6-heteroaryloxy benzimidazole and azabenzimidazole as JAK2 inhibitor

Abstract

To provide 6-heteroaryloxy benzimidazole and azabenzimidazole as JAK2 inhibitors.SOLUTION: The present disclosure provides 6-heteroaryloxy benzimidazole and azabenzimidazole compounds and compositions thereof useful for inhibiting JAK2. The present disclosure provides compounds useful for inhibiting JAK2. In some embodiments, the provided compounds are useful, inter alia, for treating and / or preventing a disease, disorder, or condition associated with JAK2.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims priority to and the benefit of U.S. Patent Application No. 63 / 277,343, filed November 9, 2021, and U.S. Patent Application No. 63 / 354,403, filed June 22, 2022, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase involved in the JAK-STAT signaling pathway, which plays a role in cellular processes such as immunity, cell division, and cell death. Dysfunction of the JAK-STAT pathway has been shown to be involved in a variety of diseases, including cancer and other proliferative disorders and disorders 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 common mutation in myeloproliferative neoplasms, occurring in approximately 70% of all patients and up to 95% of patients with polycythemia vera (Vainchenker, W., Kralovics, R. Blood 2017, 129(6):667-79). Even relatively rare mutations, such as those in MPL and CALR, have been shown to activate JAK2, thereby initiating and / or driving disease progression (Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev):82). Furthermore, JAK2 polymorphisms have been implicated in various autoimmune and inflammatory conditions, such as psoriasis and inflammatory bowel disease (O'Shea, JJ et al., Ann. Rheum. Dis. 2013 Apr, 72:ii111-ii115). Increased signaling through JAK2 and other members of the JAK family has also been associated with atopic dermatitis. (Rodrigues, MA and Torres, TJ Derm. Treat. 2019, 31(1):33-40). Inhibitors of JAKs (e.g., JAK2) are classified based on their binding mode. All currently approved JAK inhibitors are type I inhibitors, which bind to the ATP-binding site in the active conformation of the kinase domain, thereby blocking catalytic activity (Vainchenker, W. et al.). However, increased phosphorylation of the JAK2 activation loop has been observed with type I inhibitors, which may lead to acquired resistance in certain patients (Meyer SC, Levine, RL Clin. Cancer Res. 2014, 20(8):2051-9). On the other hand, type II inhibitors bind to the ATP-binding site in the inactive conformation of the kinase domain, thereby avoiding the hyperphosphorylation observed with type I inhibitors (Wu, SC et al.). al. Cancer Cell 2015 Jul 13, 28(1):29-41). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Vainchenker, W., Kralovics, R. Blood 2017, 129(6):667-79 [Non-patent document 2] Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev):82 [Non-patent document 3] O'Shea, JJ et al., Ann. Rheum. Dis. 2013 Apr, 72:ii111-ii115 [Non-patent document 4] Rodrigues, MA and Torres, TJ Derm. Treat. 2019, 31(1):33-40 [Non-Patent Document 5] Meyer SC, Levine, RL Clin. Cancer Res. 2014, 20(8):2051-9 [Non-patent document 6] Wu, SC et al. Cancer Cell 2015 Jul 13, 28(1):29-41 Summary of the Invention [Means for solving the problem]

[0004] The present disclosure provides compounds useful for inhibiting JAK2. In some embodiments, the provided compounds are useful, inter alia, for treating and / or preventing diseases, disorders, or conditions associated with JAK2.

[0005] In some embodiments, the present disclosure provides a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, n, L, W, X, Y, Z, R 1 , R 2 , R a , and R c is as defined herein.

[0006] In some embodiments, the present disclosure provides a compound of formula II [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, n, W, X, Y, Z, R 1 , R 2 , and R c is as defined herein.

[0007] In some embodiments, the present disclosure provides a compound of formula III [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R 2 , R 4 , R a , and R x is as defined herein.

[0008] In some embodiments, the present disclosure provides a compound of formula IV [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R', R 2 , R a , and R x is as defined herein. DETAILED DESCRIPTION OF THE INVENTION

[0009] Compounds and Definitions The compounds of the present invention include those broadly described above and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise stated. For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Further, the general principles of organic chemistry are identified in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0010] Unless otherwise specified, a structure depicted herein is intended to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, and 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 present disclosure. Accordingly, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the provided compounds, are within the scope of the present disclosure. For example, in some cases, Table 1 depicts one or more stereoisomers of a compound, and unless otherwise specified, each stereoisomer is represented individually and / or as a mixture. Unless otherwise specified, all tautomeric forms of the provided compounds are within the scope of the present disclosure.

[0011] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C-enriched carbon or 14 Compounds having the subject structures including the replacement of carbons with C-enriched carbons are within the scope of this disclosure.

[0012] Aliphatic: The term "aliphatic" refers to a linear (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic" or "cycloaliphatic") that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C 1-6 In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C 1-5 In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C 1-4In yet other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms (e.g., C 1-3 ), in still other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C 1-2 ). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof. In some embodiments, "aliphatic" refers to a linear (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation and has one 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 an alkyl group having 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms (unless otherwise specified) (e.g., C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 1-3 , or C 1-2 ), saturated, optionally substituted, straight-chain or branched hydrocarbon groups. Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0014] Carbocyclyl: As used herein, the terms "carbocyclyl," "carbocycle," and "carbocyclic ring" refer to a saturated or partially unsaturated cycloaliphatic monocyclic, bicyclic, or polycyclic ring system having 3 to 14 members, as described herein, which aliphatic ring system is optionally substituted as described herein. Carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, "carbocyclyl" (or "cycloaliphatic") refers to an optionally substituted monocyclic C3-C8 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule, or an optionally substituted C7-C8 hydrocarbon. 10 It refers to a bicyclic hydrocarbon. The term "cycloalkyl" refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, the cycloalkyl group has 3 to 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 alkyl group having at least one double bond and having 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (unless otherwise specified) (e.g., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3), which means an optionally substituted straight or branched hydrocarbon chain. 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 alkyl group having at least one triple bond and having 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (unless otherwise specified) (e.g., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ), means an optionally substituted straight or branched chain hydrocarbon group. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0017] Aryl: The term "aryl" refers to an alkyl group having a total of 6 to 14 ring members (e.g., C 6-14 ) refers to monocyclic and bicyclic ring systems in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used synonymously with the term "aryl ring." In some embodiments, "aryl" refers to an aromatic ring system, including, 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 such as "heteroaralkyl" or "heteroaralkoxy," refer to a monocyclic or bicyclic ring group having 5 to 10 ring atoms, having 6, 10, or 14 pi electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to the carbon atoms (e.g., a 5- or 6-membered monocyclic heteroaryl or a 9- or 10-membered bicyclic heteroaryl). Exemplary heteroaryl groups include, but are not limited to, 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, triazolopyridinyl, and benzisoxazolyl. As used herein, the terms "heteroaryl" and "heteroaryl" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring (i.e., bicyclic heteroaryl rings having 1 to 3 heteroatoms). Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one, and benzisoxazolyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which terms include rings that are optionally substituted.

[0019] Heteroatom: As used herein, the term "heteroatom" means nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized 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 that, in addition to carbon atoms, has one or more, e.g., 1 to 4, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (In the case of 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, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group can be monocyclic, bicyclic, tricyclic, or polycyclic, preferably monocyclic, bicyclic, or tricyclic, and more preferably monocyclic or bicyclic. Bicyclic heterocyclic rings also include groups in which a 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. The bicyclic heterocyclic ring may be a spirocyclic ring system (e.g., a 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) as defined above).

[0021] Partially unsaturated: As used herein, the term "partially unsaturated" with respect to a ring moiety means a ring moiety that contains at least one double or triple bond between ring atoms. The term "partially unsaturated," as defined herein, is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties.

[0022] Patient or Subject: As used herein, the term "patient" or "subject" refers to any organism to which a provided composition is or can 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, the patient is human. In some embodiments, the patient or subject suffers from or is prone to one or more disorders or conditions. In some embodiments, the patient or subject exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, the patient or subject is undergoing or has undergone a particular therapy to diagnose and / or treat a disease, disorder, or condition.

[0023] Substituted or optionally substituted: As described herein, compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified 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 explicit or implicit from the structure (e.g., [ka] At least [ka] means, [ka] At least [ka] (meaning "substituted" or "optionally substituted"). Unless otherwise specified, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituents can be the same or different at all positions. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that remains substantially unchanged when subjected to conditions that permit the compound's production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes provided herein. Groups described as "substituted" preferably have one to four substituents, more preferably one or two substituents. Groups described as "optionally substituted" can be unsubstituted or "substituted" as described above.

[0024] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are, independently, halogen; -(CH) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°; optionally substituted with R° -(CH2) 0-4 Ph; optionally substituted with R° -(CH2) 0-4 O(CH2) 0-1 Ph; optionally substituted with R° -CH=CHPh; optionally substituted with R° -(CH2) 0-4 O(CH2) 0-1-pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°, -(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;-SiR°3;-(C 1-4 linear or branched alkylene)ON(R°)2; or -(C 1-4 linear or branched alkylene)C(O)ON(R°)2, where each R° is optionally substituted as defined below and independently represents hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definitions, two independent occurrences of R°, taken together with the intervening atom(s), form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic 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 two independent occurrences of R° together with the intervening atoms) are independently halogen, —(CH) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and C 1-4Aliphatic, -CH2Ph, -O(CH2) 0-1 or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0026] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include ═O ("oxo"), ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-, where R is an independent * Each occurrence of C may be substituted as defined below, hydrogen 1-6 The "optionally substituted" group is selected from an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbon atoms of the "optionally substituted" group include -O(CR * 2) 2-3 O-, where an independent R * Each occurrence of C may be substituted as defined below, hydrogen 1-6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0027] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ●, -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 3-6 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)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, optionally substituted as defined below, 1-6 an aliphatic or unsubstituted 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, two independent R † The occurrences of, taken together with the intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] R † Suitable substituents on the aliphatic groups are, independently, halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 3-6 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 the administration of a therapy that partially or completely alleviates, improves, alleviates, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms, characteristics, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be treatment of a subject who does not exhibit symptoms of the associated disease, disorder, and / or condition and / or who exhibits only early symptoms of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be treatment of a subject who exhibits one or more established symptoms of the associated disease, disorder, and / or condition. In some embodiments, treatment may be treatment of a subject who has been diagnosed with the associated disease, disorder, and / or condition.

[0031] Provided compounds In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: W is CR w or N, X is CR x or N, Y is CR yor N, Z is -O- or -NR z - and R w , R x , and R y are each independently hydrogen, halogen, -OR 3 , -N(R 3 )2, -SR 3 , appropriately substituted C 1-6 aliphatic, or -CN; R z is hydrogen or an appropriately substituted C 1-6 is aliphatic, R 1 is -N(R)2, -N(R)C(O)R', -C(O)N(R)2, -N(R)C(O)N(R)2, or -N(R)C(O)OR; Each R c is halogen, -CN, -CO2R, -C(O)N(R)2, -NO2, -N(R)2, -OR, -SR, or an optionally substituted C 1-6 are independently selected from aliphatic n is 0, 1, 2, or 3, except that R 1 is -N(R), -N(R)C(O)R', or -C(O)N(R), where n is 1, 2, or 3; R 2 is replaced appropriately by C 1-6 is aliphatic, R 3 is hydrogen or an appropriately substituted C 1-6 is aliphatic, Ring A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7-10 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 divalent C 1-3 a linear or branched hydrocarbon chain, R a is hydrogen, halogen, optionally substituted C 1-6 an aliphatic, optionally substituted phenyl, an optionally substituted 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen, optionally substituted C 1-6 an aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's, when attached to the same nitrogen atom, together form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0 to 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' independently represents an optionally substituted C 1-6It is an aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl.

[0032] In some embodiments, the present disclosure provides a compound of formula IA: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, n, L, Z, R 1 , R 2 , R a , R c , R x , and R y are as defined above for Formula I and as described in classes and subclasses herein, either alone or in combination.

[0033] In some embodiments, the present disclosure provides a compound of formula IB: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, n, L, Z, R 1 , R 2 , R a , R c , and R y are as defined above for Formula I and as described in classes and subclasses herein, either alone or in combination.

[0034] In some embodiments, the present disclosure provides a compound of formula IC: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, n, L, Z, R 1 , R 2 , R a , R c , and R x are as defined above for Formula I and as described in classes and subclasses herein, either alone or in combination.

[0035] In some embodiments, the present disclosure provides a compound of formula ID: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, n, L, W, X, Y, Z, R 1 , R 2 , R a , and R c are, alone or in combination, as defined above for formula I and as described in classes and subclasses herein; R b are hydrogen, halogen, -CN, -OR, -O(CH2) m R, -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)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 an aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 1, 2, or 3.

[0036] In some embodiments, the present disclosure provides a compound of formula IE: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, L, W, X, Y, Z, R 1 , R 2 , and R a are as defined above for Formula I and as described in classes and subclasses herein, either alone or in combination.

[0037] In some embodiments, the present disclosure provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: W is CR w or N, X is CR x or N, Y is CR y or N, Z is -O- or -NR z - and R w , R x , and R y are each independently hydrogen, halogen, -OR 3 , -N(R 3 )2, -SR 3 , appropriately substituted C 1-6 aliphatic, or -CN; R z is hydrogen or an appropriately substituted C 1-6 is aliphatic, R 1 is -N(R)2, -N(R)C(O)R', -C(O)N(R)2, -N(R)C(O)N(R)2, or -N(R)C(O)OR; Each R c is halogen, -CN, -CO2R, -C(O)N(R)2, -NO2, -N(R)2, -OR, -SR, or an optionally substituted C 1-6 are independently selected from aliphatic n is 0, 1, 2, or 3; R 2 is replaced appropriately by C 1-6 is aliphatic, R 3 is hydrogen or an appropriately substituted C 1-6 is aliphatic, Ring A is an optionally substituted 9-16 membered bicyclic or tricyclic aryl, an optionally substituted 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 10-16 membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 7-10 membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 10-16 membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen, optionally substituted C 1-6 an aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's, when attached to the same nitrogen atom, together form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0 to 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' independently represents an optionally substituted C 1-6 It is an aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl.

[0038] In some embodiments, the present disclosure provides a compound of formula II-A: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, n, Z, R 1 , R 2 , R c , R x , and R y are, alone or in combination, as defined above for Formula II and as described in classes and subclasses herein.

[0039] In some embodiments, the present disclosure provides a compound of formula II-B: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, n, Z, R 1 , R 2 , R c , and R y are, alone or in combination, as defined above for Formula II and as described in classes and subclasses herein.

[0040] In some embodiments, the present disclosure provides a compound of formula II-C: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, n, Z, R 1 , R 2 , R c , and R x are, alone or in combination, as defined above for Formula II and as described in classes and subclasses herein.

