6-Heteroaryloxybenzimidazole and azirbenzimidazole as JAK2 inhibitors

Abstract

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

Description

[0001] Related applications

[0002] This application claims priority and benefit to U.S. Application No. 63 / 020,645, filed May 6, 2020; U.S. Application No. 63 / 087,717, filed October 5, 2020; and U.S. Application No. 63 / 130,254, filed December 23, 2020, the entire contents of which are hereby incorporated by reference. Background Technology

[0003] Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase involved in the JAK-STAT signaling pathway, which plays a role in cellular processes such as immunity, cell division, and cell death. Dysfunction of the JAK-STAT pathway is associated with a variety of diseases, including cancer and other proliferative disorders, as well as diseases of the immune system. For example, virtually all BCR-ABL1-negative myeloproliferative neoplasms are associated with mutations that activate JAK2. In particular, JAK2V617F is the most common mutation in myeloproliferative neoplasms, occurring in approximately 70% of all patients and up to 95% in patients with polycythemia vera (Vainchenker, W., Kralovics, R. Blood 2017, 129(6):667-79). Even less common mutations, such as those in MPL and CALR, have been shown to induce JAK2 activation, thereby initiating and / or driving disease progression. (Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev): 82). Furthermore, polymorphisms in JAK2 are associated with various 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, TJDerm. Treat. 2019, 31(1): 33-40).

[0004] JAK inhibitors are classified based on their binding modes. 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 catalysis (Vainchenker, W. et al.). However, type I inhibitors have been observed to increase phosphorylation of the JAK2 activation ring and may induce acquired resistance in some patients (Meyer SC, Levine, RLClin. 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 high phosphorylation observed with type I inhibitors (Wu, SC et al., Cancer Cell, July 13, 2015, 28(1):29-41). Summary of the Invention

[0005] This disclosure provides compounds that can be used to inhibit JAK2. In some embodiments, the provided compounds are particularly useful for treating and / or preventing diseases, conditions, or disorders associated with JAK2.

[0006] In some embodiments, this disclosure provides compounds of formula I-1:

[0007]

[0008] Or a pharmaceutically acceptable salt thereof, wherein rings A, L, W, X, Y, Z, R 1 、R 2 and R a As defined in this article.

[0009] In some embodiments, this disclosure provides compounds of formula I:

[0010]

[0011] Or a pharmaceutically acceptable salt thereof, wherein rings A, L, X, Y, Z, R 1 、R 2 and R a As defined in this article. Detailed Implementation

[0012] Compounds and definitions

[0013] The compounds of this invention include those outlined above, and are further illustrated by the categories, 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 (CAS edition, Handbook of Chemistry and Physics, 75th edition). Furthermore, the 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 hereby incorporated by reference.

[0014] Unless otherwise stated, the structures described herein are intended to include all stereoisomers (e.g., enantiomers or diastereomers) of the structure, as well as all geometric or conformational isomers of the structure. For example, the R and S conformations of each stereocenter are considered as part of this disclosure. Therefore, single stereochemical isomers of the provided compounds, as well as enantiomers, diastereomers, and geometric (or conformational) mixtures, are within the scope of this disclosure. For example, in some cases, Table 1 shows one or more stereoisomers of the compound, and unless otherwise indicated, represents each individual stereoisomer and / or a mixture. Unless otherwise stated, all tautomers of the provided compounds are within the scope of this disclosure.

[0015] 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 structures of this invention (including replacing hydrogen with deuterium or tritium, or using...) 13 C or 14 Compounds that are enriched by carbon and replace carbon (C) are within the scope of this disclosure.

[0016] Aliphatic: The term "aliphatic" refers to a fully saturated or optionally substituted straight-chain (i.e., unbranched) or branched hydrocarbon chain containing one or more unsaturated units, or a fully saturated or partially substituted monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic" or "alicyclic") containing one or more unsaturated units but not aromatic, having a single connection point to the rest of the molecule. Unless otherwise specified, 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 implementations, 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-C24). 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., C14-C24). 1-2 Suitable aliphatic groups include, but are not limited to, substituted or unsubstituted straight-chain or branched alkyl, alkenyl, ynyl, and hybrids thereof. In some embodiments, “aliphatic” refers to a fully saturated or optionally substituted straight-chain (i.e., unbranched) or branched hydrocarbon chain containing one or more unsaturated units, having a single connection point to the rest of the molecule.

