6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors

Abstract

This disclosure provides compounds and compositions thereof that can be used to inhibit 6-heteroaryloxybenzimidazole and azabenzimidazole of JAK2.

Description

6-Heteroaryloxybenzimidazole and aziroxane, as JAK2 inhibitors Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase associated with the JAK-STAT signaling pathway, playing a role in cellular processes such as immunity, cell division, and cell death. Dysfunction of the JAK-STAT pathway is associated with a variety of diseases, including cancer and other proliferative disorders as well as immune system diseases. For example, virtually all... BCR- ABL1-negative myeloproliferative neoplasms are all associated with mutations in activated JAK2. Specifically, JAK2V617F is the most common mutation in myeloproliferative neoplasms, occurring in approximately 70% of all patients and in up to 95% of patients with polycythemia vera (Vainchenker, W., Kralovics, R. Blood 2017, 129(6):667-79). It has been shown that mutations such as... MPL and Less common mutations in CALR enable JAK2 activation, thereby initiating and / or driving disease progression (Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev:82). Furthermore, Polymorphisms in JAK2 have caused a variety of autoimmune diseases and inflammatory disorders, such as psoriasis and inflammatory bowel disease (O'Shea, JJ et al., Ann. Rheum. Dis. 2013 Apr, 72:ii111-ii115). Increased signaling via JAK2 and other members of the JAK family is also associated with atopic dermatitis (Rodrigues, MA and Torres, TJ Derm. Treat. 2019, 31(1):33-40). Inhibitors of JAK (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 the catalytic activity (Vainchenker, W. et al.). However, increased phosphorylation of the JAK2 activation ring has been observed with type I inhibitors, and it can lead to acquired resistance in some 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, and thus avoid the hyperphosphorylation observed with type I inhibitors (Wu, SC et al. Cancer Cell 2015 July 13, 28(1):29-41). This disclosure provides compounds that can be used to inhibit JAK2. In some embodiments, the provided compounds may be used, in particular, to treat and / or prevent diseases, symptoms, or ailments associated with JAK2. In some embodiments, this disclosure provides compounds of formula I. I or its medically acceptable salt, wherein the rings A, n, L, W, X, Y, Z, R 1 R 2 R a and R c As defined in this article. In some embodiments, this disclosure provides compounds of formula II. II or its medically acceptable salt, wherein the rings A, n, W, X, Y, Z, R 1 R 2 and R c As defined in this article. In some embodiments, this disclosure provides compounds of formula III. III or its medically acceptable salts, wherein rings A, L, Z, R 2 R 4 R a and R x As defined in this article. In some embodiments, this disclosure provides Formula IV compounds. IV or its medically acceptable salts, wherein rings A, L, Z, R', R 2 R a and R x As defined in this article. Related applications This application claims priority and benefits to U.S. Application No. 63 / 277,343, filed November 9, 2021, and U.S. Application No. 63 / 354,403, filed June 22, 2022, the entire contents of which are incorporated herein by reference. Compounds and their definitions The compounds of this invention include those summarized above, and are further described according to the classes, subclasses and species disclosed herein. Unless otherwise indicated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition. Furthermore, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999; and "March's Advanced Organic Chemistry," 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference. Unless otherwise stated, the structures described herein are intended to include all stereoisomers (e.g., mirror-image or non-mirror-image isomers) and all geometric or configurational isomers of the structures. For example, the R and S configurations covering each stereocenter are included as part of this disclosure. Therefore, individual stereochemical isomers of the provided compounds, as well as mirror-image, non-mirror-image, and geometric (or configurational) mixtures, are within the scope of this disclosure. For example, in some cases, Table 1 shows one or more stereoisomers of the compounds, and unless otherwise indicated, represents each stereoisomer individually and / or as a mixture. Unless otherwise stated, all tautomeristic forms of the provided compounds are within the scope of this disclosure. Unless otherwise indicated, the structures described herein are intended to include compounds differing only in the presence of one or more isotopically enriched atoms. For example, structures having the features of this invention include deuterium or tritium replacing hydrogen or... 13 C or 14 Compounds that enrich carbon and replace carbon are within the scope of this disclosure. Aliphatic: The term "aliphatic" refers to a fully saturated or, where applicable, substituted straight-chain (i.e., unbranched) or branched hydrocarbon chain containing one or more unsaturated units, or a fully saturated or, where applicable, substituted monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic" or "cycloaliphatic") containing one or more unsaturated units but not aromatic, having a single attachment site to the rest of the molecule. Unless otherwise stated, the aliphatic group contains 1-12 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-6 aliphatic carbon atoms (e.g., C14-C14). 1-6 In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms (e.g., C15-C5). 1-5 In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms (e.g., C14). 1-4 In other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-3 In other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms (e.g., C12-C22). 1-2 Suitable aliphatic groups include (but are not limited to) straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof. In some embodiments, "aliphatic" means a fully saturated or, where applicable, substituted straight-chain (i.e., unbranched) or branched hydrocarbon chain containing one or more unsaturated units, having a single attachment site to the rest of the molecule. Alkyl: The term "alkyl" used alone or as part of a larger part refers to having (unless otherwise stated) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C12, C23, C32, C43, C53, C63, C73, C83, C93, C93, C94, C95, C96 ... 1-12 C 1-10 C 1-8 C 1-6 C 1-4 C 1-3 Or C 1-2The saturated straight-chain or branched hydrocarbon group may be substituted, as appropriate. Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl. Carbocyclic group: As used herein, the terms "carbocyclic group," "carbocyclic ring," and "carbocyclic ring" refer to a saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic system having 3 to 14 members, wherein the aliphatic ring system is 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, "carbocyclic group" (or "cycloaliphatic group") refers to a fully saturated or partially unsaturated but substituted monocyclic C-ring containing one or more unsaturated units, but not aromatic. 3-C 8 hydrocarbons or, as appropriate, substituted C 7-C 10 A bicyclic hydrocarbon having a single attachment site with the rest of the molecule. The term "cycloalkyl" refers to a saturated ring system having about 3 to about 10 ring carbon atoms, which may be substituted. In some embodiments, the cycloalkyl has 3 to 6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms, which may be substituted. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl. Alkenyl: The term "alkenyl" used alone or as part of a larger part refers to having at least one double bond and having (unless otherwise stated) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 2-12 C 2-10 C 2-8 C 2-6 C 2-4 Or C 2-3 (The alkenyl group may be a straight or branched hydrocarbon chain that has been substituted, as appropriate. Exemplary alkenyl groups include vinyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.) Alkynyl: The term "alkynyl" used alone or as part of a larger part refers to a group having at least one parabonding and having (unless otherwise stated) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C12, C23, C34, C43, C54, C64, C74, C84, C9 ... 2-12 C 2-10 C 2-8 C 2-6 C 2-4 Or C 2-3 The alkynyl group may be a straight-chain or branched hydrocarbon group that has been substituted, as appropriate. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl. Aryl: The term "aryl" refers to a group having a total of six to fourteen ring members (e.g., C14). 6-14 A monocyclic and bicyclic system, wherein at least one ring in the system is an aromatic ring and each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aromatic ring". In some embodiments, "aryl" refers to an aromatic ring system that includes (but is not limited to) phenyl, naphthyl, anthracene, and similar groups, and may contain one or more substituents. Unless otherwise stated, "aryl" is a hydrocarbon. Heteroaryl: The terms “heteroaryl” and “heteroaryl” used alone or as part of a larger portion, such as “heteroarylalkyl” or “heteroarylalkoxy”, refer to a monocyclic or bicyclic group having 5 to 10 ring atoms (e.g., 5 to 6-membered monocyclic heteroaryl or 9 to 10-membered bicyclic heteroaryl); having 6, 10 or 14 π electrons shared in a cyclic array; and having one to five heteroatoms in addition to a carbon atom. Exemplary heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonel, pyridazinyl, pyrimidinyl, indazinyl, purine, naphridyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienzopyrimidinyl, triazol[1,2-a]pyrimidinyl, and benzo[1,2-a]pyrimidinyl. As used herein, the terms "heteroaryl" and "heteroaromatic" also include groups fused with one or more aromatic rings, cycloaliphatic rings, or heterocycles, wherein the attachment group or dot is located on the heteroaromatic ring (i.e., a bicyclic heteroaromatic ring having 1 to 3 heteroatoms). Non-limiting examples include indole, isoindole, benzothiophene, benzofuran, dibenzofuran, indazole, benzimidazol, benzothiazolyl, benzothiadiazol, benzoxazol, quinolinyl, isoquinolinyl, terpineyl, phthalazinyl, quinazolinyl, quinoxolinyl, 4 H-quinazinyl, carbazolyl, acridinel, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one, and benzoisooxazolyl. The term "heteroaryl" may be used interchangeably with the terms "heteroary ring," "heteroaryl," or "heteroary group," any of which includes, where appropriate, a substituted ring. Heteroatoms: As used herein, the term “heteroatoms” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternary ammoniation of basic nitrogen. Heterocycle: As used herein, the terms "heterocycle," "heterocyclic group," and "heterocycle" are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more heteroatoms, such as one to four as defined above, in addition to a carbon atom. When referring to the ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolidyl), or NR. + (e.g., N-substituted pyrrolidyl). Heterocycles can be attached to their side groups at any heteroatom or carbon atom to create a stable structure, and any of the ring atoms may be substituted as appropriate. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazine, dioxane, dioxanecyclopentane, diazapyryl, oxonitrilepyryl, thionitrilepyryl, morpholinyl, and thiomorpholinyl. Heterocyclic groups can be monocyclic, bicyclic, tricyclic, or polycyclic, preferably monocyclic, bicyclic, or tricyclic, and more preferably monocyclic or bicyclic. Bicyclic heterocycles also include groups fused with one or more aromatic rings, heteroaromatic rings, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indololinyl, isoidololinyl, benzodioxanepentenyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. Bicyclic heterocycles may also be spirocyclic systems (e.g., 7- to 11-membered spirocyclic fused heterocycles having one or more heteroatoms as defined above (e.g., one, two, three, or four heteroatoms) in addition to a carbon atom). Partially unsaturated: As used herein, the term "partially unsaturated" when referring to a ring portion means a ring portion that includes at least one double bond or triple bond between ring atoms. The term "partially unsaturated" is intended to cover rings with multiple unsaturated sites, but not to include aromatic ring portions (e.g., aryl or heteroaryl) as defined herein. Patient or Individual: As used herein, the terms "patient" or "individual" refer to any organism to which a composition is administered or may be administered for experimental, diagnostic, preventative, cosmetic, and / or therapeutic purposes. Typical patients or individuals include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. In some embodiments, the patient or individual suffers from or is susceptible to one or more conditions or disorders. In some embodiments, the patient or individual exhibits one or more symptoms of a condition or disorder. In some embodiments, the patient or individual has been diagnosed with one or more conditions or disorders. In some embodiments, the patient or individual is receiving or has received certain therapies for the diagnosis and / or treatment of a disease, condition, or disorder. Substituted or as appropriate: As described herein, compounds of this disclosure may contain a "substituted" portion. Generally, the term "substituted" or "as appropriate" means, regardless of whether it is preceded by the term "as appropriate," that one or more hydrogens in the specified portion are replaced by a suitable substituent (i.e., as described below for groups substituted as appropriate). "Substituted" applies to one or more hydrogens explicitly or implicitly present in the structure (e.g., It refers to at least ;and It refers to at least , , or Unless otherwise indicated, a group described as "substituted as appropriate" may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from the specified group. The combinations of substituents contemplated in this invention are preferably combinations that form stable or chemically viable compounds. As used herein, "stable" means that a compound remains substantially unchanged when subjected to conditions that allow it to be generated, detected, and in some embodiments, recovered, purified, and used to achieve one or more of the purposes provided herein. A group described as "substituted" preferably has 1 to 4 substituents, more preferably 1 or 2 substituents. A group described as "substituted as appropriate" may be unsubstituted or "substituted" as described above. The suitable monovalent substituent on the substituted carbon atom of the group that is "substituted as appropriate" is independently a halogen; -(CH 2) 0-4 R°;-(CH 2) 0-4 OR°;-O(CH 2) 0-4 R o -O-(CH 2) 0-4 C(O)OR°;-(CH 2) 0-4 CH(OR°) 2; -(CH 2) 0-4 SR°;-(CH 2) 0-4 Ph, which can be substituted by R°; -(CH 2) 0-4 O(CH 2) 0-1 Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH 2) 0-4 O(CH 2) 0-1 -pyridyl group, which can be substituted via R°; -NO 2; -CN; -N 3; -(CH 2) 0-4 N(R°) 2; -(CH 2) 0-4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH 2) 0-4 N(R°)C(O)NR° 2; -N(R°)C(S)NR° 2; -(CH 2) 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°;-(CH 2) 0-4 C(O)R°;-C(S)R°;-(CH 2) 0-4 C(O)OR°;-(CH 2) 0-4 C(O)SR°;-(CH 2) 0-4 C(O)OSiR° 3;-(CH 2) 0-4 OC(O)R°;-OC(O)(CH 2) 0-4 SR°;-(CH 2) 0-4 SC(O)R°;-(CH 2) 0-4 C(O)NR° 2;-C(S)NR° 2;-C(S)SR°;-SC(S)SR°、-(CH 2) 0-4 OC(O)NR° 2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH 2C(O)R°;-C(NOR°)R°;-(CH 2) 0-4 SSR°; -(CH 2) 0-4 S(O) 2R°;-(CH 2) 0-4 S(O) 2OR°;-(CH 2) 0-4 OS(O) 2R°;-S(O) 2NR° 2;-(CH 2) 0-4S(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 alkyl) ON(R°) 2; or -(C 1-4 Straight-chain or branched alkyl groups) C(O)ON(R°) 2, where each R° can be defined as substituted and independently being hydrogen, C 1-6 Aliphatic group, -CH 2Ph、-O(CH 2) 0-1 Ph、-CH 2-(5 to 6-membered heteroaryl ring) or 3 to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 independent heteroatoms selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independently occurring R° together with their inserted atoms form a 3 to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 independent heteroatoms selected from nitrogen, oxygen or sulfur, which may be replaced as defined below. The suitable monovalent substituents on R° (or a ring formed by two independently occurring R° along with their inserted atoms) are independently halogens, -(CH 2) 0-2 R l -(halogenated R) l ), -(CH 2) 0-2 OH, -(CH 2) 0-2 OR l -(CH) 2) 0-2 CH(OR l ) 2. -O(halogenated R) l -CN, -N 3. -(CH) 2) 0-2 C(O)R l -(CH) 2) 0-2 C(O)OH, -(CH 2) 0-2 C(O)OR l -(CH) 2) 0-2 SR l -(CH) 2) 0-2 SH、-(CH 2) 0-2 NH 2. -(CH) 2) 0-2 NHR l -(CH) 2) 0-2 NR l 2. -NO 2, -SiR l 3. -OSiR l 3. -C(O)SR l -(C 1-4 (straight-chain or branched alkyl)C(O)OR l or -SSR l , where each R l It is either unsubstituted or, in the case of a preceding "halogen group," substituted with only one or more halogens, and independently selected from C. 1-4 Aliphatic group, -CH 2Ph、-O(CH 2) 0-1 Ph or a 3 to 6-member saturated, partially unsaturated, or aryl ring having 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S. Suitable divalent substituents on the saturated carbon atom of the group that is "substituted as appropriate" include the following: =O ("side oxygen"), =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 each independently occurring R * It is selected from hydrogen, and can be defined as the substituted C as follows. 1-6 The aliphatic group or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents bonded to adjacent substituted carbons of the "substituted" group include: -O(CR * 2) 2-3 O-, wherein each independently occurring R* is selected from hydrogen, and substituted C as defined below. 1-6It has an aliphatic group or an unsubstituted 5-6 member saturated, partially unsaturated or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur. Suitable substituents on the aliphatic group of R* include halogens and -R. l -(halogenated R) l -OH, -OR l -O(halogenated R) l -CN, -C(O)OH, -C(O)OR l -NH 2. -NHR l -NR l 2 or -NO 2, where each R l It is either unsubstituted or, in the case of a preceding "halogen group," substituted with only one or more halogens, and independently C. 1-4 Aliphatic group, -CH 2Ph、-O(CH 2) 0-1 Ph or has 3 to 6 saturated, partially unsaturated or aryl rings with 0 to 4 independent heteroatoms selected from nitrogen, oxygen or sulfur. Suitable substituents on the substituted nitrogen of the group that is "substituted as appropriate" include -R † -NR † 2. -C(O)R † -C(O)OR † -C(O)C(O)R † -C(O)CH 2C(O)R † -S(O) 2R † -S(O) 2NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R) † S(O) 2R † ; where each R † Independently, hydrogen, and substituted C can be defined as follows: 1-6 An aliphatic group or an unsubstituted 3 to 6-member saturated, partially unsaturated, or aryl ring having 0 to 4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur, or, despite the above definition, two independently occurring R groups. † Together with its inserted atoms, it forms an unsubstituted 3 to 12-member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring with 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. R † Suitable substituents on the aliphatic group are independently halogens, -R l -(halogenated R) l -OH, -OR l -O(halogenated R) l -CN, -C(O)OH, -C(O)OR l -NH 2. -NHR l -NR l 2 or -NO 2, where each R l It is either unsubstituted or, in the case of a preceding "halogen group," substituted with only one or more halogens, and independently C. 1-4 Aliphatic group, -CH 2Ph、-O(CH 2) 0-1 Ph or has 3 to 6 saturated, partially unsaturated or aryl rings with 0 to 4 independent heteroatoms selected from nitrogen, oxygen or sulfur. Treatment: As used herein, the term "treat" (also "treatment" or "treating") means any administration of a therapy that partially or completely alleviates, improves, regenerates, suppresses, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more of its symptoms, features, and / or causes of a particular disease, condition, and / or ailment. In some embodiments, such treatment may be for an individual who does not exhibit signs of the relevant disease, condition, and / or ailment, and / or an individual who exhibits only early signs of the disease, condition, and / or ailment. Alternatively, such treatment may be for an individual who exhibits one or more definitive signs of the relevant disease, condition, and / or ailment. In some embodiments, treatment may be for an individual who has been diagnosed with the relevant disease, condition, and / or ailment. Compounds provided In some embodiments, this disclosure provides compounds of formula I: I or its medically acceptable salt, wherein: W is CR w Or N; X is CR x Or N; Y is CR y Or N; Z is -O- or -NR z -; R w R x and R y Each independently represents hydrogen, halogen, -OR 3 -N(R) 3 ) 2. -SR 3 Depending on the circumstances, the C that has been replaced 1-6 Aliphatic group or -CN; R z Hydrogen or, depending on the case, substituted C 1-6 Aliphatic group; R 1 -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 Independently selected from halogens, -CN, -CO 2R、-C(O)N(R) 2. -NO 2. -N(R) 2. -OR, -SR, or C as appropriate 1-6 Aliphatic group; n is 0, 1, 2 or 3, provided that R 1 -N(R) 2. -N(R)C(O)R' or -C(O)N(R) When n = 2, n is 1, 2, or 3; R 2 C, to be replaced as appropriate 1-6 Aliphatic group; R 3 Hydrogen or, depending on the case, substituted C 1-6 Aliphatic group; Ring A is, as appropriate, a substituted phenyl group, a substituted 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a substituted 8-10 member bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a substituted 3-7 member saturated or partially unsaturated monocyclic carbocyclic group, a substituted 3-7 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a substituted 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a divalent carbon. 1-3 Straight-chain or branched hydrocarbon chains; R a Hydrogen, halogen, or C substituted as appropriate 1-6 Aliphatic group, substituted phenyl group, substituted 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted 3-7 member saturated or partially unsaturated monocyclic carbocyclic group, substituted 3-7 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or substituted 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, and the C is substituted as appropriate. 1-6The aliphatic group, a substituted 3 to 7-member saturated or partially unsaturated carbocyclic group, or a substituted 3 to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or two Rs attached to the same nitrogen atom to form a substituted 3 to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 0 to 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur; and each R' is independently a substituted C 1-6 Aliphatic groups or, depending on the case, 3 to 7 saturated or partially unsaturated carbocyclic groups that have been substituted. In some embodiments, this disclosure provides a compound of formula IA: IA or its medically acceptable salts, wherein, alone or in combination, the rings A, n, L, Z, R 1 R 2 R a R c R x and R y As defined above for Formula I and described in this document as categories and subclasses. In some embodiments, this disclosure provides a compound of formula IB: IB or its medically acceptable salts, wherein, alone or in combination, cyclic A, n, L, Z, R 1 R 2 R a R c and R y As defined above for Formula I and described in this document as categories and subclasses. In some embodiments, this disclosure provides a type IC compound: IC or its medically acceptable salts, wherein, alone or in combination, the rings A, n, L, Z, R 1 R 2 R a R c and R xAs defined above for Formula I and described in this document as categories and subclasses. In some embodiments, this disclosure provides for the following ID compounds: ID or its medically acceptable salts, wherein, alone and in combination, the rings A, n, L, W, X, Y, Z, R 1 R 2 R a and R c As defined above for Equation I and described in this document as categories and subclasses; and R b Hydrogen, halogen, -CN, -OR, -O(CH) 2) m R, -SR, -N(R) 2. -NO 2. -C(O)R', -C(O)OR, -C(O)N(R) 2. -OC(O)R', -OC(O)N(R) 2. -OC(O)OR, -OSO 2R, -OSO 2N(R) 2. -N(R)C(O)R', -N(R)SO 2R'、-SO 2R'、-SO 2N(R) 2. -SO 3R', or C as appropriate (substituted for) 1-6 The aliphatic group, a 3 to 6 saturated or partially unsaturated carbocyclic group substituted as appropriate, a 3 to 6 saturated or partially unsaturated monocyclic heterocyclic group substituted as appropriate having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5 to 6 saturated monocyclic heteroaryl group substituted as appropriate having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and m is 1, 2 or 3. In some embodiments, this disclosure provides IE compounds: IE or its medically acceptable salts, wherein, alone or in combination, cyclic A, L, W, X, Y, Z, R 1 R 2 and R a As defined above for Formula I and described in this document as categories and subclasses. In some embodiments, this disclosure provides compounds of formula II: II or its medically acceptable salt, wherein: W is CR w Or N; X is CR x Or N; Y is CR y Or N; Z is -O- or -NR z -; R w R x and R y Each independently represents hydrogen, halogen, -OR 3 -N(R) 3 ) 2. -SR 3 Depending on the circumstances, the C that has been replaced 1-6 Aliphatic group or -CN; R z Hydrogen or, depending on the case, substituted C 1-6 Aliphatic group; R 1 -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 Independently selected from halogens, -CN, -CO 2R、-C(O)N(R) 2. -NO 2. -N(R) 2. -OR, -SR, or C as appropriate 1-6 Aliphatic group; n is 0, 1, 2 or 3; R 2 C, to be replaced as appropriate 1-6 Aliphatic group; R 3 Hydrogen or, depending on the case, substituted C 1-6 Aliphatic group; Ring A is, depending on the substitution, a 9- to 16-membered bicyclic or tricyclic aryl group, an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 10- to 16-membered polycyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 10-membered bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10- to 16-membered polycyclic heterocyclic group having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen, and C is, depending on the substitution... 