[0041] In some embodiments, the present disclosure provides a compound of formula II-D: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, W, X, Y, Z, R 1 , and R 2 are, alone or in combination, as defined above for Formula II and as described in classes and subclasses herein.

[0042] In some embodiments, the present disclosure provides a compound of formula II-E: [ka] or a pharmaceutically acceptable salt thereof, wherein n, W, X, Y, Z, R 1 , R 2 , and R care, alone or in combination, as defined above for Formula II and as described in classes and subclasses herein; Ring A1 is an optionally substituted ring selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A1 is fused to ring A2, Ring A2 is an optionally substituted ring selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A2 is optionally (i) further fused to ring A3, or or (ii) ring A2 and ring A3 combine to form a spiro ring; Ring A3, if present, is an optionally substituted ring selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0043] In some embodiments, the present disclosure provides a compound of formula II-F: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A2, n, W, X, Y, Z, R 1 , R 2 , and R care, alone or in combination, as defined above for Formula II and as described in classes and subclasses herein.

[0044] In some embodiments, the present disclosure provides a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is -O- or -NR z - and R x is hydrogen, halogen, -OR 3 , -N(R 3 )2, -SR 3 , appropriately substituted C 1-6 aliphatic, or -CN; R z is hydrogen or an appropriately substituted C 1-6 is aliphatic, R 2 is replaced appropriately by C 1-6 is aliphatic, R 3 is hydrogen or an appropriately substituted C 1-6 is aliphatic, R 4 is halogen, —OR, —N(R)2, or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7-10 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 divalent C 1-3 a linear or branched hydrocarbon chain, R a is hydrogen, halogen, optionally substituted C 1-6 an aliphatic, optionally substituted phenyl, an optionally substituted 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen, optionally substituted C 1-6 an aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's, when attached to the same nitrogen atom, together form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0 to 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0045] In some embodiments, the present disclosure provides a compound of formula IV: [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is -O- or -NR z - and R x is hydrogen, halogen, -OR 3 , or -CN, R z is hydrogen or an appropriately substituted C 1-6 is aliphatic, R 2 is replaced appropriately by C 1-6 is aliphatic, R 3 is hydrogen or an appropriately substituted C 1-6 is aliphatic, [ka] is either (i) or (ii): [ka] wherein ring A is further substituted at least once and at least one substituent on ring A is selected from C 1-6 is haloalkyl, L is a covalent bond or a divalent C 1-3 a linear or branched hydrocarbon chain, R a is hydrogen, halogen, optionally substituted C 1-6 an aliphatic, optionally substituted phenyl, an optionally substituted 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R' is C 1-6 It is an aliphatic or 3- to 7-membered saturated or partially unsaturated carbocyclyl.

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

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

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

[0049] In some embodiments of any of formulas I, I-D, I-E, II, II-D, II-E, and II-F, W is CR w or N, and X is CR x or N, and Y is CR y or N, and no more than one of W, X, and Y is N. In some embodiments of any of formulas I, I-D, I-E, II, II-D, II-E, and II-F, W is CR w or N, and X is CR x or N, and Y is CR y Or N, and no more than two of W, X, and Y are N.

[0050] In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, Z is -O-. In some embodiments, Z is -NR z In some embodiments, Z is -NH-.

[0051] In some embodiments of any of Formulas I, I-D, I-E, II, II-D, II-E, and II-F, R w is hydrogen, halogen, or optionally substituted C 1-6 In some embodiments, R w is hydrogen. In some embodiments, R w is halogen. In some embodiments, R w is fluoro. In some embodiments, R w is chloro. In some embodiments, R w -OR 2 In some embodiments, R w -OR 2 where R 2 is replaced appropriately by C 1-6 In some embodiments, Y is N and W is CR w and R w HA-OR 2 where R 2 is replaced appropriately by C 1-6 In some embodiments, R w is -N(R 2 )2. In some embodiments, R w -SR 2 In some embodiments, R w -SR 2 where R 2 is replaced appropriately by C 1-6 In some embodiments, Y is N and W is CR w and R w Ha-SR 2 where R 2 is replaced appropriately by C 1-6 In some embodiments, R w is replaced appropriately by C 1-6 In some embodiments, R w is an optionally substituted linear or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6In some embodiments, R w is replaced appropriately by C 1-6 In some embodiments, R w is replaced appropriately by C 1-4 In some embodiments, R w is replaced appropriately by C 1-2 In some embodiments, R w is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, R w is -CN.

[0052] In some embodiments of any of Formulas I, IA, IC, ID, IE, II, II-A, II-C, II-D, II-E, II-F, III, and IV, R x is hydrogen, halogen, -CN, -OR 2 , or C as substituted accordingly 1-6 In some embodiments, R x is hydrogen, halogen, -CN, -O(C 1-4 alkyl), or C optionally substituted with one or more halogens 1-4 In some embodiments, R x is hydrogen, halogen, -OR 2 , or C as substituted accordingly 1-6 In some embodiments, R x is hydrogen, halogen, -O(C 1-4 alkyl), or C optionally substituted with one or more halogens 1-4 In some embodiments, R x is hydrogen, halogen, or optionally substituted C 1-6 In some embodiments, R x is hydrogen, halogen, -CN, or OR 2 In some embodiments, R x is hydrogen, halogen, -CN, or O(C 1-4 In some embodiments, R xis halogen or —CN. In some embodiments, R x is hydrogen. In some embodiments, R x is halogen. In some embodiments, R x is fluoro. In some embodiments, R x is chloro. In some embodiments, R x -OR 2 In some embodiments, R x -OR 2 where R 2 is replaced appropriately by C 1-6 Aliphatic (e.g., optionally substituted C 1-6 In some embodiments, R x is -O(C 1-4 In some embodiments, R x is —OCH. In some embodiments, R x is -N(R 2 )2. In some embodiments, R x -SR 2 In some embodiments, R x -SR 2 where R 2 is replaced appropriately by C 1-6 In some embodiments, R x is replaced appropriately by C 1-6 In some embodiments, R x is an optionally substituted linear or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, R x is replaced appropriately by C 1-6 Alkyl (e.g., C optionally substituted with one or more fluoro) 1-6 In some embodiments, R x is replaced appropriately by C 1-4 Alkyl (e.g., C optionally substituted with one or more fluoro) 1-4 In some embodiments, R x is replaced appropriately by C1-2 Alkyl (e.g., C optionally substituted with one or more fluoro) 1-2 In some embodiments, R x is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro, e.g., —CHF). In some embodiments, R x is -CN.

[0053] In some embodiments of any of Formulas I, IA, IB, ID, IE, II, II-A, II-B, II-D, II-E, II-F, R y is hydrogen, halogen, or optionally substituted C 1-6 In some embodiments, R y is hydrogen. In some embodiments, R y is halogen. In some embodiments, R y is fluoro. In some embodiments, R y is chloro. In some embodiments, R y -OR 2 In some embodiments, R y -OR 2 where R 2 is replaced appropriately by C 1-6 In some embodiments, W is N and Y is CR y and R y HA-OR 2 where R 2 is replaced appropriately by C 1-6 In some embodiments, R y is -N(R 2 )2. In some embodiments, R y -SR 2 In some embodiments, R y -SR 2 where R 2 is replaced appropriately by C 1-6 In some embodiments, W is N and Y is CR y and R y Ha-SR 2where R 2 is replaced appropriately by C 1-6 In some embodiments, R y is replaced appropriately by C 1-6 In some embodiments, R y is an optionally substituted linear or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, R y is replaced appropriately by C 1-6 In some embodiments, R y is replaced appropriately by C 1-4 In some embodiments, R y is replaced appropriately by C 1-2 In some embodiments, R y is optionally substituted methyl (e.g., methyl optionally substituted with one or more fluoro). In some embodiments, R y is -CN.

[0054] In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, R z is hydrogen. In some embodiments, R z is replaced appropriately by C 1-6 In some embodiments, R z is an optionally substituted linear or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, R z is replaced appropriately by C 1-6 In some embodiments, R z is replaced appropriately by C 1-4 In some embodiments, R z is the unsubstituted C 1-4 In some embodiments, R z is replaced appropriately by C 1-2In some embodiments, R z is the unsubstituted C 1-2 It is alkyl.

[0055] In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, II-E, and II-F, R 1 is —N(R)C(O)N(R) or —N(R)C(O)OR. In some embodiments, R 1 is —N(R), —N(R)C(O)R′, or —C(O)N(R). In some embodiments, R 1 is —N(R)C(O)R′ or —C(O)N(R). In some embodiments, R 1 is —N(R)C(O)R′, —C(O)N(R)2, —N(R)C(O)N(R)2, or —N(R)C(O)OR.

[0056] In some embodiments, R 1 When is —N(R), —N(R)C(O)R′, or —C(O)N(R), n is 1, 2, or 3. In some embodiments, when n is 0, R 1 is -N(R)C(O)N(R)2 or -N(R)C(O)OR.

[0057] In some embodiments, R 1 is -N(R). In some embodiments, R 1 is —N(H)(R). In some embodiments, R 1 is -NH. In some embodiments, R 1 When is -N(R)2, n is 1, 2, or 3.

[0058] In some embodiments, R 1 is —N(R)C(O)R′. In some embodiments, R 1 is —N(H)C(O)R′. In some embodiments, R 1 is -N(R)C(O) (optionally substituted C1-6 In some embodiments, R 1 is -N(H)C(O) (optionally substituted C 1-6 In some embodiments, R 1 is -N(R)C(O)(C 1-6 In some embodiments, R 1 is -N(H)C(O)(C 1-6 In some embodiments, R 1 is -N(R)C(O) (linear or branched C 1-6 In some embodiments, R 1 is -N(H)C(O) (linear or branched C 1-6 In some embodiments, R 1 is -N(R)C(O) (optionally substituted C 1-6 In some embodiments, R 1 is -N(H)C(O) (optionally substituted C 1-6 In some embodiments, R 1 is -N(R)C(O)R', where R 1 R' is halogen, -OH, -O(C 1-6 alkyl), -NH(CH2)2O(C 1-6 alkyl), -NH(C 1-4 haloalkyl), or optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur 1-6 In some embodiments, R 1 is —N(H)C(O)R′, where R 1 R' is halogen, -OH, -O(C 1-6 alkyl), -NH(CH2)2O(C 1-6 alkyl), -NH(C 1-4 haloalkyl), or optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur 1-6 In some embodiments, R 1is -N(R)C(O)(C 1-6 In some embodiments, R 1 is -N(H)C(O)(C 1-6 In some embodiments, R 1 is -N(R)C(O) (optionally substituted C 1-4 In some embodiments, R 1 is -N(H)C(O) (optionally substituted C 1-4 In some embodiments, R 1 is -N(R)C(O)R', where R 1 R' is halogen, -OH, -O(C 1-6 alkyl), -NH(CH2)2O(C 1-6 alkyl), -NH(C 1-4 haloalkyl), or optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur 1-4 In some embodiments, R 1 is —N(H)C(O)R′, where R 1 R' is halogen, -OH, -O(C 1-6 alkyl), -NH(CH2)2O(C 1-6 alkyl), -NH(C 1-4 haloalkyl), or optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur 1-4 In some embodiments, R 1 is -N(R)C(O)(C 1-4 In some embodiments, R 1 is -N(H)C(O)(C 1-4 In some embodiments, R 1 is -N(R)C(O)(C 1-2 In some embodiments, R 1 is -N(H)C(O)(C 1-2 In some embodiments, R 1is —N(R)C(O)CH. In some embodiments, R 1 is —N(H)C(O)CH. In some embodiments, R 1 is -N(R)C(O) (optionally substituted C 3-7 In some embodiments, R 1 is -N(H)C(O) (optionally substituted C 3-7 In some embodiments, R 1 is —N(R)C(O)(optionally substituted cyclopropyl). In some embodiments, R 1 is —N(H)C(O)(optionally substituted cyclopropyl). In some embodiments, R 1 is —N(R)C(O)R′, then n is 1, 2, or 3.

[0059] In some embodiments, R 1 is —C(O)N(R). In some embodiments, R 1 is -C(O)N(R)(C 1-6 In some embodiments, R 1 is -C(O)N(H)(C 1-6 In some embodiments, R 1 is -C(O)N(R) (linear or branched C 1-6 In some embodiments, R 1 is -C(O)N(H) (linear or branched C 1-6 In some embodiments, R 1 is -C(O)N(R)(C 1-6 In some embodiments, R 1 is -C(O)N(H)(C 1-6 In some embodiments, R 1 is -C(O)N(R)(C 1-4 In some embodiments, R 1 is -C(O)N(H)(C 1-4 In some embodiments, R 1 is -C(O)N(R)(C1-2 In some embodiments, R 1 is -C(O)N(H)(C 1-2 In some embodiments, R 1 is —C(O)N(R)CH. In some embodiments, R 1 is —C(O)N(H)(R). In some embodiments, R 1 is —C(O)N(R)2, then n is 1, 2, or 3.

[0060] In some embodiments, R 1 is —N(R)C(O)N(R). In some embodiments, R 1 is —N(H)C(O)N(R). In some embodiments, R 1 is -N(H)C(O)N (optionally substituted C 1-6 aliphatic). In some embodiments, R 1 is -N(H)C(O)N (optionally substituted C 1-6 In some embodiments, R 1 is -N(H)C(O)N (optionally substituted C 1-4 In some embodiments, R 1 is -N(H)C(O)N (optionally substituted C 1-2 In some embodiments, R 1 is —N(R)C(O)NH(R). In some embodiments, R 1 is —N(H)C(O)NH(R). In some embodiments, R 1 is -N(H)C(O)NH (optionally substituted C 1-6 In some embodiments, R 1 is -N(H)C(O)NH (optionally substituted C 1-6 In some embodiments, R 1 is -N(H)C(O)NH (optionally substituted C 1-4 In some embodiments, R 1 is -N(H)C(O)NH (optionally substituted C 1-2In some embodiments, R 1 is -N(H)C(O)NH (optionally substituted C 3-7 In some embodiments, R 1 is -N(H)C(O)NH (optionally substituted C 3-7 In some embodiments, R 1 is —N(H)C(O)NH(optionally substituted cyclopropyl). In some embodiments, R 1 is —N(H)C(O)NH (an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 is —N(H)C(O)NH (optionally substituted 4-6 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 is —N(H)C(O)NH (optionally substituted oxetanyl). In some embodiments, R 1 is —N(R)C(O)N(R)2, where two R groups attached to the same nitrogen together form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is —N(H)C(O)N(R)2, where two R groups attached to the same nitrogen together form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is -N(H)C(O)N(R)2, where two R groups attached to the same nitrogen together represent one or more halogens, C 1-6 Alkyl, -OH, and -O(C 1-6In some embodiments, R forms a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with an alkyl group. 1 is —N(H)C(O)N(R)2, where two R groups attached to the same nitrogen together form an optionally substituted 4-6 membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is -N(H)C(O)N(R)2, where two R groups attached to the same nitrogen together represent one or more halogens, C 1-6 Alkyl, -OH, and -O(C 1-6 In some embodiments, R forms a 4-6 membered saturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with alkyl. 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, when X is CH, R 1 teeth, [ka] isn't it.

