or partially unsaturated carbocyclyl, wherein the compound is not: .

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

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

45. A method of inhibiting JAK2 in a subject comprising administering the compound of any one of claims 1-43 or the composition of claim 44.

46. 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 1-43 or the composition of claim 44.

47. A method of treating cancer, comprising administering to a subject in need thereof the compound of any one of claims 1-43 or the composition of claim 44.

48. A method of treating a hematological malignancy, comprising administering to a subject in need thereof the compound of any one of claims 1-43 or the composition of claim 44.

49. The method of claim 48, wherein the hematological malignancy is leukemia or lymphoma.

50. A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof the compound of any one of claims 1-43 or the composition of claim 44.

51. The method of claim 50, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia or myelofibrosis.