1-6 The aliphatic group, a substituted 3 to 7-member saturated or partially unsaturated carbocyclic group, or a substituted 3 to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or two Rs attached to the same nitrogen atom to form a substituted 3 to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 0 to 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur; and each R' is independently a substituted C 1-6 Aliphatic groups or, depending on the case, 3 to 7 saturated or partially unsaturated carbocyclic groups that have been substituted. In some embodiments, this disclosure provides compounds of formula II-A: II-A or its medically acceptable salts, wherein, alone or in combination, cyclic A, n, Z, R 1 R 2 R c R x and R y As defined above for Equation II and described in this document as categories and subclasses. In some embodiments, this disclosure provides compounds of formula II-B: II-B or its medically acceptable salts, wherein, alone or in combination, rings A, n, Z, R 1 R 2 R c and R y As defined above for Equation II and described in this document as categories and subclasses. In some embodiments, this disclosure provides compounds of formula II-C: II-C or its medically acceptable salts, in both single and combined forms, cyclic A, n, Z, R 1 R 2 R c and R x As defined above for Formula II and described in this document as categories and subclasses. In some embodiments, this disclosure provides compounds of formula II-D: II-D or its medically acceptable salts, wherein, alone or in combination, the rings A, W, X, Y, Z, R 1 and R 2 As defined above for Equation II and described in this document as categories and subclasses. In some embodiments, this disclosure provides compounds of formula II-E: II-E or its medically acceptable salts, wherein, alone and in combination, n, W, X, Y, Z, R 1 R 2 and R c As defined above for Formula II and described herein by categories and subcategories; and ring A1 is a ring selected from the following, which may be substituted: phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein ring A1 is fused with ring A2; ring A2 is a ring selected from the following, which may be substituted: phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein ring A2 is further fused with ring A3, if (i) Or (ii) ring A2 and ring A3 combine to form a spirocycle; and ring A3, when present, is a ring selected from the following, which may be substituted: phenyl, 5 to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 7-membered saturated or partially unsaturated monocyclic carbocyclic group and 3 to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, this disclosure provides compounds of formula II-F: II-F or its medically acceptable salts, wherein, alone or in combination, the rings A2, n, W, X, Y, Z, R 1 R 2 and R c As defined above for Equation II and described in this document as categories and subclasses. In some embodiments, this disclosure provides compounds of formula III: III or a medically acceptable salt thereof, wherein: Z is -O- or -NR. z -; R x For hydrogen, halogen, -OR 3 -N(R) 3 ) 2. -SR 3 Depending on the circumstances, the C that has been replaced 1-6 Aliphatic group or -CN; R z Hydrogen or, depending on the case, substituted C 1-6 Aliphatic group; R 2 C, to be replaced as appropriate 1-6 Aliphatic group; R 3 Hydrogen or, depending on the case, substituted C 1-6 Aliphatic group; R 4 For halogens, -OR, -N(R) 2 or, depending on the case, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 independently selected heteroatoms from nitrogen, oxygen, and sulfur; ring A is, depending on the case, a substituted phenyl group, a substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 independently selected heteroatoms from nitrogen, oxygen, and sulfur, a substituted 8- to 10-membered bicyclic heteroaryl group having 1-4 independently selected heteroatoms from nitrogen, oxygen, and sulfur, a substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, a substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 independently selected heteroatoms from nitrogen, oxygen, and sulfur, or a substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 independently selected heteroatoms from nitrogen, oxygen, and sulfur; L is a covalent bond or a divalent C. 1-3 Straight-chain or branched hydrocarbon chains; R a Hydrogen, halogen, or C substituted as appropriate 1-6 Aliphatic group, substituted phenyl group, substituted 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted 3-7 member saturated or partially unsaturated monocyclic carbocyclic group, substituted 3-7 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or substituted 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and each R is independently hydrogen, substituted C 1-6 Aliphatic group, substituted 3 to 7 saturated or partially unsaturated carbocyclic group, or substituted 3 to 7 saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independent heteroatoms selected from nitrogen, oxygen and sulfur, or two Rs attached to the same nitrogen atom to form substituted 3 to 7 saturated or partially unsaturated monocyclic heterocyclic group having 0 to 2 additional heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, this disclosure provides a compound of formula IV: IV or its medically acceptable salt, wherein: Z is -O- or -NR. z -; R x For hydrogen, halogen, -OR 3 Or -CN; R z Hydrogen or, depending on the case, substituted C 1-6 Aliphatic group; R 2 C, to be replaced as appropriate 1-6 Aliphatic group; R 3 Hydrogen or, depending on the case, substituted C 1-6 aliphatic groups; The option is selected from (i) or (ii): (i) , , , or ; or (ii) or In which ring A is further substituted at least once, and at least one substituent on ring A is C. 1-6 Haloalkyl; L is a covalent bond or a divalent C 1-3 Straight-chain or branched hydrocarbon chains; R a Hydrogen, halogen, or C substituted as appropriate 1-6 Aliphatic group, substituted phenyl group, substituted 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted 3-7 member saturated or partially unsaturated monocyclic carbocyclic group, substituted 3-7 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or substituted 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and R' is C 1-6 Aliphatic groups or 3 to 7 saturated or partially unsaturated carbocyclic groups. In some embodiments of any of Equations I, ID, IE, II, II-D, II-E, and II-F, W is CR w In some embodiments, W is N. In some embodiments of any of Equations I, ID, IE, II, II-D, II-E, and II-F, X is CR x In some embodiments, X is N. In some embodiments of any of Equations I, ID, IE, II, II-D, II-E, and II-F, Y is CR y In some embodiments, Y is N. In some embodiments of any of Equations I, ID, IE, II, II-D, II-E, and II-F, W is CR w Or N, 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 Equations I, ID, IE, II, II-D, II-E, and II-F, W is CR w Or N, 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. 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-. In some embodiments of any of formulas I, ID, IE, II, II-D, II-E, and II-F, R w C is hydrogen, halogen, or, where appropriate, substituted. 1-6 Aliphatic group. In some embodiments, R w It is hydrogen. In some embodiments, R is... w It is a halogen. In some embodiments, R w It is fluorine-based. In some embodiments, R w It is a chlorine group. In some embodiments, R w For -OR 2 In some embodiments, R w For -OR 2 , where R 2 C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, Y is N and W is CR. w And R w For -OR 2 , where R 2 C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, R w -N(R) 2 ) 2. In some embodiments, R w For -SR 2 In some embodiments, R w For -SR 2 , where R 2 C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, Y is N and W is CR. w And R w For -SR 2 , where R 2 C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, R w C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, R w For the straight or branched chain C, which may be replaced as appropriate. 1-6 Aliphatic groups (i.e., noncyclic C groups that are substituted, depending on the case) 1-6 Aliphatic groups). In some embodiments, R w C, to be replaced as appropriate 1-6 Alkyl group. In some embodiments, R w C, to be replaced as appropriate 1-4Alkyl group. In some embodiments, R w C, to be replaced as appropriate 1-2 Alkyl group. In some embodiments, R w The methyl group is substituted as appropriate (e.g., a methyl group substituted with one or more fluorinated groups as appropriate). In some embodiments, R w For -CN. 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 For hydrogen, halogen, -CN, -OR 2 Or, depending on the circumstances, replace C 1-6 Aliphatic group. In some embodiments, R x Hydrogen, halogen, -CN, -O(C) 1-4 Alkyl groups or C groups substituted with one or more halogens, as appropriate. 1-4 Alkyl group. In some embodiments, R x For hydrogen, halogen, -OR 2 Or, depending on the circumstances, replace C 1-6 Aliphatic group. In some embodiments, R x Hydrogen, halogen, -O(C) 1-4 Alkyl groups or C groups substituted with one or more halogens, as appropriate. 1-4 Alkyl group. In some embodiments, R x C is hydrogen, halogen, or, where appropriate, substituted. 1-6 Aliphatic group. In some embodiments, R x Hydrogen, halogen, -CN or OR 2 In some embodiments, R x It can be hydrogen, halogen, -CN or O(C) 1-4 Alkyl). In some embodiments, R x It is halogen or -CN. In some embodiments, R x It is hydrogen. In some embodiments, R is... x It is a halogen. In some embodiments, R x It is fluorine-based. In some embodiments, R x It is a chlorine group. In some embodiments, R x For -OR 2 In some embodiments, R x For -OR 2 , where R 2 C, to be replaced as appropriate 1-6 Aliphatic groups (e.g., C-substituted groups, depending on the case) 1-6 Alkyl). In some embodiments, R x -O(C) 1-4 Alkyl). In some embodiments, R x -OCH 3. In some embodiments, R x -N(R) 2 ) 2. In some embodiments, R x For -SR 2 In some embodiments, R x For -SR 2 , where R 2 C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, R x C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, R xFor the straight or branched chain C, which may be replaced as appropriate. 1-6 Aliphatic groups (i.e., noncyclic C groups that are substituted, depending on the case) 1-6 Aliphatic groups). In some embodiments, R x C, to be replaced as appropriate 1-6 Alkyl groups (e.g., C-shaped groups substituted with one or more fluorine groups, depending on the case) 1-6 Alkyl). In some embodiments, R x C, to be replaced as appropriate 1-4 Alkyl groups (e.g., C-shaped groups substituted with one or more fluorine groups, depending on the case) 1-4 Alkyl). In some embodiments, R x C, to be replaced as appropriate 1-2 Alkyl groups (e.g., C-shaped groups substituted with one or more fluorine groups, depending on the case) 1-2 Alkyl). In some embodiments, R x The methyl group is substituted as appropriate (e.g., methyl group substituted with one or more fluorinated groups, such as -CHF). 2). In some embodiments, R x For -CN. In some embodiments of any of formulas I, IA, IB, ID, IE, II, II-A, II-B, II-D, II-E, and II-F, R y C is hydrogen, halogen, or, where appropriate, substituted. 1-6 Aliphatic group. In some embodiments, R y It is hydrogen. In some embodiments, R is... y It is a halogen. In some embodiments, R y It is fluorine-based. In some embodiments, R y It is a chlorine group. In some embodiments, R y For -OR 2 In some embodiments, R y For -OR 2 , where R 2 C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, W is N and Y is CR. y And R y For -OR 2 , where R 2 C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, R y -N(R) 2 ) 2. In some embodiments, R y For -SR 2 In some embodiments, R y For -SR 2 , where R 2 C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, W is N and Y is CR. y And R y For -SR 2 , where R 2 C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, R y C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, R y For the straight or branched chain C, which may be replaced as appropriate. 1-6 Aliphatic groups (i.e., noncyclic C groups that are substituted, depending on the case) 1-6Aliphatic groups). In some embodiments, R y C, to be replaced as appropriate 1-6 Alkyl group. In some embodiments, R y C, to be replaced as appropriate 1-4 Alkyl group. In some embodiments, R y C, to be replaced as appropriate 1-2 Alkyl group. In some embodiments, R y The methyl group is substituted as appropriate (e.g., a methyl group substituted with one or more fluorinated groups as appropriate). In some embodiments, R y For -CN. 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 It is hydrogen. In some embodiments, R is... z C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, R z For the straight or branched chain C, which may be replaced as appropriate. 1-6 Aliphatic groups (i.e., noncyclic C groups that are substituted, depending on the case) 1-6 Aliphatic groups). In some embodiments, R z C, to be replaced as appropriate 1-6 Alkyl group. In some embodiments, R z C, to be replaced as appropriate 1-4 Alkyl group. In some embodiments, R z For unreplaced C 1-4 Alkyl group. In some embodiments, R z C, to be replaced as appropriate 1-2 Alkyl group. In some embodiments, R z For unreplaced C 1-2 alkyl. 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 -N(R)C(O)N(R) 2 or -N(R)C(O)OR. In some embodiments, R 1 -N(R) 2. -N(R)C(O)R' or -C(O)N(R) 2. In some embodiments, R 1 For -N(R)C(O)R' or -C(O)N(R) 2. In some embodiments, R 1 For -N(R)C(O)R', -C(O)N(R) 2. -N(R)C(O)N(R) 2 or -N(R)C(O)OR. In some embodiments, when R 1 -N(R) 2. -N(R)C(O)R' or -C(O)N(R) When n is 2, then n is 1, 2, or 3. In some embodiments, when n is 0, then R 1 -N(R)C(O)N(R) 2 or -N(R)C(O)OR. In some embodiments, R 1 -N(R) 2. In some embodiments, R 1 For -N(H)(R). In some embodiments, R 1 -NH 2. In some embodiments, when R 1 -N(R) When n = 2, then n can be 1, 2, or 3. In some embodiments, R 1 For -N(R)C(O)R'. In some embodiments, R 1 It is -N(H)C(O)R'. In some embodiments, R 1 -N(R)C(O) (C may be replaced as appropriate) 1-6 Aliphatic groups). In some embodiments, R 1 -N(H)C(O) (C may be replaced as appropriate) 1-6 Aliphatic groups). In some embodiments, R 1 -N(R)C(O)(C 1-6 Aliphatic groups). In some embodiments, R 1 -N(H)C(O)(C 1-6 Aliphatic groups). In some embodiments, R 1 -N(R)C(O) (straight-chain or branched C) 1-6 Aliphatic groups). In some embodiments, R 1 -N(H)C(O) (straight-chain or branched C) 1-6 Aliphatic groups). In some embodiments, R 1 -N(R)C(O) (C may be replaced as appropriate) 1-6 Alkyl). In some embodiments, R 1 -N(H)C(O) (C may be replaced as appropriate) 1-6 Alkyl). In some embodiments, R 1 It is -N(R)C(O)R', where R 1 R' is C replaced by the following, depending on the situation. 1-6 Alkyl groups: halogens, -OH, -O(C) 1-6 alkyl), -NH(CH 2) 2O(C 1-6 alkyl), -NH(C) 1-4 Halogenated alkyl groups or, where appropriate, substituted 3- to 7-membered saturated monocyclic heterocyclic groups having 1-2 independently selected heteroatoms from nitrogen, oxygen, and sulfur. In some embodiments, R 1 It is -N(H)C(O)R', where R 1 R' is C replaced by the following, depending on the situation. 1-6 Alkyl groups: halogens, -OH, -O(C) 1-6 alkyl), -NH(CH 2) 2O(C 1-6 alkyl), -NH(C) 1-4 Halogenated alkyl groups or, where appropriate, substituted 3- to 7-membered saturated monocyclic heterocyclic groups having 1-2 independently selected heteroatoms from nitrogen, oxygen, and sulfur. In some embodiments, R 1 -N(R)C(O)(C 1-6 Alkyl). In some embodiments, R 1 -N(H)C(O)(C 1-6 Alkyl). In some embodiments, R 1 -N(R)C(O) (C may be replaced as appropriate) 1-4 Alkyl). In some embodiments, R 1 -N(H)C(O) (C may be replaced as appropriate) 1-4 Alkyl). In some embodiments, R 1 It is -N(R)C(O)R', where R 1 R' is C replaced by the following, depending on the situation. 1-4 Alkyl groups: halogens, -OH, -O(C) 1-6 alkyl), -NH(CH 2) 2O(C 1-6 alkyl), -NH(C) 1-4 Halogenated alkyl groups or, where appropriate, substituted 3- to 7-membered saturated monocyclic heterocyclic groups having 1-2 independently selected heteroatoms from nitrogen, oxygen, and sulfur. In some embodiments, R 1 It is -N(H)C(O)R', where R 1 R' is C replaced by the following, depending on the situation. 1-4 Alkyl groups: halogens, -OH, -O(C) 1-6 alkyl), -NH(CH 2) 2O(C 1-6 alkyl), -NH(C) 1-4 Halogenated alkyl groups or, where appropriate, substituted 3- to 7-membered saturated monocyclic heterocyclic groups having 1-2 independently selected heteroatoms from nitrogen, oxygen, and sulfur. In some embodiments, R 1 -N(R)C(O)(C 1-4 Alkyl). In some embodiments, R 1 -N(H)C(O)(C 1-4 Alkyl). In some embodiments, R 1 -N(R)C(O)(C 1-2 Alkyl). In some embodiments, R 1 -N(H)C(O)(C 1-2 Alkyl). In some embodiments, R 1 -N(R)C(O)CH 3. In some embodiments, R 1 -N(H)C(O)CH 3. In some embodiments, R 1 -N(R)C(O) (C may be replaced as appropriate) 3-7 cycloalkyl). In some embodiments, R 1 -N(H)C(O) (C may be replaced as appropriate) 3-7 cycloalkyl). In some embodiments, R 1 -N(R)C(O) (with substituted cyclopropyl groups, depending on the case). In some embodiments, R 1 -N(H)C(O) (substituted cyclopropyl group, depending on the case). In some embodiments, when R 1 When n is -N(R)C(O)R', then n is 1, 2 or 3. In some embodiments, R 1 -C(O)N(R) 2. In some embodiments, R 1 -C(O)N(R)(C 1-6 Aliphatic groups). In some embodiments, R 1 -C(O)N(H)(C 1-6 Aliphatic groups). In some embodiments, R 1 -C(O)N(R) (straight or branched C) 1-6 Aliphatic groups). In some embodiments, R 1 -C(O)N(H) (straight-chain or branched C) 1-6 Aliphatic groups). In some embodiments, R 1 -C(O)N(R)(C 1-6 Alkyl). In some embodiments, R 1 -C(O)N(H)(C 1-6 Alkyl). In some embodiments, R 1 -C(O)N(R)(C 1-4 Alkyl). In some embodiments, R 1 -C(O)N(H)(C 1-4 Alkyl). In some embodiments, R 1 -C(O)N(R)(C 1-2 Alkyl). In some embodiments, R 1 -C(O)N(H)(C 1-2 Alkyl). In some embodiments, R 1 -C(O)N(R)CH 3. In some embodiments, R 1 For -C(O)N(H)(R). In some embodiments, when R 1 -C(O)N(R) When n = 2, then n can be 1, 2, or 3. In some embodiments, R 1 -N(R)C(O)N(R) 2. In some embodiments, R 1 -N(H)C(O)N(R) 2. In some embodiments, R 1 -N(H)C(O)N (C may be substituted as appropriate) 1-6 aliphatic group) 2. In some embodiments, R 1 -N(H)C(O)N (C may be substituted as appropriate) 1-6 alkyl) 2. In some embodiments, R 1 -N(H)C(O)N (C may be substituted as appropriate) 1-4 alkyl) 2. In some embodiments, R 1 -N(H)C(O)N (C may be substituted as appropriate) 1-2 alkyl) 2. In some embodiments, R 1 It is -N(R)C(O)NH(R). In some embodiments, R 1 It is -N(H)C(O)NH(R). In some embodiments, R 1 -N(H)C(O)NH (C may be substituted as appropriate) 1-6 Aliphatic groups). In some embodiments, R 1 -N(H)C(O)NH (C may be substituted as appropriate) 1-6 Alkyl). In some embodiments, R 1 -N(H)C(O)NH (C may be substituted as appropriate) 1-4 Alkyl). In some embodiments, R 1 -N(H)C(O)NH (C may be substituted as appropriate) 1-2 Alkyl). In some embodiments, R 1 -N(H)C(O)NH (C may be substituted as appropriate) 3-7 Cyclic aliphatic groups). In some embodiments, R 1 -N(H)C(O)NH (C may be substituted as appropriate) 3-7 cycloalkyl). In some embodiments, R 1 -N(H)C(O)NH (substituted cyclopropyl group, depending on the case). In some embodiments, R 1 It is -N(H)C(O)NH (substituted, depending on the situation, a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 It is -N(H)C(O)NH (substituted, depending on the situation, a 4- to 6-membered saturated monocyclic heterocyclic group having 1-2 independently selected heteroatoms of nitrogen, oxygen, and sulfur). In some embodiments, R 1 -N(H)C(O)NH (substituted oxobutane, depending on the case). In some embodiments, R 1 -N(R)C(O)N(R) 2, wherein two R groups attached to the same nitrogen atom together form, as appropriate, a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 -N(H)C(O)N(R) 2, wherein two R groups attached to the same nitrogen atom together form, as appropriate, a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 -N(H)C(O)N(R) 2, wherein two R groups attached to the same nitrogen atom are combined to form, depending on the case, one or more halogens, C 1-6 Alkyl groups, -OH groups, and -O(C) 1-6 Alkyl) substituted with a 3 to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 0 to 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 -N(H)C(O)N(R) 2, wherein two R groups attached to the same nitrogen atom together form, as appropriate, a 4- to 6-membered saturated monocyclic heterocyclic group having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 -N(H)C(O)N(R) 2, wherein two R groups attached to the same nitrogen atom are combined to form, depending on the case, one or more halogens, C 1-6 Alkyl groups, -OH groups, and -O(C) 1-6 Alkyl)-substituted with a 4- to 6-membered saturated monocyclic heterocyclic group having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 The series is selected from: , , , , , , , , , , , and In some embodiments, R 1 Not for In some embodiments, when X is CH, then R 1Not for . In some embodiments, R 1 It is -N(R)C(O)OR. In some embodiments, R 1 It is -N(H)C(O)OR. In some embodiments, R 1 It is -N(H)C(O)OR, where R 1 R is C that has been replaced, depending on the circumstances. 1-6 An aliphatic group or, where appropriate, a substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 independently selected heteroatoms from nitrogen, oxygen, and sulfur. In some embodiments, R 1 It is -N(H)C(O)OR, where R 1 R is C that has been replaced, depending on the circumstances. 1-6 Alkyl groups or, where appropriate, substituted groups comprising 4 to 6 saturated monocyclic heterocyclic groups having 1 to 2 independent heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 It is -N(H)C(O)OR, where R 1 R is determined by one or more -OH, -O(C) groups, depending on the situation. 1-6 alkyl), -N(C) 1-6 alkyl) 2 or C having 1-2 independently selected heteroatoms of nitrogen, oxygen, and sulfur, with 4 to 6 saturated monocyclic heterocyclic groups substituted. 1-6 Alkyl group. In some embodiments, R 1 It is -N(H)C(O)OR, where R 1 R is determined by one or more Cs, depending on the situation. 1-6 The alkyl-substituted group has 1-2 independently selected heteroatoms of nitrogen, oxygen, and sulfur, and consists of a 4- to 6-membered saturated monocyclic heterocyclic group. In some embodiments, R 1 The series is selected from: , , , , , , and . 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 For the straight or branched chain C, which may be replaced as appropriate. 1-6 Aliphatic groups (i.e., noncyclic C groups that are substituted, depending on the case) 1-6 Aliphatic groups). In some embodiments, R 2 C, to be replaced as appropriate 1-6 Alkyl group. In some embodiments, R 2 C, to be replaced as appropriate 1-4 Alkyl group. In some embodiments, R 2 For unreplaced C 1-4 Alkyl group. In some embodiments, R 2 C, to be replaced as appropriate 1-2 Alkyl group. In some embodiments, R 2 For unreplaced C 1-2 Alkyl group. In some embodiments, R 2 It is a methyl group. 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 Independent of hydrogen or, depending on the case, substituted C 1-4 Aliphatic groups. In some embodiments, each R 3 Independent of hydrogen or, depending on the case, substituted C 1-2 Aliphatic groups. In some embodiments, each R 3 It is hydrogen. In some embodiments, each R... 3 Independently, as appropriate, C is replaced 1-6 Aliphatic groups. In some embodiments, each R 3 Independently, as appropriate, the straight or branched C chain is substituted. 1-6 Aliphatic groups (i.e., noncyclic C groups that are substituted, depending on the case) 1-6 (Aliphatic group). In some embodiments, each R 3 Independently, as appropriate, C is replaced 1-4 Aliphatic groups. In some embodiments, each R 3 Independently, as appropriate, the straight or branched C chain is substituted. 1-4 Aliphatic groups (i.e., noncyclic C groups that are substituted, depending on the case) 1-4 (Aliphatic group). In some embodiments, each R 3 Independently, as appropriate, C is replaced 1-2 Aliphatic groups. In some embodiments, each R 3 Independently hydrogen or C 1-6 Alkyl groups. In some embodiments, each R... 3 Independently hydrogen or C 1-4 Alkyl groups. In some embodiments, each R... 3 Independently hydrogen or C 1-2 alkyl. In some embodiments of Formula III, R 4 It is a halogen. In some embodiments, R 4 It is fluorine-based. In some embodiments, R 4 It is a chlorine group. In some embodiments, R 4 For -OR. In some embodiments, R 4 -OH or -O (depending on the case, the C is substituted) 1-6 Alkyl). In some embodiments, R 4 -OH or -O(C) 1-6 Alkyl). In some embodiments, R 4 -OH or -OCH 3. In some embodiments, R 4 -N(R) 2. In some embodiments, R 4 For -NH(R). In some embodiments, R 4 -NH (C may be replaced as appropriate) 1-6 Alkyl). In some embodiments, R 4 It is -NH(R), where R 4 R is, depending on the situation, derived from one or more halogens or -O(C) 1-6 Alkyl) substituted C 1-6 Alkyl group. In some embodiments, R 4 -NH(CH) 2) 2F or -NH(CH) 2) 2OCH 3. In some embodiments, R 4 The substituted group is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independently selected heteroatoms from nitrogen, oxygen, and sulfur, depending on the specific embodiment. In some embodiments, R 4 The substituted group is a 4- to 6-membered saturated monocyclic heterocyclic group having 1-3 independently selected heteroatoms from nitrogen, oxygen, and sulfur, depending on the specific embodiment. In some embodiments, R 4 Depending on the circumstances, via one or more Cs 1-6 The alkyl-substituted group comprises 1 to 3 4- to 6-membered saturated monocyclic heterocyclic groups independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 Depending on the circumstances, via one or more Cs 1-6 Alkyl-substituted tetrahydropiperanyl or morpholinoyl. 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 Independently selected from halogens, -CN, -CO 2R、-C(O)N(R) 2. -NO 2. -N(R) 2. -OR, -SR, or C as appropriate 1-6 Alkyl, wherein R c Each R is independently hydrogen or C 1-6 Alkyl group. In some embodiments, R c It is a halogen (e.g., fluorine). In some embodiments, R c -CN, -CO 2R、-C(O)N(R) 2 or -NO 2. In some embodiments, R c -N(R) 2. -OR or -SR. In some embodiments, R c C, to be replaced as appropriate 1-6 Aliphatic groups (e.g., C) 1-6 alkyl). 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. In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, and III, ring A is, as appropriate, a 5- to 6-member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-member bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-member saturated or partially unsaturated monocyclic carbocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 10-member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is, as appropriate, a 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 member bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is, as appropriate, a 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 8-10 member bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted phenyl group, as appropriate. In some embodiments, ring A is not a substituted phenyl group, as appropriate. In some embodiments, ring A is a substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted 5- to 6-membered monocyclic heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted 5-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted pyrazolyl group. In some embodiments, ring A is a substituted 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted pyridone group. In some embodiments, ring A is, as appropriate, an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is, as appropriate, an 8-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is, as appropriate, a 9-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is, as appropriate, a tetrahydropyrazolo[1,5-a]pyridyl or dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl. In some embodiments, ring A is, as appropriate, a 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a substituted 3- to 7-member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring A is a substituted 3-member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring A is a substituted 4-member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring A is a substituted 5-member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring A is a substituted 6-member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring A is not a substituted 6-member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring A is a substituted 7-member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring A is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, ring A is a 3-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, ring A is a 4-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, ring A is a 5-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, ring A is a 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, ring A is a 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, ring A is, as appropriate, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is, as appropriate, a 7-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is, as appropriate, an 8-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is, as appropriate, a 9-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is, as appropriate, a 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is , or . In some embodiments of any of formulas II, II-A, II-B, II-C, II-D, II-E, and II-F, ring A is, as appropriate, a bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur of 8 to 10 members; a polycyclic heteroaryl group having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur of 10 to 16 members; a bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur of 7 to 10 members; or a polycyclic heterocyclic group having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur of 10 to 16 members. In some embodiments, ring A is, as appropriate, a bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur of 8 to 10 members; or a polycyclic heteroaryl group having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur of 10 to 16 members. In some embodiments, ring A is, as appropriate, a 7- to 10-membered bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, as appropriate, a 10- to 16-membered polycyclic heterocyclic group having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each ring in the bicyclic or polycyclic ring system of ring A contains at least one heteroatom. In some embodiments, one and only one ring in the bicyclic or polycyclic ring system of ring A does not contain a heteroatom. In some embodiments, each ring in the bicyclic or multicyclic ring system of ring A is an aromatic ring. In some embodiments, one and only one ring in the bicyclic or multicyclic ring system of ring A is an aromatic ring. In some embodiments, no ring in the bicyclic or multicyclic ring system of ring A is an aromatic ring. In some embodiments, ring A is a substituted 9- to 16-membered bicyclic or tricyclic aryl group. In some embodiments, ring A is a substituted 9- to 10-membered bicyclic aryl group. In some embodiments, ring A is a substituted 9-membered bicyclic aryl group (e.g., a 5-membered carbon ring fused to a benzene ring). In some embodiments, ring A is not a substituted indane (e.g., an indane substituted with one or more halogens). In some embodiments, ring A is a substituted 10-membered bicyclic aryl group (e.g., a naphthyl or a 6-membered carbon ring fused to a benzene ring). In some embodiments, ring A is, as appropriate, an 8- to 10-membered bicyclic heteroaryl group having 1 to 4 independently selected heteroatoms from nitrogen, oxygen, and sulfur. In some embodiments, ring A is, as appropriate, substituted with one or more side oxygen groups, halogens, or C... 1-6 The alkyl-substituted ring is an 8- to 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 8-membered bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, ring A is a dihydro-1H-imidazo[1,2-b]pyrazolyl group, depending on the substitution; in some embodiments, ring A is a 9-membered bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, ring A is substituted with one or more side oxygen groups, halogens, or C, depending on the substitution. 