[0061] In some embodiments, R 1 is —N(R)C(O)OR. In some embodiments, R 1 is —N(H)C(O)OR. In some embodiments, R 1 is -N(H)C(O)OR, where R 1 R is an optionally substituted C 1-6aliphatic or optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is -N(H)C(O)OR, where R 1 R is an optionally substituted C 1-6 alkyl, or an optionally substituted 4-6 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 is -N(H)C(O)OR, where R 1 R is one or more of -OH, -O(C 1-6 alkyl), -N(C 1-6 C optionally substituted with alkyl)2, or 4-6 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur 1-6 In some embodiments, R 1 is -N(H)C(O)OR, where R 1 R is 1 or more C 1-6 In some embodiments, R is a 4-6 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with alkyl. 1 teeth, [ka] is selected from.

[0062] In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, R 2 is an optionally substituted linear or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, R 2 is replaced appropriately by C 1-6 In some embodiments, R 2 is replaced appropriately by C1-4 In some embodiments, R 2 is the unsubstituted C 1-4 In some embodiments, R 2 is replaced appropriately by C 1-2 In some embodiments, R 2 is the unsubstituted C 1-2 In some embodiments, R 2 is methyl.

[0063] In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, each R 3 are independently hydrogen or optionally substituted C 1-4 In some embodiments, each R 3 are independently hydrogen or optionally substituted C 1-2 In some embodiments, each R 3 is hydrogen. In some embodiments, each R 3 are independently optionally substituted C 1-6 In some embodiments, each R 3 are independently optionally substituted linear or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, each R 3 are independently optionally substituted C 1-4 In some embodiments, each R 3 are independently optionally substituted linear or branched C 1-4 Aliphatic (i.e., optionally substituted acyclic C 1-4 In some embodiments, each R 3 are independently optionally substituted C 1-2 In some embodiments, each R 3 are independently hydrogen or C 1-6 In some embodiments, each R 3 are independently hydrogen or C 1-4In some embodiments, each R 3 are independently hydrogen or C 1-2 It is alkyl.

[0064] In some embodiments of Formula III, R 4 is halogen. In some embodiments, R 4 is fluoro. In some embodiments, R 4 is chloro. In some embodiments, R 4 is -OR. In some embodiments, R 4 is -OH or -O (optionally substituted C 1-6 In some embodiments, R 4 is -OH or -O(C 1-6 In some embodiments, R 4 is —OH or —OCH. In some embodiments, R 4 is -N(R). In some embodiments, R 4 is —NH(R). In some embodiments, R 4 is -NH(optionally substituted C 1-6 In some embodiments, R 4 is -NH(R), where R 4 R is one or more halogen or -O(C 1-6 C optionally substituted with alkyl 1-6 In some embodiments, R 4 is —NH(CH)F or —NH(CH)OCH. In some embodiments, R 4 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is an optionally substituted 4-6 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is 1 or more C 1-6In some embodiments, R is a 4-6 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with alkyl. 4 is 1 or more C 1-6 and tetrahydropyranyl or morpholinyl optionally substituted with alkyl.

[0065] In some embodiments of any of Formulas I, IA, IB, IC, ID, II, II-A, II-B, II-C, II-E, and II-F, each R c is halogen, -CN, -CO2R, -C(O)N(R)2, -NO2, -N(R)2, -OR, -SR, or an optionally substituted C 1-6 alkyl, where R c each R is independently hydrogen or C 1-6 In some embodiments, R c is halogen (e.g., fluoro). In some embodiments, R c is —CN, —COR, —C(O)N(R), or —NO. In some embodiments, R c is -N(R), -OR, or -SR. In some embodiments, R c is replaced appropriately by C 1-6 Aliphatic (e.g., C 1-6 alkyl).

[0066] In some embodiments of any of Formulas I, IA, IB, IC, ID, 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 Formulas I, IA, IB, IC, ID, IE, and III, ring A is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 8-10 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 an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 5 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted pyrazolyl. In some embodiments, ring A is an optionally substituted 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted pyridonyl.

[0070] In some embodiments, ring A is an optionally substituted 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 8-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 9-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted tetrahydropyrazolo[1,5-a]pyridyl or dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl. In some embodiments, ring A is an optionally substituted 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

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

[0072] In some embodiments, ring A is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 3-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an 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 an optionally substituted 7-10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 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 an 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 an 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 an optionally substituted 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0074] In some embodiments, ring A is [ka] is.

[0075] In some embodiments of any of Formulas II, II-A, II-B, II-C, II-D, II-E, and II-F, ring A is an optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 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 an optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 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 an optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 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 the bicyclic or polycyclic ring system of Ring A contains at least one heteroatom. In some embodiments, one ring, and only one ring, of the bicyclic or polycyclic ring system of Ring A does not contain a heteroatom.

[0077] In some embodiments, each ring in the bicyclic or polycyclic ring system of ring A is aromatic. In some embodiments, one ring, and only one ring, of the bicyclic or polycyclic ring system of ring A is aromatic. In some embodiments, none of the rings in the bicyclic or polycyclic ring system of ring A is aromatic.

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

[0079] In some embodiments, ring A is an optionally substituted 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is one or more oxo, halogen, or C 1-6 In some embodiments, ring A is an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with alkyl. In some embodiments, ring A is an optionally substituted 8-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted dihydro-1H-imidazo[1,2-b]pyrazolyl. In some embodiments, ring A is an optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is one or more oxo, halogen, or C 1-6In some embodiments, ring A is an optionally substituted 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with alkyl. In some embodiments, ring A is an 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 an optionally substituted 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur ... 1-6 and 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with alkyl. 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 an optionally substituted 10- to 16-membered polycyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 11-membered polycyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 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 an 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 an 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 an optionally substituted 7-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 8-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 9-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 10-membered bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

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

[0083] In some embodiments, ring A is [ka] is selected from.

[0084] In some embodiments, ring A is [ka] wherein ring A1 and ring A2, alone or in combination, are as defined in formula II-E and as described in classes and subclasses herein, and ring A1 is fused to ring A2, which is optionally (i) further fused to ring A3, or (ii) ring A2 and ring A3 combine to form a spiro ring.

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

[0088] In some embodiments, ring A1 is an optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, when ring A1 is an 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 an optionally substituted 5- to 7-membered saturated monocyclic carbocyclyl. In some embodiments, ring A1 is an optionally substituted 5- to 7-membered partially saturated monocyclic carbocyclyl.

[0089] In some embodiments, ring A1 is an optionally substituted 5-7 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 an optionally substituted 5-7 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is an optionally substituted 5-7 membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0090] In some embodiments, the optionally substituted ring A1 fused to ring A2 is [ka] is.

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

[0094] In some embodiments, ring A2 is an optionally substituted 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, when ring A2 is an 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 an optionally substituted 5- to 7-membered saturated monocyclic carbocyclyl. In some embodiments, ring A2 is an optionally substituted 5- to 7-membered partially saturated monocyclic carbocyclyl.

[0095] In some embodiments, ring A2 is an optionally substituted 5-7 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 an optionally substituted 5-7 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is an optionally substituted 5-7 membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 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 A2 is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having one or more C 1-6 In some embodiments, ring A2 is an optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with alkyl. In some embodiments, ring A2 is an optionally substituted pyrrolidine or imidazolidine. In some embodiments, ring A2 is an optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur ... 1-6In some embodiments, ring A2 is an optionally substituted 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with alkyl. In some embodiments, ring A2 is an optionally substituted piperidine, hexahydropyrimidine, morpholine, or piperazinone. In some embodiments, ring A2 is an optionally substituted 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur ... or more C 1-6 and 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with alkyl. In some embodiments, Ring A2 is azepane, diazepane, or oxazepane.

[0096] In some embodiments, the optionally substituted ring A2 fused to ring A1 is [ka] 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 to 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 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is an optionally substituted 5-membered monocyclic heteroaryl having 1 to 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 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is an optionally substituted 5-membered monocyclic heteroaryl having 1 to 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 to 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 spiro ring. In some embodiments, when ring A2 and ring A3 combine to form a spiro ring, ring A3 is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0099] In some embodiments, ring A3, if present, is optionally substituted phenyl. In some embodiments, ring A3, if present, is optionally substituted 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A3, if present, is optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring A3, when not fused to aromatic ring A2, is 3-7 membered saturated monocyclic carbocyclyl. In some embodiments, ring A3 is 3-7 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 3-7 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 aromatic ring A2, is a 3- to 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A3 is a 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, which is fused to ring A1 and combines with ring A3 to form a spiro ring, is [ka] is selected from.

[0101] In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, Ring A may be substituted at any substitutable carbon atom with oxo, halogen, R°, —CN, —OR°, —O(CH) 1-4 R o , —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) at a substitutable nitrogen atom, —R † , -NR † 2. -C(O)R † , -C(O)OR † , -S(O)2R † , and -S(O)NR † 2. In some embodiments, ring A is optionally substituted with one or more groups selected from (i) oxo, halogen, R°, —OR°, and —O(CH) at a substitutable carbon atom. 1-4 R o and (ii) at a substitutable nitrogen atom, -R † In some embodiments, Ring A is optionally substituted (i) at a substitutable carbon atom with one or more groups independently selected from oxo, halogen, and R°, and (ii) at a substitutable nitrogen atom with —R † and optionally substituted with one or more groups selected from:

[0102] In some embodiments, ring A is one or more R b is substituted as appropriate (e.g., -LR, if present) a in addition to being replaced by ), where R bis as defined above in Formula ID and as described in the classes and subclasses herein. In some embodiments, ring A contains 0, 1, 2, 3, 4, or 5 R, as valences allow. b is replaced by

[0103] In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, III, and IV, L is a covalent bond. In some embodiments, L is a divalent C 1-3 In some embodiments, L is a divalent C 1-2 It is a straight or branched hydrocarbon chain. In some embodiments, L is methylene (i.e., -CH2-). In some embodiments, L is -CH2CH2-. In some embodiments, L is -CH2CH2CH2-. In some embodiments, L is -C(CH3)2-. In some embodiments, L is a covalent bond or -CH2-.

[0104] In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, III, and IV, R a is halogen, optionally substituted C 1-6 an aliphatic, optionally substituted phenyl, an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. a is replaced appropriately by C 1-6an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from aliphatic, nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is hydrogen, halogen, optionally substituted C 1-6 an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from aliphatic, nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0105] In some embodiments, R a is hydrogen. In some embodiments, R a is not hydrogen.

[0106] In some embodiments, R a is halogen. In some embodiments, R a is fluoro, chloro, bromo, or iodo. In some embodiments, R a is fluoro. In some embodiments, R a is chloro.

[0107] In some embodiments, R a is replaced appropriately by C 1-6 In some embodiments, R a is an optionally substituted linear or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, R a is one or more halogens, -N(C 1-6 C optionally substituted with alkyl), -OH, or -O (optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl) 1-6In some embodiments, R a is replaced appropriately by C 1-6 In some embodiments, R a is one or more halogens, -N(C 1-6 C optionally substituted with alkyl), -OH, or -O (optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl) 1-6 In some embodiments, R a is replaced appropriately by C 1-4 In some embodiments, R a is one or more halogens, -N(C 1-6 C optionally substituted with alkyl), -OH, or -O (optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl) 1-4 In some embodiments, R a is -CH3, -CD3, -CF3, -CH2N(CH3)2, -CH2CH2OH, or [ka] is.

[0108] In some embodiments, R a is optionally substituted phenyl.

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

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

[0111] In some embodiments, R a is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 4-7 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 3-membered saturated monocyclic heterocyclyl having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 4-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 5-membered saturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ais optionally substituted pyrrolidinyl or tetrahydrofuranyl. In some embodiments, R a is an optionally substituted 6-membered saturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 7-membered saturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

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

[0113] In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, III, and IV, [ka] -R a (i.e., L is a covalent bond). In some embodiments, [ka] is -(C 1-3 alkylene)-R a (i.e., L is C 1-3 In some embodiments, [ka] is -(C 1-2 alkylene)-R a (i.e., L is C 1-2 In some embodiments, [ka] is -CH2-R a (i.e., L is a C1 hydrocarbon chain). In some embodiments, [ka] is -CH2CH2-R a (i.e., L is a C2 linear hydrocarbon chain). In some embodiments, [ka] is -CH2CH2CH2-R a (i.e., L is a C3 linear hydrocarbon chain). In some embodiments, [ka] is -C(CH3)2-R a (i.e., L is a C3 branched hydrocarbon chain).

[0114] In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, where valence rules permit, R b There may be up to five of these, each independently representing a halogen, -CN, -OR, -O(CH2) m R, -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)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 aliphatic, optionally substituted 3-6 membered saturated or partially unsaturated carbocyclyl, optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b each occurrence independently represents a halogen, optionally substituted C 1-6 Aliphatic, -OR, or -O(CH2) m R. In some embodiments, R b each occurrence independently represents a halogen, optionally substituted C 1-6 alkyl, -OR, or -OCHR, where R b R is an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b Each occurrence of is a halogen or C optionally substituted with one or more halogens. 1-6It is alkyl.

[0115] In some embodiments, R b In some embodiments, R b In some embodiments, there are two R b In some embodiments, there are three R b In some embodiments, there are four R b In some embodiments, there are five R b is absent. In some embodiments, R b In some embodiments, R b There are one or two.

[0116] In some embodiments, R b is hydrogen.

[0117] In some embodiments, R b is halogen. In some embodiments, R b is fluoro, chloro, bromo, or iodo. In some embodiments, R b is fluoro. In some embodiments, R b is chloro.

[0118] In some embodiments, R b are -CN, -OR, -O(CH2) m R, -SR, -N(R), -NO, -C(O)R', -C(O)OR, -C(O)N(R), -OC(O)R', -OC(O)N(R), -OC(O)OR, -OSOR, -OSOR, -N(R)C(O)R', -N(R)SOR', -SOR, -SOR, or -SOR'. In some embodiments, R b is -CN. In some embodiments, R b is -N(R). In some embodiments, R b is -C(O)N(R)2.

[0119] In some embodiments, R b is -OR. In some embodiments, R b is -OR, where R is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is —OR, where R is an optionally substituted 4-6 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is —OR, where R has 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and one or more C 1-6 In some embodiments, R is a 4-6 membered saturated monocyclic heterocyclyl optionally substituted with alkyl (e.g., methyl). b is —OR, where R is optionally substituted azetidinyl or pyrrolidinyl. In some embodiments, R b is -OR, where R is 1 or more C 1-6 azetidinyl or pyrrolidinyl optionally substituted with alkyl (e.g., methyl). In some embodiments, R b teeth, [ka] is.