[0017] Alkyl: The term "alkyl" when used alone or as part of a larger part refers to having 1-12, 1-10, 1-8, 1-6, 1-4, 1-3 or 1-2 carbon atoms (e.g., C12, C23, C33, C43, C53, C63, C73, C83, C9 ... 1-12 C 1-10 C 1-8 C 1-6 C 1-4 C 1-3 or C 1-2 The alkyl group may be a straight-chain or branched saturated hydrocarbon group with optional substitution. Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0018] Carbocyclic group: As used herein, the terms “carbocyclic group,” “carbocycle,” and “carbocyclic ring” refer to a saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic system having 3 to 14 members, as described herein, wherein the aliphatic ring system is optionally substituted as described herein. Carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclic group” (or “alicyclic”) refers to a fully saturated or optionally substituted monocyclic C3-C8 hydrocarbon or optionally substituted C7-C hydrocarbon containing one or more unsaturated units but not aromatic. 10 A bicyclic hydrocarbon having a single connection point with the rest of the molecule. The term "cycloalkyl" refers to an optionally substituted saturated ring system having about 3 to about 10 ring carbon atoms. In some embodiments, the cycloalkyl has 3-6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0019] Alkenyl: The term "alkenyl," when used alone or as part of a larger body, refers to having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., 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-chain or branched hydrocarbon chain with optional substitutions. Exemplary alkenyl groups include vinyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0020] Alkynyl: The term "alkynyl" when used alone or as part of a larger body refers to having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C12, C23, C34, C43, C53, C64, C73, C84, C94, C95, C96 ... 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 optionally substituted. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0021] Aryl: The term "aryl" refers to a group having a total of 6 to 14 ring members (e.g., C14, C24, C34, C44, C54, C6 ... 6-14 A monocyclic and bicyclic system, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments, "aryl" refers to an aromatic ring system, including but not limited to phenyl, naphthyl, anthracene, and the like, which may have one or more substituents. Unless otherwise specified, "aryl" refers to a hydrocarbon.

[0022] Heteroaryl: The terms “heteroaryl” and “heteroaryl-”, when used alone or as part of a larger part (e.g., “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 1 to 5 heteroatoms in addition to carbon atoms. Exemplary heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridonel, pyridazinyl, pyrazinyl, indazinyl, purine, naphridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thiophene-pyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. As used herein, the terms “heteroaryl” and “heteroary-” also include groups in which a heteroaryl ring is fused with one or more aryl, alicyclic, or heterocyclic rings, wherein the linking group or linking point is located on the heteroaryl ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Non-limiting examples include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, inzolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, terpineyl, phthalazinyl, quinazolinyl, quinoxolinyl, 4H-quinazinyl, carbazoleyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one, and benzoisooxazolyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which includes optionally substituted rings.

[0023] Heteroatoms: As used herein, the term “heteroatoms” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen.

[0024] Heterocycle: As used herein, the terms “heterocycle,” “heterocyclic group,” and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7- to 10-membered bicyclic heterocyclic portion that is saturated or partially unsaturated and has one or more (e.g., one to four) heteroatoms as defined above, in addition to a carbon atom. When referring to the ring atom of a heterocycle, the term “nitrogen” includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (e.g., in 3,4-dihydro-2H-pyrrole), NH (e.g., in pyrrolealkyl), or NR. +(e.g., in N-substituted pyrrolidinyl groups). The heterocycle may be attached to its side group at any heteroatom or carbon atom to obtain a stable structure, and any ring atom may optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazineyl, dioxalyl, dioxopentyl, diazaphenyl, oxazphenyl, thioazphenyl, morpholinyl, and thiomorpholinyl. The heterocyclic group may be monocyclic, bicyclic, tricyclic, or polycyclic, preferably monocyclic, bicyclic, or tricyclic, more preferably monocyclic or bicyclic. Bicyclic heterocycles also include groups in which the heterocycle is fused with one or more aryl, heteroaryl, or alicyclic 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).

[0025] Partially unsaturated: As used herein, the term “partially unsaturated” when referring to a ring moiety means a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to cover rings with multiple unsaturated sites, but not to include aromatic (e.g., aryl or heteroaryl) moiety as defined herein.

[0026] Patient or Subject: As used herein, the terms "patient" or "subject" refer to any organism to which the provided composition is applied or to which it may be applied for, for example, experimental, diagnostic, preventative, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. In some embodiments, the patient or subject has or is susceptible to one or more conditions or disorders. In some embodiments, the patient or subject exhibits one or more symptoms of a condition or disorder. In some embodiments, the patient or subject has been diagnosed with one or more conditions or disorders. In some embodiments, the patient or subject is receiving or has received a therapy for the diagnosis and / or treatment of a disease, condition, or disorder.