1-6 The alkyl-substituted ring is a 9-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is, as appropriate, a substituted tetrahydropyrazolo[1,5-a]pyridyl, dihydropyrazolo[1,5-a]pyrazin-4(5H)-keto, tetrahydropyrazolo[1,5-a]pyrimidinyl, or dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl. In some embodiments, ring A is, as appropriate, a 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is, as appropriate, substituted with one or more C... 1-6 The alkyl-substituted group is a 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is, as appropriate, a substituted tetrahydro-4H-pyrazolo[1,5-a][1,4]diazapunyl, tetrahydro-4H-pyrazolo[1,5-d][1,4]diazapunyl, tetrahydropyrazolo[1,5-d][1,4]oxonyl or tetrahydro-4H-pyrazolo[1,5-a]azapunyl. In some embodiments, ring A is a 10- to 16-membered polycyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be substituted as appropriate. In some embodiments, ring A is an 11-membered polycyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be substituted as appropriate. In some embodiments, ring A is a 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], which may be substituted as appropriate. In some embodiments, ring A is a 7- to 10-membered bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, ring A is a 7- to 10-membered fused bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, ring A is a 7-membered bicyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, ring A is an 8-membered bicyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, ring A is a 9-membered bicyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, ring A is a 10-membered bicyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, ring A is, as appropriate, a 10 to 16-membered polycyclic heterocyclic group having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is selected from: , , , , , , , , , , , , , , , and . In some embodiments, ring A is In the case of individual and combined rings, rings A1 and A2 are as defined in formulas II-E and described herein by categories and subclasses; and rings A1 and A2 are fused together; and ring A2 is further fused with ring A3 as appropriate (i) or (ii) rings A2 and A3 are combined to form a spiral ring. In some embodiments, ring A1 is a ring selected from the following, which may be substituted: a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is a substituted phenyl group, as appropriate. In some embodiments, when ring A1 is phenyl, ring A2 contains at least one heteroatom. In some embodiments, ring A1 is a substituted 5- to 6-membered monocyclic heteroaryl group 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 group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is a substituted 5-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is a substituted pyrazole. In some embodiments, ring A1 is a substituted 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is a substituted 5- to 7-member saturated or partially unsaturated monocyclic carbocyclic group, as appropriate. In some embodiments, when ring A1 is a substituted 5- to 7-member saturated or partially unsaturated monocyclic carbocyclic group, ring A2 contains at least one heteroatom. In some embodiments, when ring A2 is not an aromatic ring, ring A1 is a substituted 5- to 7-member saturated monocyclic carbocyclic group, as appropriate. In some embodiments, ring A1 is a substituted 5- to 7-member partially saturated monocyclic carbocyclic group, as appropriate. In some embodiments, ring A1 is, as appropriate, a 5- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, when ring A2 is not an aromatic ring, ring A1 is, as appropriate, a 5- to 7-member saturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is, as appropriate, a 5- to 7-member partially saturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the ring A1 that is fused with ring A2 and subsequently replaced is... . In some embodiments, ring A2 is a ring selected from the following, which may be substituted: a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is a substituted phenyl group, as appropriate. In some embodiments, when ring A2 is a phenyl group, ring A1 contains at least one heteroatom. In some embodiments, ring A2 is a substituted 5- to 6-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is a substituted 5-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is a substituted 6-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is a substituted 5- to 7-member saturated or partially unsaturated monocyclic carbocyclic group, as appropriate. In some embodiments, when ring A2 is a substituted 5- to 7-member saturated or partially unsaturated monocyclic carbocyclic group, ring A1 contains at least one heteroatom. In some embodiments, when ring A1 is not an aromatic ring, ring A2 is a substituted 5- to 7-member saturated monocyclic carbocyclic group, as appropriate. In some embodiments, ring A2 is a substituted 5- to 7-member partially saturated monocyclic carbocyclic group, as appropriate. In some embodiments, ring A2 is, as appropriate, a substituted 5- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, when ring A1 (and ring A3 (if present)) is not an aromatic ring, ring A2 is, as appropriate, a substituted 5- to 7-member saturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is, as appropriate, a substituted 5- to 7-member partially saturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is, as appropriate, a substituted 5-member saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is, as appropriate, a substituted 5-member saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is, as appropriate, substituted with one or more C... 1-6 The alkyl-substituted group is a 5-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is a substituted pyrrolidine or imidazoidine. In some embodiments, ring A2 is a substituted 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is substituted with one or more side oxygen groups, halogens, and C. 1-6The alkyl-substituted group is a 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is, as appropriate, a substituted piperidine, hexahydropyrimidine, morpholine, or piperazine. In some embodiments, ring A2 is, as appropriate, a 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is, as appropriate, substituted with one or more C... 1-6 The alkyl-substituted group is a 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is azirheptanane, diazirheptanane, or oxazirheptanane. In some embodiments, the ring A2, which may be substituted and fused with ring A1, is selected from the group consisting of: , , , , , , , , , and . In some embodiments, ring A1 is, as appropriate, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring A2 is, as appropriate, a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is, as appropriate, a 5-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring A2 is, as appropriate, a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is, as appropriate, a 5-membered monocyclic heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring A2 is, as appropriate, a 5-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is, as appropriate, a substituted 5-membered monocyclic heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring A2 is, as appropriate, a substituted 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A1 is, as appropriate, a substituted 5-membered monocyclic heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring A2 is, as appropriate, a substituted 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A2 is further fused with ring A3. In some embodiments, ring A2 and ring A3 combine to form a spirocycle. In some embodiments, when ring A2 and ring A3 combine to form a spirocycle, ring A3 is, as appropriate, a substituted 3 to 7-member saturated or partially unsaturated monocyclic carbocyclic group or, as appropriate, a substituted 3 to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A3, when present, is a substituted phenyl group. In some embodiments, ring A3, when present, is a substituted 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A3, when present, is a substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring A3 is a 3- to 7-membered saturated monocyclic carbocyclic group when not fused with aromatic ring A2. In some embodiments, ring A3 is a 3- to 7-membered partially saturated monocyclic carbocyclic group. In some embodiments, ring A3 is a substituted C group. 3-C 7. Cycloalkyl (e.g., cyclopropyl or cyclobutyl). In some embodiments, ring A3 is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A3 is a 3- to 7-membered saturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur when not fused with aromatic ring A2. In some embodiments, ring A3 is a 3- to 7-membered partially saturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the ring A2, which is optionally replaced and fused with ring A1 and forms a helical ring with ring A3, is selected from: , , and . 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 is optionally substituted on the substituted carbon atom by one or more independent groups selected from: oxy group, halogen, R°, -CN, -OR°, -O(CH 2) 1-4 R°, -SR°, -N(R°) 2. -NO 2. -C(O)R°, -C(O)OR°, -C(O)NR° 2. -OC(O)R°, -OC(O)NR° 2. -OC(O)OR°, -OS(O) 2R°、-OS(O) 2NR° 2. -N(R°)C(O)R°, -N(R°)S(O) 2R°、-S(O) 2R°、-SO 2NR° 2 and -S(O) 2OR°, and (ii) substitution on the substituted nitrogen atom by one or more groups selected from: -R † -NR † 2. -C(O)R † -C(O)OR † -S(O) 2R † and -S(O) 2NR † 2. In some embodiments, ring A (i) is optionally substituted on a substituted carbon atom by one or more independent groups selected from: oxy group, halogen, R°, -OR° and -O(CH). 2) 1-4 R°, and (ii) substitution on the substituted nitrogen atom by one or more groups selected from: -R † In some embodiments, ring A (i) is substituted on the substituted carbon atom by one or more groups independently selected from: oxy group, halogen, and R°, and (ii) is substituted on the substituted nitrogen atom by one or more groups selected from: -R † . In some embodiments, ring A may be routed via one or more R... b (For example, except for -LR) a (When present) Substitution outside) Substitution, where R bAs defined in the above formula ID and described herein by categories and subclasses. In some embodiments, as permitted by the valence, ring A passes through zero, one, two, three, four, or five Rs. b replace. 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 bond. 1-3 Straight-chain or branched hydrocarbon chain. In some embodiments, L is divalent carbon. 1-2 Straight-chain or branched hydrocarbon chain. In some embodiments, L is methylene (i.e., -CH). 2-). In some embodiments, L is -CH 2CH 2-. In some embodiments, L is -CH 2CH 2CH 2-. In some embodiments, L is -C(CH) 3) 2-. In some embodiments, L is a covalent bond or -CH 2-. In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, III, and IV, R a Halogen, or C substituted as appropriate 1-6 Aliphatic group, substituted phenyl group, substituted 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted 3-7 member saturated or partially unsaturated monocyclic carbocyclic group, substituted 3-7 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or substituted 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a C, to be replaced as appropriate 1-6 Aliphatic group, or, depending on the substitution, a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 independently selected heteroatoms from nitrogen, oxygen, and sulfur, or, depending on the substitution, a 7- to 10-member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 independently selected heteroatoms from nitrogen, oxygen, and sulfur. In some embodiments, R aHydrogen, halogen, or C substituted as appropriate 1-6 Aliphatic group, or, depending on the case, a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, depending on the case, a 7- to 10-member saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is hydrogen. In some embodiments, R is... a It is not hydrogen. In some embodiments, R a It is a halogen. In some embodiments, R a It can be fluorinated, chlorolated, bromine, or iodinated. In some embodiments, R a It is fluorine-based. In some embodiments, R a It is a chlorine group. In some embodiments, R a C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, R a For the straight or branched chain C, which may be replaced as appropriate. 1-6 Aliphatic groups (i.e., noncyclic C groups that are substituted, depending on the case) 1-6 Aliphatic groups). In some embodiments, R a Depending on the situation, via one or more halogens, -N(C 1-6 alkyl) 2. C-substituted with -OH or -O (depending on the case, by a 3 to 7 member saturated or partially unsaturated monocyclic heterocyclic group) 1-6 Aliphatic group. In some embodiments, R a C, to be replaced as appropriate 1-6 Alkyl group. In some embodiments, R a Depending on the situation, via one or more halogens, -N(C 1-6 alkyl) 2. C-substituted with -OH or -O (depending on the case, by a 3 to 7 member saturated or partially unsaturated monocyclic heterocyclic group) 1-6 Alkyl group. In some embodiments, R a C, to be replaced as appropriate 1-4 Alkyl group. In some embodiments, R a Depending on the situation, via one or more halogens, -N(C 1-6 alkyl) 2. C-substituted with -OH or -O (depending on the case, by a 3 to 7 member saturated or partially unsaturated monocyclic heterocyclic group) 1-4 Alkyl group. In some embodiments, R a -CH 3. -CD 3. -CF 3. -CH 2N(CH 3) 2. -CH 2CH 2OH or . In some embodiments, R a The phenyl group is substituted as appropriate. In some embodiments, R a The substituted 5- to 6-membered monocyclic heteroaryl group having 1 to 4 independently selected heteroatoms from nitrogen, oxygen, and sulfur, depending on the specific embodiment. In some embodiments, R a The substituted 5- to 6-membered monocyclic heteroaryl group having 1-2 independently selected heteroatoms from nitrogen, oxygen, and sulfur, depending on the specific embodiment. In some embodiments, R a It is, as appropriate, a substituted 5-membered monocyclic heteroaryl group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 6-membered monocyclic heteroaryl group, which may be substituted as appropriate, having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a The substituted 3 to 7 saturated or partially unsaturated monocyclic carbocyclic groups, depending on the situation. In some embodiments, R a The substituted 3 to 6-member saturated monocyclic carbocyclic group is used, depending on the situation. In some embodiments, R a The substituted 3-member saturated monocyclic carbocyclic group is used as appropriate. In some embodiments, R a The substituted 4-member saturated monocyclic carbocyclic group is used as appropriate. In some embodiments, R a The substituted 5-member saturated monocyclic carbocyclic group is used as appropriate. In some embodiments, R a The substituted 6-member saturated monocyclic carbocyclic group is used as appropriate. In some embodiments, R a It is a 7-member saturated monocyclic carbon cyclo group that is substituted as appropriate. In some embodiments, R a The substituted group is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independently selected heteroatoms from nitrogen, oxygen, and sulfur, depending on the specific embodiment. In some embodiments, R a The substituted 4- to 7-membered saturated monocyclic heterocyclic group having 1-2 independently selected heteroatoms from nitrogen, oxygen, and sulfur, depending on the specific embodiment. In some embodiments, R a This is, as appropriate, a substituted 3-membered saturated monocyclic heterocyclic group having one independently selected heteroatom from nitrogen, oxygen, and sulfur. In some embodiments, R a This is, depending on the situation, a substituted 4-membered saturated monocyclic heterocyclic group having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, R a This is, depending on the situation, a 5-membered saturated monocyclic heterocyclic group having 1-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, R a This may be a substituted pyrrolidyl or tetrahydrofuranyl group, depending on the specific embodiment. In some embodiments, R a This is, depending on the situation, a 6-membered saturated monocyclic heterocyclic group having 1-3 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 7-membered saturated monocyclic heterocyclic group, which may be substituted as appropriate, having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R aThe substituted group is a 7- to 10-member saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 independently selected heteroatoms from nitrogen, oxygen, and sulfur, depending on the specific embodiment. In some embodiments, R a The substituted group is, as appropriate, a 7- to 10-member saturated, spirocyclic, or bicyclic heterocyclic group having 1 to 4 independently selected heteroatoms from nitrogen, oxygen, and sulfur. In some embodiments, R a The substituted group is, as appropriate, a 7- to 9-membered saturated, spirocyclic, or bicyclic heterocyclic group having 1-2 independently selected heteroatoms from nitrogen, oxygen, and sulfur. In some embodiments, R a The substituted group is, as appropriate, a 7-membered saturated, spirocyclic, or bicyclic heterocyclic group having 1-4 independently selected heteroatoms from nitrogen, oxygen, and sulfur. In some embodiments, R a 2-oxaspiro[3.3]heptyl group, substituted as appropriate. In some embodiments, R a The substituted group is, as appropriate, an 8-membered saturated, spirocyclic, or bicyclic heterocyclic group having 1-4 independently selected heteroatoms from nitrogen, oxygen, and sulfur. In some embodiments, R a The substituted group is, as appropriate, a 9-membered saturated, spirocyclic, or bicyclic heterocyclic group having 1-4 independently selected heteroatoms from nitrogen, oxygen, and sulfur. In some embodiments, R a The 7-oxaspiro[3.5]nonyl group is substituted, as appropriate. In some embodiments, R a It is a 10-membered saturated, spirocyclic, or bicyclic heterocyclic group, which may be substituted, depending on the situation, having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments of any of formulas I, IA, IB, IC, ID, IE, III, and IV, -R a (That is, L is a covalent bond). In some embodiments, For -(C 1-3 (alkyl)-R a (That is, L is C) 1-3 (Straight-chain or branched hydrocarbon chain). In some embodiments, For -(C 1-2 (alkyl)-R a (That is, L is C) 1-2 (Straight-chain or branched hydrocarbon chain). In some embodiments, -CH 2-R a (That is, L is C) 1 hydrocarbon chain). In some embodiments, -CH 2CH 2-R a (That is, L is C) 2. Straight-chain hydrocarbon chain). In some embodiments, -CH 2CH 2CH 2-R a (That is, L is C) 3. Straight-chain hydrocarbon chain). In some embodiments, -C(CH) 3) 2-R a (That is, L is C) (3-branched hydrocarbon chain). In some embodiments of any of Equations I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV, R may occur up to five times, as permitted by the valence rules. b And each is independently a halogen, -CN, -OR, -O(CH) 2) m R, -SR, -N(R) 2. -NO 2. -C(O)R', -C(O)OR, -C(O)N(R) 2. -OC(O)R', -OC(O)N(R) 2. -OC(O)OR, -OSO 2R, -OSO 2N(R) 2. -N(R)C(O)R', -N(R)SO 2R'、-SO 2R'、-SO 2N(R) 2. -SO 3R', or C as appropriate (substituted for) 1-6 Aliphatic group, substituted 3 to 6 saturated or partially unsaturated carbocyclic group, substituted 3 to 6 saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted 5 to 6 saturated monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each occurrence of R b Independent of halogen, or C substituted as appropriate 1-6 Aliphatic group, -OR or -O (CH 2) m R. In some embodiments, R occurs each time. b Independent of halogen, or C substituted as appropriate 1-6 Alkyl, -OR or -OCH 2R, where R b R is, depending on the situation, a substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 independently selected heteroatoms from nitrogen, oxygen, and sulfur. In some embodiments, each occurrence of R... b C is a halogen or, depending on the case, a carbon substituted with one or more halogens. 1-6 alkyl. In some embodiments, there exists an R that occurs once. b In some embodiments, R appears twice. b Existence. In some embodiments, there exists an R that occurs three times. b In some embodiments, R appears four times. b Existence. In some embodiments, there exists an R that occurs five times. b In some embodiments, R b It does not exist. In some embodiments, R occurs 1-4 times. b In some embodiments, R appears once or twice. b . In some embodiments, R b It is hydrogen. In some embodiments, R b It is a halogen. In some embodiments, R b It can be fluorinated, chlorolated, bromine, or iodinated. In some embodiments, R b It is fluorine-based. In some embodiments, R b It is a chlorine group. In some embodiments, R b For -CN, -OR, -O(CH) 2) m R, -SR, -N(R) 2. -NO 2. -C(O)R', -C(O)OR, -C(O)N(R) 2. -OC(O)R', -OC(O)N(R) 2. -OC(O)OR, -OSO 2R, -OSO 2N(R) 2. -N(R)C(O)R', -N(R)SO 2R'、-SO 2R, -SO 2N(R) 2 or -SO 3R'. In some embodiments, R b -CN. In some embodiments, R b -N(R) 2. In some embodiments, R b -C(O)N(R) 2. In some embodiments, R b For -OR. In some embodiments, R b -OR, where R is a substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independently selected heteroatoms from nitrogen, oxygen, and sulfur, depending on the specific embodiment. In some embodiments, R b -OR, where R is a substituted 4- to 6-membered saturated monocyclic heterocyclic group having 1-2 independently selected heteroatoms from nitrogen, oxygen, and sulfur, depending on the specific embodiment. In some embodiments, R b -OR, where R is a heteroatom having 1-2 independent heteroatoms selected from nitrogen, oxygen, and sulfur, and depending on the case, via one or more C atoms. 1-6 Alkyl (e.g., methyl)-substituted 4- to 6-membered saturated monocyclic heterocyclic groups. In some embodiments, R b -OR, where R is, as appropriate, a substituted azacyclic butyl or pyrrolidyl group. In some embodiments, R b -OR, where R is the result of one or more Cs depending on the situation. 1-6 Alkyl (e.g., methyl)-substituted azahexacyclic butyl or pyrrolidyl group. In some embodiments, R b for or . In some embodiments, R b -O(CH) 2) m R. In some embodiments, R b -OCH 2R. In some embodiments, R b -O(CH) 2) m R, wherein R is, as appropriate, a substituted 3 to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b -O(CH) 2) m R, wherein R is, as appropriate, a 4- to 6-membered saturated monocyclic heterocyclic group having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, R b -O(CH) 2) m R, where R is a heteroatom having 1-2 independently selected from nitrogen, oxygen, and sulfur, and depending on the case, via one or more C atoms. 1-6 Alkyl (e.g., methyl)-substituted 4- to 6-membered saturated monocyclic heterocyclic groups. In some embodiments, R b -O(CH) 2) m R, where R is a substituted pyrrolidyl group, as appropriate. In some embodiments, R b -O(CH) 2) m R, where R is the number of Cs depending on the situation. 1-6 Alkyl (e.g., methyl)-substituted pyrrolidyl group. In some embodiments, R b for . In some embodiments, R b C, to be replaced as appropriate 1-6 Aliphatic group. In some embodiments, R b For the straight or branched chain C, depending on the situation. 1-6 Aliphatic groups (i.e., noncyclic C groups that are substituted, depending on the case) 1-6 Aliphatic groups). In some embodiments, R b C, to be replaced as appropriate 1-6 Alkyl group. In some embodiments, R b C, to be replaced as appropriate 1-4 Alkyl group. In some embodiments, R b C is a C that has been substituted with one or more halogens, depending on the situation. 1-4 Alkyl group. In some embodiments, R b -CH 3. -CF 3 or -C(CH) 3) 3. In some embodiments, R bThe substituted 3 to 6 saturated or partially unsaturated monocyclic carbocyclic groups, depending on the situation. In some embodiments, R b C, to be replaced as appropriate 3-C 6-Cycloalkyl. In some embodiments, R b The substituted group is a 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independently selected heteroatoms from nitrogen, oxygen, and sulfur, depending on the specific embodiment. In some embodiments, R b It is, as appropriate, a 3 to 6 member saturated monocyclic heterocyclic group having 1 to 2 independent heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, R b It is a 5- to 6-membered monocyclic heteroaryl group, which may be substituted, having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 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. In some embodiments of any of Formulas I, IA, IB, IC, ID, IE, and III, the following may be replaced as appropriate. for In some embodiments, it may be replaced as appropriate. To be replaced as appropriate , , or In some embodiments, for , , or In some embodiments, for , , or In some embodiments, The group is composed of the following components: , , , and . In some embodiments of Formula IV, The group is composed of the following components: , , , and In some embodiments, The group is composed of the following components: , , and In some embodiments, when for When -LR a C 1-6 Halogenated compounds. In some embodiments, for or In which ring A is further substituted at least once, and at least one substituent on ring A is C. 1-6 Halogenated groups (e.g., -CF) 3). In some embodiments, when for or Then, ring A passes through R as defined in this paper and described by categories and subclasses. b Further substitution, and at least one substituent on ring A (i.e., R) b or -LR a ) is C 1-6 Halogenated groups (e.g., -CF) 3). In some embodiments, The group is composed of the following components: , , , , , , , , , , , , , and . In some embodiments of any of formulas II, II-A, II-B, II-C, II-D, II-E, and II-F, the substitutions may be made as appropriate. for In some embodiments, it may be replaced as appropriate. for , , , , , , , , , , , or In some embodiments, it may be replaced as appropriate. The group is composed of the following components: , , , , , , , , , , , , , , , and . 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 hydrogen, and C is substituted as appropriate. 1-6 An aliphatic group or, depending on the substitution, a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1-2 independently selected heteroatoms from nitrogen, oxygen, and sulfur; or two Rs attached to the same nitrogen atom together to form, depending on the substitution, a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional independently selected heteroatoms from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently hydrogen or, depending on the substitution, a C. 1-6 Aliphatic group. In some embodiments, each R is independently hydrogen, and C is substituted as appropriate. 1-6The aliphatic group or, depending on the case, a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently a C, depending on the case, substituted. 1-6 An aliphatic group or, depending on the substitution, a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently hydrogen, and the C is, depending on the substitution, a hydrogen atom. 1-6 Alkyl or, where appropriate, substituted, 4 to 6-membered saturated monocyclic heterocyclic groups having 1 to 2 independent heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R is hydrogen. In some embodiments, R is, where appropriate, a replacement of C. 1-6 Aliphatic group. In some embodiments, R is a substituted straight or branched C, depending on the situation. 1-6 Aliphatic groups (i.e., noncyclic C groups that are substituted, depending on the case) 1-6 Aliphatic group). In some embodiments, R is a substituted C, as appropriate. 1-6 Alkyl group. In some embodiments, R is, as appropriate, alkyl with one or more -OH, -O(C) groups. 1-6 alkyl), -N(C) 1-6 alkyl) 2 or C having 1-2 independently selected nitrogen, oxygen, and sulfur heteroatoms, 4 to 6 saturated monocyclic heterocyclic groups substituted. 1-6 Alkyl group. In some embodiments, R is a substituted C group, as appropriate. 1-4 Alkyl group. In some embodiments, R is a substituted C group, as appropriate. 1-2 alkyl. In some embodiments, R is a substituted 3 to 7 saturated or partially unsaturated carbocyclic group, depending on the specific embodiment. In some embodiments, R is a substituted C 3-7 Cycloalkyl. In some embodiments, R is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, R is a 4- to 6-membered saturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, depending on the substitution. In some embodiments, R is a C-terminated monocyclic heterocyclic group having one or more C-terminated monocyclic heteroatoms, depending on the substitution. 1-6 The alkyl-substituted group is a 4- to 6-membered saturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is, where appropriate, a substituted oxobutyric group. In some embodiments, when two R groups are attached to the same nitrogen atom, they together form a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be substituted. In some embodiments, two R groups attached to the same nitrogen atom together form a 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and are optionally substituted with one or more halogens, C... 1-6 Alkyl, -OH or -O (C 1-6 Alkyl)-substituted 3 to 7 nucleotide saturated or partially unsaturated monocyclic heterocyclic groups. In some embodiments, two R groups attached to the same nitrogen atom together form, as appropriate, a substituted 4 to 6 nucleotide saturated monocyclic heterocyclic group having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups attached to the same nitrogen atom together form, as appropriate, a substituted 4 to 6 nucleotide monocyclic heterocyclic group having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-6 Alkyl groups, -OH groups, and -O(C) 1-6 Alkyl) substituted with a 4 to 6-member saturated monocyclic heterocyclic group having 0 to 1 additional heteroatoms independently selected from nitrogen, oxygen and sulfur. 