[0120] In some embodiments, R b is -O(CH2) m R. In some embodiments, R b is -OCHR. In some embodiments, R b is -O(CH2) m R, where R is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is -O(CH2) mR, where R is an optionally substituted 4-6 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is -O(CH2) m R, where R has 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and one or more C 1-6 In some embodiments, R is a 4-6 membered saturated monocyclic heterocyclyl optionally substituted with alkyl (e.g., methyl). b is -O(CH2) m R, where R is optionally substituted pyrrolidinyl. In some embodiments, R b is -O(CH2) m R, where R is 1 or more C 1-6 In some embodiments, R is pyrrolidinyl optionally substituted with alkyl (e.g., methyl). b teeth, [ka] is.

[0121] In some embodiments, R b is replaced appropriately by C 1-6 In some embodiments, R b is an optionally substituted linear or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, R b is replaced appropriately by C 1-6 In some embodiments, R b is replaced appropriately by C 1-4 In some embodiments, R b is C optionally substituted with one or more halogens 1-4 In some embodiments, R b is -CH3, -CF3, or -C(CH3)3.

[0122] In some embodiments, R bis an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R b is optionally substituted C3-C6 cycloalkyl.

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

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

[0125] In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, 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 Formulas I, IA, IB, IC, ID, IE, and III, optionally substituted [ka] teeth, [ka] In some embodiments, optionally substituted [ka] is replaced appropriately [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0127] In some embodiments of Formula IV, [ka] teeth, [ka] In some embodiments, the compound is selected from the group consisting of: [ka] teeth, [ka] In some embodiments, the compound is selected from the group consisting of: [ka] but [ka] If -LR a is C 1-6 In some embodiments, [ka] teeth, [ka] wherein ring A is further substituted at least once, and at least one substituent on ring A is C 1-6 haloalkyl (e.g., —CF). In some embodiments, [ka] but [ka] where ring A is R as defined herein and described in classes and subclasses. b and at least one substituent on ring A (i.e., R b or -LR a (either of these) is C 1-6 haloalkyl (e.g., —CF). In some embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0128] In some embodiments of any of Formulas II, II-A, II-B, II-C, II-D, II-E, and II-F, optionally substituted [ka] teeth, [ka] In some embodiments, optionally substituted [ka] teeth, [ka] In some embodiments, optionally substituted [ka] teeth, [ka] is selected from the group consisting of:

[0129] In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, each R is independently selected from hydrogen, optionally substituted C 1-6 aliphatic or optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's, when attached to the same nitrogen atom, together form an optionally substituted 3-7 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 C 1-6 In some embodiments, each R is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 In some embodiments, each R is independently an optionally substituted C 1-6In some embodiments, each R is independently selected from hydrogen, optionally substituted C 1-6 alkyl, or an optionally substituted 4-6 membered saturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0130] In some embodiments, R is hydrogen.

[0131] In some embodiments, R is optionally substituted C 1-6 In some embodiments, R is an optionally substituted linear or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, R is optionally substituted C 1-6 In some embodiments, R is one or more of -OH, -O(C 1-6 alkyl), -N(C 1-6 C optionally substituted with alkyl)2, or 4-6 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur 1-6 In some embodiments, R is optionally substituted C alkyl. 1-4 In some embodiments, R is optionally substituted C alkyl. 1-2 It is alkyl.

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

[0133] In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 4-6 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is one or more C 1-6 In some embodiments, R is an optionally substituted oxetanyl.

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

[0135] In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, each R′ independently represents an optionally substituted C 1-6 Alkyl or optionally substituted C 3-7 In some embodiments, R' is optionally substituted C 1-6 In some embodiments, R' is an optionally substituted straight or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, R' is optionally substituted C 1-6 In some embodiments, R' is a halogen, -OH, -O(C 1-6 alkyl), -NH(CH2)2O(C 1-6 alkyl), -NH(C 1-4 haloalkyl), or optionally substituted 3- to 7-membered saturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur 1-6 In some embodiments, R' is optionally substituted C 1-4 In some embodiments, R' is optionally substituted C 1-2 In some embodiments, R' is alkyl. In some embodiments, R' is methyl. In some embodiments, R' is an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R' is an optionally substituted C 3-7 In some embodiments, R' is optionally substituted cyclopropyl. In some embodiments, R' is cyclopropyl.

[0136] In some embodiments of any of the formulas described herein, the compound is [ka] isn't it.

[0137] In some embodiments, the compound is [ka] isn't it.

[0138] In some embodiments, the compound is [ka] isn't it.

[0139] In some embodiments, the compound is [ka] isn't it.

[0140] In some embodiments of any of Formulas I, IA, IB, IC, ID, and IE, R 1 but [ka] and Y is N, then R x is not hydrogen. In some embodiments, R 1 but [ka] In some embodiments, when ring A is pyrazolyl, R 1 is not —N(R)C(O)N(R). In some embodiments, when ring A is pyrazolyl and Y is N, R x is not hydrogen.

[0141] In some embodiments of any of Formulas II, II-A, II-B, II-C, II-D, II-E, and II-F, ring A is [ka] In some embodiments, ring A is not [ka] If R 1 is not —N(H)C(O)CH3. In some embodiments, ring A is [ka] If X is N, then R x is not -CN.

[0142] In some embodiments of Formula III, R 4 is not tetrahydropyranyl. In some embodiments, R 4 When is tetrahydropyranyl and Y is N, R x is not Chrollo.

[0143] In some embodiments of Formula IV, Y is N and R x If is not hydrogen, -LR a is -CH3 or [ka] isn't it.

[0144] In some embodiments, the present disclosure provides: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, the present disclosure encompasses the recognition that provided compounds exhibit certain desirable characteristics, e.g., compared to other known compounds. For example, in some embodiments, provided compounds are more potent than other known compounds 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 discovery, e.g., 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 profile (e.g., based on the assays described in the Examples below). In some embodiments, provided compounds exhibit certain desirable characteristics, e.g., compared to other known compounds, in one or more assays described herein. Without wishing to be bound by any particular theory, the present disclosure encompasses the recognition that 6-heteroaryloxybenzimidazoles and azabenzimidazoles (e.g., compounds described herein) exhibit certain more desirable characteristics (e.g., better performance in one or more assays described herein) compared to the corresponding 5-heteroaryloxybenzimidazoles and azabenzimidazoles.

[0146] In some embodiments, the provided compounds are provided and / or utilized in the form of a salt (e.g., a pharmaceutically acceptable salt). Reference to a compound provided herein is understood to include a reference to its salt unless otherwise specified. Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977).

[0147] It will be understood that throughout this disclosure, unless otherwise stated, a reference to a compound of formula I is intended to include species of compounds of formula I, IA, IB, IC, ID, and IE, and species of such formulae disclosed herein; a reference to a compound of formula II is intended to include species of compounds of formula II, II-A, II-B, II-C, II-D, II-E, and II-F, and species of such formulae disclosed herein; a reference to a compound of formula III is intended to include species of compounds of such formulae disclosed herein; and a reference to a compound of formula IV is intended to include species of compounds of such formulae disclosed herein.

[0148] Preparation of the provided compounds The provided compounds can generally be made by the processes described in the following schemes and examples. In some embodiments, the provided compounds are prepared according to the following schemes: [ka] wherein PG is a suitable protecting group (e.g., p-methoxybenzyl, acetyl, methylcarbamate, etc.), and rings A, n, L, W, X, Y, R, R 2 , R a , and R care as defined above for Formula I and as described in classes and subclasses herein, either alone or in combination. Thus, 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, the 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 a process 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, optionally in the presence of a suitable base (e.g., triethylamine).

[0149] In some embodiments, provided compounds are prepared according to the following scheme: [ka] wherein PG is a suitable protecting group (e.g., p-methoxybenzyl, acetyl, methylcarbamate, etc.), and rings A, n, W, X, Y, R, R 2 , and R care as defined above for Formula II, alone or in combination, and as described in classes and subclasses herein. Thus, 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, the 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, optionally in the presence of a suitable base (e.g., triethylamine).

[0150] In some embodiments, provided compounds are prepared according to the following scheme: [ka] wherein LG is a suitable leaving group (e.g., halogen, e.g., chloro or bromo), and the rings A, n, L, W, X, Y, Z, R 1 , R 2 , R a , and R care as defined above for Formula I and / or II, alone or in combination, and as described in classes and subclasses herein. Thus, 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., KPO, KCO, or CsCO), 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., KPO, KCO, or CsCO), 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, the process for preparing compound B-1 or B-2 further comprises a deprotection step under suitable conditions. In some embodiments, the process for preparing compound B-1 or B-2 further comprises a functionalization step (e.g., cyanation) under suitable conditions.

[0151] In some embodiments, provided compounds are prepared according to the following scheme: [ka] In the formula, rings A, n, L, W, X, Y, R 1 , R 2 , R a , and R care as defined above for Formula I and as described in classes and subclasses herein, alone or in combination. Thus, 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, the 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: [ka] In the formula, rings A, n, W, X, Y, R 1 , R 2 , and R c are as defined above for Formula II and as described in classes and subclasses herein, alone or in combination. Thus, 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, the process for preparing compound C-2 further comprises a deprotection and / or functionalization (e.g., cyanation) step under suitable conditions.

[0153] composition The present disclosure also provides compositions comprising the compounds provided herein together with one or more other ingredients. In some embodiments, the provided compositions comprise and / or provide a compound described herein (e.g., a compound of Formula I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV).

[0154] In some embodiments, provided compositions are pharmaceutical compositions that contain and / or deliver a compound provided herein (e.g., a compound of Formula I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV) and further comprise a pharmaceutically acceptable carrier. Pharmaceutical compositions typically contain an amount of an active agent (e.g., a compound described herein) effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions contain a compound described herein and one or more fillers, disintegrants, lubricants, glidants, antiadhesive agents, and / or antistatic agents, etc. Provided pharmaceutical compositions can be in a variety of forms, including oral dosage forms, topical creams, topical patches, iontophoretic forms, suppositories, nasal sprays and / or inhalers, eye drops, intraocular injection forms, depot forms, and injectable and infusible solutions. Methods for preparing pharmaceutical compositions are well known in the art.

[0155] In some embodiments, provided compounds are formulated in unit dosage forms for ease of administration and uniformity of dosage. As used herein, the phrase "unit dosage form" 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 amount of the active agent. In some embodiments, a unit dosage form contains an entire single dose of a drug. 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 necessary or anticipated to be necessary to achieve the intended effect. A unit dosage form can be, for example, a liquid pharmaceutical composition containing a predetermined amount of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, capsule, etc.) containing a predetermined amount of one or more active agents, a sustained-release formulation containing a predetermined amount of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents.

[0156] The provided compositions can be administered using any amount and any dosage form effective to treat or lessen the severity of any disease or disorder described herein.

[0157] use The present disclosure provides uses of the compounds and compositions described herein. In some embodiments, the provided compounds and compositions are useful in medicine (e.g., as therapeutics). In some embodiments, the provided compounds and compositions are useful in research, for example, as analytical tools and / or control compounds in biological assays.

[0158] In some embodiments, the present disclosure provides methods of administering a provided compound or composition to a subject in need thereof, hi some embodiments, the present disclosure provides methods of administering a provided compound or composition to a subject suffering from or susceptible to a JAK2-associated disease, disorder, or condition.

[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 a method of inhibiting JAK2 in a subject, comprising administering a provided compound or composition. In some embodiments, the present disclosure provides a method of inhibiting JAK2 in a biological sample, comprising contacting the sample with a provided compound or composition.

[0160] JAKs (e.g., JAK2) are involved in the pathogenesis of myeloproliferative neoplasms (Vainchenker, W. et al., F1000 Research 2018, 7 (F1000 Faculty Rev:82), atopic dermatitis (Rodrigues, MA and Torres, TJ 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 a method of treating a JAK2-associated disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a provided compound or composition. In some embodiments, the disease, disorder, or condition is associated with overexpression of JAK2.

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

[0162] In some embodiments, the present disclosure provides a method of treating a hematological malignancy, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the hematological malignancy is a 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, the hematological malignancy is a lymphoma (e.g., Burkitt's lymphoma, Hodgkin's lymphoma, or non-Hodgkin's lymphoma). In some embodiments, the non-Hodgkin's lymphoma is a B-cell lymphoma. In some embodiments, the non-Hodgkin's lymphoma is an NK / T-cell lymphoma (e.g., cutaneous T-cell lymphoma). In some embodiments, the hematological malignancy is a myeloma (e.g., multiple myeloma). In some embodiments, the hematological malignancy is a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or myelofibrosis). In some embodiments, the hematological malignancy is a 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, provided compounds or compositions are administered as part of a combination therapy. As used herein, the term "combination therapy" refers to a situation 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, the regimens may be administered sequentially (e.g., all "doses" of a first regimen are administered before any doses of a second regimen). In some embodiments, the agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may include administering one or more agent(s) or modality(s) in combination to a subject receiving other agent(s) or modality(s). For clarity, combination therapy does not require that the individual agents be administered together in a single composition (or even necessarily simultaneously), although in some embodiments, two or more agents or their active portions may be administered together in a combined composition.

[0165] For example, in some embodiments, provided compounds or compositions are administered to a subject who is receiving or has received one or more additional therapies (e.g., anti-cancer therapies and / or therapies to address one or more side effects of such anti-cancer therapies or otherwise provide palliative care). Exemplary additional therapies include BCL2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mibebrexit), proteasome inhibitors (e.g., bortezomib), LSD1 inhibitors (e.g., IMG-7289), and CXCR2 inhibitors. Useful combinations of JAK2 inhibitors with BCL2, HDAC, BET, and proteasome inhibitors have been demonstrated in cells derived from patients with cutaneous T-cell lymphoma (Yumeen, S., et al., Blood Adv. 2020, 4(10), 2213-2226). The combination of a JAK2 inhibitor and an LSD1 inhibitor demonstrated good efficacy in a mouse model of myeloproliferative neoplasms (Jutzi, JS, et al., HemaSphere 2018, 2(3), http: / / dx.doi.org / 10.1097 / HS9.0000000000000054). CXCR2 activity has been shown to modulate signaling pathways, including the JAK-STAT3 pathway, that are involved in tumor growth, angiogenesis, and / or metastasis (Jaffer, T., Ma, D. Transl. Cancer Res. 2016, 5(Suppl. 4), S616-S628).