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 a C that has been substituted as appropriate. 1-6 Alkyl or, where appropriate, substituted C 3-7 Cycloalkyl. In some embodiments, R' is a C that has been substituted, as appropriate. 1-6 Aliphatic group. In some embodiments, R' is a substituted straight or branched C group, depending on the specific embodiment. 1-6 Aliphatic groups (i.e., noncyclic C groups that are substituted, depending on the case) 1-6 Aliphatic group). In some embodiments, R' is a substituted C group, as appropriate. 1-6 Alkyl group. In some embodiments, R' is C substituted as appropriate. 1-6 Alkyl groups: halogens, -OH, -O(C) 1-6 alkyl), -NH(CH 2) 2O(C 1-6 alkyl), -NH(C) 1-4 (Halogenated) or, as appropriate, a 3- to 7-membered saturated monocyclic heterocyclic group having 1-2 independently selected heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R' is, as appropriate, a substituted C 1-4 Alkyl group. In some embodiments, R' is a C group that has been substituted, as appropriate. 1-2 Alkyl group. In some embodiments, R' is methyl. In some embodiments, R' is a substituted 3 to 7-member saturated or partially unsaturated carbocyclic group, depending on the embodiment. In some embodiments, R' is a substituted C... 3-7 Cycloalkyl. In some embodiments, R' is a substituted cyclopropyl group, as appropriate. In some embodiments, R' is cyclopropyl. In some embodiments of any of the formulas described herein, the compound is not: or . In some embodiments, the compound is not: In some embodiments, the compound is not: or . In some embodiments, the compound is not: In some embodiments of any of Equations I, IA, IB, IC, ID, and IE, when R 1 for And when Y is N, then R x Not hydrogen. In some embodiments, when R... 1 for When ring A is pyrazol, then ring A is not a pyrazol group. In some embodiments, when ring A is a pyrazol group, then R 1 Not -N(R)C(O)N(R) 2. In some embodiments, when ring A is a pyrazolyl group and Y is N, then R x It is not hydrogen. In some embodiments of any of formulas II, II-A, II-B, II-C, II-D, II-E, and II-F, ring A is not... In some embodiments, when ring A is When, then R 1 Not -N(H)C(O)CH 3. In some embodiments, when ring A is When X is not N and R is R, then X is not N and R is R. x Not -CN. In some embodiments of Formula III, R 4 Not tetrahydropiperanyl. In some embodiments, when R... 4 When Y is tetrahydropiperanyl and Y is N, then R x It is not chlorine-based. In some embodiments of Equation IV, when Y is N and R x If it is not hydrogen, then -LR a Not for -CH 3 or . In some embodiments, this disclosure provides compounds selected from Table 1: Or a medically acceptable salt. In some embodiments, this disclosure covers the understanding that the provided compound exhibits certain desired characteristics, for example, compared to other known compounds. For instance, in some embodiments, the provided compound is more effective in one or more biochemical or cellular analyses (e.g., the JAK2 binding assay, SET2-pSTAT5 cell assay, hPBMC-GMCSF-STAT5 assay, hPBMC-IL12-STAT4 assay, or hPBMC-IL2-STAT5 assay described herein), and / or has one or more other characteristics that make it more suitable for drug development compared to other known compounds, such as better selectivity and / or better ADME (absorption, distribution, metabolism, and excretion) properties than other kinases, including but not limited to better permeability, cytotoxicity, hepatocyte stability, solubility, and / or plasma protein binding profile (e.g., based on analyses described in subsequent examples). In some embodiments, the provided compound exhibits certain desired characteristics, for example, compared to other known compounds, in one or more of the analyses described herein. Without being bound by any particular theory, this disclosure covers the following understanding: 6-heteroaryloxybenzimidazoles and azirbezimidazoles (such as the compounds described herein) exhibit certain desirable characteristics (such as properties that are superior in one or more analyses described herein) compared to their corresponding 5-heteroaryloxybenzimidazoles and azirbezimidazoles. In some embodiments, the provided compounds are provided and / or utilized in salt form (e.g., a pharmaceutically acceptable salt form). Unless otherwise indicated, it should be understood that references to the compounds provided herein include references to their salts. Pharmaceutically acceptable salt forms are known in the art. For example, pharmaceutically acceptable salts are described in detail by SM Berge et al. in J. Pharmaceutical Sciences, 66:1-19 (1977). It should be understood that throughout this disclosure, unless otherwise indicated, references to compounds of formula I are intended to include compounds of formulas I, IA, IB, IC, ID, and IE, as well as compounds of such formulas disclosed herein; references to compounds of formula II are intended to include compounds of formulas II, II-A, II-B, II-C, II-D, II-E, and II-F, as well as compounds of such formulas disclosed herein; references to compounds of formula III are intended to include compounds of such formulas disclosed herein; and references to compounds of formula IV are intended to include compounds of such formulas disclosed herein. Preparation of the provided compound The provided compounds can generally be obtained by the processes described in the subsequent processes and examples. In some embodiments, the provided compounds are prepared according to the following process: Where PG is a suitable protecting group (e.g., p-methoxybenzyl, acetyl, methyl aminoformate, etc.), and whether alone or in combination, the rings A, n, L, W, X, Y, R, R 2 R a and R c As defined above for Formula I and described herein by categories and subcategories. Therefore, in some embodiments, intermediate A.3 is prepared by a process comprising contacting intermediate A.1 and 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, as appropriate, 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: reacting intermediate A.4 with R... 2N-H are contacted, depending on the situation, in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound A-2 is prepared by a process comprising: reacting intermediate A.3 with R... 2N-C(O)-Cl is contacted in the presence of a suitable base (e.g., triethylamine). In some embodiments, the provided compound is prepared according to the following process: Where PG is a suitable protecting group (e.g., p-methoxybenzyl, acetyl, methyl aminoformate, etc.), and whether alone or in combination, the rings A, n, W, X, Y, R, R 2 and R cAs defined above for Formula II and described herein by categories and subcategories. Therefore, 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, as appropriate, 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: reacting intermediate A.7 with R... 2N-H are contacted, depending on the situation, in the presence of a suitable base (e.g., triethylamine). In some embodiments, compound A-4 is prepared by a process comprising: reacting intermediate A.6 with R... 2N-C(O)-Cl is contacted in the presence of a suitable base (e.g., triethylamine). In some embodiments, the provided compound is prepared according to the following process: Where LG is a suitable leaving group (e.g., halogen, such as chloro or bromine), and alone or in combination, the rings A, n, L, W, X, Y, Z, R 1 R 2 R a and R c As defined above with respect to Formulas I and / or II and described herein by categories and subcategories. Therefore, in some embodiments, compound B-1 is prepared by a process comprising: reacting intermediate B.1 and intermediate B.2 in a suitable base (e.g., K). 3PO 4. K 2CO 3 or Cs 2CO 3) In the presence of, and as appropriate in, a suitable metal complex (e.g., a palladium complex, such as tris(dibenzylacetone)palladium(O)) and / or a suitable ligand (e.g., 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopiperan). In some embodiments, compound B-2 is prepared by a process comprising: reacting intermediate B.1 and intermediate B.3 in a suitable base (e.g., K). 3PO 4. K 2CO 3 or Cs 2CO 3) Contact in the presence of, and as appropriate, a suitable metal complex (e.g., a palladium complex, such as tris(dibenzylacetone)dipalladium(O)) and / or a suitable ligand (e.g., 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopiperanan). In some embodiments, the process for preparing compound B-1 or B-2 further includes a deprotection step under suitable conditions. In some embodiments, the process for preparing compound B-1 or B-2 further includes a functionalization step (e.g., cyanidation) under suitable conditions. In some embodiments, the provided compound is prepared according to the following process: In both individual and combined cases, the rings A, n, L, W, X, Y, R 1 R 2 R a and R c As defined above for Formula I and described herein by categories and subcategories. Therefore, in some embodiments, compound C-1 is prepared by a process comprising contacting intermediate C.1 and 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., cyanidation) step under suitable conditions. In some embodiments, the provided compound is prepared according to the following process: In both individual and combined cases, the rings A, n, W, X, Y, and R... 1 R 2 and R cAs defined above for Formula II and described herein by categories and subcategories. Therefore, 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 includes a deprotection and / or functionalization (e.g., cyanidation) step under suitable conditions. Composition This disclosure also provides compositions comprising the compounds provided herein and one or more other components. In some embodiments, the provided compositions comprise and / or deliver the compounds described herein (e.g., compounds of formulas I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV). In some embodiments, the provided composition is a pharmaceutical composition comprising and / or delivering compounds described herein (e.g., compounds of formulas I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, II-E, II-F, III, and IV) and further comprising a pharmaceutically acceptable carrier. Pharmaceutical compositions typically contain an amount of active agent (e.g., compounds described herein) that effectively achieves the desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, the provided pharmaceutical composition comprises compounds described herein and one or more fillers, disintegrants, lubricants, flow aids, anti-adhesives, and / or antistatic agents. The provided pharmaceutical compositions may be in various forms, including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppositories, nasal sprays and / or inhalers, eye drops, intraocular injection forms, reservoir forms, and injectable and infusionable solutions. Methods for preparing pharmaceutical compositions are well known in the art. In some embodiments, the provided compound is formulated into unit dosage forms to facilitate dosing and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically discrete unit of an active agent (such as the compound described herein) for administration to an individual. Typically, each such unit contains a predetermined amount of active agent. In some embodiments, a unit dosage form contains the entire single dose of the drug. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, it is necessary or anticipated to administer multiple unit dosage forms to achieve the desired effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing predetermined amounts of one or more active agents, a solid pharmaceutical composition (e.g., tablets, capsules, or the like) containing predetermined amounts of one or more active agents, a sustained-release formulation containing predetermined amounts of one or more active agents, or a drug delivery device containing predetermined amounts of one or more active agents, etc. The provided compositions may be administered in any amount and via any route of administration to effectively treat or reduce the severity of any of the diseases or conditions described herein. use This disclosure provides for the use of the compounds and compositions described herein. In some embodiments, the provided compounds and compositions may be used in pharmaceuticals (e.g., as a therapy). In some embodiments, the provided compounds and compositions may be used in research, such as as analytical tools and / or control compounds in bioanalysis. In some embodiments, this disclosure provides a method of administering a compound or composition to an individual in need. In some embodiments, this disclosure provides a method of administering a compound or composition to an individual who suffers from or is susceptible to a JAK2-related disease, condition, or disorder. In some embodiments, the provided compound can be used as a JAK2 inhibitor. In some embodiments, the provided compound can be used as a type II JAK2 inhibitor. In some embodiments, this disclosure provides a method for inhibiting JAK2 in an individual, comprising administering the provided compound or composition. In some embodiments, this disclosure provides a method for inhibiting JAK2 in a biological sample, comprising contacting the sample with the provided compound or composition. JAK (e.g., JAK2) is associated with a variety of diseases, conditions, and disorders, such as myeloproliferative neoplasm (Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev:82), atopic dermatitis (Rodrigues, MA and Torres, TJ Derm. Treat. 2019, 31(1), 33-40), and acute respiratory syndrome, excessive inflammation, and / or interstitial storm syndrome (The Lancet. doi:10.1016 / S0140-6736(20)30628-0). Therefore, in some embodiments, this disclosure provides a method of treating a JAK2-related disease, condition, or disorder in an individual in need, comprising administering the provided compound or composition to the individual. In some embodiments, the disease, condition, or disorder is associated with JAK2 overexpression. In some embodiments, this disclosure provides a method of treating cancer, comprising administering a provided compound or composition to an individual in need. In some embodiments, this disclosure provides a method of treating proliferative diseases, comprising administering a provided compound or composition to an individual in need. In some embodiments, this disclosure provides a method of treating a hematologic malignancy, comprising administering a provided compound or composition to an individual in need. In some embodiments, the hematologic malignancy is leukemia (e.g., chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia, or acute monocytic leukemia). In some embodiments, the hematologic malignancy is lymphoma (e.g., Burkitt's lymphoma, Hodgkin's lymphoma, or non-Hodgkin's lymphoma). In some embodiments, non-Hodgkin's lymphoma is B-cell lymphoma. In some embodiments, non-Hodgkin's lymphoma is NK / T-cell lymphoma (e.g., cutaneous T-cell lymphoma). In some embodiments, the hematologic malignancy is myeloma (e.g., multiple myeloma). In some embodiments, the hematologic malignancy is myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenic purpura, or myelofibrosis). In some embodiments, hematologic malignancies are myelodysplastic syndromes. In some embodiments, this disclosure provides a method of treating inflammatory diseases, conditions, or disorders (such as acute respiratory syndrome, excessive inflammation and / or cytokine storm syndrome (including COVID-19-related cytokine storm syndrome) or atopic dermatitis), which includes administering the provided compound or composition to an individual in need. In some embodiments, the provided compound or composition is administered as part of a combination therapy. As used herein, the term "combination therapy" refers to a situation where an individual is simultaneously exposed to two or more treatment or preventative regimens (e.g., two or more therapeutic agents or prophylactic agents). In some embodiments, two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., a first regimen of all "doses" is administered before any dose of a second regimen); in some embodiments, such agents are administered in an overlapping dosing regimen. In some embodiments, "administration" of a combination therapy may involve administering one or more agents or modalities to an individual receiving other agents or modalities in the combination. For clarity, combination therapy does not require individual agents to be administered together in a single composition (or even simultaneously), but in some embodiments, two or more agents or their active portions may be administered together in a combination composition. For example, in some embodiments, the provided compound or composition is administered to an individual who is receiving or has received one or more alternative therapies (e.g., anticancer therapy and / or therapies to address one or more side effects of such anticancer therapy or to otherwise provide palliative care). Exemplary alternative therapies include BCL2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mivebresib), proteasome inhibitors (e.g., bortezomib), LSD1 inhibitors (e.g., IMG-7289), and CXCR2 inhibitors. Useful combinations of 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 JAK2 inhibitors and LSD1 inhibitors has 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 regulate signaling pathways associated with tumor growth, angiogenesis, and / or metastasis, including the JAK-STAT3 pathway (Jaffer, T., Ma, D. Transl. Cancer Res. 2016, 5 (Supplement 4), S616-S628). Exemplary embodiments The following numbered examples illustrate certain aspects of this disclosure, and are not limiting: 1. A compound of formula I: I or its medically acceptable salt, wherein: W is CR w Or N; X is CR x Or N; Y is CR y Or N; Z is -O- or -NR z -; R w R x and R y Each independently represents hydrogen, halogen, -OR 3 -N(R) 3 ) 2. -SR 3 Depending on the circumstances, the C that has been replaced 1-6 Aliphatic group or -CN; R z Hydrogen or, depending on the case, substituted C 1-6 Aliphatic group; R 1 -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 Independently selected from halogens, -CN, -CO 2R、-C(O)N(R) 2. -NO 2. -N(R) 2. -OR, -SR, or C as appropriate 1-6 Aliphatic group; n is 0, 1, 2 or 3, provided that R 1 -N(R) 2. -N(R)C(O)R' or -C(O)N(R) When n = 2, then n is 1, 2, or 3; R 2 C, to be replaced as appropriate 1-6 Aliphatic group; R 3 Hydrogen or, depending on the case, substituted C 1-6 Aliphatic group; Ring A is, as appropriate, a substituted phenyl group, a substituted 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a substituted 8-10 member bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a substituted 3-7 member saturated or partially unsaturated monocyclic carbocyclic group, a substituted 3-7 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a substituted 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a divalent carbon. 1-3 Straight-chain or branched hydrocarbon chains; R a Hydrogen, halogen, or C substituted as appropriate 1-6 Aliphatic group, substituted phenyl group, substituted 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted 3-7 member saturated or partially unsaturated monocyclic carbocyclic group, substituted 3-7 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or substituted 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, and the C is substituted as appropriate. 1-6 The aliphatic group, a substituted 3 to 7-member saturated or partially unsaturated carbocyclic group, or a substituted 3 to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or two Rs attached to the same nitrogen atom to form a substituted 3 to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 0 to 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur; and each R' is independently a substituted C 1-6 Aliphatic group or, where appropriate, substituted 3 to 7 saturated or partially unsaturated carbocyclic groups. 2. The compound of Example 1, wherein the compound is not: or 3. The compound of Example 1 or Example 2, wherein ring A is, as appropriate, a 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 member bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 4. The compound of any of the foregoing embodiments, wherein ring A is, as appropriate, a substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, as appropriate, a substituted 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 5. The compound of any of the foregoing embodiments, wherein ring A is, as appropriate, a substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6. The compound of any of the foregoing embodiments, wherein R… a Halogen, or C substituted as appropriate 1-6 Aliphatic group, substituted phenyl group, substituted 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted 3-7 member saturated or partially unsaturated monocyclic carbocyclic group, substituted 3-7 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or substituted 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 7. The compound of any of the foregoing examples, wherein R a C, to be replaced as appropriate 1-6 Aliphatic group, or, depending on the substitution, a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, depending on the substitution, a 7- to 10-member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8. The compound of any of the foregoing examples, wherein R... a C, to be replaced as appropriate 1-6 Aliphatic group or, where applicable, substituted 7 to 10 saturated or partially unsaturated bicyclic heterocyclic groups having 1 to 4 independently selected heteroatoms from nitrogen, oxygen, and sulfur. 9. The compound of any of the foregoing examples, wherein: as permitted by the valence, After 1-5 R b Replace; and each R b Independently hydrogen, halogen, -CN, -OR, -O(CH) 2) m R, -SR, -N(R) 2. -NO 2. -C(O)R', -C(O)OR, -C(O)N(R) 2. -OC(O)R', -OC(O)N(R) 2. -OC(O)OR, -OSO 2R, -OSO 2N(R) 2. -N(R)C(O)R', -N(R)SO 2R'、-SO 2R'、-SO 2N(R) 2. -SO 3R', or C as appropriate (substituted for) 1-6 Aliphatic group, substituted 3 to 6 saturated or partially unsaturated carbocyclic group, substituted 3 to 6 saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted 5 to 6 saturated monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 1, 2, or 3. 10. The compound of Example 9, wherein each R b Independently halogen, -CN, -OR, -O(CH) 2) m R, -SR, -N(R) 2. -NO 2. -C(O)R', -C(O)OR, -C(O)N(R) 2. -OC(O)R', -OC(O)N(R) 2. -OC(O)OR, -OSO 2R, -OSO 2N(R) 2. -N(R)C(O)R', -N(R)SO 2R'、-SO 2R'、-SO 2N(R) 2. -SO 3R', or C as appropriate (substituted for) 1-6 Aliphatic group, substituted 3 to 6 saturated or partially unsaturated carbocyclic group, substituted 3 to 6 saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted 5 to 6 saturated monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 11. The compound as in Example 9 or 10, wherein each R b C is halogenated independently or, where appropriate, substituted. 1-6 Aliphatic group. 12. The compound as described in any one of Examples 9-11, wherein... for , , or 13. The compound of any of the foregoing embodiments, wherein L is a covalent bond. 14. The compound of any of Examples 1-12, wherein L is -CH 2-. 15. The compound of any of the foregoing embodiments, wherein the compound has the formula IC: IC or a pharmaceutically acceptable salt thereof. 16. A compound as described in any of the foregoing embodiments, wherein the compound has the formula ID: ID or its medically acceptable salt, wherein: R b Hydrogen, halogen, -CN, -OR, -O(CH) 2) m R, -SR, -N(R) 2. -NO 2. -C(O)R', -C(O)OR, -C(O)N(R) 2. -OC(O)R', -OC(O)N(R) 2. -OC(O)OR, -OSO 2R, -OSO 2N(R) 2. -N(R)C(O)R', -N(R)SO 2R'、-SO 2R'、-SO 2N(R) 2. -SO 3R', or C as appropriate (substituted for) 1-6 Aliphatic group, substituted 3 to 6 saturated or partially unsaturated carbocyclic group, substituted 3 to 6 saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted 5 to 6 saturated monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and m is 1, 2 or 3. 17. A compound as described in any of the foregoing examples, wherein the compound has the formula IE: IE or its pharmaceutically acceptable salt. 18. A compound of formula II: II or its medically acceptable salt, wherein: W is CR w Or N; X is CR x Or N; Y is CR yOr N; Z is -O- or -NR z -; R w R x and R y Each independently represents hydrogen, halogen, -OR 3 -N(R) 3 ) 2. -SR 3 Depending on the circumstances, the C that has been replaced 1-6 Aliphatic group or -CN; R z Hydrogen or, depending on the case, substituted C 1-6 Aliphatic group; R 1 -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 Independently selected from halogens, -CN, -CO 2R、-C(O)N(R) 2. -NO 2. -N(R) 2. -OR, -SR, or C as appropriate 1-6 Aliphatic group; n is 0, 1, 2 or 3; R 2 C, to be replaced as appropriate 1-6 Aliphatic group; R 3 Hydrogen or, depending on the case, substituted C 1-6Aliphatic group; Ring A is, depending on the substitution, a 9- to 16-membered bicyclic or tricyclic aryl group, an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 10- to 16-membered polycyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 10-membered bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10- to 16-membered polycyclic heterocyclic group having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen, and C is, depending on the substitution... 1-6 The aliphatic group, a substituted 3 to 7-member saturated or partially unsaturated carbocyclic group, or a substituted 3 to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or two Rs attached to the same nitrogen atom to form a substituted 3 to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 0 to 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur; and each R' is independently a substituted C 1-6 Aliphatic group or, where appropriate, substituted 3 to 7 saturated or partially unsaturated carbocyclic groups. 19. The compound of Example 18, wherein the compound is not: 20. The compound of Example 18 or 19, wherein ring A is, as appropriate, a bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur of 8 to 10 members; a polycyclic heteroaryl group having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur of 10 to 16 members; a bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur of 7 to 10 members; or a polycyclic heterocyclic group having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur of 10 to 16 members. 21. The compound of any one of Examples 18-20, wherein ring A is, as appropriate, a bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur of 8 to 10 members; or a polycyclic heteroaryl group having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur of 10 to 16 members. 22. The compound of any one of Examples 18-21, wherein ring A is, as appropriate, via one or more side oxygen groups, halogens, or C. 1-6 Alkyl-substituted compounds having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, comprising 8 to 10 members of a bicyclic heteroaryl group. 23. Compounds of any one of Examples 18-22, wherein ring A is, as appropriate, a substituted 10-16 member polycyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 24. Compounds of any one of Examples 18-23, wherein: ring A is... Ring A1 is a ring selected from the following, which may be substituted: phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1- to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein ring A1 is fused with ring A2; Ring A2 is a ring selected from the following, which may be substituted: phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1- to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1- to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein ring A2 is further fused with ring A3, in case (i) Or (ii) ring A2 and ring A3 combine to form a spirocyclic ring; and ring A3, when present, is a ring selected from the following, substituted as appropriate: phenyl, a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 25. The compound of Example 24, wherein ring A1 is, as appropriate, a substituted 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 26. The compound of Example 24 or 25, wherein the substituted ring A is, as appropriate, a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 27. The compound of any one of Examples 24-26, wherein ring A2 is, as appropriate, a substituted 5- to 7-member partially saturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 28. The compound of any one of Examples 24-27, wherein, as appropriate, the substituted ring A is selected from the group consisting of: , , , , , , , , and 29. The compound of any one of Examples 24-27, wherein the substituted ring A is selected from the group consisting of: , , , , , , , , , and 30. A compound as described in any of Examples 18-29, wherein: as permitted by the valence, After 1-5 R b Replace; and each R b Independently hydrogen, halogen, -CN, -OR, -O(CH) 2) m R, -SR, -N(R) 2. -NO 2. -C(O)R', -C(O)OR, -C(O)N(R) 2. -OC(O)R', -OC(O)N(R) 2. -OC(O)OR, -OSO 2R, -OSO 2N(R) 2. -N(R)C(O)R', -N(R)SO 2R'、-SO 2R'、-SO 2N(R) 2. -SO 3R', or C as appropriate (substituted for) 1-6 Aliphatic group, substituted 3 to 6 saturated or partially unsaturated carbocyclic group, substituted 3 to 6 saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted 5 to 6 saturated monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 1, 2, or 3. 