[0166] Illustrative Embodiments The following numbered embodiments are illustrative, but non-limiting, of certain aspects of the present disclosure. 1. Compounds of Formula I: [ka] [In the formula, W is CR w or N, X is CR x or N, Y is CR y or N, Z is -O- or -NR z - and R w , R x , and R y are each independently hydrogen, halogen, -OR 3 , -N(R 3 )2, -SR 3 , appropriately substituted C 1-6 aliphatic, or -CN; R z is hydrogen or an appropriately substituted C 1-6 is aliphatic, R 1 is -N(R)2, -N(R)C(O)R', -C(O)N(R)2, -N(R)C(O)N(R)2, or -N(R)C(O)OR; Each R c is halogen, -CN, -CO2R, -C(O)N(R)2, -NO2, -N(R)2, -OR, -SR, or an optionally substituted C 1-6 are independently selected from aliphatic n is 0, 1, 2, or 3, except that R 1 is -N(R), -N(R)C(O)R', or -C(O)N(R), where n is 1, 2, or 3; R 2 is replaced appropriately by C 1-6 is aliphatic, R 3 is hydrogen or an appropriately substituted C 1-6 is aliphatic, Ring A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7-10 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 divalent C 1-3 a linear or branched hydrocarbon chain, R a is hydrogen, halogen, optionally substituted C 1-6 an aliphatic, optionally substituted phenyl, an optionally substituted 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen, optionally substituted C 1-6 an aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's, when attached to the same nitrogen atom, together form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0 to 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' independently represents an optionally substituted C 1-6aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl; or a pharmaceutically acceptable salt thereof. 2. The compound is [ka] The compound of embodiment 1, which is not 3. The compound of embodiment 1 or embodiment 2, wherein Ring A is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4. The compound of any one of the preceding embodiments, wherein Ring A is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 8-10 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 an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6. R a is halogen, optionally substituted C 1-6The compound of any one of the preceding embodiments, which is an aliphatic, optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7. R a is replaced appropriately by C 1-6 The compound of any one of the preceding embodiments, which is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from aliphatic, nitrogen, oxygen, and sulfur, or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8. R a is replaced appropriately by C 1-6 8. The compound of any one of the preceding embodiments, which is an aliphatic or optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound of any one of the preceding embodiments, [ka] is 1 to 5 R as long as valence allows. b is replaced by Each R b are 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)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 an aliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The compound wherein m is 1, 2, or 3. 10. Each R b are independently halogen, -CN, -OR, -O(CH2) m R, -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)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 The compound of embodiment 9, which is an aliphatic, optionally substituted 3-6 membered saturated or partially unsaturated carbocyclyl, optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 11. Each R b are independently halogen or optionally substituted C 1-6 The compound of embodiment 9 or 10, which is aliphatic. 12. A compound according to any one of embodiments 9 to 11, [ka] teeth, [ka] The compound, 13. 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, having formula IC: [ka] or a pharmaceutically acceptable salt thereof. 16. 2. The compound of any one of the preceding embodiments, comprising: [ka] or a pharmaceutically acceptable salt thereof, wherein R b are hydrogen, halogen, -CN, -OR, -O(CH2) m R, -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)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 an aliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 1, 2, or 3]. 17. The compound of any one of the preceding embodiments, having the formula IE: [ka] or a pharmaceutically acceptable salt thereof. 18. Compounds of Formula II: [ka] [In the formula, W is CR w or N, X is CR x or N, Y is CR y or N, Z is -O- or -NR z - and R w , R x , and R y are each independently hydrogen, halogen, -OR 3 , -N(R 3 )2, -SR 3 , appropriately substituted C 1-6 aliphatic, or -CN; R z is hydrogen or an appropriately substituted C 1-6 is aliphatic, R 1 is -N(R)2, -N(R)C(O)R', -C(O)N(R)2, -N(R)C(O)N(R)2, or -N(R)C(O)OR; Each R c is halogen, -CN, -CO2R, -C(O)N(R)2, -NO2, -N(R)2, -OR, -SR, or an optionally substituted C 1-6 are independently selected from aliphatic n is 0, 1, 2, or 3; R 2 is replaced appropriately by C 1-6 is aliphatic, R 3 is hydrogen or an appropriately substituted C 1-6 is aliphatic, Ring A is an optionally substituted 9-16 membered bicyclic or tricyclic aryl, an optionally substituted 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 10-16 membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 7-10 membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 10-16 membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen, optionally substituted C 1-6 an aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's, when attached to the same nitrogen atom, together form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0 to 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' independently represents an optionally substituted C 1-6 aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl; or a pharmaceutically acceptable salt thereof. 19. The compound is [ka] The compound of embodiment 18, which is not 20. Compounds of embodiment 18 or 19, wherein Ring A is an optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 10- to 16-membered polycyclic heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. twenty one. The compound of any one of embodiments 18-20, wherein Ring A is an optionally substituted 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 10-16 membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. twenty two. Ring A is one or more oxo, halogen, or C 1-6 The compound of any one of embodiments 18-21, which is an 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with alkyl. twenty three. The compound of any one of embodiments 18-22, wherein Ring A is an optionally substituted 10-16 membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. twenty four. A compound according to any one of embodiments 18 to 23, Ring A is [ka] and Ring A1 is an optionally substituted ring selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A1 is fused to ring A2, Ring A2 is an optionally substituted ring selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A2 is optionally (i) further fused to ring A3, or or (ii) ring A2 and ring A3 combine to form a spiro ring; The compound, wherein ring A3, if present, is an optionally substituted ring selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. twenty five. Compounds according to embodiment 24, wherein Ring A1 is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 26. The optionally substituted ring A is [ka] 26. The compound of embodiment 24 or 25, wherein 27. Compounds according to any one of embodiments 24-26, wherein Ring A2 is an optionally substituted 5-7 membered partially saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 28. The optionally substituted ring A is [ka] 28. The compound of any one of embodiments 24-27, selected from the group consisting of: 29. The optionally substituted ring A is [ka] 28. The compound of any one of embodiments 24-27, selected from the group consisting of: 30. A compound according to any one of embodiments 18 to 29, [ka] is 1 to 5 R as long as valence allows. b is replaced by Each R b are independently hydrogen, halogen, -CN, -OR, -O(CH2) m R, -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)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 an aliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The compound wherein m is 1, 2, or 3. 31. Each R b are independently halogen, -CN, -OR, -O(CH2) m R, -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)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 The compound of embodiment 30, which is an aliphatic, optionally substituted 3-6 membered saturated or partially unsaturated carbocyclyl, optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 32. Each R b are independently halogen, optionally substituted C 1-6 Aliphatic, -OR, or -O(CH2) m The compound of embodiment 30 or embodiment 31, wherein R 33. A compound according to any one of embodiments 30-32, [ka] teeth, [ka] The compound is selected from the group consisting of: 34. A compound according to any one of embodiments 30-32, [ka] teeth, [ka] The compound is selected from the group consisting of: 35. 35. The compound of any one of embodiments 18-34, having formula II-C: [ka] or a pharmaceutically acceptable salt thereof. 36. 36. The compound of any one of embodiments 18-35, having formula II-D: [ka] or a pharmaceutically acceptable salt thereof. 37. 37. The compound of any one of embodiments 18-36, having formula II-E: [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A1 is an optionally substituted ring selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A1 is fused to ring A2, Ring A2 is an optionally substituted ring selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A2 is optionally (i) further fused to ring A3, or or (ii) ring A2 and ring A3 combine to form a spiro ring; Ring A3, if present, is an optionally substituted ring selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 38. W is CR w The compound of any one of the preceding embodiments, wherein 39. R w The compound of embodiment 38, wherein 40. The compound of any one of embodiments 1-37, wherein W is N. 41. X is CR x The compound of any one of the preceding embodiments, wherein 42. R x is hydrogen, halogen, -CN, -OR 3 , or C as substituted accordingly 1-6 The compound of any one of the preceding embodiments, which is aliphatic. 43. The compound of any one of embodiments 1-40, wherein X is N. 44. Y is CR y The compound of any one of the preceding embodiments, wherein 45. R y The compound of embodiment 44, wherein is hydrogen. 46. The compound of any one of embodiments 1-43, wherein Y is N. 47. R 1 is —N(R)C(O)N(R), or —N(R)C(O)OR. 48. R 1The compound of any one of the preceding embodiments, wherein is —N(R)C(O)N(R)2. 49. R 1 is -N(H)C(O)N(R)2, and R 1 each R is independently hydrogen, optionally substituted C 1-6 The compound of any one of the preceding embodiments, which is an aliphatic or optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl, or two R groups attached to the same nitrogen together form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. 50. R 1 The compound of any one of embodiments 1-47, wherein is —N(R)C(O)OR. 51. R 1 is -N(H)C(O)OR, and R 1 R is an optionally substituted C 1-6 The compound of any one of embodiments 1-47, which is an aliphatic or optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 52. R 1 The compound of any one of embodiments 1-46, wherein is —N(R)C(O)R′. 53. R 1 is -N(H)C(O) (optionally substituted C 1-6 The compound of any one of embodiments 1-46, wherein the aryl group is aliphatic. 54. Each R c

[0023] The compound of any one of the preceding embodiments, wherein is independently halogen. 55. The compound of any one of the preceding embodiments, wherein n is 0. 56. Compounds of Formula III: [ka] [In the formula, Z is -O- or -NR z - and R x is hydrogen, halogen, -OR 3 , -N(R 3 )2, -SR 3 , appropriately substituted C 1-6 aliphatic, or -CN; R z is hydrogen or an appropriately substituted C 1-6 is aliphatic, R 2 is replaced appropriately by C 1-6 is aliphatic, R 3 is hydrogen or an appropriately substituted C 1-6 is aliphatic, R 4 is halogen, —OR, —N(R)2, or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7-10 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 divalent C 1-3 a linear or branched hydrocarbon chain, R a is hydrogen, halogen, optionally substituted C 1-6an aliphatic, optionally substituted phenyl, an optionally substituted 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen, optionally substituted C 1-6 an aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclyl, or an 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's, when attached to the same nitrogen atom, 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; or a pharmaceutically acceptable salt thereof. 57. The compound is [ka] The compound of embodiment 56, wherein 58. R 4 is halogen, —OR, —N(R)2, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 4 each R independently represents hydrogen or an optionally substituted C 1-6 The compound of embodiment 56 or embodiment 57, which is aliphatic. 59. The compound of any one of embodiments 56-58, wherein Ring A is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 60. Compounds of any one of embodiments 56-59, wherein Ring A is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 61. Compounds according to any one of embodiments 56-60, wherein Ring A is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 62. R a is halogen, optionally substituted C 1-6 The compound of any one of embodiments 56-61, which is an aliphatic, optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 63. Ra is replaced appropriately by C 1-6 The compound of any one of embodiments 56-62, which is aliphatic. 64. 64. The compound of any one of embodiments 56-63, [ka] is 1 to 5 R as long as valence allows. b is replaced by Each R b are independently hydrogen, halogen, -CN, -OR, -O(CH2) m R, -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)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 an aliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The compound wherein m is 1, 2, or 3. 65. Each R b are independently halogen, -CN, -OR, -O(CH2) m R, -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)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6Compounds of embodiment 64 that are aliphatic, optionally substituted 3-6 membered saturated or partially unsaturated carbocyclyl, optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 66. Each R b are independently optionally substituted C 1-6 The compound of embodiment 64 or 65, which is aliphatic. 67. 67. A compound according to any one of embodiments 64 to 66, [ka] teeth, [ka] The compound, 68. 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. Each R is independently hydrogen, optionally substituted C 1-6 The compound of any one of the preceding embodiments, which is an aliphatic or optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's, when attached to the same nitrogen atom, together form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. 71. Each R is independently hydrogen or an optionally substituted C 1-6 The compound of any one of the preceding embodiments, which is aliphatic. 72. Each R' independently represents an optionally substituted C 1-6 Alkyl or optionally substituted C 3-7 The compound of any one of the preceding embodiments, wherein the compound is cycloalkyl. 73. Each R' independently represents an optionally substituted C 1-6 The compound of any one of the preceding embodiments, which is aliphatic. 74. Compound of Formula IV: [ka] [In the formula, Z is -O- or -NR z - and R x is hydrogen, halogen, -OR 3 , or -CN, R z is hydrogen or an appropriately substituted C 1-6 is aliphatic, R 2 is replaced appropriately by C 1-6 is aliphatic, R 3 is hydrogen or an appropriately substituted C 1-6 is aliphatic, [ka] is either (i) or (ii): [ka] wherein ring A is further substituted at least once and at least one substituent on ring A is selected from C 1-6 is haloalkyl, L is a covalent bond or a divalent C 1-3 a linear or branched hydrocarbon chain, R a is hydrogen, halogen, optionally substituted C 1-6an aliphatic, optionally substituted phenyl, an optionally substituted 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R' is C 1-6 aliphatic or 3- to 7-membered saturated or partially unsaturated carbocyclyl; or a pharmaceutically acceptable salt thereof. 75. The compound is [ka] The compound of embodiment 74, wherein 76. R a is halogen, optionally substituted C 1-6 Compounds of embodiments 74 or 75 that are aliphatic, optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 77. R a is replaced appropriately by C 1-6The compound of any one of embodiments 74-76, which is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from aliphatic, nitrogen, oxygen, and sulfur, or an optionally substituted 7-10 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. R x is hydrogen, halogen, -CN, -OR 3 , or C as substituted accordingly 1-6 The compound of any one of embodiments 56-80, which is aliphatic. 82. R x is hydrogen, halogen, -OR 3 or —CN. 83. R x The compound of any one of embodiments 56-82, wherein is halogen or —CN. 84. R 2 is C 1-4 The compound of any one of the preceding embodiments, wherein is alkyl. 85. The compound of any one of the preceding embodiments, wherein Z is —O—. 86. Z is -NR z - . 87. R z The compound of embodiment 86, wherein is hydrogen. 88. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof. 89. A pharmaceutical composition comprising a compound according to 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 a compound of any one of embodiments 1-88 or a composition of embodiment 89. 91. A method for treating a disease, disorder, or condition associated with JAK2, comprising administering to a subject in need thereof a compound of any one of embodiments 1-88 or a composition of embodiment 89. 92. A method of treating cancer, comprising administering to a subject in need thereof a compound of any one of embodiments 1-88 or a composition of embodiment 89. 93. A method of treating a hematological malignancy, comprising administering to a subject in need thereof a compound of any one of embodiments 1-88 or a composition of embodiment 89. 94. 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 a compound of any one of embodiments 1-88 or a composition of embodiment 89. 96. 96. The method of embodiment 95, wherein said myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or myelofibrosis. [Example]

[0167] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the general methods illustrate the synthesis of specific compounds of the present disclosure, it will be understood that the following general methods, and other methods known to those of skill in the art, can be applied to all compounds described herein and each subclass and species of these compounds.

[0168] Preparation of intermediates Preparation of Intermediate Int-1: 5-Fluoro-N-methyl-2-nitropyridin-3-amine [ka] Synthesis of Compound Int-1.1. Hydrogen peroxide (30% by weight, 31 mL) was added dropwise to concentrated sulfuric acid (60 mL) at 0° C. To this solution, a solution of 3,5-difluoropyridin-2-amine (5.0 g, 38.43 mmol, 1.0 equiv.) in concentrated sulfuric acid (60 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 48 hours. It was carefully poured onto crushed ice and stirred. The aqueous mixture was basified with saturated aqueous sodium bicarbonate. The precipitate was 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 provide Int-1.1. 1 H 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), aqueous methylamine solution (40%, 1.1 mL, 14.37 mmol, 1.0 equiv.) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 hour. It was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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).