31. The compound of Example 30, wherein each R b Independently halogen, -CN, -OR, -O(CH) 2) m R, -SR, -N(R) 2. -NO 2. -C(O)R', -C(O)OR, -C(O)N(R) 2. -OC(O)R', -OC(O)N(R) 2. -OC(O)OR, -OSO 2R, -OSO 2N(R) 2. -N(R)C(O)R', -N(R)SO 2R'、-SO 2R'、-SO 2N(R) 2. -SO 3R', or C as appropriate (substituted for) 1-6 Aliphatic group, substituted 3 to 6 saturated or partially unsaturated carbocyclic group, substituted 3 to 6 saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted 5 to 6 saturated monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 32. The compounds of Example 30 or Example 31, wherein each R b Independent of halogen, or C substituted as appropriate 1-6 Aliphatic group, -OR or -O (CH 2) m R. 33. The compound of any one of Examples 30-32, wherein The group is composed of the following components: , , , , , , , , , , and 34. The compound of any one of Examples 30-32, wherein... The group is composed of the following components: , , , , , , , , , , , and 35. A compound of any one of Examples 18-34, wherein the compound has the formula II-C: II-C or a pharmaceutically acceptable salt thereof. 36. A compound of any one of Examples 18-35, wherein the compound has the formula II-D: II-D or a pharmaceutically acceptable salt thereof. 37. A compound of any one of Examples 18-36, wherein the compound has the formula II-E: II-E or its pharmaceutically acceptable salt, wherein: ring A1 is a ring selected from the following, which may be substituted: phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein ring A1 is fused with ring A2; ring A2 is a ring selected from the following, which may be substituted: phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein ring A2 is further fused with ring A3, whichever is more specific. Or (ii) ring A2 and ring A3 combine to form a spirocycle; and ring A3, when present, is a ring selected from the following, if substituted: phenyl, 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1- to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 38. The compound of any of the foregoing examples, wherein W is CR w 39. The compound of Example 38, wherein R w 40. A compound of any one of Examples 1-37, wherein W is N. 41. A compound of any one of the foregoing Examples, wherein X is CR. x 42. The compound of any of the foregoing embodiments, wherein R x For hydrogen, halogen, -CN, -OR 3 Or, depending on the circumstances, replace C 1-6 Aliphatic group. 43. A compound of any one of Examples 1-40, wherein X is N. 44. A compound of any one of the foregoing examples, wherein Y is CR. y 45. The compound of Example 44, wherein R y46. ​​A compound as described in any of Examples 1-43, wherein Y is N. 47. A compound as described in any of the preceding examples, wherein R is N. 1 -N(R)C(O)N(R) 2 or -N(R)C(O)OR. 48. The compound of any of the foregoing embodiments, wherein R... 1 -N(R)C(O)N(R) 2. 49. The compound of any of the foregoing embodiments, wherein R 1 -N(H)C(O)N(R) 2, and each R 1 R is independently hydrogen, and C is substituted as appropriate. 1-6 An aliphatic group or, where appropriate, a substituted 3 to 7-member saturated or partially unsaturated carbocyclic group, or two R groups attached to the same nitrogen atom together forming, where appropriate, a substituted 3 to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 0 to 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. 50. A compound as described in any of Examples 1-47, wherein R... 1 The compound is -N(R)C(O)OR. 51. The compound of any one of Examples 1-47, wherein R... 1 It is -N(H)C(O)OR, and R 1 R is C that has been replaced, depending on the circumstances. 1-6 Aliphatic group or, where applicable, a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1-2 independently selected heteroatoms from nitrogen, oxygen, and sulfur. 52. The compound of any one of Examples 1-46, wherein R 1 The compound is -N(R)C(O)R'. 53. The compound of any one of Examples 1-46, wherein R... 1 -N(H)C(O) (C may be replaced as appropriate) 1-6 Aliphatic group). 54. The compound of any of the foregoing examples, wherein each R c Independently a halogen. 55. A compound as described in any of the foregoing examples, wherein n is 0. 56. A compound of formula III: III or a medically acceptable salt thereof, wherein: Z is -O- or -NR. z -; R x For hydrogen, halogen, -OR 3 -N(R) 3 ) 2. -SR 3 Depending on the circumstances, the C that has been replaced 1-6 Aliphatic group or -CN; R z Hydrogen or, depending on the case, substituted C 1-6 Aliphatic group; R 2 C, to be replaced as appropriate 1-6 Aliphatic group; R 3 Hydrogen or, depending on the case, substituted C 1-6 Aliphatic group; R 4 For halogens, -OR, -N(R) 2 or, depending on the case, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 independently selected heteroatoms from nitrogen, oxygen, and sulfur; ring A is, depending on the case, a substituted phenyl group, a substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 independently selected heteroatoms from nitrogen, oxygen, and sulfur, a substituted 8- to 10-membered bicyclic heteroaryl group having 1-4 independently selected heteroatoms from nitrogen, oxygen, and sulfur, a substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, a substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 independently selected heteroatoms from nitrogen, oxygen, and sulfur, or a substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 independently selected heteroatoms from nitrogen, oxygen, and sulfur; L is a covalent bond or a divalent C. 1-3 Straight-chain or branched hydrocarbon chains; R a Hydrogen, halogen, or C substituted as appropriate 1-6Aliphatic group, substituted phenyl group, substituted 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted 3-7 member saturated or partially unsaturated monocyclic carbocyclic group, substituted 3-7 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or substituted 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and each R is independently hydrogen, substituted C 1-6 Aliphatic group, substituted 3 to 7 saturated or partially unsaturated carbocyclic group, or substituted 3 to 7 saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or two Rs attached to the same nitrogen atom together forming, substituted 3 to 7 saturated or partially unsaturated monocyclic heterocyclic group having 0 to 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur. 57. The compound of Example 56, wherein the compound is not: or 58. The compound of Example 56 or Example 57, wherein R 4 For halogens, -OR, -N(R) 2 or, depending on the case, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 independently selected heteroatoms from nitrogen, oxygen, and sulfur, and R 4 Each R is independently hydrogen or, depending on the case, a substituted C. 1-6Aliphatic group. 59. The compound of any one of Examples 56-58, wherein ring A is, as appropriate, a 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 member bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3-7 member saturated or partially unsaturated monocyclic carbocyclic group, a 3-7 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 60. A compound of any one of Examples 56-59, wherein ring A is, as appropriate, a substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, as appropriate, a substituted 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 61. A compound of any one of Examples 56-60, wherein ring A is, as appropriate, a substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 62. A compound of any one of Examples 56-61, wherein R... a Halogen, or C substituted as appropriate 1-6 Aliphatic group, substituted phenyl group, substituted 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted 3-7 member saturated or partially unsaturated monocyclic carbocyclic group, substituted 3-7 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or substituted 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 63. The compound of any one of Examples 56-62, wherein R a C, to be replaced as appropriate 1-6 Aliphatic group. 64. The compound of any one of Examples 56-63, wherein: as permitted by the valence, After 1-5 R b Replace; and each R b Independently hydrogen, halogen, -CN, -OR, -O(CH) 2) m R, -SR, -N(R) 2. -NO 2. -C(O)R', -C(O)OR, -C(O)N(R) 2. -OC(O)R', -OC(O)N(R) 2. -OC(O)OR, -OSO 2R, -OSO 2N(R) 2. -N(R)C(O)R', -N(R)SO 2R'、-SO 2R'、-SO 2N(R) 2. -SO 3R', or C as appropriate (substituted for) 1-6 Aliphatic group, substituted 3 to 6 saturated or partially unsaturated carbocyclic group, substituted 3 to 6 saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted 5 to 6 saturated monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m is 1, 2, or 3. 65. The compound of Example 64, wherein each R b Independently halogen, -CN, -OR, -O(CH) 2) m R, -SR, -N(R) 2. -NO 2. -C(O)R', -C(O)OR, -C(O)N(R) 2. -OC(O)R', -OC(O)N(R) 2. -OC(O)OR, -OSO 2R, -OSO 2N(R) 2. -N(R)C(O)R', -N(R)SO 2R'、-SO 2R'、-SO 2N(R) 2. -SO 3R', or C as appropriate (substituted for) 1-6Aliphatic group, substituted 3 to 6 saturated or partially unsaturated carbocyclic group, substituted 3 to 6 saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted 5 to 6 saturated monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 66. The compounds of Examples 64 or 65, wherein each R b Independently, as appropriate, C is replaced 1-6 Aliphatic group. 67. The compound of any one of Examples 64-66, wherein... for or 68. A compound of any one of Examples 56-67, wherein L is a covalent bond. 69. A compound of any one of Examples 56-67, wherein L is -CH 2-. 70. The compound of any of the foregoing examples, wherein each R is independently hydrogen, and C is substituted as appropriate. 1-6 An aliphatic group or, depending on the substitution, a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur; or, when two Rs are attached to the same nitrogen atom, together forming, depending on the substitution, a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms chosen from nitrogen, oxygen, and sulfur. 71. The compound of any of the foregoing examples, wherein each R is independently hydrogen or, depending on the substitution, a C 1-6 Aliphatic group. 72. The compound of any of the foregoing examples, wherein each R' is independently a substituted C, as appropriate. 1-6 Alkyl or, where appropriate, substituted C 3-7 Cycloalkyl. 73. The compound of any of the foregoing examples, wherein each R' is independently a substituted C, as appropriate. 1-6 Aliphatic group. 74. A compound of formula IV: IV or its medically acceptable salt, wherein: Z is -O- or -NR. z -; R x For hydrogen, halogen, -OR 3 Or -CN; R z Hydrogen or, depending on the case, substituted C 1-6 Aliphatic group; R 2 C, to be replaced as appropriate 1-6 Aliphatic group; R 3 Hydrogen or, depending on the case, substituted C 1-6 aliphatic groups; The option is selected from (i) or (ii): (i) , , , or ; or (ii) or In which ring A is further substituted at least once, and at least one substituent on ring A is C. 1-6 Haloalkyl; L is a covalent bond or a divalent C 1-3 Straight-chain or branched hydrocarbon chains; R a Hydrogen, halogen, or C substituted as appropriate 1-6 Aliphatic group, substituted phenyl group, substituted 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted 3-7 member saturated or partially unsaturated monocyclic carbocyclic group, substituted 3-7 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or substituted 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and R' is C 1-6 Aliphatic group or 3 to 7 nucleotides of saturated or partially unsaturated carbocyclic group. 75. The compound of Example 74, wherein the compound is not: 76. The compound as described in Examples 74 or 75, wherein R a Halogen, or C substituted as appropriate 1-6Aliphatic group, substituted phenyl group, substituted 5-6 member monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted 3-7 member saturated or partially unsaturated monocyclic carbocyclic group, substituted 3-7 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or substituted 7-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 77. The compound of any one of Examples 74-76, wherein R a C, to be replaced as appropriate 1-6 Aliphatic group, or, depending on the substitution, a 3- to 7-member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, depending on the substitution, a 7- to 10-member saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 78. The compound of any one of Examples 74-77, wherein L is covalently bonded. 79. The compound of any one of Examples 74-77, wherein L is -CH 2-. 80. A compound of any one of Examples 74-79, wherein R' is methyl or cyclopropyl. 81. A compound of any one of Examples 56-80, wherein R... x For hydrogen, halogen, -CN, -OR 3 Or, depending on the circumstances, replace C 1-6 Aliphatic group. 82. The compound of any one of Examples 56-81, wherein R x For hydrogen, halogen, -OR 3 Or -CN. 83. The compound of any one of Examples 56-82, wherein R x It is a halogen or -CN. 84. The compound of any of the foregoing examples, wherein R 2 C 1-4 Alkyl group. 85. The compound of any of the foregoing examples, wherein Z is -O-. 86. The compound of any of Examples 1-84, wherein Z is -NR. z - 87. The compound as in Example 86, wherein R z88. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof. 89. A pharmaceutical composition comprising a compound of any of the foregoing examples or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 90. A method of inhibiting JAK2 in an individual, comprising administering a compound of any of Examples 1-88 or the composition of Example 89. 91. A method of treating a disease, symptom, or ailment related to JAK2, comprising administering a compound of any of Examples 1-88 or the composition of Example 89 to an individual in need. 92. A method of treating cancer, comprising administering a compound of any of Examples 1-88 or the composition of Example 89 to an individual in need. 93. A method of treating a hematologic malignancy, comprising administering a compound of any of Examples 1-88 or the composition of Example 89 to an individual in need. 94. The method of Example 93, wherein the hematologic malignancy is leukemia or lymphoma. 95. A method for treating myeloproliferative neoplasm, comprising administering to an individual in need a compound of any one of Examples 1-88 or a composition of Example 89. 96. The method of Example 95, wherein the myeloproliferative neoplasm is polycythemia vera, primary thrombocytopenia, or myelofibrosis. Example As described in the following examples, in some exemplary embodiments, the compounds are prepared according to the following general procedure. It should be understood that although general methods describe the synthesis of certain compounds of this disclosure, the following general methods and other methods known to those skilled in the art can be applied to all compounds as described herein and to subclasses and substances of such compounds. Preparation of intermediates Preparation of intermediates Int-1 5-Fluoro- N-Methyl-2-nitropyridine-3-amine Synthetic compounds Int-1.1, hydrogen peroxide (30 wt%, 31 mL) was added dropwise to concentrated sulfuric acid (60 mL) at 0 °C. 3,5-Difluoropyridine-2-amine (5.0 g, 38.43 mmol, 1.0 equivalent) was added dropwise to a solution of concentrated sulfuric acid (60 mL) 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 alkalized with a saturated aqueous sodium bicarbonate solution. 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 give... Int-1.1. 1H NMR (CDCl 3, 400 MHz): δ 8.35 (bs, 1H), 7.62-7.58 (m, 1H). Synthetic compounds Int-1. At 0℃ Int-1.1 (2.3 g, 14.37 mmol, 1.0 equivalent) was added dropwise to a solution of acetonitrile (20 mL) with an aqueous solution of methylamine (40%, 1.1 mL, 14.37 mmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 1 hour. It was poured over ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give… Int-1. 1 H NMR (CDCl 3, 400 MHz): δ 7.93 (bs, 1H), 7.78-7.75 (d, 1H), 7.02-6.99 (m, 1H), 3.06 (s, 3H). Preparation of intermediates Int-2 4-Chloro-5-Fluoro- N-Methyl-2-nitropyridine-3-amine Synthetic compounds Int-2.1. To a solution of 3,5-difluoropyridine-2-amine (10 g, 76.87 mmol, 1.0 equivalent) in THF (200 mL), add n-butyllithium (2.5 M in hexane, 61.4 mL, 153.7 mmol, 2.0 equivalent). Stir the reaction mixture at -78 °C for 40 min. Add hexachloroethane (36.3 g, 153.7 mmol, 2.0 equivalent) and stir the reaction mixture at -78 °C for 30–40 min. Carefully add a saturated ammonium chloride solution to quench the reaction. Warm the mixture to room temperature and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel rapid column chromatography (CombiFlash®, 12% ethyl acetate in hexane) to give Int-2.1. 1 H NMR (DMSO-d 6, 400 MHz): δ 7.98-7.94 (m, 1H), 6.48 (bs, 2H). Synthetic compounds Int-2.2. At room temperature, add concentrated sulfuric acid (3 mL, 6 volumes) dropwise to potassium persulfate (2.05 g, 7.6 mmol, 2.5 equivalents) and stir for 15 minutes. Add in small portions to the mixture. Int-2.1 (0.5 g, 3.04 mmol, 1.0 equivalent), maintain the temperature at 30-40 °C. Stir the reaction mixture at room temperature for 3-4 hours. Pour it onto crushed ice, stir, alkalize with saturated sodium bicarbonate and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel rapid column chromatography (CombiFlash®, 2-3% ethyl acetate in hexane) to give Int-2.2. 1 H NMR (DMSO-d 6, 400MHz): δ 8.78 (s, 1H). Synthetic compounds Int-2. At 0℃, to Int -2.2 (0.970 g, 4.99 mmol, 1.0 equivalent) of an aqueous solution of methylamine (40%, 0.8 mL, 9.98 mmol, 2.0 equivalent) was added dropwise to a solution of acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 10–20 minutes. It was poured over ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 10% ethyl acetate in hexane) to give Int-2. 1 H NMR (DMSO-d 6, 400 MHz): δ 7.98 (s, 1H), 7.05 (bs, 1H), 2.79 (d, 3H). Preparation of intermediates Int-3 :( S)-5-(tert-butyl)-3-isocyanothio-1-(tetrahydrofuran-3-yl)-1 H-pyrazole Synthetic compounds Int-3.1. Fill a round-bottom flask equipped with a Dean-Stark apparatus and a condenser with 5-(tert-butyl)-1 H-pyrazole-3-amine (5.0 g, 35.92 mmol, 1.0 equivalent), 2,5-hexanedione (4.09 g, 35.92 mmol, 1.0 equivalent), toluene (100 mL), and a few drops of acetic acid. The reaction mixture was heated to reflux for 3 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, with 12% ethyl acetate in hexane as the solvent) to give Int-3.1. MS (ES): m / z218.3 [M+H] + . Synthetic compounds Int-3.2 and Int-3.3. Under nitrogen atmosphere Int-3.1 (2.5 g, 11.50 mmol, 1.0 equivalent), methanesulfonic acid ( A mixture of R)-tetrahydrofuran-3-yl ester (1.91 g, 11.50 mmol, 1.0 equivalent) and cesium carbonate (7.49 g, 23 mmol, 2.0 equivalent) in DMF (15 mL) was stirred at 70 °C for 12 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 silica gel rapid column chromatography (CombiFlash®, with 2% ethyl acetate in hexane as the solvent) 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] + . Synthetic compounds Int-3.4. To Int-3.3 (0.120 g, 0.417 mmol, 1.0 equivalent) was added to a solution of ethanol-water (2:1, 2 mL) with hydroxylamine hydrochloride (0.287 g, 4.17 mmol, 10 equivalent). The reaction mixture was stirred in a microwave reactor at 120 °C for 1 hour. The mixture was poured over ice water, alkalized with 2 N sodium hydroxide, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give... Int-3.4. MS (ES): m / z 210.3 [M+H] + . Synthetic compounds Int-3. At 0℃ A solution of Int-3.4 (0.070 g, 0.334 mmol, 1.0 equivalent) in dichloromethane (2 mL) was followed by a solution of sodium bicarbonate (0.140 g, 1.67 mmol, 5.0 equivalent) in water (1 mL), and then phosgene (0.096 g, 0.835 mmol, 2.5 equivalent). The reaction mixture was stirred at room temperature for 2 hours. It was poured over ice water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give… Int-3. MS (ES): m / z252.3 [M+H] + . Preparation of intermediates Int-4 :( R)-5-(tert-butyl)-3-isocyanothio-1-(tetrahydrofuran-3-yl)-1 H-pyrazole Synthetic compounds Int-4. Compounds Int-4 system based on synthesis The program described in Int-3, from Int-3.2 preparation. MS (ES): m / z252.3 [M+H] + . Preparation of intermediates Int-5 3-Isocyanothio-1-methyl-5-(trifluoromethyl)pyridine-2(1 H)-ketone Synthetic compounds Int-5.1. 3-nitro-5-(trifluoromethyl)pyridine-2 (1 A mixture of H)-ketone (1.0 g, 4.81 mmol, 1.0 equivalent) and potassium carbonate (1.3 g, 9.62 mmol, 2.0 equivalent) in DMF (15 mL) was stirred for 15 minutes, followed by the addition of methyl iodine (1.0 g, 7.21 mmol, 1.5 equivalent). The reaction mixture was stirred at 70 °C for 2 hours. It was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 40% ethyl acetate in hexane) to give Int-5.1. MS(ES): m / z223.12 [M+H] + . Synthetic compounds Int-5.2. The compound A mixture of Int-5.1 (0.57 g, 2.57 mmol, 1.0 equivalent) and 10% palladium / carbon (0.3 g) in methanol (18 mL) was stirred at hydrogen (1 atm) for 1 hour. The mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure to obtain… Int-5.2. MS(ES): m / z193.14 [M+H] + . Synthetic compounds Int-5. At 0℃ Int-5.2 (0.200 g, 1.04 mmol, 1.0 equivalent) and triethylamine (0.4 mL, 2.49 mmol, 2.4 equivalent) were added to a solution of phosgene (0.143 g, 1.25 mmol, 1.2 equivalent) in THF (6 mL). The reaction mixture was stirred at room temperature for 30 minutes. It was then transferred to 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 Int-5. MS(ES): m / z192.15 [M+H] + . Preparation of intermediates Int-6 :1-(2-oxaspiro[3.3]heptane-6-yl)-5-(trifluoromethyl)-1 H-pyrazole-3-amine Synthetic compounds Int-6.1. Sodium borohydride (0.203 g, 5.35 mmol, 1.0 equivalent) was added fractionally to a solution of 2-oxaspiro[3.3]hepta-6-one (0.600 g, 5.35 mmol, 1.0 equivalent) in methanol (10 mL) at 0 °C. The reaction mixture was stirred for 2 hours. It was then transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Int-6.1. MS (ES): m / z 115.2 [M+H] + . Synthetic compounds Int-6.2. At 0℃ to Int-6.1 (0.540 g, 4.73 mmol, 1.0 equivalent) was added to a solution of dichloromethane (10 mL) followed by triethylamine (1.64 mL, 11.82 mmol, 2.5 equivalent), and then methanesulfonyl chloride (0.71 mL, 9.46 mmol, 2.0 equivalent). The reaction mixture was stirred at room temperature for 12 hours. It was then transferred to ice water, stirred, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 40% ethyl acetate in hexane) to give... Int-6.2. MS (ES): m / z 193.2 [M+H] + . Synthetic compounds Int-6. Towards Int-6.2 (0.4 g, 2.08 mmol, 1.0 equivalent) and 5-(trifluoromethyl)-1 H-pyrazole-3-amine (0.314 g, 2.08 mmol, 1.0 equivalent) was added to a solution of cesium carbonate (1.352 g, 4.16 mmol, 2.0 equivalent) in DMF (7 mL). The reaction mixture was heated at 80 °C for 5 hours. It was then transferred to ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain… Int-6. MS (ES): m / z 248.2 [M+H] + . Preparation of intermediates Int-7 4,4-Difluoro-2-isocyanothio-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridine Synthetic compounds Int-7.1. To 1 A solution of diethyl H-pyrazole-3,5-dicarboxylate (100 g, 471 mmol, 1.0 equivalent) and ethyl 4-bromobutyrate (91.92 g, 471 mmol, 1.0 equivalent) in acetonitrile (1000 mL) was mixed with potassium carbonate (64.99 g, 471 mmol, 1.0 equivalent), 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 layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by wet milling with diethyl ether to obtain… Int-7.1. MS(ES): m / z327.2 [M+H] + . Synthetic compounds Int-7.2. To at room temperature Int-7.1 (120 g, 367 mmol, 1.0 equivalent) was added to a solution of potassium tert-butoxide (1 M in THF) in 1000 mL of toluene (403 mL, 403.7 mmol, 1.1 equivalent). 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 wet milling with diethyl ether to give Int-7.2. m / z: 281.2 [M+H] + . Synthetic compounds Int-7.3. To Hydrochloric acid:water (2:1, 600 mL) was added to Int-7.2 (65 g, 231 mmol 1.0 equivalent), and the reaction mixture was heated at 100 °C for 6 hours. The mixture 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 / z181.1 [M+H] + . Synthetic compounds Int-7.4. To Int-7.3 (38 g, 210 mmol, 1.0 equivalent) was added to a solution in DMF (4000 mL) with potassium carbonate (57.96 g, 420 mmol, 2.0 equivalent), followed by the addition of methyl iodine (15.7 mL, 252 mmol, 1.2 equivalent), and the reaction mixture was stirred at room temperature for 4 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 silica gel rapid column chromatography (CombiFlash®, 25% ethyl acetate in hexane) to give... Int-7.4. MS(ES): m / z 195.0 [M+H] + . Synthetic compounds Int-7.5. To Int-7.4 (22 g, 113.29 mmol, 1.0 equivalent) was added to a solution of 1,2-dichloroethane (130 mL) with diethylaminotrifluoride (150 mL, 1132.9 mmol, 10.0 equivalent), and the reaction mixture was stirred at room temperature for 5 days. The mixture was transferred to an ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 20% ethyl acetate in hexane) to give... Int-7.5. MS(ES): m / z217.1 [M+H] + . Synthetic compounds Int-7.6. To A solution of Int-7.5 (11.2 g, 51.81 mmol, 1.0 equivalent) in THF (110 mL) was mixed with lithium hydroxide (4.35 g, 103.62 mmol, 2.0 equivalent) and water (11 mL). The reaction mixture was stirred at room temperature for 16 hours. It was then 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 / z203.0 [M+H] + . Synthetic compounds Int-7.7. To Int-7.6 (8.0 g, 39.57 mmol, 1.0 equivalent) was suspended in toluene (100 mL) and then triethylamine (11 mL, 79.14 mmol, 2.0 equivalent) was added, followed by benzyl alcohol (21.4 g, 197.85 mmol, 5.0 equivalent) and diphenylphosphoazide (21.77 g, 79.14 mmol, 2.0 equivalent). 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 a crude product. This crude product was further purified by silica gel rapid column chromatography (CombiFlash®, 15% ethyl acetate in hexane) to obtain... Int-7.7. MS(ES): m / z308.2 [M+H] + . Synthetic compounds Int-7.8. Will A mixture of Int-7.7 (5.4 g, 17.57 mmol, 1.0 equivalent) and 10% palladium / charcoal (2.0 g) in methanol (100 mL) was stirred at hydrogen (1 atm) for 2 hours. The mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure to obtain… Int-7.8. MS(ES): m / z 174.1 [M+H] + . Synthetic compounds Int-7. compound Int-7 series based on synthesis The program described in Int-3, from Prepared using Int-7.8. It was used without purification. MS (ES): m / z 216.2 [M+H] + . Preparation of intermediates Int-8 2-Isocyanothio-5-methyl-6,7-dihydropyrazolo[1,5- a] Pyrazine-4(5 H)-ketone Synthetic compounds Int-8.1. At -5°C, to 5-nitro-1 H-pyrazole-3-carboxylic acid (2.0 g, 12.73 mmol, 1.0 equivalent) and 2-(methylamino)ethanol-1-ol (1.43 g, 19.10 mmol, 1.5 equivalent) were added dropwise to a solution in DCM (20 mL) with thionyl chloride (4.6 mL, 63.65 mmol, 5.0 equivalent) and one drop of DMF. The reaction mixture was stirred for 10 hours and heated at 50 °C for 16 hours. It was then 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 equivalent) was added, and the mixture was stirred for 16 hours. The mixture was poured into ice water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silicone rapid column chromatography (CombiFlash®, 1.0% methanol in DCM) to obtain... Int-8.1. MS (ES): m / z197.1 [M+H] + . Synthetic compounds Int-8.2. A mixture of Int-8.1 (1.3 g, 6.63 mmol, 1.0 equivalent), ammonium chloride (1.79 g, 33.15 mmol, 5.0 equivalent), and iron powder (1.85 g, 33.15 mmol, 5.0 equivalent) 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 Celite® pad. The filtrate was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silicone rapid column chromatography (CombiFlash®, 1.5% methanol in DCM) to obtain... Int-8.2. MS(ES): m / z 167.0 [M+H] + . Synthetic compounds Int-8 compound Int-8 series based on synthesis The program described in Int-3, from Int-8.2 preparation. The product was purified by silicone rapid column chromatography (CombiFlash®, 0.5% methanol in DCM). MS (ES): m / z209.1 [M+H] + . Preparation of intermediates Int-9 2-Isocyanthio-4,4-dimethyl-6,7-dihydro-4 H-pyrazolo[5,1- c][1,4]oxazine Synthetic compounds Int-9.1. To 5-amino-1 Ethyl H-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) were mixed with p-toluenesulfonic acid (0.919 g, 4.83 mmol, 0.05 equivalent). The reaction mixture was heated to reflux using a Dean-Stark trap to remove water for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 10% ethyl acetate in hexane) to give... Int-9.1. MS (ES): m / z 234.2 [M+H] + . Synthetic compounds Int-9.2 .Will A mixture of Int-9.1 (10 g, 42.87 mmol, 1.0 equivalent), (2-bromoethoxy)(tert-butyl)dimethylsilane (15.38 g, 64.30 mmol, 1.0 equivalent), and potassium carbonate (17.74 g, 128.61 mmol, 3.0 equivalent) 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 layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 15% ethyl acetate in hexane) to give... Int-9.2. MS(ES): m / z392.2 [M+H] + . Synthetic compounds Int-9.3. At 0℃ to Int-9.2 (7.2 g, 18.39 mmol, 1.0 equivalent) was added to a solution of magnesium methyl bromide (3 M in diethyl ether, 18.4 mL, 55.17 mmol, 3.0 equivalent) in 70 mL of THF. 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 silica gel rapid column chromatography (CombiFlash®, 18% ethyl acetate in hexane) to give Int-9.3. m / z: 378.5 [M+H] + . Synthetic compounds Int-9.4. At 0℃ Int-9.3 (5.3 g, 14.04 mmol, 1.0 equivalent) was added to a solution of tetrabutylammonium fluoride (1 M, 35 mL, 35.1 mmol, 2.5 equivalent in THF) in 50 mL of THF. 