[0170] Preparation of Intermediate Int-2: 4-chloro-5-fluoro-N-methyl-2-nitropyridin-3-amine [ka] 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 hexanes, 61.4 mL, 153.7 mmol, 2.0 equiv.). The reaction mixture was stirred at −78°C for 40 minutes. Hexachloroethane (36.3 g, 153.7 mmol, 2.0 equiv.) was added, and the reaction mixture was stirred at −78°C for 30–40 minutes. The reaction was quenched by the careful addition of saturated ammonium chloride solution. 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 / hexane) to give Int-2.1. 1 H 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 volumes) was added dropwise to potassium persulfate (2.05 g, 7.6 mmol, 2.5 equiv.) at room temperature and stirred for 15 minutes. To this mixture, Int-2.1 (0.5 g, 3.04 mmol, 1.0 equiv.) was added in small portions while maintaining the temperature at 30–40°C. The reaction mixture was stirred at room temperature for 3–4 hours. It was poured onto 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 / hexanes) to give Int-2.2. 1 H 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), aqueous methylamine (40%, 0.8 mL, 9.98 mmol, 2.0 equiv.) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 10-20 minutes. It was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate / hexane) to give Int-2. 1 H NMR (DMSO-d6, 400 MHz): δ 7.98 (s, 1H), 7.05 (bs, 1H), 2.79 (d, 3H).

[0173] Preparation of Intermediate Int-3: (S)-5-(tert-butyl)-3-isothiocyanato-1-(tetrahydrofuran-3-yl)-1H-pyrazole [ka] 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 to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, eluent: 12% ethyl acetate / hexane) to give Int-3.1. MS (ES): m / z 218.3 [M+H] + .

[0174] Synthesis of Compounds 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 hours under nitrogen. The mixture was poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layer was 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®, eluent: 2% ethyl acetate / hexane) to give 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 in a microwave reactor at 120° C. for 1 hour. It was poured into ice water, basified with 2N sodium hydroxide, and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 the addition of thiophosgene (0.096 g, 0.835 mmol, 2.5 equiv.) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. It was poured into ice water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Int-3. MS (ES): m / z 252.3 [M+H] + .

[0177] Preparation of Intermediate Int-4: (R)-5-(tert-butyl)-3-isothiocyanato-1-(tetrahydrofuran-3-yl)-1H-pyrazole [ka] Synthesis of Compound Int-4. Compound Int-4 was prepared from Int-3.2 according to the procedure described in the synthesis of Int-3. MS (ES): m / z 252.3 [M+H] + .

[0178] Preparation of Intermediate Int-5: 3-Isothiocyanato-1-methyl-5-(trifluoromethyl)pyridin-2(1H)-one [ka] 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 minutes, and then methyl iodide (1.0 g, 7.21 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at 70° C. for 2 hours. It was poured into ice water, and the 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. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 40% ethyl acetate / hexane) to give 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 hour. This was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 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 (6 mL) was added thiophosgene (0.143 g, 1.25 mmol, 1.2 equiv.) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. It was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Int-5. MS (ES): m / z 192.15 [M+H] + .

[0181] Preparation of Intermediate Int-6: 1-(2-oxaspiro[3.3]heptan-6-yl)-5-(trifluoromethyl)-1H-pyrazol-3-amine [ka] 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 small portions at 0° C. The reaction mixture was stirred for 2 hours. 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 give 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 the addition of methanesulfonyl chloride (0.71 mL, 9.46 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 12 hours. It was transferred to ice water, stirred, and extracted with dichloromethane. The combined organic layer was 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 / hexane) to give Int-6.2. MS (ES): m / z 193.2 [M+H] + .

[0183] Synthesis of Compound Int-6. To a DMF solution (7 mL) 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.) was added cesium carbonate (1.352 g, 4.16 mmol, 2.0 equiv.). The reaction mixture was heated at 80° C. for 5 hours. It was poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Int-6. MS (ES): m / z 248.2 [M+H] + .

[0184] Preparation of Intermediate Int-7: 4,4-Difluoro-2-isothiocyanato-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine [ka] 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), potassium carbonate (64.99 g, 471 mmol, 1.0 equiv.) was added, and the reaction mixture was stirred at 80° C. for 4 hours. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to give 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), potassium tert-butoxide (1 M in THF) (403 mL, 403.7 mmol, 1.1 equiv.) was added at room temperature. The reaction mixture was stirred at 90° C. for 3 hours. The reaction mixture was poured into ice water, and the 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. The residue was purified by trituration with diethyl ether to give 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 was heated at 100° C. for 6 hours. It was then concentrated under reduced pressure. The residue was dissolved in acetonitrile-THF (1:4, 250 mL), and the solution was concentrated under reduced pressure to give 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 the reaction mixture was stirred at room temperature for 4 hours. It was poured into ice water and extracted with ethyl acetate. The combined organic layer was 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 / hexane) to give 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), diethylaminosulfur trifluoride (150 mL, 1132.9 mmol, 10.0 equiv.) was added, and the reaction mixture was stirred at room temperature for 5 days. This was transferred to an ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layer was 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 / hexane) to give 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 hours. It was poured into ice water, and the pH was adjusted to 5 by adding 2 M hydrochloric acid. The 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 give 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 hours. 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 give the crude material. This was further purified by flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate / hexane) to give 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 hours. This was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 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 according to the procedure described for the synthesis of Int-3. It was used without purification. MS (ES): m / z 216.2 [M+H] + .

[0193] Preparation of Intermediate Int-8: 2-Isothiocyanato-5-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one [ka] Synthesis of Compound Int-8.1. To a DCM solution (20 mL) 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, 1.5 equiv.) was added 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 minutes, then heated at 50°C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DMF (20 mL), and triethylamine (5.3 mL, 38.19 mmol, 3.0 equiv.) was added. The mixture was stirred for 16 hours. The mixture was poured into ice water and extracted with DCM. The combined organic layer was 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 / DCM) to give 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 hours. The mixture 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 layer was 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 / DCM) to give 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 according to the procedure described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, 0.5% methanol / DCM). MS (ES): m / z 209.1 [M+H] + .

[0196] Preparation of Intermediate Int-9: 2-Isothiocyanato-4,4-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine [ka] 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 equivalent) and hexane-2,5-dione (16.55 g, 145.01 mmol, 1.5 equivalent) in toluene (150 mL) was added p-toluenesulfonic acid (0.919 g, 4.83 mmol, 0.05 equivalent). The reaction mixture was heated to reflux with a Dean-Stark trap for 2 hours to remove water. 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 / hexane) to give Int-9.1. MS (ES): m / z 234.2 [M+H] + .

[0197] Synthesis of Compound Int-9.2. 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 hour. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was 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 / hexane) to give 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 methylmagnesium 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 hour. The reaction mixture was poured into ice water, and the 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. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 18% ethyl acetate / hexane) to give 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 hour. It was poured into ice water, and the 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. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 25% ethyl acetate / hexane) to give Int-9.4. m / z: 264.2 [M+H] + .

[0200] Synthesis of Compound Int-9.5. To a DCM solution (25 mL) 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.), a DCM solution (5 mL) of 4-toluenesulfonyl chloride (2.16 g, 11.34 mmol, 1.3 equiv.) and triethylamine (3.7 mL, 26.19 mmol, 3.0 equiv.) were added at 0° C. The reaction mixture was stirred at room temperature for 1 hour. It was poured into ice water, and the product was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product. To a THF solution (50 mL) of this crude material, sodium hydride (1.05 g, 26.19 mmol, 3.0 equiv.) was added at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. It was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layer was 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 / hexane) to give 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 hour. It was poured into ice water and neutralized with 2N 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 / DCM) to give 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 according to 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] + .

[0203] Preparation of Intermediate Int-10: 2'-Isothiocyanato-5',6'-dihydrospiro[cyclobutane-1,4'-pyrrolo[1,2-b]pyrazole] [ka] 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 minutes and then allowed to warm to room temperature with stirring for 2 hours. The mixture was transferred to a 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 give a residue that was purified by flash column chromatography on silica gel (CombiFlash®, 20% ethyl acetate / hexanes) to give Int-10.1. 1 H 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 hours. The reaction mixture was cooled to room temperature, and carbon dioxide was bubbled through it for 1 hour. The mixture was concentrated under reduced pressure. Methanol (15 mL) was added to the residue, and the mixture was stirred for a while. The precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure to give 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 hours. It was slowly transferred to a 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 give a residue that was purified by flash column chromatography on silica gel (CombiFlash®, 2% methanol / dichloromethane) to give 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 according to 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] + .

[0207] Preparation of Intermediate Int-11: 2'-Isothiocyanato-6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyridine] [ka] 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., acetonitrile (1.3 g, 32 mmol, 2 equiv.) was added dropwise. The resulting solution was stirred for 1 hour, 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 an additional 2 hours. It was allowed to warm to room temperature, quenched with saturated 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 give 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 in an autoclave at 120° C. for 16 hours. The reaction mixture was cooled to room temperature, and dry ice was added slowly over 15 minutes. The solution was decanted, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 6.0% methanol / DCM) to give 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 hour. The reaction mixture was cooled to room temperature, quenched with saturated aqueous potassium carbonate, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 eq.) and K2CO3 (1.38 g, 10.02 mmol, 2 eq.) in acetonitrile (20 mL) was stirred at 80 °C for 16 h. It was cooled to room temperature, poured into water, and extracted with DCM. The combined organic layer was 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 / DCM) to give 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 according to the procedure described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, 40% ethyl acetate / hexane). MS (ES): m / z 205.28 [M+H] + .

[0212] Preparation of Intermediate Int-12: 2-Isothiocyanato-4,4-dimethyl-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxazepane [ka] 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 hour. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was 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 / hexane) to give 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 stirred for 30 minutes. The mixture was poured into ethyl acetate, and the precipitate was removed by filtration through a pad of Celite®. The filtrate was concentrated under reduced pressure to give 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 stirred for 20 minutes. The mixture was transferred into ice water and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Acetonitrile was added to the residue, followed by the addition of tetrabutylammonium cyanide (55.59 g, 207.38 mmol, 2.0 equiv.). The mixture was stirred at 80° C. for 1 hour. The mixture was transferred into water and extracted with ethyl acetate. The combined organic layer was 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 / hexanes) to give 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 hour. 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®, 17% ethyl acetate / hexane) to give Int-12.4. MS (ES): m / z: 363.61 [M+H] + .

[0216] Synthesis of Compound Int-12.5. To a DCM solution (25 mL) of Int-12.4 (2.0 g, 5.52 mmol, 1.0 equiv.), diisobutylaluminum hydride (1.0 M in hexane, 10.0 mL) was added at −78° C. and stirred for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of sodium potassium tartrate and stirred for 1 hour. This was filtered through a pad of Celite®, and the filtrate was extracted with ethyl acetate. The combined organic layer was 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 / hexane) to give Int-12.5. MS (ES): m / z: 366.61 [M+H] + .

[0217] Synthesis of Compound Int-12.6. Sodium borohydride (11.4 g, 62.46 mmol, 2.0 equiv.) was added to a methanol solution (125 mL) of Int-12.5 (11.4 g, 31.23 mmol, 1.0 equiv.) at 0° C. and stirred for 1 hour. This mixture was poured into dilute hydrochloric acid (30 mL) and extracted with ethyl acetate. The combined organic layer was 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 / hexane) to give 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 minutes, poured 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 / hexane) to give 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), trifluoromethanesulfonic acid (20.0 mL) was added at 0° C. and stirred for 15 minutes. This was poured into a saturated aqueous solution of sodium bicarbonate and extracted with DCM. The combined organic layer was 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 / DCM) to give 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), sodium hydride (60%, 2.30 g, 57.74 mmol, 5.0 equiv.) was added at room temperature and stirred for 2 hours. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was 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 / hexane) to give 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 hours. 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 / DCM) to give 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 according to 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 224.1 [M+H] + .

[0223] Preparation of Intermediate Int-13: 1-(tert-butyl)-6-isothiocyanato-2,3-dihydro-1H-imidazo[1,2-b]pyrazole [ka] 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 hours. The mixture was cooled to room temperature, transferred to ice water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Int-13.1. MS (ES): m / z 319.1 [M+H] + .

[0224] Synthesis of Compound Int-13.2. 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 a nitrogen atmosphere for 16 hours. This 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 give 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 diphenylphosphoryl azide (30.9 g, 112.39 mmol, 1.2 equiv.) at room temperature under nitrogen. The reaction mixture was stirred at 80° C. for 3 hours. 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®, 25-30% ethyl acetate / hexanes) to give 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 / hydroxide (5.25 g) in methanol (210 mL) was stirred under hydrogen for 8 hours. This was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 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-butylphosphine (15.93 g, 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 hours. 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®, 50-55% ethyl acetate / hexanes) to give Int-13.5. MS (ES): m / z: 268.7 [M+H] + .

[0228] Synthesis of Compound Int-13.6. To a mixture of Int-13.5 (13.0 g, 48.64 mmol, 1.0 equiv.) in THF and methanol (100 mL, 5:1) was added an aqueous solution of lithium hydroxide (6.1 g, 145.92 mmol, 3.0 equiv.) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the pH was 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 give 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.), diphenylphosphoryl 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 hours. 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 in a mixture of ethyl acetate:methanol (1:1) to give 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 hours. It was transferred to a mixture of ice and saturated aqueous 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 give 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 DCM:toluene mixture (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 hours. It was transferred to 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 / DCM) to give 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 / hydroxide (0.700 g) in methanol (42 mL) was stirred under hydrogen (1 atm) for 3 hours. 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 / DCM) to give 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 equivalent) in acetonitrile (15 mL), imidazole (0.096 g, 1.66 mmol, 0.3 equivalent) was added, followed by thiocarbonyldiimidazole (1.9 g, 11.1 mmol, 2.0 equivalent), and the mixture was stirred at room temperature for 1 hour. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was 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 give Int-13. MS (ES): m / z: 223 [M+H] + .

[0234] Preparation of Intermediate Int-14: 2-Isothiocyanato-6,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine [ka] 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), DMF (0.1 mL) and oxalyl chloride (3.58 mL, 9.50 mmol, 1.3 equiv.) were added dropwise at 0° C. and stirred at room temperature for 2 hours. Most of the solvent was removed under reduced pressure, and the residue was dissolved in THF. Lithium borohydride (24 mL, 4.70 mmol, 1.3 equiv.) was added. The mixture was stirred at room temperature for 16 hours. The mixture 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®, 2.5% methanol / DCM) to give 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 stirred at 70° C. for 3 hours. The mixture was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layer was 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 / DCM) to give 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 hours. It was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layer was 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 / DCM) to give 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 hours. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 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 according to the procedure described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol / DCM). MS (ES): m / z 210.27 [M+H] + .