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 silica gel rapid column chromatography (CombiFlash®, 25% ethyl acetate in hexane) to give Int-9.4. m / z: 264.2 [M+H] + . Synthetic compounds Int-9.5. At 0℃ A solution of Int-9.4 (2.3 g, 8.73 mmol, 1.0 equivalent) and 4-dimethylaminopyridine (0.010 g, 0.087 mmol, 0.01 equivalent) in DCM (25 mL) was followed by a solution of 4-toluenesulfonyl chloride (2.16 g, 11.34 mmol, 1.3 equivalent) in DCM (5 mL) and triethylamine (3.7 mL, 26.19 mmol, 3.0 equivalent). 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 layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude substance. Sodium hydride (1.05 g, 26.19 mmol, 3.0 equivalent) was added to a solution of this crude substance in THF (50 mL) at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. Pour the mixture into ice water and extract the product with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel rapid column chromatography (CombiFlash®, 30% ethyl acetate in hexane) to obtain... Int-9.5. m / z: 246.2 [M+H] + . Synthetic compounds Int-9.6. To Int-9.5 (0.900 g, 3.67 mmol, 1.0 equivalent) was added to a solution of ethanol-water (2:1, 20 mL) with hydroxylamine hydrochloride (12.75 g, 183.5 mmol, 50 equivalent). The reaction mixture was stirred at 120 °C for 1 hour. It was poured into ice water and neutralized with 2 N sodium hydroxide. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 2% methanol in DCM) to give Int-9.6. MS(ES): m / z 168.1 [M+H] + . Synthetic compounds Int-9 compound Int-9 series based on synthesis The program described in Int-3, from Int-9.6 was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, DCM). MS (ES): m / z210.1 [M+H] + . Preparation of intermediates Int-10 2'-Isocyanothio-5',6'-dihydrospiro[cyclobutane-1,4'-pyrrolo[1,2- b]Pyrazole] Synthetic compounds Int-10.1. At -78°C, a solution of 6-oxaspiro[3.4]oct-5-one (1.0 g, 7.93 mmol, 1.0 equivalent) and acetonitrile (0.83 mL, 15.86 mmol, 2.0 equivalent) in tetrahydrofuran (8 mL) was added to a solution of bis(trimethylsilyl)aminolithium (1 M in THF, 17.4 mL, 17.44 mmol, 2.2 equivalent) in anhydrous tetrahydrofuran (25 mL). The reaction mixture was stirred at -78°C for 30 min and then warmed to room temperature and stirred for 2 h. It was transferred to a saturated aqueous solution of ammonium chloride and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel rapid column chromatography (CombiFlash®, 20% ethyl acetate in hexane) to give Int-10.1. 1 H NMR (DMSO-d 6, 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). Synthetic compounds Int-10.2. To Int-10.1 (0.800 g, 4.78 mmol, 1.0 equivalent) was dissolved in ethanol (10 mL) with hydrazine monohydrate (0.358 g, 7.17 mmol, 1.5 equivalent). The reaction mixture was heated at 60 °C for 72 hours. The reaction mixture was then cooled to room temperature and bubbled through it with carbon dioxide for 1 hour. It was concentrated under reduced pressure. Methanol (15 mL) was added to the residue and stirred briefly. The precipitated solids were removed by filtration. The filtrate was concentrated under reduced pressure to obtain... Int-10.2. MS(ES): m / z 182.1 [M+H] + . Synthetic compounds Int-10.3. To Int-10.2 (0.610 g, 3.37 mmol, 1.0 equivalent) was added to a solution of thionyl chloride (1.22 mL, 16.85 mmol, 5.0 equivalent) in 10 mL of THF. The reaction mixture was stirred at room temperature for 3 hours. It was then slowly transferred to a mixture of ammonium hydroxide aqueous solution and ice (1:1), stirred, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel rapid column chromatography (CombiFlash®, 2% methanol in dichloromethane) to give Int-10.3. MS(ES): m / z 164.1 [M+H] + . Synthetic compounds Int-10. Compound Int-10 series based on synthesis The program described in Int-3, from Int-10.3 was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, dichloromethane). MS (ES): m / z 205.9 [M+H] + . Preparation of intermediates Int-11: 2'-Isocyanothio-6',7'-Dihydro-5' H-spiro[cyclopropane-1,4'-pyrazolo[1,5-] [a]pyridine] Synthetic compounds Int-11.1. Acetonitrile (1.3 g, 32 mmol, 2 equivalents) was added dropwise to a solution of LiHMDS (35 mL, 35 mmol, 2.2 equivalents) in THF (40 mL) at -78 °C. The resulting solution was stirred for 1 hour, and 5-oxaspiro[2.5]oct-4-one (2 g, 15.85 mmol, 1 equivalent) was added dropwise to a solution of THF (10 mL). The reaction mixture was stirred at -78 °C for another 2 hours. It was then heated to room temperature and quenched with a 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 obtain Int-11.1. MS(ES): m / z: 167.21 [M+H] + . Synthetic compounds Int-11.2. To Int-11.1 (1.7 g, 10.17 mmol, 1 equivalent) was dissolved in methanol (50 mL) and hydrazine hydrate (1.52 g, 30.51 mmol, 3 equivalents) was added. The reaction mixture was stirred in an autoclave at 120 °C for 16 h. The reaction mixture was cooled to room temperature and dry ice was slowly added over 15 minutes. The solution was decanted and the solvent was removed under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 6.0% methanol in DCM) to obtain... Int-11.2. MS(ES): m / z 181.24 [M+H] + . Synthetic compounds Int-11.3. Stir at room temperature Int-11.2 (1.2 g, 6.62 mmol, 1 equivalent) was added to a solution of dichloroethane (24 mL) with thionyl chloride (0.937 g, 7.94 mmol, 1.2 equivalent). The reaction mixture was stirred at 90 °C for 1 hour. The reaction mixture was cooled to room temperature, quenched with a saturated aqueous potassium carbonate 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 obtain... Int-11.3. MS(ES): m / z: 199.68 [M+H] + . Synthetic compounds Int-11.4. Int-11.3 (1 g, 5.01 mmol, 1 equivalent) and K 2CO The mixture of 3 (1.38 g, 10.02 mmol, 2 equivalents) in acetonitrile (20 mL) was stirred at 80 °C for 16 hours. It was then cooled to room temperature, decanted into water, and extracted by DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 5.0% methanol in DCM) to obtain... Int-11.4. MS(ES): m / z: 163.22 [M+H] + . Synthetic compounds Int-11. Compound Int-11 series based on synthesis The program described in Int-3, from Int-11.4 was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, 40% ethyl acetate in hexane). MS (ES): m / z 205.28 [M+H] + . Preparation of intermediates Int-12 2-Isocyanothio-4,4-dimethyl-4,5,7,8-tetrahydropyrazolo[1,5- d][1,4]oxazine-heptanane Synthetic compounds Int-12.1. will A mixture of Int-9.1 (40 g, 171.67 mmol, 1.0 equivalent), ((2-bromoethoxy)methyl)benzene (46.13 g, 214.59 mmol, 1.25 equivalent), and potassium carbonate (71.07 g, 515.02 mmol, 3.0 equivalent) in acetonitrile (100 mL) was stirred at 80 °C for 1 hour. The mixture was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 15% ethyl acetate in hexane) to give... Int-12.1. MS(ES): m / z369.2 [M+H] + . Synthetic compounds Int-12.2. At 0℃ to Int-12.1 (34.8 g, 94.56 mmol, 1.0 equivalent) was added to a solution of lithium aluminum hydride (1 M, 60.0 mL, 94.56 mmol, 1.0 equivalent in THF, 350 mL) and stirred for 30 minutes. The solution was poured into ethyl acetate, and the precipitate was removed by filtration through a Celite® pad. The filtrate was concentrated under reduced pressure to obtain… Int-12.2. MS(ES): m / z326.1 [M+H] + . Synthetic compounds Int-12.3. At 0℃ to A solution of Int-12.2 (30.6 g, 94.15 mmol, 1.0 equivalent) and triethylamine (23.77 g, 235.38 mmol, 2.5 equivalent) in DCM (300 mL) was mixed with methanesulfonyl chloride (16.1 g, 141.23 mmol, 1.5 equivalent) and stirred for 20 minutes. The mixture was transferred to ice water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Acetonitrile was added to the residue, followed by tetrabutylammonium cyanide (55.59 g, 207.38 mmol, 2.0 equivalent). The mixture was stirred at 80 °C for 1 hour. The mixture was 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 silicone rapid column chromatography (CombiFlash®, 28% ethyl acetate in hexane) to obtain... Int-12.3. MS(ES): m / z: 335.3 [M+H] + . Synthetic compounds Int-12.4. At 0℃ Int-12.3 (20.8 g, 62.27 mmol, 1.0 equivalent) was added to a solution in DMF (220 mL) with sodium hydride (60%, 7.47 g, 186.82 mmol, 3.0 equivalent), followed by the addition of methyl iodine (44.21 g, 311.37 mmol, 5.0 equivalent). The reaction mixture was stirred at room temperature for 1 hour. It was then transferred to 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 silica gel rapid column chromatography (CombiFlash®, 17% ethyl acetate in hexane) to give Int-12.4. MS(ES): m / z: 363.61 [M+H] + . Synthetic compounds Int-12.5. At -78℃ Int-12.4 (2.0 g, 5.52 mmol, 1.0 equivalent) was added to a solution of diisobutylaluminum hydride in DCM (25 mL). (1.0 M, 10.0 mL in hexane) and stirred for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of potassium sodium tartrate and stirred for 1 hour. It was filtered through a Celite® pad and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 20% ethyl acetate in hexane) to give... Int-12.5. MS(ES): m / z: 366.61 [M+H] + . Synthetic compounds Int-12.6. At 0℃ to Int-12.5 (11.4 g, 31.23 mmol, 1.0 equivalent) was added to a solution of sodium borohydride (11.4 g, 62.46 mmol, 2.0 equivalent) in methanol (125 mL) and stirred for 1 hour. The solution was poured into dilute hydrochloric acid (30 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 40% ethyl acetate in hexane) to obtain… Int-12.6. MS(ES): m / z: 368.41 [M+H] + . Synthetic compounds Int-12.7. At 0℃ to Int-12.6 (9.75 g, 26.56 mmol, 1.0 equivalent) and triethylamine (10.7 g, 106.26 mmol, 4.0 equivalent) were added to a solution of methanesulfonyl chloride (6.05 g, 53.13 mmol, 2.0 equivalent) in DCM (130 mL). The reaction mixture was stirred at room temperature for 30 minutes, transferred to 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 silica gel rapid column chromatography (CombiFlash®, 28% ethyl acetate in hexane) to give Int-12.7. MS(ES): m / z: 446.81 [M+H] + . Synthetic compounds Int-12.8. at 0℃ Int-12.7 (7.8 g, 17.52 mmol, 1.0 equivalent) was added to a solution of trifluoromethanesulfonic acid (20.0 mL) in DCM (150 mL) and stirred for 15 minutes. The solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 2% methanol in DCM) to obtain… Int-12.8. MS(ES): m / z: 356.36 [M+H] + . Synthetic compounds Int-12.9. at room temperature Int-12.8 (4.1 g, 11.54 mmol, 1.0 equivalent) was added to a solution of dimethyl sulfoxide (60 mL) with sodium hydride (60%, 2.30 g, 57.74 mmol, 5.0 equivalent) and stirred for 2 hours. The solution was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 25% ethyl acetate in hexane) to give... Int-12.9. MS(ES): m / z: 260.26 [M+H] + . Synthetic compounds Int-12.10. At room temperature to Int-12.9 (1.9 g, 7.33 mmol, 1.0 equivalent) was added to a solution of ethanol and water (1:1, 25 mL) with hydroxylamine hydrochloride (20.24 g, 293.43 mmol, 40.0 equivalent). The reaction mixture was stirred at 120 °C for 4 hours. It was then 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 silica gel rapid column chromatography (CombiFlash®, 4.2% methanol in DCM) to give... Int-12.10. MS(ES): m / z: 182.27 [M+H] + . Synthetic compound Int-12. Compound Int-12 is prepared according to the synthesis procedure described in Int-3, starting from Int-12.10. The product was purified by silica gel flash column chromatography (CombiFlash®, DCM). MS(ES): m / z 224.1 [M+H] + . Preparation of intermediate Int-13 : 1-(tert-Butyl)-6-isothiocyanato-2,3-dihydro-1 H-imidazo[1,2- b]pyrazole Synthetic compound Int-13.1. A mixture of dimethyl 1H-pyrazole-3,5-dicarboxylate (25 g, 135.76 mmol, 1.0 equivalent), potassium carbonate (28.10 g, 203.64 mmol, 1.5 equivalents) and ((2-bromoethoxy)methyl)benzene (37.96 g, 176.49 mmol, 1.3 equivalents) in acetonitrile (250 mL) was stirred at 80 °C for 4 h. It was cooled to room temperature, transferred to 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 Int-13.1. MS(ES): m / z 319.1 [M+H] m / z 319.1 [M+H] + . Synthetic compound Int-13.2. A solution of Int-13.1 (32.5 g, 102.10 mmol, 1.0 equivalent) and potassium hydroxide (5.61 g, 102.10 mmol, 1.0 equivalent) in methanol (200 mL) was stirred at room temperature under a nitrogen atmosphere for 16 h. It was concentrated under reduced pressure. The residue was added to water, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-13.2. MS(ES): Int-13.2. MS(ES): m / z 305.2 [M+H] +. Synthetic compounds Int-13.3. The compound was introduced into the atmosphere under nitrogen at room temperature. Diphenylphosphoazide (30.9 g, 112.39 mmol, 1.2 equivalents) was added to a solution of Int-13.2 (28.50 g, 93.66 mmol, 1.0 equivalents) and triethylamine (16.2 mL, 112.39 mmol, 1.2 equivalents) in tert-butanol (40 mL). The reaction mixture was stirred at 80 °C for 3 hours. It was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 25-30% ethyl acetate in hexane) to give Int-13.3. MS(ES): m / z: 376.7 [M+H] + . Synthetic compounds Int-13.4. The compound A mixture of Int-13.3 (21.0 g, 55.94 mmol, 1.0 equivalent) and 20% palladium hydroxide (5.25 g) in methanol (210 mL) was stirred under hydrogen for 8 hours. The mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure to obtain… Int-13.4. MS(ES): m / z:286 [M+H] + . Synthetic compounds Int-13.5. At 0°C, the compound... Int-13.4 (15 g, 52.58 mmol, 1.0 equivalent) was added to a solution of tri-tert-butylphosphine (15.93 g, 78.87 mmol, 1.5 equivalent) in THF (300 mL), followed by the addition of diethyl azodicarbonate (19.87 g, 78.87 mmol, 1.5 equivalent). The reaction mixture was stirred at room temperature for 2 hours. It was then transferred to 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 silica gel rapid column chromatography (CombiFlash®, 50-55% ethyl acetate in hexane) to give Int-13.5. MS(ES): m / z: 268.7 [M+H] + . Synthetic compounds Int-13.6. To A solution of Int-13.5 (13.0 g, 48.64 mmol, 1.0 equivalent) in a mixture of THF and methanol (100 mL, 5:1) was mixed with an aqueous solution of lithium hydroxide (6.1 g, 145.92 mmol, 3.0 equivalent) 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] + . Synthetic compounds Int-13.7. To the compound at room temperature Int-13.6 (9.5 g, 37.51 mmol, 1.0 equivalent) was suspended in toluene (20 mL) and then mixed with benzyl alcohol (4.8 g, 45.01 mmol, 1.2 equivalent), diphenylphosphoazide (12.33 g, 45.01 mmol, 1.2 equivalent), and triethylamine (6.8 mL, 48.76 mmol, 1.3 equivalent). The reaction mixture was stirred at 100 °C for 6 hours. It was then transferred to 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 wet milling in a mixture of ethyl acetate and methanol (1:1) to obtain... Int-13.7. MS(ES): m / z: 359.7 [M+H] + . Synthetic compounds Int-13.8. at room temperature Int-13.7 (8.2 g, 22.88 mmol, 1.0 equivalent) was added to a solution of trifluoroacetic acid (82 mL) in DCM (5 mL). The reaction mixture was stirred for 3 hours. It was then transferred to a mixture of ice and saturated sodium bicarbonate solution and extracted with 10% methanol from 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 / z259 [M+H] + . Synthetic compounds Int-13.9. To Int-13.8 (7.0 g, 27.10 mmol, 1.0 equivalent) was added to a solution of boron trifluoride in a mixture of DCM and toluene (1:1, 350 mL) (7 mL), followed by the addition of tert-butyl 2,2,2-trichloroacetyliminolate (11.84 g, 54.20 mmol, 2.0 equivalent) at room temperature. The reaction mixture was stirred for 16 hours. It was then transferred to an aqueous sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 2.3–2.5% methanol in DCM) to give Int-13.9. MS(ES): m / z 315.2 [M+H] + . Synthetic compounds Int-13.10. [The compound] A mixture of Int-13.9 (2.8 g, 8.91 mmol, 1.0 equivalent) and 20% palladium hydroxide (0.700 g) in methanol (42 mL) was stirred at hydrogen (1 atm) for 3 hours. The reaction mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by silicone rapid column chromatography (CombiFlash®, 3-3.5% methanol in DCM) to obtain Int-13.10. MS(ES): m / z: 181.6 [M+H] + . Synthetic compounds Int-13. Towards Int-13.10 (1.0 g, 5.55 mmol, 1.0 equivalent) was dissolved in acetonitrile (15 mL), followed by the addition of imidazole (0.096 g, 1.66 mmol, 0.3 equivalent), and then thiocarbonyl diimidazole (1.9 g, 11.1 mmol, 2.0 equivalent). The mixture was stirred at room temperature for 1 hour. The solution was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 100% DCM) to obtain… Int-13. MS(ES): m / z:223 [M+H] + . Preparation of intermediates Int-14 2-Isocyanothio-6,6-dimethyl-6,7-dihydro-4 H-pyrazolo[5,1- c][1,4]oxazine Synthetic compounds Int-14.1. At 0°C, 5-nitro-1 H-pyrazole-3-carboxylic acid (5.0 g, 8.51 mmol, 1.0 equivalent) was added dropwise to a solution in THF (100 mL) with DMF (0.1 mL) and oxalic acid (3.58 mL, 9.50 mmol, 1.3 equivalent) and stirred at room temperature for 2 hours. Most of the solvent was removed under reduced pressure, and the residue was dissolved in THF with the addition of lithium borohydride (24 mL, 4.70 mmol, 1.3 equivalent). The mixture was stirred at room temperature for 16 hours. It was then transferred to 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 silica gel rapid column chromatography (CombiFlash®, 2.5% methanol in DCM) to obtain... Int-14.1. MS (ES): m / z 143.10 [M+H] + . Synthetic compounds Int-14.2. A mixture of Int-14.1 (1.7 g, 11.77 mmol, 1.0 equivalent) and cesium carbonate (0.772 g, 2.377 mmol, 0.2 equivalent) in 30 mL of 2,2-dimethylethylene oxide was stirred at 70 °C for 3 hours. The mixture was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 1.2% methanol in DCM) to obtain… Int-14.2. MS (ES): m / z 216.81 [M+H] + . Synthetic compounds Int-14.3. will A solution of Int-14.2 (0.5 g, 2.32 mmol, 1.0 equivalent) in sulfuric acid (10 mL) was stirred at 45 °C for 16 hours. The solution was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 0.5% methanol in DCM) to obtain… Int-14.3. MS (ES): m / z198.19 [M+H] + . Synthetic compounds Int-14.4. Palladium / carbon (10%; 0.200 g) and compounds A mixture of Int-14.3 (350 g, 5.72 mmol, 1.0 equivalent) in methanol (5 mL) was stirred under hydrogen for 2 hours. The reaction mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure to give Int-14.4. MS(ES): m / z 168.21 [M+H] + . Synthetic compounds Int-14. Compound Int-14 series based on synthesis The program described in Int-3, from Int-14.4 was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, 1.5% methanol in DCM). MS (ES): m / z 210.27 [M+H] + . Preparation of intermediates Int-15 : 1-(2-(benzyloxy)ethyl)-3-isocyanothio-5-(trifluoromethyl)pyridine-2(1 H)-ketone Synthetic compounds Int-15.1. At 0°C, 5-(trifluoromethyl)pyridine-2(1 H)-ketone (5.0 g, 30.66 mmol, 1.0 equivalent) was dissolved in concentrated sulfuric acid (25 mL) with fuming nitric acid (8 mL). The reaction mixture was stirred at 65 °C for 6 hours. It was then 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 silica gel rapid column chromatography (CombiFlash®, 2.5% methanol in DCM) to give... Int-15.1. MS(ES): m / z 209.10 [M+H] + . Synthetic compounds Int-15.2. A mixture of Int-15.1 (0.5 g, 2.4 mmol, 1.0 equivalent) and potassium carbonate (0.662 g, 4.8 mmol, 2.0 equivalent) in DMF (7 mL) was stirred for 15 minutes. (2-bromoethoxy)methyl)benzene (0.775 g, 3.6 mmol, 1.5 equivalent) was added to the mixture at 110 °C and stirred for 2 hours. The mixture was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 30% ethyl acetate in hexane) to give... Int-15.2. MS(ES): m / z343.2 [M+H] + . Synthetic compounds Int-15.3. will A mixture of Int-15.2 (0.322 g, 0.940 mmol, 1.0 equivalent), iron powder (0.263 g, 4.7 mmol, 5.0 equivalent), and ammonium chloride (0.253 g, 4.7 mmol, 5.0 equivalent) in ethanol:water (2:1, 10 mL) was stirred at 80 °C for 2 hours. The mixture was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 2.5% methanol in DCM) to obtain… Int-15.3. MS(ES): m / z313.3 [M+H] + . Synthetic compounds Int-15. Compound Int-15 series based on synthesis The program described in Int-3, from Int-15.3 was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, 1.5% methanol in DCM). MS (ES): m / z355.3 [M+H] + . Hello, preparation of intermediates Int-16 3-Isocyanthio-1-(methyl- d 3)-5-(trifluoromethyl)pyridine-2(1 H)-ketone Synthetic compounds Int-16.1. will The mixture of Int-15.1 (12 g, 57.67 mmol, 1.0 equivalent) and potassium carbonate (23.87 g, 173.01 mmol, 3.0 equivalent) in DMF (140 mL) was stirred for 15 minutes, followed by the addition of iodomethane-d 3 (10.03 g, 69.20 mmol, 1.2 equivalents). The reaction mixture was stirred at 70 °C for 1 hour. It was then transferred to 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 / z226.1 [M+H] + . Synthetic compounds Int-16.2. A mixture of Int-16.1 (10 g, 44.42 mmol, 1.0 equivalent), iron powder (12.43 g, 222.1 mmol, 5.0 equivalent), and acetic acid (17.76 g, 222.1 mmol, 5.0 equivalent) 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 silica gel rapid column chromatography (CombiFlash®, 2.5% methanol in DCM) to give Int-16.2. MS(ES): m / z 196.2 [M+H] + . Synthetic compounds Int-16. compound Int-16 series based on synthesis The program described in Int-3, from Int-16.2 was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, 30% ethyl acetate in hexane). MS (ES): m / z238.1 [M+H] + . Preparation of intermediates (±)-Int-17 2-(tetrahydrofuran-3-yl)-6-(trifluoromethyl)pyridin-4-amine Synthetic compounds A mixture of Int-17.1,2-chloro-6-(trifluoromethyl)pyridin-4-amine (0.600 g, 3.05 mmol, 1.0 equivalent), 2-(4,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (0.898 g, 4.58 mmol, 1.5 equivalent) and potassium carbonate (1.26 g, 9.15 mmol, 3.0 equivalent) in 1,4-dioxane (10 mL) and water (1 mL) was degassed by bubbling with an argon stream for 10 minutes. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM complex (0.125 g, 0.152 mmol, 0.05 equivalent) was added and degassed for 5 minutes. The reaction mixture was stirred at 120 °C for 3 hours. The mixture was cooled to room temperature and filtered through a Celite® pad. The filtrate was 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 silicone rapid column chromatography (CombiFlash®, 1% methanol in DCM) to obtain... Int-17.1. MS(ES): m / z231.19 [M+H] + . Synthetic compounds (±)-Int-17. Palladium / carbon (10%, 0.2 g) and compounds A mixture of Int-17.1 (0.308 g, 1.34 mmol, 1.0 equivalent) in methanol (5 mL) was stirred at hydrogen (1 atm) for 12 hours. The reaction mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure to give (±)-Int-17. MS(ES): m / z233.21 [M+H] + . Preparation of intermediates Int-18 1-(4-Isocyanothio-2-(trifluoromethyl)phenyl)- N, N-Dimethylmethylamine Synthetic compounds Int-18.1. A solution of 4-nitro-2-(trifluoromethyl)benzoic acid (2.0 g, 8.51 mmol, 1.0 equivalent), HATU (1.2 g, 2.92 mmol, 1.1 equivalent), and triethylamine (3.5 g, 2.92 mmol, 3.0 equivalent) in DCM (30 mL) was stirred at room temperature for 30 min. Dimethylamine (4.1 mL, 2.9 mmol, 2.5 equivalent) was added and stirred for 16 h. The mixture was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 2,4-methanol in DCM) to give Int-18.1. MS (ES): m / z262.19 [M+H] + . Synthetic compounds Int-18.2. Palladium / carbon (10%, 0.800 g) and compounds A mixture of Int-18.1 (1.5 g, 5.72 mmol, 1.0 equivalent) in methanol (5 mL) was stirred at hydrogen (1 atm) for 2 hours. The reaction mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure to give Int-18.2. MS(ES): m / z233.21 [M+H] + . Synthetic compounds Int-18.3. To Int-18.2 (0.900 g, 4.58 mmol, 1.0 equivalent) was added to a solution of lithium aluminum hydride (1.088 g, 13.76 mmol, 5.0 equivalent) in THF (15 mL). The mixture was heated to reflux for 1 hour. It was then cooled to room temperature and quenched by stirring with sodium sulfate hydrate powder. The mixture was filtered and washed with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 2.8% methanol in DCM) to give Int-18.3. MS(ES): m / z219.22 M+H] + . Synthetic compounds Int-18. compound Int-18 series based on synthesis The program described in Int-13, since Int-18.3 was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, 2.4% methanol in DCM). MS (ES): m / z261.28 [M+H] + . Preparation of intermediates Int-19 :( S)-2-((3-Isocyanothio-5-(trifluoromethyl)phenoxy)methyl)-1-methylpyrrolidone Synthetic compounds Int-19.1. The reaction of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (0.7 g, 3.35 mmol, 1.0 equivalent) and (…) at 0 °C 0.808 g (4.02 mmol, 1.2 equivalents) of tert-butyl 2-(hydroxymethyl)pyrrolidone-1-carboxylate in DMF (12 mL) was mixed with sodium hydride (0.201 g, 5.025 mmol, 1.5 equivalents), and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 15-17% ethyl acetate in hexane) to give... Int-19.1. MS(ES): m / z 391.0 [M+H] + . Synthetic compounds Int-19.2. The compound A mixture of Int-19.1 (0.420 g, 1.08 mmol, 1.0 equivalent) and 10% palladium / carbon (0.200 g) in methanol (10 mL) was stirred at hydrogen (1 atm) for 2 hours. The reaction mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by silicone rapid column chromatography (CombiFlash®, 20-23% ethyl acetate in hexane) to give Int-19.2. MS(ES): m / z361.2 [M+H] +. Synthetic compounds Int-19.3. At 0℃ to Int-19.2 (0.270 g, 0.749 mmol, 1.0 equivalent) was added to a solution of lithium aluminum hydride (1 M, 5.2 mL, 5.243 mmol, 7.0 equivalent in THF) in 5 mL of THF. 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 silica gel rapid column chromatography (CombiFlash®, 60-65% ethyl acetate in hexane) to give Int-19.3. MS(ES): m / z 275.1 [M+H] + . Synthetic compounds Int-19. compound Int-19 series based on synthesis The program described in Int-13, since Int-19.3 was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, 1.5% methanol in DCM). MS (ES): m / z 317.2 [M+H] + . Preparation of intermediates Int-20 :( R)-2-((3-Isocyanothio-5-(trifluoromethyl)phenoxy)methyl)-1-methylpyrrolidone Synthetic compounds Int-20. Compound The Int-20 series is based on synthesis The product was prepared using the procedure described in Int-19. The product was purified by silicone rapid column chromatography (CombiFlash®, 1.5% methanol in DCM). MS (ES): m / z317.3 [M+H] + . Preparation of intermediates Int-21 :( S)-3-(3-Isocyanthio-5-(trifluoromethyl)phenoxy)-1-methylpyrrolidone Synthetic compounds Int-21.1. The reaction of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (1.0 g, 4.78 mmol, 1.0 equivalent) and (…) at 0 °C S)-1-methylpyrrolidin-3-ol (0.580 g, 5.74 mmol, 1.2 equivalents) was added to a solution of sodium hydride (0.382 g, 9.56 mmol, 2.0 equivalents) in DMF (10 mL) and stirred at room temperature for 30 minutes. The solution was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 3.0% methanol in DCM) to give... Int-21.1. MS(ES): m / z 291.2 [M+H] + . Synthetic compounds Int-21.2. The compound A mixture of Int-21.1 (0.670 g, 2.31 mmol, 1.0 equivalent) and 10% palladium / carbon (0.350 g) in methanol (5 mL) was stirred at hydrogen (1 atm) for 1 hour. The reaction mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure to obtain Int-21.1. MS(ES): m / z261.1 [M+H] + . Synthetic compounds Int-21. Compound The Int-21 series is based on synthesis The program described in Int-13, since Int-21.2 was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, 2.0% methanol in DCM). MS (ES): m / z303.2 [M+H] + . Preparation of compounds Int-22 :( S)-3-(3-Isocyanthio-5-(trifluoromethyl)phenoxy)-1-methylpyrrolidone Synthetic compounds Int-22. Compound The Int-22 series is based on the synthesis The product was prepared using the procedure described in Int-21. The product was purified by silicone rapid column chromatography (CombiFlash®, 2.0% methanol in DCM). MS (ES): m / z303.2 [M+H] + . Preparation of intermediates Int-23 3-((3-amino-5-(trifluoromethyl)benzyl)oxy)azacyclobutane-1-carboxylic acid tributyl ester Synthetic compounds Int-23.1. Triphenylphosphine (4.74 g, 18.09 mmol, 2.0 equivalent) was added to a solution of (3-nitro-5-(trifluoromethyl)phenyl)methanol (2.0 g, 9.04 mmol, 1.0 equivalent) in THF (30 mL) at 0 °C, followed by the addition of N-bromosuccinimide (3.22 g, 18.09 mmol, 2.0 equivalent). The reaction mixture was stirred at room temperature for 16 hours. It was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 15% ethyl acetate in hexane) to give Int-23.1. MS(ES): m / z 285.32 [M+H] + . Synthetic compounds Int-23.2. At 0℃ to Int-23.1 (0.800 g, 4.62 mmol, 1.0 equivalent) was added fractionally to a solution of THF (10 mL) with NaH (60%, 0.277 g, 6.93 mmol, 1.5 equivalent), and the mixture was stirred for 20 minutes. 3-hydroxyazacyclobutane-1-carboxylic acid tributyl ester (1.6 g, 5.54 mmol, 1.2 equivalent) was added dropwise to a solution of THF (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. It was then transferred to 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 silica gel rapid column chromatography (CombiFlash®, 20% ethyl acetate in hexane) to obtain… Int-23.2. MS(ES): m / z 377.62 [M+H] + . Synthetic compounds Int-23. will A mixture of Int-23.2 (0.850 g, 2.26 mmol, 1.0 equivalent) and 10% palladium / carbon (0.450 g) in methanol (15 mL) was stirred at hydrogen (1 atm) for 2 hours. The reaction mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure to obtain Int-23. MS(ES): m / z 347.51 [M+H] + . Preparation of intermediates Int-24-a and I-24-b :( R)-2-(3-isocyanothio-5-(trifluoromethyl)phenyl)-1-methylpyrrolidone and ( S)-2-(3-isocyanothio-5-(trifluoromethyl)phenyl)-1-methylpyrrolidone Synthetic compounds Int-24.1,3-bromo-5-(trifluoromethyl)aniline (2.5 g, 10.42 mmol, 1.0 equivalent), (1-(tert-butoxycarbonyl)-1 A mixture of H-pyrrolo-2-yl)boronic acid (4.4 g, 20.83 mmol, 2.0 equivalent) and sodium carbonate (3.31 g, 31.26 mmol, 3.0 equivalent) in dimethoxyethane (25 mL) was degassed by bubbling through a stream of argon for 10 minutes. Tetra(triphenylphosphine)palladium(0) (1.2 g, 1.042 mmol, 0.1 equivalent) was added and degassed for 5 minutes. The reaction mixture was stirred at 80 °C for 5 hours. It was 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 silica gel rapid column chromatography (CombiFlash®, 2.5% methanol in DCM) to obtain... Int-24.1. MS(ES): m / z 327.2 [M+H] + . Synthetic compounds (±)-Int-24.2. The compound A mixture of Int-24.1 (2.1 g, 6.44 mmol, 1.0 equivalent) and 20% palladium hydroxide (1.0 g) in methanol (20 mL) was stirred at hydrogen (1 atm) for 1 hour. The reaction mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure to obtain (±)-Int-24.2. MS(ES): m / z331.1 [M+H] + . Synthetic compounds (±)-Int-24.3. At 0℃ (±)-Int-24.2 (1.37 g, 4.15 mmol, 1.0 equivalent) was added to a solution of lithium aluminum hydride (1 M, 29 mL, 29.05 mmol, 7.0 equivalent in THF) in 10 mL. 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] +The racemic mixture was separated by chiral HPLC (CHIRALPAK AD-H column (250 mm × 21 mm, 5 μm); mobile phase: (A) 0.1% DEA in n-hexane, (B) 0.1% DEA in isopropanol; flow rate = 30 mL / min), yielding the first precipitate ( Int-24.3-a) and the second precipitation part ( Int-24.3-b). MS(ES): m / z: 245.1 [M+H] + . Synthetic compounds Int-24 -a and Int-24-b compound Int-24-a and Int-24-b series based on synthesis The programs described in Int-13, respectively from Int-24.3-a and Int-24.4-b was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, 12% ethyl acetate in hexane). MS (ES): m / z 287.2 [M+H] + . Preparation of intermediates Int-25 3-(3-amino-5-(trifluoromethyl)phenoxy)azacyclobutane-1-carboxylic acid tributyl ester Synthetic compounds Int-25.1. Sodium hydride (0.313 g, 7.17 mmol, 1.5 equivalent) was added to a solution of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (1.0 g, 4.78 mmol, 1.0 equivalent) in DMF (10 mL) at 0 °C and stirred for 1 h. Tertiary butyl 3-hydroxyazacyclobutane-1-carboxylate (1.24 g, 7.17 mmol, 1.5 equivalent) was added to the mixture. The reaction mixture was stirred at room temperature for 2 h. It was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 38% ethyl acetate in hexane) to give Int-25.1. MS(ES): m / z: 363.31 [M+H] + . Synthetic compounds Int-25. will A mixture of Int-25.1 (0.700 g, 1.93 mmol, 1.0 equivalent), iron powder (0.541 g, 9.66 mmol, 5.0 equivalent), and ammonium chloride (0.512 g, 9.66 mmol, 5.0 equivalent) in ethanol:water (8:2, 6 mL) was stirred at 80 °C for 2 hours. The reaction mixture was filtered through a Celite® pad and washed with ethanol. The filtrate was concentrated under reduced pressure. The residue was purified by silicone rapid column chromatography (CombiFlash®, 63% ethyl acetate in hexane) to give Int-25. MS(ES): m / z333.32 [M+H] + . Preparation of intermediates Int-26 3-Isocyanthio-1-(7-oxaspiro[3.5]nonane-2-yl)-5-(trifluoromethyl)-1 H-pyrazole Synthetic compounds Int-26.1. At 0°C, 4-methylenetetrahydro-2 A solution of H-piperanone (5.0 g, 50.95 mmol, 1.0 equivalent) in tert-butyl methyl ether (100 mL) was followed by the addition of a zinc-copper coupling agent (71.73 g, 560.45 mmol, 11.0 equivalent), and then a solution of diphosgene (37.10 g, 204.08 mmol, 4.0 equivalent) in dimethoxyethane (40 mL). The mixture was stirred at room temperature for 18 hours. It was filtered through a Celite® pad, and the filtrate was washed with sodium bicarbonate solution and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain… Int-26.1. MS(ES): m / z: 210.0 [M+H] + . Synthetic compounds Int-26.2. will A mixture of Int-26.1 (8.9 g, 42.58 mmol, 1.0 equivalent), saturated ammonium chloride aqueous solution, and zinc (27.67 g, 425.8 mmol, 10.0 equivalent) in methanol (200 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered through a Celite® pad, washed with ether, and concentrated under reduced pressure. The residue was purified by silicone rapid column chromatography (CombiFlash®, 30% ethyl acetate in hexane) to give Int-26.2. MS(ES): m / z: 141.1 [M+H] + . Synthetic compounds Int-26.3. At 0℃ Int-26.2 (3.9 g, 27.82 mmol, 1.0 equivalent) was dissolved in methanol (40 mL) and sodium borohydride (0.308 g, 8.34 mmol, 0.3 equivalent) was added and stirred at room temperature for 16 hours. The solution was transferred to 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… Int-26.3. MS(ES): m / z: 143.1 [M+H] + . Synthetic compounds Int-26.4. At 0℃ Int-26.3 (3.0 g, 21.1 mmol, 1.0 equivalent) and triethylamine (8.8 mL, 63.3 mmol, 3.0 equivalent) were added to a solution of methanesulfonyl chloride (2.4 mL, 31.65 mmol, 1.5 equivalent) in DCM (30 mL). The reaction mixture was stirred at room temperature for 30 minutes. It was then 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 give Int-26.4. MS(ES): m / z: 221.0 [M+H] + . Synthetic compounds Int-26.5. Int-26.4 (2.8 g, 12.22 mmol, 1.0 equivalent), 3-(2,5-dimethyl-1 H-pyrrolo-1-yl)-5-(trifluoromethyl)-1 A mixture of H-pyrazole (4.04 g, 18.32 mmol, 1.3 equivalents) and cesium carbonate (7.94 g, 24.44 mmol, 2.0 equivalents) 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 layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 4.0% ethyl acetate in hexane) to give... Int-26.5. MS (ES): m / z 354.2 [M+H] + . Synthetic compounds Int-26.6. will A solution of Int-26.5 (1.5 g, 4.24 mmol, 1.0 equivalent) and hydroxylamine hydrochloride (11.4 g, 169.6 mmol, 40 equivalent) in ethanol:water (2:1, 50 mL) was heated to reflux for 3 hours. The solution was transferred to ice water and 2 N sodium hydroxide was added to adjust the pH to 10. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 2.5% methanol in DCM) to obtain... Int-26.6. MS(ES): m / z276.0 [M+H] + . Synthetic compounds Int-26. compound The Int-26 series is based on synthesis The program described in Int-3, from Int-26.6 was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, DCM). MS (ES): m / z318.2 [M+H] + . Preparation of intermediates Int-27-a and Int-27-b :( R)-2-(4-isocyanothio-2-(trifluoromethyl)phenyl)-1-methylpyrrolidone and ( S)-2-(4-Isocyanothio-2-(trifluoromethyl)phenyl)-1-methylpyrrolidone Synthetic compounds Int-27.1. To 4-bromo-3-(trifluoromethyl)aniline (3.0 g, 12.5 mmol, 1.0 equivalent), (1-(tert-butoxycarbonyl)-1 A mixture of H-pyrrolo-2-yl)boronic acid (3.9 g, 18.7 mmol, 1.5 equivalents) and sodium carbonate (5.2 g, 50.02 mmol, 4.0 equivalents) in dimethoxyethane (40 mL) was degassed by bubbling with argon for 10 minutes. Tetra(triphenylphosphine)palladium(0) (1.2 g, 1.3 mmol, 0.9 equivalents) was added, and degassed for 5 minutes. The reaction mixture was stirred at 80 °C for 5 hours. It was 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 silica gel rapid column chromatography (CombiFlash®, 8.0% methanol in DCM) to obtain... Int-27.1. MS(ES): m / z 327.32 [M+H] + . Synthetic compounds (±)-Int-27.2. The compound A mixture of Int-27.1 (1.4 g, 4.29 mmol, 1.0 equivalent) and 20% palladium hydroxide (1.0 g) in methanol (38 mL) was stirred at hydrogen (1 atm) for 7 hours. The reaction mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure to give (±)-Int-27.2. MS(ES): m / z331.35 [M+H] + Racemic fractions were separated by chiral SFC: (Column: CHIRALPAK AD-H (250 mm × 4.6 mm, 5 μm); Mobile phase: (A) CO 2(B) Isopropanol:acetonitrile (50:50) with 0.1% diethylamine; flow rate = 75 mL / min), yielding the first precipitate ( Int-27.2-a) and the second precipitation part ( Int-27.2-b). Synthetic compounds Int-27.3-a and Int-27.3-b. at 0°C Int-27.2-a (0.410 g, 1.24 mmol, 1.0 equivalent) was added to a solution of lithium aluminum hydride (1 M, 8.6 mL, 8.69 mmol, 7.0 equivalent in THF) in 10 mL. The reaction mixture was heated to reflux for 30 minutes. It was cooled to room temperature and stirred with sodium sulfate decahydrate. The solid was removed by filtration and washed with ethyl acetate. The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Int-27.2-a. MS(ES): m / z 245.26 [M+H] + . The Int-27.3-b series follows the same procedure, from... Preparation of Int-27.2-b. Synthetic compounds Int-27-a and Int-27-b compound Int-27-a series based on synthesis The program described in Int-13, since Int-27.3-a was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, 2.1% methanol in DCM). MS (ES): m / z 287.32 [M+H] + . The Int-27-b series follows the same method. Preparation of Int-27.3-b. Preparation of intermediates Int-28 4-Isocyanthio-2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridine Synthetic compounds Int-28.1. A mixture of 2-chloro-6-(trifluoromethyl)pyridin-4-amine (0.500 g, 2.54 mmol, 1.0 equivalent), pyrrolidine (0.271 g, 3.82 mmol, 1.5 equivalent), and potassium carbonate (1.05 g, 7.62 mmol, 3.0 equivalent) in DMF (5 mL) was stirred at 150 °C for 18 hours. The mixture was 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 silica gel rapid column chromatography (CombiFlash®, 20-30% ethyl acetate in hexane) to give... Int-28.1. MS(ES): m / z 232.5 [M+H] + . Synthetic compounds Int-28 compound Int-28 series based on synthesis The program described in Int-3, from Int-28.1 was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, 5-10% ethyl acetate in hexane). MS (ES): m / z 274.5 [M+H] + . Preparation of intermediates Int-29 2'-Isocyanothio-5',6'-dihydrospiro[cyclobutane-1,4'-pyrrolo[1,2- b]Pyrazole] Synthetic compounds Int-29.1. At -78°C, a solution of 6-oxaspiro[3.4]oct-5-one (1.0 g, 7.93 mmol, 1.0 equivalent) and acetonitrile (0.83 mL, 15.86 mmol, 2.0 equivalent) in anhydrous THF (25 mL) was added to a solution of bis(trimethylsilyl)aminolithium (1 M in THF, 17.4 mL, 17.44 mmol, 2.2 equivalent) in anhydrous THF (8 mL). The reaction mixture was stirred at -78°C for 30 min and then warmed to room temperature and stirred for 2 h. It was transferred to a saturated aqueous solution of ammonium chloride 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, which was purified by silica gel rapid column chromatography (CombiFlash®, 20% ethyl acetate in hexane) to obtain Int-29.1. Synthetic compounds Int-29.2. To Int-29.1 (0.800 g, 4.78 mmol, 1.0 equivalent) was dissolved in ethanol (10 mL) with hydrazine monohydrate (0.358 g, 7.17 mmol, 1.5 equivalent). The reaction mixture was stirred at 60 °C for 72 hours. The reaction mixture was then cooled to room temperature and bubbled through it with carbon dioxide for 1 hour. The reaction mixture was concentrated under reduced pressure. Methanol (15 mL) was added to the residue, and the mixture was stirred, with the precipitated solids removed by filtration. The filtrate was concentrated under reduced pressure to obtain... Int-29.2. MS(ES): m / z 182.1 [M+H] + . Synthetic compounds Int-29.3. To Int-29.2 (0.610 g, 3.37 mmol, 1.0 equivalent) was added to a solution of thionyl chloride (1.22 mL, 16.85 mmol, 5.0 equivalent) in 10 mL of THF. The reaction mixture was stirred at room temperature for 3 hours. It was then 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, which was purified by silica gel rapid column chromatography (CombiFlash®, 2% methanol in DCM) to obtain... Int-29.3. MS(ES): m / z 164.1 [M+H] + . Synthetic compounds Int-29 compound Int-29 series based on synthesis The program described in Int-3, from Int-29.3 was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, DCM). MS (ES): m / z 205.9 [M+H] + . Preparation of intermediates Int-30 2'-Isocyanothio-5'-methyl-6',7'-dihydro-5' H-spiro[cyclopropane-1,4'-pyrazolo[1,5-] [a]Pyrazine Synthetic compounds Int-30.1. At room temperature to Int-8.2 (0.600 g, 4.81 mmol, 1.0 equivalent) was added to a solution of toluene (6 mL) with hexane-2,5-dione (0.618 g, 5.41 mmol, 1.5 equivalent), followed by the addition of acetic acid (catalyst). The reaction mixture was stirred at 130 °C for 3 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 0.5% methanol in DCM) to obtain... Int-30.1. MS(ES): m / z245 [M+H] + . Synthetic compounds Int-30.2. At 80℃ Int-30.2 (0.500 g, 2.55 mmol, 1.0 equivalent) was added to a solution of titanium isopropoxide (1.45 g, 5.102 mmol, 2.0 equivalent) in THF (10 mL), followed by the addition of ethyl magnesium bromide (1 M in THF, 3.4 mL, 10.2 mmol, 4.0 equivalent). The reaction mixture was stirred for 30 minutes. It was transferred to 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 substance. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 15% ethyl acetate in hexane) to give... Int-30.2. MS(ES): m / z:257[M+H] + . Synthetic compounds Int-30.3. To Int-30.3 (0.450 g, 1.75 mmol, 1.0 equivalent) was added to a solution of ethanol (8 mL) and water (2 mL) with hydroxylamine hydrochloride (3.65 g, 52.5 mmol, 30.0 equivalent). The reaction mixture was stirred at 60 °C for 1 hour. It was then transferred to 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 wet milling with diethyl ether to obtain... Int-30.3. MS(ES): m / z:179 [M+H] + . Synthetic compounds Int-30. Compound The Int-30 series is based on synthesis The program described in Int-3, from Int-30.3 was prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, 0.5% methanol in DCM). MS (ES): m / z221 [M+H] + . Preparation of the provided compound Example 1 :( R)- N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1) H-pyrazole-3-yl)amino)-1-methyl-1 H-Imidazo[4,5- b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxyazine-1-methylamine Synthetic compounds 1.1. Sodium hydride (12.61 g, 315.38 mmol, 1.0 equivalent) was added aliquots to a solution of benzyl alcohol (17.05 g, 157.69 mmol, 1.0 equivalent) in THF (250 mL) at 0 °C. The mixture was stirred for 1 hour and 2-chloro-4-nitropyridine (25 g, 157.69 mmol, 1.0 equivalent) was added aliquots. 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 silica gel rapid column chromatography (CombiFlash®, with 10% ethyl acetate in hexane as the solvent) to give 1.1. MS (ES): m / z220.13 [M+H] + . Synthetic compounds 1. 2. Compounds 1. A solution of 1 (20 g, 91.05 mmol, 1.0 equivalent) in THF (200 mL) was degassed by bubbling with argon for 10 min. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (4.34 g, 9.105 mmol, 0.1 equivalent) and tris(benzylacetone)palladium (4.17 g, 4.55 mmol, 0.05 equivalent) were added under an argon atmosphere and degassed by bubbling with argon for 5 min. A solution of bis(trimethylsilyl)aminolithium (1 M in THF, 182 mL, 182.1 mmol, 2.0 equivalent) was added to the mixture and stirred at 60 °C for 1 h. The reaction mixture was cooled to room temperature, poured over ice water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silicone rapid column chromatography (CombiFlash®, 3% methanol as solvent in DCM) to obtain... 1.2. MS (ES): m / z201.2 [M+H] + . Synthetic compounds 1.3. At 0℃ 1.2 phenyl chloroformate (4.67 g, 29.97 mmol, 3.0 equivalent) was added dropwise to a solution of 1.2 (2.0 g, 9.99 mmol, 1.0 equivalent) and triethylamine (4.2 mL, 29.97 mmol, 3.0 equivalent) in THF (20 mL). The reaction mixture was stirred at room temperature for 3 hours. It was then 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... 1.1. MS (ES): m / z321.3 [M+H] + It was used in the next step without further purification. Synthetic compounds 1.4. At 0℃ 1.3 (3.0 g, 9.36 mmol, 1.0 equivalent) and triethylamine (12.5 mL, 84.24 mmol, 9.0 equivalent) were added dropwise to a solution of 3-methoxyazinesepane (1.06 g, 12.17 mmol, 1.3 equivalent) in 20 mL of DMF. The reaction mixture was stirred at room temperature for 16 hours. It was 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 silica gel rapid column chromatography (CombiFlash®, 2.5% methanol in DCM) to give 1.4. MS (ES): m / z314.3 [M+H] + . Synthetic compounds 1.5. The compound A mixture of 1.4 g (1.1 g, 3.51 mmol, 1.0 equivalent) and 10% palladium / carbon (0.5 g) in methanol (10 mL) was stirred at hydrogen (1 atm) for 3 hours. The mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure to obtain… 1.5. MS(ES): m / z 224.2 [M+H] + . Synthetic compounds 1.6. 1.5 (0.760 g, 3.4 mmol, 1.0 equivalent) in DMF (10 mL), The mixture of Int-1 (0.699 g, 4.09 mmol, 1.2 equivalents) and sodium carbonate (0.720 g, 6.8 mmol, 2.0 equivalents) was stirred at 90 °C for 12 hours. It was then 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 silica gel rapid column chromatography (CombiFlash®, 2.8% methanol in DCM) to obtain... 1.6. MS(ES): m / z 375.3 [M+H] + . Synthetic compounds 1.7. To 1.6 Iron powder (0.733 g, 13.09 mmol, 7.0 equivalent) was added to a solution of 1.6 g (0.700 g, 1.87 mmol, 1.0 equivalent) in ethanol-water (2:1, 10 mL), followed by ammonium chloride (0.706 g, 13.09 mmol, 7.0 equivalent). 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 silica gel rapid column chromatography (CombiFlash®, 3.5% methanol in DCM) to give... 1.6. MS(ES): m / z 345.5 [M+H] + . Synthetic compounds 1.8. To 1.7% (0.400 g, 1.16 mmol, 1.0 equivalent) of 1,1'-thiocarbonyldiimidazole (1.03 g, 5.8 mmol, 5.0 equivalent) was added to a solution of 1,1'-thiocarbonyldiimidazole in THF (5 mL). The reaction mixture was stirred at 70 °C for 1 hour. It was then cooled to room temperature and poured into ice water. The precipitated solid was collected by filtration and wet-milled with hexane to obtain... 1.8. MS(ES): m / z: 387.4 [M+H] + . Synthetic compounds 1.9. At 0℃ 1.8 μg (0.350 g, 0.905 mmol, 1.0 equivalent) of sulfonyl chloride (2.7 mL, 33.48 mmol, 37 equivalent) was added to a solution in DCM (5 mL) and stirred for 10 min. The solution was transferred to a saturated sodium bicarbonate solution, stirred, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 2.4% methanol in DCM) to obtain… 1.9. MS (ES): m / z 389.8 [M+H] + . Synthetic compounds 1. 1.9 (0.080 g, 0.205 mmol, 1.0 equivalent) A mixture of Int-3 (0.052 g, 0.246 mmol, 1.2 equivalents) and potassium carbonate (0.070 g, 0.512 mmol, 2.5 equivalents) in 1,4-dioxane (2 mL) was degassed by bubbling through an argon stream for 10 minutes. 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopiperanan (0.023 g, 0.041 mmol, 0.2 equivalents) and tris(dibenzylacetone)dipalladium(0) (0.01 g, 0.021 mmol, 0.1 equivalents) were added, followed by further degassed for 5 minutes. The reaction mixture was stirred at 80 °C for 3 hours. After cooling to room temperature, it was 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 silicone rapid column chromatography (CombiFlash®, 3.0% methanol in DCM) to obtain the compound. 1. MS(ES): m / z: 562.6 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 9.89 (s, 1H), 9.20 (s, 1H), 8.11-8.10 (d, J = 5.6 Hz, 1H), 7.96-7.95 (d, J = 2.4Hz, 1H), 7.63-7.62 (d, J= 2.4Hz, 1H), 7.47 (bs, 1H), 6.60-6.58 (m, 2H), 5.77(s, 1H), 5.26 (bs, 1H), 4.13-4.07 (m, 5H), 3.88-3.83 (m, 2H), 3.75-3.73 (m, 2H), 3.68 (s, 3H), 3.19 (s, 3H), 2.27-2.24 (m, 1H), 1.41 (s, 9H). Example 3 :(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b] Pyridin-6-yl)oxy)pyridin-2-yl)aminocarbamate methyl ester Synthetic compounds 3.1. A mixture of benzyl alcohol (102.3 g, 946.13 mmol, 1.0 equivalent) and cesium carbonate (768.7 g, 2365.3 mmol, 2.5 equivalent) 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 equivalent) in DMF (500 mL) was added and stirred for 16 hours. The mixture was poured into ice water, stirred, and the precipitated solid was collected by filtration and dried under vacuum to obtain... 3.1. MS (ES): m / z 220.5 [M+H] + . Synthetic compounds 3.2. 3.1 A solution of 150 g (682.85 mmol, 1.0 equivalent) in THF (1500 mL) was degassed by bubbling with an argon stream for 10 minutes. 2-Dicyclohexyl[2′,4′,6′-tris(propane-2-yl)[1,1′-biphenyl]-2-yl]phosphine (32.55 g, 68.28 mmol, 0.1 equivalent) and tris(benzylacetone)dipalladium(0) (31.26 g, 34.14 mmol, 0.05 equivalent) were added to the solution, followed by further degassed for 10 minutes. A solution of bis(trimethylsilyl)aminolithium (1 M in THF, 1365 mL, 1365.7 mmol, 2.0 equivalent) was added, and the reaction mixture was stirred at 60 °C for 1 hour. The mixture was then concentrated under reduced pressure. The residue was added to ice and slowly extracted with 6 N hydrochloric acid (1500 mL) 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 / z201.2 [M+H] + It was used in the next step without being purified. Synthetic compounds 3.3. At 0℃ 3.2 Dibutyl dicarbonate (130.5 g, 598.8 mmol, 1.2 equivalents) was added to a solution of 100 g (499 mmol, 1.0 equivalent) in 1000 mL of methanol. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the precipitated solid was filtered off, washed with methanol, and dried under vacuum to obtain... 3.3. MS(ES): m / z 259.2 [M+H] + . Synthetic compounds 3.4. A mixture of 3.3 (106 g, 410.4 mmol, 1.0 equivalent) and 10% palladium / carbon (100 g) in methanol (1000 mL) was stirred at hydrogen (1 atm) for 1 hour. The mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure to obtain... 3.4. MS(ES): m / z 169.1 [M+H] + . Synthetic compounds 3.5. To 3.4 (66 g, 392.5 mmol, 1.0 equivalent) was added to a solution in DMF (660 mL). Int-2 (64.55 g, 314 mmol, 0.8 equivalents) was added, followed by sodium carbonate (124.8 g, 1177.5 mmol, 3.0 equivalents). The reaction mixture was stirred at 60°C for 3 hours. It was then poured into ice water, and the precipitated solid was collected by filtration and vacuum dried to obtain... 3.5. MS(ES): m / z 354.5 [M+H] + . Synthetic compounds 3.6. Compounds 3.6 series based on the synthesized compound The procedure described in 1.7, from compound 3.5 Preparation. The product was purified by silicone rapid column chromatography (CombiFlash®, 7.0% methanol in DCM) to obtain... 3.6. MS(ES): m / z 324.5 [M+H] + . Synthetic compounds 3.7. At 0℃ 3.6 (38 g, 117.38 mmol, 1.0 equivalent) and Int-5 (41.23 g, 176 mmol, 1.5 equivalents) was added to a solution of potassium terbutoxide (1 M in THF, 704 mL, 704.28 mmol, 6.0 equivalents) in 1300 mL of THF. 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 silica gel rapid column chromatography (CombiFlash®, 12% methanol in DCM) to give 3.7. MS(ES): m / z: 524.2 [M+H] + . Synthetic compounds 3.8. To 3.7 Zinc (0.012 g, 0.190 mmol, 0.2 equivalent) and zinc cyanide (0.056 g, 0.477 mmol, 0.5 equivalent) were added to a solution of DMA (11 mL). The reaction mixture was degassed by bubbling with an argon stream for 10 minutes. Tris(benzylacetone)dipalladium(0) (0.131 g, 0.143 mmol, 0.15 equivalent) and 1,1′-bis(diphenylphosphine)ferrocene (0.158 g, 0.286 mmol, 0.3 equivalent) were added, and the mixture was degassed for 5 minutes. The reaction mixture was stirred in a microwave reactor at 190 °C for 2 hours. After cooling to room temperature, the mixture was 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 obtain the substance. synthesis I-3. At 0℃ 3.8 g (9.6 g, 21.03 mmol, 1.0 equivalent) of triethylamine (5.9 mL, 42.06 mmol, 2.0 equivalent) was added to a solution of triethylamine in 200 mL of THF, followed by the addition of methyl chloroformate (1.8 mL, 23.13 mmol, 1.1 equivalent). The reaction mixture was stirred at room temperature for 4 hours. It was then 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 silica gel rapid column chromatography (CombiFlash®, 2.4% methanol in DCM) to give... I-3. MS(ES): m / z: 515.2 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz): δ 10.41 (s, 1H), 9.07 (s, 1H), 8.66 (s, 1H), 8.34 (s, 1H), 8.23-8.21 (d, J= 6.8Hz 2H), 7.49 (s, 1H), 6.76-6.75 (d, J= 5.2Hz 1H), 3.98 (s, 3H), 3.68 (s, 3H), 3.64 (s, 3H). Example 4 3-(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1-dimethylurea synthesis I-4. At 0℃ 3.8 (0.040 g, 0.087 mmol, 1.0 equivalent) and dimethylaminomethylchlorodimethyl chloride (0.010 g, 0.096 mmol, 1.1 equivalent) were added to a solution of potassium tert-butoxide (1 M in THF) in 2 mL of THF (0.52 mL, 0.522 mmol, 6.0 equivalent) 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 layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 2.5% methanol in DCM) to give I-4. MS(ES): m / z: 528.3 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 9.04-9.03 (d, J= 6.8Hz 2H), 8.66 (s, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.48 (s, 1H), 6.69 (bs, 1H), 3.97 (s, 3H), 3.67 (s, 3H), 2.90 (s, 6H). Example 5 :1-(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)-3-methylurea synthesis I-5. At 0℃ 3.8 (0.040 g, 0.087 mmol, 1.0 equivalent) and methylaminomethyl chloride (0.009 g, 0.105 mmol, 1.2 equivalent) in a solution of potassium terebutoxide (1 M in THF) (0.35 mL, 0.348 mmol, 4.0 equivalent) were added 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 layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 4.5% methanol in DCM) to give I-5. MS(ES): m / z: 514.2 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz): δ 9.21 (s, 1H), 9.07 (s, 1H), 8.66-8.65 (d, J= 1.6Hz, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 8.14-8.13 (d, J= 6.0Hz, 1H), 7.80 (bs, 1H), 7.09-7.07 (d, J= 7.2Hz, 1H), 7.04 (s, 1H), 3.98 (s, 3H), 3.67 (s, 3H), 2.70-2.69 (d, 3H). Example 6 : N-(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]pyridin-6-yl)oxy)pyridin-2-yl)-4-methylpiperazine-1-methylamine Synthetic compounds 6.1 At 0℃ 3.8 Phenyl chloroformate (0.012 g, 0.081 mmol, 1.5 equivalent) was added to a solution of 3.8 g (0.025 g, 0.054 mmol, 1.0 equivalent) and triethylamine (0.016 g, 0.162 mmol, 3.0 equivalent) in THF (3 mL). 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 layers were 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] + . synthesis I-6. To 6.1 A solution of 0.030 g (0.052 mmol, 1.0 equivalent) and triethylamine (0.015 g, 0.156 mmol, 3.0 equivalent) in dimethyl sulfoxide (3 mL) was mixed with 1-methylpiperazine (0.008 g, 0.078 mmol, 1.5 equivalent). The reaction mixture was stirred at 80 °C for 15 min. It was then transferred to 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 silica gel rapid column chromatography (CombiFlash®, 7.0% methanol in DCM) to give I-6. MS(ES): m / z: 583.3 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 9.37 (s, 1H), 9.06 (s, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 8.20 (bs, 2H), 7.47 (s, 1H), 6.70 (s, 1H), 3.98 (s, 3H), 3.68 (s, 3H), 3.43 (bs, 4H), 2.45 (bs, 4H), 2.29 (s, 3H). Example 7 : N-(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]pyridin-6-yl)oxy)pyridin-2-yl)azacyclobutane-1-methylamine synthesis I-7 compound I-7 series based on synthesis The procedure described in I-6, from 6.1 Preparation of aziridine hydrochloride. The product was purified by preparative HPLC. MS (ES): m / z: 540.4 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz): δ 9.23 (s, 1H), 9.06 (s, 1H), 8.66 (s, 1H), 8.31 (s, 1H), 8.20 (bs, 1H), 8.18-8.17 (d, J = 6Hz, 1H), 7.58 (s, 1H), 6.68 (s, 1H), 3.98 (s, 3H), 3.95 (bs, 4H), 3.67 (s, 3H), 2.16-2.12 (m, 2H). Example 8 : N-(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]pyridin-6-yl)oxy)pyridin-2-yl)-3-hydroxyazine-1-methylamine synthesis I-8 compound I-8 series based on synthesis The procedure described in I-6, from 6.1 and aziridine-3-ol hydrochloride were prepared. The product was purified by silica gel rapid column chromatography (CombiFlash®, 3.0% methanol in DCM). MS (ES): m / z: 556.3 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 9.29 (s, 1H), 9.05 (s, 1H), 8.66 (s, 1H), 8.31 (s, 1H), 8.20 (bs, 1H), 8.18-8.17 (d, J = 5.6Hz, 1H), 7.58 (bs, 1H), 6.69-6.67 (m, 1H), 5.63-5.62 (d, J = 6.4Hz, 1H), 4.40-4.38 (m, 1H), 4.14-4.11 (m, 2H), 3.97 (s, 3H), 3.67 (s, 3H), 3.19-3.17 (m, 2H). Example 9 : N-(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxyazine-1-methylamine synthesis I-9 compound I-9 series based on synthesis The procedure described in I-6, from 6.1 and 3-methoxyazinocyclic butane hydrochloride were prepared. The product was purified by silica gel rapid column chromatography (CombiFlash®, 3.0% methanol in DCM). MS (ES): m / z: 570.3 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 9.38 (s, 1H), 9.05 (s, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 8.19-8.18 (m, 2H), 7.57 (bs, 1H), 6.69 (bs, 1H), 4.14 (bs, 4H), 3.98 (s, 3H), 3.76 (bs, 1H), 3.68 (s, 3H), 3.20 (s, 3H). Example 10 :(4-((2-((1-(2-oxaspiro[3.3]heptane-6-yl)-5-(trifluoromethyl)-1 H-pyrazole-3-yl)amino)-7-chloro-1-methyl-1 H-Imidazo[4,5- b] Pyridin-6-yl)oxy)pyridin-2-yl)aminocarbamate methyl ester Synthetic compounds 10.1. To 3.6% (8.0 g, 24.71 mmol, 1.0 equivalent) of 1,1'-thiocarbonyldiimidazole (21.99 g, 123.5 mmol, 5.0 equivalent) was added to a solution of 3,1'-thiocarbonyldiimidazole in 80 mL of THF. The reaction mixture was stirred at 70 °C for 1 hour. It was then cooled to room temperature and poured into ice water. The precipitated solid was collected by filtration and wet-milled with hexane to obtain... 10.1. MS(ES): m / z: 332.2 [M+H] + . Synthetic compounds 10.2. At 0℃ 10.1 g (2.0 g, 5.47 mmol, 1.0 equivalent) of sulfonyl chloride (16.4 mL, 202.39 mmol, 37 equivalent) was added to a solution in DCM (20 mL), and the reaction mixture was stirred for 10 minutes. The mixture was transferred to a saturated sodium bicarbonate solution, stirred, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 2.3% methanol in DCM) to obtain... 10.2. MS (ES): m / z 369.1 [M+H] + . synthesis I-10. 