[0239] Preparation of Intermediate Int-15: 1-(2-(benzyloxy)ethyl)-3-isothiocyanato-5-(trifluoromethyl)pyridin-2(1H)-one [ka] 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 hours. It was transferred to 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 / DCM) to give 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 minutes. ((2-Bromoethoxy)methyl)benzene (0.775 g, 3.6 mmol, 1.5 equiv.) was added to the mixture and stirred at 110° C. for 2 hours. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was 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 / hexane) to give 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 hours. The mixture was poured into ice water, filtered, and extracted with ethyl acetate. The combined organic layer was 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 / DCM) to give 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 according to the procedure described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol / DCM). MS (ES): m / z 355.3 [M+H] + .

[0243] Preparation of Intermediate Int-16: 3-Isothiocyanato-1-(methyl-d3)-5-(trifluoromethyl)pyridin-2(1H)-one [ka] 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 minutes, after which iodomethane-d3 (10.03 g, 69.20 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at 70° C. for 1 hour. It was poured 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 give 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.), and 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 hours. The reaction mixture was concentrated under reduced pressure. The residue was transferred to 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 / DCM) to give 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 according to the procedure described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate / hexane). MS (ES): m / z 238.1 [M+H] +.

[0246] Preparation of intermediate (±)-Int-17: 2-(tetrahydrofuran-3-yl)-6-(trifluoromethyl)pyridin-4-amine [ka] 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 a stream of argon through it for 10 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM complex (0.125 g, 0.152 mmol, 0.05 equiv.) was added and degassed for 5 minutes. The reaction mixture was stirred at 120 °C for 3 hours. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was poured 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 / DCM) to give 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 hours. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give (±)-Int-17. MS (ES): m / z 233.21 [M+H] + .

[0248] Preparation of Intermediate Int-18: 1-(4-Isothiocyanato-2-(trifluoromethyl)phenyl)-N,N-dimethylmethanamine [ka] 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 minutes. Dimethylamine (4.1 mL, 2.9 mmol, 2.5 equiv.) was added and stirred for 16 hours. The mixture was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layer was 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 / DCM) to give 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 hours. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 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 room temperature 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 / DCM) to give 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 according to the procedure described in the synthesis of Int-13. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.4% methanol / DCM). MS (ES): m / z 261.28 [M+H] + .

[0252] Preparation of Intermediate Int-19: (S)-2-((3-Isothiocyanato-5-(trifluoromethyl)phenoxy)methyl)-1-methylpyrrolidine [ka] Synthesis of Compound Int-19.1. To a DMF solution (12 mL) 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.), sodium hydride (0.201 g, 5.025 mmol, 1.5 equiv.) was added at 0° C., and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 15-17% ethyl acetate / hexane) to give 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 hours. 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 / hexanes) to give 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 minutes. It was cooled to room temperature, transferred to 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 / hexanes) to give 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 according to the procedure described in the synthesis of Int-13. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol / DCM). MS (ES): m / z 317.2 [M+H] + .

[0256] Preparation of Intermediate Int-20: (R)-2-((3-Isothiocyanato-5-(trifluoromethyl)phenoxy)methyl)-1-methylpyrrolidine [ka] Synthesis of Compound Int-20. Compound Int-20 was prepared according to the procedure described in the synthesis of Int-19. The product was purified by flash column chromatography on silica gel (CombiFlash®, 1.5% methanol / DCM). MS (ES): m / z 317.3 [M+H] + .

[0257] Preparation of Intermediate Int-21: (S)-3-(3-Isothiocyanato-5-(trifluoromethyl)phenoxy)-1-methylpyrrolidine [ka] Synthesis of Compound Int-21.1. To a DMF solution (10 mL) of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (1.0 g, 4.78 mmol, 1.0 equivalent) and (S)-1-methylpyrrolidin-3-ol (0.580 g, 5.74 mmol, 1.2 equivalents), sodium hydride (0.382 g, 9.56 mmol, 2.0 equivalents) was added at 0° C. and stirred at room temperature for 30 minutes. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol / DCM) to give 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 hour. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 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 according to the procedure described in the synthesis of Int-13. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.0% methanol / DCM). MS (ES): m / z 303.2 [M+H] + .

[0260] Preparation of Compound Int-22: (S)-3-(3-isothiocyanato-5-(trifluoromethyl)phenoxy)-1-methylpyrrolidine [ka] Synthesis of Compound Int-22. Compound Int-22 was prepared according to the procedure described in the synthesis of Int-21. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.0% methanol / DCM). MS (ES): m / z 303.2 [M+H] + .

[0261] Preparation of Intermediate Int-23: tert-butyl 3-((3-amino-5-(trifluoromethyl)benzyl)oxy)azetidine-1-carboxylate [ka] 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 hours. 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 / hexane) to give 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), NaH (60%, 0.277 g, 6.93 mmol, 1.5 equiv.) was added in small portions at 0° C. and stirred for 20 minutes. 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 hours. The mixture 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®, 20% ethyl acetate / hexane) to give 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 hours. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give Int-23. MS (ES): m / z 347.51 [M+H] + .

[0264] Preparation of Intermediates 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 [ka] 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 a stream of argon through it for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.042 mmol, 0.1 equiv.) was added and degassed for 5 minutes. The reaction mixture was stirred at 80° C. for 5 hours. It was poured 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 / DCM) to give 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 hour. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give (±)-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 minutes. It was cooled to room temperature, transferred to 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 give (±)-Int-24.3. MS (ES): m / z 245.1 [M+H] + .Chiral HPLC separation of the racemic compound (CHIRALPAK column) The mixture was subjected to an AD-H column (250 mm x 21 mm, 5 μm); mobile phase: (A) 0.1% DEA / n-hexane, (B) 0.1% DEA / isopropanol; flow rate = 30 mL / min) to obtain the first elution fraction (Int-24.3-a) and the second elution fraction (Int-24.3-b). MS (ES): m / z: 245.1 [M+H] + .

[0267] Synthesis of Compounds Int-24-a and Int-24-b. Compounds Int-24-a and Int-24-b were prepared from Int-24.3-a and Int-24.4-b, respectively, according to the procedure described for the synthesis of Int-13. The products were purified by flash column chromatography on silica gel (CombiFlash®, 12% ethyl acetate / hexane). MS (ES): m / z 287.2 [M+H] + .

[0268] Preparation of Intermediate Int-25: tert-butyl 3-(3-amino-5-(trifluoromethyl)phenoxy)azetidine-1-carboxylate [ka] Synthesis of Compound Int-25.1. Sodium hydride (0.313 g, 7.17 mmol, 1.5 equiv.) was added to a DMF solution (10 mL) of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (1.0 g, 4.78 mmol, 1.0 equiv.) at 0° C. and stirred for 1 hour. To this 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 hours. The mixture 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®, 38% ethyl acetate / hexane) to give 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, 9.66 mmol, 5.0 equiv.) in ethanol:water (8:2, 6 mL) was stirred at 80° C. for 2 hours. 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 / hexanes) to give Int-25. MS (ES): m / z 333.32 [M+H] + .

[0270] Preparation of Intermediate Int-26: 3-Isothiocyanato-1-(7-oxaspiro[3.5]nonan-2-yl)-5-(trifluoromethyl)-1H-pyrazole [ka] 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 pair (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 hours. It was filtered through a pad of Celite®, and the filtrate was washed with a solution of sodium bicarbonate and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 hours. The reaction mixture was filtered through a pad of Celite®, rinsed with diethyl ether, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate / hexanes) to give Int-26.2. MS (ES): m / z: 141.1 [M+H] + .

[0272] Synthesis of Compound Int-26.3. Sodium borohydride (0.308 g, 8.34 mmol, 0.3 equiv.) was added to a methanol solution (40 mL) of Int-26.2 (3.9 g, 27.82 mmol, 1.0 equiv.) at 0° C. and stirred at room temperature for 16 hours. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 minutes. It was transferred to 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 provide 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 hours. The mixture was transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layer was 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 / hexane) to give 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 hours. This was transferred to ice water, and the pH was adjusted to 10 by adding 2N sodium hydroxide. 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 / DCM) to give 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 according to 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 318.2 [M+H] + .

[0277] Preparation of Intermediates 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 [ka] Synthesis of Compound Int-27.1. A 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 minutes. Tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.3 mmol, 0.9 equiv.) was added and degassed for 5 minutes. The reaction mixture was stirred at 80° C. for 5 hours. It was poured 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 / DCM) to give 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 under hydrogen (1 atm) for 7 hours. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give (±)-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 phase: (A) CO2, (B) 0.1% diethylamine / isopropanol:acetonitrile (50:50); Flow rate = 75 mL / min) to obtain the first elution fraction (Int-27.2-a) and the second elution fraction (Int-27.2-b).

[0279] Synthesis of Compounds 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 minutes. 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, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide Int-27.2-a. MS (ES): m / z 245.26 [M+H] + Following the same procedure, Int-27.3-b was prepared from Int-27.2-b.

[0280] Synthesis of Compounds Int-27-a and Int-27-b. Compound Int-27-a was prepared from Int-27.3-a according to the procedure described in the synthesis of Int-13. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.1% methanol / DCM). MS (ES): m / z 287.32 [M+H] + Int-27-b was prepared in the same manner from Int-27.3-b.

[0281] Preparation of Intermediate Int-28: 4-Isothiocyanato-2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridine [ka] 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 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic layer was 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 / hexanes) to give 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 according to the procedure described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, 5-10% ethyl acetate / hexane). MS (ES): m / z 274.5 [M+H] + .

[0283] Preparation of Intermediate Int-29: 2'-Isothiocyanato-5',6'-dihydrospiro[cyclobutane-1,4'-pyrrolo[1,2-b]pyrazole] [ka] 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 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 THF (8 mL). The reaction mixture was stirred at −78° C. for 30 minutes and then allowed to warm to room temperature with stirring for 2 hours. The mixture was transferred to a 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 give a residue that was purified by flash column chromatography on silica gel (CombiFlash®, 20% ethyl acetate / hexanes) to give 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 hours. The reaction mixture was cooled to room temperature, and carbon dioxide was bubbled through it for 1 hour. The reaction mixture was concentrated under reduced pressure. Methanol (15 mL) was added to the residue, stirred, and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure to give 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.). The reaction mixture was stirred at room temperature for 3 hours. It was slowly transferred to a mixture of aqueous ammonium hydroxide and ice, stirred, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by flash column chromatography on silica gel (CombiFlash®, 2% methanol / DCM) to give 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 according to 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 205.9 [M+H] + .

[0287] Preparation of Intermediate Int-30: 2'-Isothiocyanato-5'-methyl-6',7'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-a]pyrazine] [ka] 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), hexane-2,5-dione (0.618 g, 5.41 mmol, 1.5 equiv.) was added, followed by acetic acid (catalyst) at room temperature. The reaction mixture was stirred at 130° C. for 3 hours. It was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 0.5% methanol / DCM) to give 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 the addition of ethylmagnesium bromide (1 M in THF, 3.4 mL, 10.2 mmol, 4.0 equiv.) at 80° C. The reaction mixture was stirred for 30 minutes. 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 give the material. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate / hexane) to give Int-30.2. MS (ES): m / z: 257 [M+H] + .

[0289] Synthesis of Compound Int-30.3. To a 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 an 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 give 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 according to the procedure described in the synthesis of Int-3. The product was purified by flash column chromatography on silica gel (CombiFlash®, 0.5% methanol / DCM). MS (ES): m / z 221 [M+H] + .

[0291] Preparation of the 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 [ka] 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., sodium hydride (12.61 g, 315.38 mmol, 2.0 equiv.) was added in small portions. The mixture was stirred for 1 hour, and 2-chloro-4-nitropyridine (25 g, 157.69 mmol, 1.0 equiv.) was added in small portions. The reaction mixture was stirred at 0° C. for 2 hours. It was poured onto ice, stirred, and extracted three times 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®, eluent: 10% ethyl acetate / hexane) to give 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 it for 10 minutes. 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 an argon atmosphere, and the mixture was degassed by bubbling a stream of argon through it for 5 minutes. A solution of lithium bis(trimethylsilyl)amide (1 M in THF, 182 mL, 182.1 mmol, 2.0 equiv.) was added to the mixture, which was then stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, eluent: 3% methanol / DCM) to give 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 hours. It was poured 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 give 1.1. MS (ES): m / z 321.3 [M+H] + This 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 hours. It was poured 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 / DCM) to give 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 hours. This was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 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 hours. The mixture was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The combined organic layer was 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 / DCM) to give 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 hours. 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 / DCM) to give 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 precipitated solid was collected by filtration and triturated with hexane to give 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 minutes. This was transferred to saturated sodium bicarbonate solution, stirred, and extracted with DCM. The combined organic layer was 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 / DCM) to give 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 a stream of argon through it for 10 minutes. 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 the mixture was degassed for an additional 5 minutes. The reaction mixture was stirred at 80 °C for 3 hours. The mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The combined organic layer was 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 / DCM) to give compound 1. MS (ES): m / z: 562.6 [M+H] + , 1 H 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).

[0301] 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 [ka] 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 hours. 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 hours. The mixture was poured into ice water and stirred. The precipitated solid was collected by filtration and dried under vacuum to give 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 a stream of argon through it for 10 minutes. 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.) were added to the solution, which was then degassed for another 10 minutes. 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 hour. The mixture was concentrated under reduced pressure. The residue was slowly added to ice and 6N hydrochloric acid (1500 mL) and extracted with ethyl acetate. The aqueous layer was separated, neutralized with solid 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 to give 3.2. MS(ES): m / z 201.2 [M+H] + This 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 hours. After completion of the reaction, the precipitated solid was filtered off, rinsed with methanol, and dried under vacuum to give 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 hour. This was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 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 the precipitated solid was collected by filtration and dried under vacuum to give 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 according to 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 / DCM) to give 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 hour. It was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layer was 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 / DCM) to give 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 with argon for 10 minutes. 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 minutes. The reaction mixture was stirred at 190 °C in a microwave reactor for 2 hours. The mixture was cooled to room temperature, transferred to 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 give the 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 the addition of methyl chloroformate (1.8 mL, 23.13 mmol, 1.1 equiv.). The reaction mixture was stirred at room temperature for 4 hours. It was poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layer was 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 / DCM) to give I-3. MS (ES): m / z: 515.2 [M+H] + . 1 H 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).

[0310] 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 [ka] Synthesis of I-4. To a THF solution (2 mL) of 3.8 (0.040 g, 0.087 mmol, 1.0 equiv.) and dimethylcarbamic acid chloride (0.010 g, 0.096 mmol, 1.1 equiv.), potassium tert-butoxide (1 M in THF) (0.52 mL, 0.522 mmol, 6.0 equiv.) was added at 0° C. and stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layer was 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 / DCM) to give I-4. MS (ES): m / z: 528.3 [M+H] + , 1 H 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).