10.2 (0.050 g, 0.135 mmol, 1.0 equivalent) and A mixture of Int-6 (0.043 g, 0.176 mmol, 1.3 equivalents) and cesium carbonate (0.131 g, 0.405 mmol, 3.0 equivalents) in 1,4-dioxane (2 mL) was degassed by bubbling through an argon stream for 10 minutes. 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopiperanan (0.015 g, 0.027 mmol, 0.2 equivalents) and tris(dibenzylacetone)dipalladium(0) (0.012 g, 0.013 mmol, 0.1 equivalents) were added, and degassed for 5 minutes. The reaction mixture was stirred at 110 °C for 2 hours. It was then 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 silicone rapid column chromatography (CombiFlash®, 3.0% methanol in DCM) to obtain... I-10. MS(ES): m / z: 579.4 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 10.58 (s, 1H), 10.32 (s, 1H), 8.15 (bs, 2H), 7.36 (s, 1H), 7.31 (s, 1H), 6.65-6.64 (d, J= 3.6Hz, 1H), 4.88-4.82 (m, 1H), 4.70 (bs, 2H), 4.58 (bs, 2H), 3.96 (s, 3H), 3.60 (s, 3H), 2.81 (bs, 4H). Example 11 : N-(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)pyrrolidine-1-methylamine synthesis I-11. Compound I-11 series based on synthesis The procedure described in I-6, from 6.1 Preparation of pyrrolidine. The product was purified by silica gel rapid column chromatography (CombiFlash®, 3.2% methanol in DCM). MS (ES): m / z: 554.3 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz): δ 9.05 (s, 1H), 8.85 (s, 1H), 8.67-8.66 (d, J= 2.0Hz, 1H), 8.32 (s, 1H), 8.20-8.18 (m, 2H), 7.57 (bs, 1H), 6.70-6.69 (d, J= 3.2Hz, 1H), 3.98 (s, 3H), 3.68 (s, 3H), 2.47 (bs, 4H), 1.82 (bs, 4H). Example 12 :(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)aminocarbamate 2-methoxyethyl ester synthesis I-12.will A solution of 6.1 (0.110 g, 0.190 mmol, 1.0 equivalent), 2-methoxyethyl-1-ol (0.022 g, 0.286 mmol, 1.5 equivalent), and triethylamine (0.115 g, 1.14 mmol, 6.0 equivalent) in dimethyl sulfoxide (5 mL) was stirred at 100 °C for 16 hours. The solution was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 3.5% methanol in DCM) to obtain... I-12. MS(ES): m / z: 559.2 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 10.41 (s, 1H), 9.06 (s, 1H), 8.66 (s, 1H), 8.34 (s, 1H), 8.22-8.21 (m, 2H), 7.47 (bs, 1H), 6.76-6.75 (d, J= 2.8Hz, 1H), 4.19 (bs, 2H), 3.98 (s, 3H), 3.68 (s, 3H), 3.53 (bs, 2H), 3.27 (s, 3H). Example 13 :( R)- N-(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxypyrrolidine-1-methylamine synthesis I-13. Compound I-13 series based on synthesis The procedure described in I-6, from 6.1 and ( R)-3-methoxypyrrolidine was prepared. The product was purified by silica gel rapid column chromatography (CombiFlash®, 4.7% methanol in DCM). MS (ES): m / z: 584.3 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 9.04 (s, 1H), 8.94 (s, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 8.19-8.17 (m, 2H), 7.55-7.54 (d, J= 2.0Hz, 1H), 6.70-6.68 (m, 1H), 3.96 (s, 3H), 3.66 (s, 3H), 3.46 (bs, 2H), 3.38 (bs, 1H), 3.21 (s, 3H), 2.54 (bs, 2H), 1.93 (bs, 2H). Example 14 :( S)- N-(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxypyrrolidine-1-methylamine synthesis I-14 compound I-14 series based on synthesis The procedure described in I-6, from 6.1 and ( S)-3-methoxypyrrolidine was prepared. The product was purified by silica gel rapid column chromatography (CombiFlash®, 4.9% methanol in DCM). MS (ES): m / z: 584.3 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 9.04 (s, 1H), 8.94 (s, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 8.18-8.17 (m, 2H), 7.54 (z, 1H), 6.69-6.68 (m, 1H), 3.96 (s, 3H), 3.66 (s, 3H), 3.46 (bs, 2H), 3.39 (bs, 1H), 3.21 (s, 3H), 2.54 (bs, 2H), 1.93 (bs, 2H). Example 15 :(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)aminocarbamate 2-N-morpholinoethyl ester synthesis I-15. Compound I-15 series based on synthesis The procedure described in I-6, from 6.1 and 2-N-morpholinyl ethanol-1-ol were prepared. The product was purified by silica gel rapid column chromatography (CombiFlash®, 2.5% methanol in DCM). MS (ES): m / z: 614.3 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 10.37 (s, 1H), 9.06 (s, 1H), 8.65 (s, 1H), 8.33 (s, 1H), 8.19 (bs, 2H), 7.45 (s, 1H), 6.74 (s, 1H), 4.16 (bs, 2H), 3.96 (s, 3H), 3.66 (s, 3H), 3.53 (bs, 4H), 2.40 (bs, 6H). Example 16 :(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)aminocarbamate oxetane-3-yl ester synthesis I-16. Compound The I-16 series is based on synthesis The procedure described in I-6, from 6.1 Preparation of oxetane-3-ol. The product was purified by silica gel rapid column chromatography (CombiFlash®, 2.7% methanol in DCM). MS (ES): m / z: 557.2 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 10.63 (s, 1H), 9.05 (s, 1H), 8.65 (s, 1H), 8.32 (s, 1H), 8.23-8.22 (d, J= 5.6Hz, 1H), 8.19 (s, 1H), 7.40 (s, 1H), 6.78 (bs, 1H), 5.36 (bs, 1H), 4.77-4.75 (m, 2H), 4.50 (bs, 2H), 3.96 (s, 3H), 3.66 (s, 3H). Example 17 :( S)-(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)aminocarbamate tetrahydrofuran-3-yl ester synthesis I-17. Compound 6.1 (0.110 g, 0.190 mmol, 1.0 equivalent) and ( S)-Tetrahydrofuran-3-ol (0.084 g, 0.954 mmol, 5.0 equivalents) was stirred in triethylamine (1.0 mL) at 110 °C for 6 hours. The mixture was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 3.2% methanol in DCM) to give... I-17. MS(ES): m / z: 571.3 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz): δ 10.37 (s, 1H), 9.06 (s, 1H), 8.65 (s, 1H), 8.33 (s, 1H), 8.21-8.20 (m, 2H), 7.43 (s, 1H), 6.76-6.75 (d, J= 4.0Hz, 1H), 5.20 (bs, 1H), 3.96 (s, 3H), 3.78-3.72 (m, 4H), 3.66 (s, 3H), 2.16-2.10 (m, 1H), 1.92-1.89 (m, 1H). Example 18 :( R)-(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)aminocarbamate tetrahydrofuran-3-yl ester synthesis I-18 compound I-18 series based on synthesis The procedures described in I-17, since 6.1 and ( R)-Tetrahydrofuran-3-ol was prepared. The product was purified by silica gel rapid column chromatography (CombiFlash®, 3.2% methanol in DCM). MS (ES): m / z: 571.3 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz): δ 10.38 (s, 1H), 9.07 (s, 1H), 8.67 (s, 1H), 8.34 (s, 1H), 8.22-8.21 (m, 2H), 7.45 (s, 1H), 6.77 (bs, 1H), 5.21 (bs, 1H), 3.98 (s, 3H), 3.79-3.70 (m, 4H), 3.68 (s, 3H), 2.15-2.11 (m, 1H), 1.92 (bs, 1H). Example 19 :(4-((7-chloro-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)aminocarbamate 2-(dimethylamino)ethyl ester Synthetic compounds 19.1. A solution of 1.3 (0.400 g, 1.25 mmol, 1.0 equivalent), triethylamine (0.87 mL, 6.25 mmol, 5.0 equivalent), and 2-(dimethylamino)ethanol-1-ol (0.166 g, 1.87 mmol, 1.5 equivalent) was stirred at 70 °C for 30 min. The solution was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 3.0% methanol in DCM) to obtain... 19.1. MS(ES): m / z: 316.3 [M+H] + . Synthetic compounds 19.2. The compound A mixture of 19.1 (0.230 g, 0.729 mmol, 1.0 equivalent) and 10% palladium / carbon (0.200 g) in methanol (5 mL) was stirred under hydrogen (1 atm) for 30 minutes. The mixture was filtered through a Celite® pad and washed with methanol. The filtrate was concentrated under reduced pressure to obtain... 19.2. MS(ES): m / z226.1 [M+H] + . Synthetic compounds 19.3. 19.2 (0.150 g, 0.665 mmol, 1.0 equivalent) A mixture of Int-2 (0.109 g, 0.532 mmol, 0.8 equivalents) and potassium carbonate (0.275 g, 1.995 mmol, 3.0 equivalents) 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 layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 7.0% methanol in DCM) to obtain… 19.3. MS(ES): m / z411.5 [M+H] + . Synthetic compounds 19.4. Compounds 19.4 is based on the synthesis of compounds The procedure described in section 3.6, from 19.3 Preparation. The product was purified by silicone rapid column chromatography (CombiFlash®, 9.0% methanol in DCM). MS (ES): m / z381.5 [M+H] + . synthesis I-19. At 0℃ 19.4 (0.080 g, 0.210 mmol, 1.0 equivalent) was added to a solution of THF (3.0 mL). Int-5 (0.098 g, 0.420 mmol, 2.0 equivalents) was added, followed by the addition of potassium tert-butoxide (1 M in THF, 0.63 mL, 0.630 mmol, 3.0 equivalents). 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 equivalents) was added. The reaction mixture was stirred at 70°C for 1.5 hours. It was transferred to water, and the product was extracted with ethyl acetate. This was further purified by silica gel rapid column chromatography (CombiFlash®, 10% methanol in DCM) to give I-19. MS(ES): m / z: 581.2 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz): δ 10.31 (s, 1H), 8.87 (s, 1H), 8.63 (s, 1H), 8.25 (s, 1H), 8.16 (bs, 2H), 7.36 (s, 1H), 6.67 (bs, 1H), 4.17 (bs, 2H), 3.99 (s, 3H), 3.66 (s, 3H), 3.52-3.45 (m, 2H), 2.30 (bs, 6H). Example 20 :(4-((7-cyano-1-methyl-2-((1-methyl-2-sideoxy-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)aminocarbamate 2-hydroxyethyl ester Synthetic compounds 20.1. Sodium hydride (0.049 g, 1.248 mmol, 3.0 equivalent) was added to a solution of 2-(benzyloxy)ethanol-1-ol (0.063 g, 0.416 mmol, 1.0 equivalent) in DMF (5 mL) at 0 °C and stirred for 30 minutes. Add [the following to the mixture]... 6.1 (0.200 g, 0.346 mmol, 1.0 equivalent) and stirred at room temperature for 30 minutes. Poured onto 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 obtain the substance, which was further purified by silica gel rapid column chromatography (CombiFlash®, 2.2% methanol in DCM) to obtain... 20.1. MS(ES): m / z: 635.4 [M+H] + . synthesis I-20. At 0℃ 20.1 (0.040 g, 0.063 mmol, 1.0 equivalent) of trifluoromethanesulfonic acid (1 mL) was added to a solution in DCM (3 mL) and stirred for 10 min. The solution was transferred to an ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 3.0% methanol in DCM) to obtain… I-20. MS(ES): m / z: 545.2 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz): δ 10.63 (s, 1H), 8.99 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 8.14 (bs, 2H), 7.41 (s, 1H), 6.68 (bs, 1H), 4.74 (s, 1H), 4.02 (bs, 2H), 3.91 (s, 3H), 3.61 (s, 3H), 3.51 (bs, 2H). Example twenty one :3-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)amino)-1-methyl-1 H-Imidazo[4,5- b]pyridin-6-yl)oxy)pyridin-2-yl)-1,1-dimethylurea Synthetic compounds 21.1. Add n-butyllithium (2.5 M in hexane) (61.4 mL, 153.7 mmol, 2.0 equivalent) to a solution of 3,5-difluoropyridine-2-amine (10 g, 76.87 mmol, 1.0 equivalent) in THF (200 mL) at -78 °C and stir for 40 min. Add hexachloroethane (36.3 g, 153.7 mmol, 2.0 equivalent) and stir the reaction mixture at -78 °C for 40 min. Carefully add saturated ammonium chloride aqueous solution to quench the reaction. Extract the mixture with ethyl acetate. Wash the combined organic layer with brine, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was subjected to silicone rapid column chromatography (CombiFlash®, 12% ethyl acetate in hexane) to obtain... 21.1. 1 H NMR (DMSO-d 6, 400 MHz): δ 7.98-7.94 (m, 1H), 6.48 (bs, 2H). Synthetic compounds 21.2. At room temperature, add concentrated sulfuric acid (3 mL) dropwise to potassium persulfate (2.05 g, 7.6 mmol, 2.5 equivalents) and stir for 15 minutes. Add the solution to the mixture in small portions. 21.1 (0.5 g, 3.04 mmol, 1.0 equivalent), while maintaining the temperature in the range of 30-40 °C. After addition, the reaction mixture was stirred at room temperature for 3-4 hours. It was poured onto crushed ice, stirred, alkalized 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 silica gel rapid column chromatography (CombiFlash®, 2-3% ethyl acetate in hexane) to give 21.2. 1 H NMR (DMSO-d 6, 400 MHz): δ 8.78 (s, 1H). Synthetic compounds 21.3. At 0℃ 21.2 A solution of methylamine (40%) (0.8 mL, 9.98 mmol, 2.0 equivalent) was added dropwise to acetonitrile (10 mL). The reaction mixture was heated to room temperature and stirred for 20 minutes. It was poured over ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 10% ethyl acetate in hexane) to give... 21.3. 1 H NMR (DMSO-d 6, 400 MHz): δ 7.98 (s, 1H), 7.05 (bs, 1H), 2.79 (d, 3H). Synthetic compounds 21.4. 21.3 (0.930 g, 4.52 mmol, 1.0 equivalent) A mixture of N-(4-hydroxypyridin-2-yl)acetamide (0.895 g, 5.88 mmol, 1.3 equivalents) and sodium carbonate (0.958 g, 9.04 mmol, 2.0 equivalents) in DMF (10 mL) was stirred at 50 °C for 6 hours. The reaction mixture was cooled to room temperature and poured over ice water. The precipitated solid was collected by filtration, washed with water, and dried under vacuum to obtain... 21.4. MS (ES): m / z338.7 [M+H] + . Synthetic compounds 21.5. To compounds 21.4 Iron powder (0.705 g, 12.6 mmol, 5.0 equivalent) was added to a solution of 21.4 (0.850 g, 2.52 mmol, 1.0 equivalent) in ethanol-water (8:2, 10 mL), followed by ammonium chloride (0.673 g, 12.6 mmol, 5.0 equivalent). The reaction mixture was stirred at 80 °C for 2 hours. It was filtered through a Celite® pad and washed with ethanol. The filtrate was concentrated under reduced pressure. The residue was purified by silicone rapid column chromatography (CombiFlash®, 2.4% methanol in dichloromethane) to give 21.5. MS (ES): m / z 308.5 [M+H] + . Synthetic compounds 21.6. Compounds 21.6 series based on synthesis The procedures described in I-19, since 21.5 and Int-7 preparation. The product was purified by silicone rapid column chromatography (CombiFlash®, 3.0% methanol in DCM). MS (ES): m / z: 489.6 [M+H] + . Synthetic compounds 21.7. To 21.6 Zinc (0.006 g, 0.094 mmol, 0.2 equivalent) and zinc cyanide (0.275 g, 2.35 mmol, 5.0 equivalent) were added to a solution of DMA (5 mL). The reaction mixture was degassed by bubbling with an argon stream for 10 minutes. Tris(benzylacetone)dipalladium(0) (0.030 g, 0.032 mmol, 0.07 equivalent) and 1,1′-bis(diphenylphosphine)ferrocene (0.039 g, 0.070 mmol, 0.15 equivalent) were added, and the mixture was degassed for 5 minutes. The reaction mixture was stirred in a microwave reactor at 210 °C for 1 hour. After cooling to room temperature, the mixture was 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 silicone rapid column chromatography (CombiFlash®, DCM with 4.5% methanol as the solvent) to obtain the desired product. 21.7. MS (ES): m / z438.2 [M+H] + . synthesis I-21. At 0°C 21.7 (0.050 g, 0.114 mmol, 1.0 equivalent) of dimethylaminomethyl chloride (0.013 g, 0.125 mmol, 1.1 equivalent) was added to a solution of 2 mL of THF, followed by the addition of potassium tert-butoxide (1 M in THF) (0.57 mL, 0.57 mmol, 5.0 equivalent), and the mixture was 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 layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain... I-21. MS(ES): m / z: 509.3 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz): δ 10.69 (s, 1H), 9.01 (s, 1H), 8.19 (s, 1H), 8.16-8.15 (d, J= 6.0Hz, 1H), 7.45 (s, 1H), 7.10 (s, 1H), 6.66-6.65 (d, J= 3.6Hz, 1H), 4.16 (bs, 2H), 3.92 (s, 3H), 2.89 (s, 6H), 2.69-2.67 (m, 2H), 2.19 (bs, 2H). Example twenty two :(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)amino)-1-methyl-1 H-Imidazo[4,5- b] Pyridin-6-yl)oxy)pyridin-2-yl)aminocarbamate methyl ester synthesis I-22. At 0°C to 21.7 Methyl chloroformate (0.011 g, 0.125 mmol, 1.1 equivalent) was added to a solution of triethylamine (0.023 g, 0.228 mmol, 2.0 equivalent) in THF (2 mL). The reaction mixture was stirred at room temperature for 4 hours. It was then poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain... I-22. MS(ES): m / z: 496.2 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz): δ 10.72 (s, 1H), 10.43 (s, 1H), 8.22-8.21 (d, J= 2.4Hz, 1H), 8.19 (s, 1H), 7.43 (s, 1H), 7.08 (s, 1H), 6.74-6.73 (m, 1H), 4.16 (bs, 2H), 3.92 (s, 3H), 3.63 (s, 3H), 2.45 (bs, 2H), 2.19 (bs, 2H). Example twenty three : N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)amino)-1-methyl-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)pyrrolidine-1-methylamine synthesis I-23. At 0°C 21.7 phenyl chloroformate (0.027 g, 0.171 mmol, 1.5 equivalent) was added to a solution of 0.050 g (0.050 g, 0.114 mmol, 1.0 equivalent) and triethylamine (0.034 g, 0.342 mmol, 3.0 equivalent) in THF (3 mL). The reaction mixture was stirred for 15 minutes, followed by the addition of pyrrolidine (0.040 g, 0.57 mmol, 5.0 equivalent). The reaction mixture was stirred at 50 °C for 15 minutes. It was then transferred to 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 silica gel rapid column chromatography (CombiFlash®, 4.5% methanol in DCM) to give I-23. MS(ES): m / z: 535.4 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz): δ 10.67 (s, 1H), 8.80 (s, 1H), 8.19 (s, 1H), 8.16-8.15 (d, J= 5.6Hz, 1H), 7.54 (s, 1H), 7.09 (s, 1H), 6.83-6.81 (d, J= 7.2Hz, 1H), 4.16 (bs, 2H), 3.93 (s, 3H), 3.39-3.33 (m, 4H), 1.92-1.84 (m, 4H), 1.80-1.76 (m, 4H). Example twenty four : N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)amino)-1-methyl-1 H-Imidazo[4,5- b]pyridin-6-yl)oxy)pyridin-2-yl)-4-methylpiperazine-1-methylamine Synthetic compounds 24.1. At 0℃ 21.7 A solution of phenyl chloroformate (0.042 g, 0.274 mmol, 1.5 equivalents) in THF (3 mL) was added to a mixture of 0.080 g (0.080 g, 0.182 mmol, 1.0 equivalents) and triethylamine (0.055 g, 0.546 mmol, 3.0 equivalents). The reaction mixture was stirred for 15 minutes. It was then 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… 24.1. MS(ES): m / z: 558.4 [M+H] + . synthesis I-24. To 24.1 N-methylpiperazine (0.024 g, 0.242 mmol, 1.5 equivalent) was added to a solution of 24.1 (0.090 g, 0.161 mmol, 1.0 equivalent) and triethylamine (0.097 g, 0.966 mmol, 6.0 equivalent) in dimethyl sulfoxide (3 mL). The reaction mixture was stirred at 90 °C for 15 min. It was then transferred to 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 silica gel rapid column chromatography (CombiFlash®, 7.5% methanol in DCM) to give I-24. MS(ES): m / z: 562.5 [MH] + . 1 H NMR (DMSO-d 6, 400MHz): δ 10.67 (s, 1H), 9.33 (s, 1H), 8.19-8.18 (d, J= 4.0Hz, 1H), 8.17 (s, 1H), 7.45 (s, 1H), 7.10 (s, 1H), 6.84 (bs, 1H), 4.17 (bs, 2H), 3.93 (s, 3H), 3.43 (bs, 4H), 2.31 (bs, 4H), 2.20 (s, 3H), 1.56 (bs, 2H), 1.25 (bs, 2H). Example 25 : N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)amino)-1-methyl-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)morpholine-4-methylamine synthesis I-25. Compound The I-25 series is based on synthesis The procedures for I-24, since... 24.1 Preparation of morpholine. The product was purified by silica gel rapid column chromatography (CombiFlash®, 3.0% methanol in DCM). MS (ES): m / z: 551.3 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz): δ 10.68 (s, 1H), 9.36 (s, 1H), 8.19-8.18 (d, J= 4.0Hz, 1H), 8.16 (s, 1H), 7.09 (s, 1H), 7.06 (s, 1H), 6.83 (bs, 1H), 4.16 (bs, 2H), 3.92 (s, 3H), 3.55 (bs, 4H), 3.40 (bs, 4H), 1.55 (bs, 2H), 1.23 (bs, 2H). Example 26 :N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxyazacyclobutane-1-methylamine synthesis I-26. Compound The I-26 series is based on synthesis The procedures for I-24, since... 24.1 and 3-methoxyazinobutane hydrochloride were prepared. The product was purified by silica gel rapid column chromatography (CombiFlash®, 3.2% methanol in DCM). MS (ES): m / z: 551.4 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 10.73 (s, 1H), 10.05 (s, 1H), 8.26 (bs, 1H), 7.32 (s, 1H), 7.08 (s, 1H), 6.96 (s, 1H), 6.84 (s, 1H), 4.18 (bs, 4H), 3.96 (bs, 2H), 3.94 (s, 3H), 3.82 (s, 3H), 3.74 (bs, 1H), 2.21 (bs, 2H), 1.56 (bs, 2H). Example 27 :1-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)amino)-1-methyl-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)-3-methylurea synthesis I-27. Compound I-27 is based on synthetic The procedures for I-23, since... 21.7 and preparation of methylamine. The product was purified by silicone rapid column chromatography (CombiFlash®, 4.0% methanol in DCM). MS (ES): m / z: 495.3 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 10.67 (s, 1H), 8.80 (s, 1H), 8.19 (s, 1H), 8.16-8.15 (d, J= 5.6Hz, 1H), 7.54 (s, 1H), 7.09 (s, 1H), 6.83 (bs, 1H), 6.66-6.65 (d, J = 3.6Hz, 1H), 4.16 (bs, 2H), 3.93 (s, 3H), 3.38 (s, 3H), 2.19 (bs, 2H), 1.89-1.87 (m, 2H). Example 28 :( R)- N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)amino)-1-methyl-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)-3-hydroxypyrrolidine-1-methylamine synthesis I-28. Compound I-28 series based on synthesis The procedures for I-23, since... 21.7 and ( R)-pyrrolidone-3-ol was prepared. The product was purified by silica gel rapid column chromatography (CombiFlash®, 3.4% methanol in DCM). MS (ES): m / z: 551.4 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 10.68 (s, 1H), 8.86 (s, 1H), 8.20-8.16 (m, 2H), 7.54 (s, 1H), 7.10 (s, 1H), 6.84 (s, 1H), 5.36 (s, 1H), 4.95 (bs, 2H), 4.26 (bs, 1H), 4.11 (bs, 2H), 4.00 (bs, 2H), 3.94 (s, 3H), 2.20 (bs, 2H), 1.56 (bs, 4H). Example 29 :( S)- N-(4-((7-cyano-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)amino)-1-methyl-1 H-Imidazo[4,5- b]Pyridin-6-yl)oxy)pyridin-2-yl)-3-hydroxypyrrolidine-1-methylamine synthesis I-29. Compound The I-29 series is based on synthesis The procedures for I-23, since... 21.7 and ( S)-pyrrolidone-3-ol was prepared. The product was purified by silica gel rapid column chromatography (CombiFlash®, 3.5% methanol in DCM). MS (ES): m / z: 551.4 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 10.69 (s, 1H), 8.86 (s, 1H), 8.20-8.16 (m, 2H), 7.54 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 5.36 (s, 1H), 4.95 (bs, 2H), 4.26 (s, 1H), 4.11 (bs, 2H), 4.00 (bs, 2H), 3.94 (s, 3H), 2.20 (bs, 2H), 1.56 (bs, 4H). Example 30 :6-((2-aminopyridin-4-yl)oxy)-2-((4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)amino)-1-methyl-1 H-Imidazo[4,5- b] Pyridine-7-carboxynitrile synthesis I-30. Compound The I-30 series is based on synthesis The procedures for I-23, since... 21.7 and azacyclic butane were prepared. The product was purified by silicone rapid column chromatography (CombiFlash®, 4.0% methanol in DCM). MS (ES): m / z: 521.4 [M+H] + LCMS purity: 98.49%, HPLC purity: 96.93%. 1 H NMR (DMSO-d 6, 400MHz): δ 10.69 (s, 1H), 9.18 (s, 1H), 8.18 (s, 1H), 8.15 (bs, 1H), 7.55 (s, 1H), 7.09 (s, 1H), 6.23 (bs, 1H), 4.16 (bs, 2H), 3.95 (bs, 4H), 3.92 (s, 3H), 2.19-2.13 (m, 6H). Example 31 :(4-((2-((1-(2-oxaspiro[3.3]heptane-6-yl)-5-(trifluoromethyl)-1 H-pyrazole-3-yl)amino)-7-cyano-1-methyl-1 H-Imidazo[4,5- b] Pyridin-6-yl)oxy)pyridin-2-yl)aminocarbamate methyl ester Synthetic compounds 31.1 Sodium hydride (111 g, 2773.9 mmol, 4.8 equivalents) was added fractionally to a solution of 4-bromopyridin-2-amine (100 g, 577.9 mmol, 1.0 equivalents) in DMF (1300 mL) at 0 °C, and the mixture was stirred for 2 hours. 4-Methoxybenzyl chloride (434 g, 2773.9 mmol, 4.8 equivalents) was added to the mixture, and the mixture was stirred at 0 °C for 30 minutes. The mixture was transferred to ice water, and the precipitated solid was filtered and dried under vacuum to obtain… 1.1 (150 g, yield: 62.79%) MS (ES): m / z 414.2 [M+H] + . Synthetic compounds 31.2. Towards 31.1 (60 g, 145 mmol, 1.0 equivalent) of copper chloride (I) (1.14 g, 11.6 mmol, 0.08 equivalent) was added to a solution of DMSO (1000 mL), followed by the addition of N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxadiazine (3.8 g, 11.6 mmol, 0.08 equivalent). 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 equivalent) was added. The mixture was stirred at 110 °C for 48 hours. It was then cooled to room temperature, transferred to 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 wet milling with diethyl ether to obtain... 31.2. MS(ES): m / z 351.2 [M+H] + . Synthetic compounds 31.3. 31.2 (39 g, 111.3 mmol, 1.0 equivalent), sodium carbonate (23.59 g, 222.6 mmol, 2.0 equivalent) and The mixture of Int-2 (18.3 g, 89.04 mmol, 0.8 eq) in DMF (390 mL) was stirred at 80 °C for 1 hour. The mixture was filtered, and the filtrate was transferred to 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 silica gel rapid column chromatography (CombiFlash®, 28% ethyl acetate in hexane) to give... 31.3. MS(ES): m / z536.6 [M+H] + . Synthetic compounds 31.4. Compounds 31.4 is based on the synthesis of compounds The procedure described in section 3.6, from 31.3 Preparation. The product was purified by silicone rapid column chromatography (CombiFlash®, 70% ethyl acetate in hexane). MS (ES): m / z506.9 [M+H] + . Synthetic compounds 31.5. Compounds 31.5 is based on the synthetic compound The procedure described in 21.7, from 31.4 Preparation. The product was further purified by silica gel rapid column chromatography (CombiFlash®, 1.8% methanol in DCM). MS (ES): m / z497.5 [M+H] + . Synthetic compounds 31.6. To 31.5 g (1.0 g, 2.01 mmol, 1.0 equivalent) of 1,1'-thiocarbonyldiimidazole (1.788 g, 10.05 mmol, 5.0 equivalent) was added to a solution of 1,1'-thiocarbonyldiimidazole in 10 mL of THF. The reaction mixture was stirred at 80 °C for 6 hours. It was concentrated under reduced pressure. The residue was purified by silicone rapid column chromatography (CombiFlash®, 30% ethyl acetate in hexane) to give 31.6. MS(ES): m / z: 539.5 [M+H] + . Synthetic compounds 31.7. At -40℃ 31.6 (0.510 g, 0.946 mmol, 1.0 equivalent) of sulfonyl chloride (0.15 mL, 1.892 mmol, 2.0 equivalent) was added to a solution of acetonitrile (7 mL) and the reaction mixture was stirred for 10 minutes. It was then transferred to a saturated sodium bicarbonate solution, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 40% ethyl acetate in hexane) to give... 31.7. MS (ES): m / z 541.9 [M+H] + . Synthetic compounds 31.8. At 0℃ 31.7 g (0.230 g, 0.425 mmol, 1.0 equivalence) of trifluoromethanesulfonic acid (0.2 mL) was added to a solution in DCM (8 mL) and stirred for 5 minutes. The solution was transferred to an ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 3.0% methanol in DCM) to obtain… 31.8. MS(ES): m / z: 301.5 [M+H] + . Synthetic compounds 31.9. At 0℃ 31.8 g (0.070 g, 0.232 mmol, 1.0 equivalent) of triethylamine (0.070 g, 0.696 mmol, 3.0 equivalent) was added to a solution of 3 mL of THF, followed by the addition of methyl chloroformate (0.033 g, 0.349 mmol, 1.5 equivalent). The reaction mixture was stirred at room temperature for 15 minutes. It was then concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (CombiFlash®, 2.8% methanol in DCM) to obtain... 31.9. MS(ES): m / z: 359.5 [M+H] + . synthesis I-31. Compound The I-31 series is based on synthesis The I-10 procedure, from 31.9 and Preparation of Int-6. The product was purified by silicone rapid column chromatography (CombiFlash®, 3.5% methanol in DCM). MS (ES): m / z: 570.3 [M+H] + , 1 H NMR (DMSO-d 6, 400MHz): δ 10.59 (s, 1H), 10.32 (s, 1H), 8.17 (bs, 2H), 7.37 (s, 1H...

Claims

1. A compound selected from the following or a pharmaceutically acceptable salt thereof:

2. A pharmaceutical composition comprising a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: I-3 or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a compound as claimed in claim 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: I-4 or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound as claimed in claim 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: I-7 or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound as claimed in claim 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: I-14 or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound as claimed in claim 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: I-15 or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound as claimed in claim 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: I-18 or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound as claimed in claim 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: I-26 or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound as claimed in claim 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: I-30 or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound as claimed in claim 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: I-48 or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound as claimed in claim 19 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: I-56 or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound as claimed in claim 21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: I-57 or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a compound as claimed in claim 23 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: I-60 or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound as claimed in claim 25 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: I-61 or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound as claimed in claim 27 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: I-62 or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising a compound as claimed in claim 29 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

31. Use of a compound or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 or 29, or a pharmaceutical composition thereof, as claimed in any one of claims 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 or 30, for the preparation of a medicament for treating diseases, symptoms or ailments related to JAK2.

32. For the purposes of claim 31, wherein the disease, ailment or ailment is cancer.

33. For the purposes of claim 31, wherein the disease, symptom or ailment is a blood malignancy.

34. As requested in claim 33, wherein the hematologic malignancy is leukemia or lymphoma.

35. As used in claim 31, wherein the disease, symptom or ailment is myeloproliferative neoplasm.

36. As claimed in claim 35, wherein the myeloproliferative neoplasm is polycythemia vera, primary thrombocytopenia, or myelofibrosis.

37. As claimed in claim 35, wherein the myeloproliferative neoplasm is myelofibrosis.