[0311] 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 [ka] Synthesis of I-5. To a THF solution (2 mL) of 3.8 (0.040 g, 0.087 mmol, 1.0 equiv.) and methylcarbamic acid chloride (0.009 g, 0.105 mmol, 1.2 equiv.), potassium tert-butoxide (1 M in THF) (0.35 mL, 0.348 mmol, 4.0 equiv.) was added at 0° C. and stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layer was 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 / DCM) to give I-5. MS (ES): m / z: 514.2 [M+H] + . 1 H 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).

[0312] 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 [ka] 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 minutes. It was poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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), 1-methylpiperazine (0.008 g, 0.078 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at 80° C. for 15 minutes. It was poured 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 / DCM) to give I-6. MS (ES): m / z: 583.3 [M+H] + , 1 H 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).

[0314] 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 [ka] Synthesis of I-7. Compound I-7 was prepared from 6.1 and azetidine hydrochloride according to the procedure described in the synthesis of I-6. The product was purified by preparative HPLC. MS (ES): m / z: 540.4 [M+H] + . 1 H 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).

[0315] 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 [ka] Synthesis of I-8. Compound I-8 was prepared from 6.1 and azetidin-3-ol hydrochloride according to the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol / 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).

[0316] 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 [ka] Synthesis of I-9. Compound I-9 was prepared from 6.1 and 3-methoxyazetidine hydrochloride according to the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol / DCM). MS (ES): m / z: 570.3 [M+H] - , 1 H 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).

[0317] 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 [ka] 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 precipitated solid was collected by filtration and triturated with hexane to give 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 minutes. This was transferred to saturated sodium bicarbonate solution, stirred, and extracted with DCM. The combined organic layer was 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 / DCM) to give 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.), 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 a stream of argon through it for 10 minutes. 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 minutes. The reaction mixture was stirred at 110 °C for 2 hours. The mixture was cooled to room temperature, poured 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 / DCM) to give I-10. MS (ES): m / z: 579.4 [M+H] + , 1 H 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).

[0320] 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 [ka] Synthesis of I-11. Compound I-11 was prepared from 6.1 and pyrrolidine according to the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.2% methanol / DCM). MS (ES): m / z: 554.3 [M+H] + . 1 H 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).

[0321] 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 [ka] 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 hours. The mixture was poured into water, stirred, and extracted with ethyl acetate. The combined organic layer was 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 / DCM) to give I-12. MS (ES): m / z: 559.2 [M+H] + , 1 H 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).

[0322] 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 [ka] Synthesis of I-13. Compound I-13 was prepared from 6.1 and (R)-3-methoxypyrrolidine according to the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.7% methanol / DCM). MS (ES): m / z: 584.3 [M+H] - , 1 H 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).

[0323] 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 [ka] Synthesis of I-14. Compound I-14 was prepared from 6.1 and (S)-3-methoxypyrrolidine according to the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.9% methanol / DCM). MS (ES): m / z: 584.3 [M+H] - , 1 H 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).

[0324] 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 [ka] Synthesis of I-15. Compound I-15 was prepared from 6.1 and 2-morpholinoethan-1-ol according to the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol / DCM). MS (ES): m / z: 614.3 [M+H] + , 1 H 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).

[0325] 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 [ka] Synthesis of I-16. Compound I-16 was prepared from 6.1 and oxetan-3-ol according to the procedure described in the synthesis of I-6. The product was purified by flash column chromatography on silica gel (CombiFlash®, 2.7% methanol / DCM). MS (ES): m / z: 557.2 [M+H] + , 1 H 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).

[0326] 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 [ka] 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) were stirred at 110° C. for 6 hours. This was transferred to water, stirred, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.2% methanol / DCM) to give I-17. MS (ES): m / z: 571.3 [M+H] + . 1 H 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).

[0327] 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 [ka] Synthesis of I-18. Compound I-18 was prepared from 6.1 and (R)-tetrahydrofuran-3-ol according to the procedure described in the synthesis of I-17. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.2% methanol / DCM). MS (ES): m / z: 571.3 [M+H] + . 1 H 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).

[0328] 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 [ka] 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 minutes. This was poured into water, stirred, and extracted with ethyl acetate. The combined organic layer was 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 / DCM) to give 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 minutes. This was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give 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 hours. The mixture was poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layer was 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 / DCM) to give 19.3. MS (ES): m / z 411.5 [M+H] + .

[0331] Synthesis of Compound 19.4. Compound 19.4 was prepared from 19.3 according to 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 / 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 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 minutes. The reaction mixture was poured into ice water, and the 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. 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 hours. This was transferred into water and the product was extracted with ethyl acetate, which was further purified by flash column chromatography on silica gel (CombiFlash®, 10% methanol / DCM) to give I-19. MS(ES): m / z: 581.2 [M+H] + . 1 H 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).

[0333] 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 [ka] 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), sodium hydride (0.049 g, 1.248 mmol, 3.0 equiv.) was added at 0° C. and stirred for 30 minutes. 6.1 (0.200 g, 0.346 mmol, 1.0 equiv.) was added to the mixture and stirred at room temperature for 30 minutes. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the material. This was further purified by flash column chromatography on silica gel (CombiFlash®, 2.2% methanol / DCM) to obtain 20.1. MS (ES): m / z: 635.4 [M+H] + .

[0334] Synthesis of I-20. To a DCM solution (3 mL) of 20.1 (0.040 g, 0.063 mmol, 1.0 equiv.) was added triflic acid (1 mL) at 0° C. and stirred for 10 minutes. This was transferred into ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layer was 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 / DCM) to give 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).

[0335] 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 [ka] 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), n-butyllithium (2.5 M in hexanes) (61.4 mL, 153.7 mmol, 2.0 equiv.) was added at −78° C. and stirred for 40 minutes. Hexachloroethane (36.3 g, 153.7 mmol, 2.0 equiv.) was added, and the reaction mixture was stirred at −78° C. for 40 minutes. The reaction was quenched by careful addition of saturated aqueous ammonium chloride solution. 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®, 12% ethyl acetate / hexane) to give 21.1. 1 H 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 minutes. To this mixture, 21.1 (0.5 g, 3.04 mmol, 1.0 equiv.) was added in small portions while maintaining the temperature in the range of 30–40°C. After the addition, the reaction mixture was stirred at room temperature for 3–4 hours. It was poured onto crushed ice, stirred, 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 / hexanes) to give 21.2. 1 H NMR (DMSO-d6, 400MHz): 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), aqueous methylamine (40%) (0.8 mL, 9.98 mmol, 2.0 equiv.) was added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 minutes. It was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate / hexane) to give 21.3. 1 H 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 and poured into ice water. The precipitated solid was collected by filtration, rinsed with water, and dried under vacuum to give 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 hours. 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 column chromatography on silica gel (CombiFlash®, 2.4% methanol / dichloromethane) to give 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 according to the procedure described in the synthesis of I-19. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol / 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 with argon for 10 minutes. 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 minutes. The reaction mixture was stirred at 210 °C in a microwave reactor for 1 hour. The mixture was cooled to room temperature, transferred to 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®, eluent: 4.5% methanol / DCM) to give 21.7. MS (ES): m / z 438.2 [M+H] + .

[0342] Synthesis of I-21. Dimethylcarbamic acid chloride (0.013 g, 0.125 mmol, 1.1 equiv.) was added to a solution of 21.7 (0.050 g, 0.114 mmol, 1.0 equiv.) in THF (2 mL) at 0° C., followed by potassium tert-butoxide (1 M in THF) (0.57 mL, 0.57 mmol, 5.0 equiv.) at the same temperature and stirring for 15 minutes. The reaction mixture was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give I-21. MS (ES): m / z: 509.3 [M+H] + . 1 H 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).

[0343] 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 [ka] 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 hours. It was poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give I-22. MS(ES): m / z: 496.2 [M+H] + . 1 H 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).

[0344] 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 [ka] 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. After stirring the reaction mixture for 15 minutes, pyrrolidine (0.040 g, 0.57 mmol, 5.0 equiv.) was added. The reaction mixture was stirred at 50° C. for 15 minutes. The mixture was poured 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 / DCM) to give I-23. MS (ES): m / z: 535.4 [M+H] + . 1 H 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).

[0345] 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 [ka] 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 minutes. It was poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 minutes. It was poured 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 / DCM) to give 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).

[0347] 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 [ka] Synthesis of I-25. Compound I-25 was prepared from 24.1 and morpholine according to the procedure for the synthesis of I-24. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol / DCM). MS (ES): m / z: 551.3 [M+H] + . 1 H 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).

[0348] 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 [ka] Synthesis of I-26. Compound I-26 was prepared from 24.1 and 3-methoxyazetidine hydrochloride according to the procedure for the synthesis of I-24. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.2% methanol / DCM). MS (ES): m / z: 551.4 [M+H] + , 1 H 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).

[0349] 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 [ka] Synthesis of I-27. Compound I-27 was prepared from 21.7 and methylamine according to the procedure for the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol / DCM). MS (ES): m / z: 495.3 [M+H] + , 1 H 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).

[0350] 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 [ka] Synthesis of I-28. Compound I-28 was prepared from 21.7 and (R)-pyrrolidin-3-ol according to the procedure for the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.4% methanol / 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).

[0351] 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 [ka] Synthesis of I-29. Compound I-29 was prepared from 21.7 and (S)-pyrrolidin-3-ol according to the procedure for the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol / DCM). MS (ES): m / z: 551.4 [M+H] + , 1 H 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).

[0352] 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 [ka] Synthesis of I-30. Compound I-30 was prepared from 21.7 and azetidine according to the procedure for the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol / DCM). MS (ES): m / z: 521.4 [M+H] + .LCMS purity: 98.49%, HPLC purity: 96.93%, 1 H 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).

[0353] 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 [ka] 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), sodium hydride (111 g, 2773.9 mmol, 4.8 equiv.) was added in small portions at 0° C. and stirred for 2 hours. 4-Methoxybenzyl chloride (434 g, 2773.9 mmol, 4.8 equiv.) was added to the mixture and stirred at 0° C. for 30 minutes. The mixture was poured into ice water, and the precipitated solid was filtered and dried under vacuum to give Compound 31.1 (150 g, 62.79% yield). 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 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 minutes, and an aqueous solution of sodium hydroxide (11.6 g, 290 mmol, 2.0 equiv) was added. The mixture was stirred at 110° C. for 48 hours. It was cooled to room temperature, transferred to 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 give 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, 0.8 equiv.) in DMF (390 mL) was stirred at 80° C. for 1 hour. It was filtered, and the filtrate was poured into water, stirred, and extracted with ethyl acetate. The combined organic layer was 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 / hexane) to give 31.3. MS (ES): m / z 536.6 [M+H] + .

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

[0357] Synthesis of Compound 31.5. Compound 31.5 was prepared from 31.4 according to the procedure described in the synthesis of Compound 21.7. The product was further purified by flash column chromatography on silica gel (CombiFlash®, 1.8% methanol / 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 hours. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate / hexane) to give 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 the reaction mixture was stirred for 10 minutes. This was transferred into saturated sodium bicarbonate solution, stirred, and extracted with ethyl acetate. The combined organic layer was 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 / hexane) to give 31.7. MS (ES): m / z 541.9 [M+H] + .

[0360] Synthesis of Compound 31.8. To a 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 minutes. This was transferred into ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layer was 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 / DCM) to give 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 the addition of methyl chloroformate (0.033 g, 0.349 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 15 minutes. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.8% methanol / DCM) to give 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 according to the procedure for the synthesis of I-10. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol / DCM). MS (ES): m / z: 570.3 [M+H] + , 1 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).

[0363] 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 [ka] Synthesis of I-32. Compound I-32 was prepared from 21.7 and 2-methoxyethan-1-ol according to the procedure for the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.5% methanol / DCM). MS (ES): m / z: 540.2 [M+H] + , 1 H 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).

[0364] 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 [ka] Synthesis of I-33. Compound I-33 was prepared from 21.7 and (R)-3-methoxypyrrolidine hydrochloride according to the procedure for the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.3% methanol / DCM). MS (ES): m / z: 565.4 [M+H] + , 1 H 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).

[0365] 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 [ka] Synthesis of I-34. Compound I-34 was prepared from 21.7 and (S)-3-methoxypyrrolidine hydrochloride according to the procedure for the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.3% methanol / DCM). MS (ES): m / z: 565.3 [M+H] + , 1 H 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).

[0366] 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 [ka] Synthesis of I-35. Compound I-35 was prepared from 21.7 and azetidin-3-ol hydrochloride according to the procedure for the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.2% methanol / DCM). MS (ES): m / z: 537.3 [M+H] + , 1 H 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).

[0367] 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 [ka] Synthesis of I-36. Compound I-36 was prepared from 21.7 and (S)-tetrahydrofuran-3-ol according to the procedure for the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.2% methanol / 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).

[0368] 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 [ka] Synthesis of I-37. Compound I-37 was prepared from 21.7 and (R)-tetrahydrofuran-3-ol according to the procedure for the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.2% methanol / DCM). MS (ES): m / z: 552.3 [M+H] + , 1 H 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).

[0369] 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 [ka] Synthesis of I-38. Compound I-38 was prepared from 21.7 and 2-(dimethylamino)ethan-1-ol according to the procedure for the synthesis of I-23. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.5% methanol / DCM). MS (ES): m / z: 553.4 [M+H] + , 1 H 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).

[0370] 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 [ka] Synthesis of I-39. 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 hours. This was transferred to water, stirred, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give I-39. MS(ES): m / z: 570.4 [M+H] + , 1 H 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).

[0371] 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 [ka] Synthesis of Compound 40.1. To a THF solution (5 mL) of 31.4 (0.500 g, 0.988 mmol, 1.0 equiv.) and Int-8 (0.308 g, 1.48 mmol, 1.5 equiv.), potassium tert-butoxide (1 M in THF, 2.96 mL, 2.964 mmol, 3.0 equiv.) was added at 0° C. The reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layer was 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 hour. The reaction mixture was poured into water, and the 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. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol / DCM) to give 40.1. MS (ES): m / z: 681.1 [M+H] + .

[0372] Synthesis of Compound 40.2. To a 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 5 minutes. This was transferred into ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to give 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 hours and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 5.0% methanol / DCM) to give I-40. MS (ES): m / z: 498.3 [M+H] + , 1 H 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).

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

[0375] Synthesis of Compound 41.2. Compound 41.2 was prepared from 41.1 according to the procedure described for 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 according to the procedure described in the synthesis of I-40. The product was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol / DCM). MS (ES): m / z: 489.3 [M+H] + , 1 H 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...

Claims

[Claim 1] The invention described in the specification.

Images