[0027] Substituted or Optionally Substituted: As described herein, compounds of this disclosure may contain an "optionally substituted" moiety. Generally, the term "substituted," regardless of whether it is preceded by the term "optionally," means that one or more hydrogens of the specified moiety are replaced by suitable substituents. "Substituted" applies to one or more hydrogens explicitly or implicitly present in the structure (e.g., It means at least and It means at least Unless otherwise indicated, an "optionally substituted" group 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 may be substituted by more than one substituent selected from the specified group. The combinations of substituents contemplated by the present invention are preferably those combinations that can form stable or chemically viable compounds. As used herein, the term "stable" means a compound that does not undergo substantial change when subjected to conditions to allow its production, detection, and, in some embodiments, its recovery, purification, and use for one or more purposes provided herein. A group described as "substituted" preferably has between 1 and 4 substituents, more preferably 1 or 2 substituents. A group described as "optionally substituted" may be unsubstituted or "substituted" as described above.

[0028] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group is independently a halogen; -(CH2) 0- 4R o ;-(CH2) 0-4 OR o ;-O(CH2) 0-4 R o -O-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 CH(OR o )2;-(CH2) 0-4 SR o ;-(CH2) 0-4 Ph, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be R o Substitution; -CH=CHPh, which can be replaced by R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which can be R o Substitution; -NO2; -CN; -N3; ​​-(CH2)0-4N(R) o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH2) 0-4 N(R o )C(O)NR o 2; -N(R) o )C(S)NR o 2;-(CH2) 0-4N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3;-(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0- 4SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o 、-(CH2) 0-4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2;-(CH2) 0-4 S(O)R o ;-N(R o)S(O)2NR o 2; -N(R) o )S(O)2R o ;-N(OR) o )R o ;-C(NH)NR o 2; -P(O)2R o ;-P(O)R o 2; -OP(O)R o 2; -OP(O)(OR o )2;-SiR o 3; -(C 1-4 (linear or branched alkylene)ON(R) o )2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R) o )2, where each R o It can be replaced and independently of hydrogen and C as defined below. 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (5- to 6-membered heteroaryl ring) or 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur, or, although defined above, two independently occurring R... o Together with its intermediate atom, it forms a 3 to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring with 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0029] R o (or two independent Rs) o The suitable monovalent substituents on the ring formed together with its intermediate atom are independently halogens, -(CH2). 0-2 R · -(halogenated R) · -(CH2) 0-2 OH, -(CH2) 0-2 OR · -(CH2) 0-2 CH(OR · 2. -O(halogenated R) · -CN, -N3, -(CH2) 0-2 C(O)R · -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · -(CH2) 0-2 SR · -(CH2) 0- 2SH、-(CH2)0-2 NH2、-(CH2) 0-2 NHR · -(CH2) 0-2 NR · 2, -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · -(C 1-4 (straight-chain or branched alkylene)C(O)OR · or -SSR · , where each R · It is either unsubstituted or, in the case of a preceding "halogen group," substituted only with one or more halogens, and independently selected from C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. R o Suitable divalent substituents on saturated carbon atoms include =O and =S.

[0030] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O ("oxo"), =S, =NNR. * 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * 、=NR * =NOR * -O(C(R) * 2)) 2-3 O- or -S(C(R) * 2)) 2-3 S-, where each independently occurring R * Selected from hydrogen, and C that can be substituted as defined below. 1-6 Aliphatic or unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl rings having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents for the ortho-substituted carbon atom attached to the "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independently occurring R * Selected from hydrogen, and C that can be substituted as defined below. 1-6 Aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0031] R * Suitable substituents on aliphatic groups include halogens, -R ·-(halogenated R) · -OH, -OR · -O(halogenated R) · -CN, -C(O)OH, -C(O)OR · -NH2, -NHR · -NR · 2 or -NO2, where each R · It is either unsubstituted or, in the case of a preceding "halogen group," substituted only with one or more halogens, and independently C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0032] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include or Each of them Independently, hydrogen, and C that can be substituted as defined below. 1-6 Aliphatic or having 0-4 independently selected heteroatoms from nitrogen, oxygen, or sulfur, unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl rings, or, although defined above, two independently occurring... Together with its intermediate atom, it forms an unsubstituted 3 to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring with 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0033] Suitable substituents on the aliphatic group are independently halogens, -R · -(halogenated R) · -OH, -OR · -O(halogenated R) · -CN, -C(O)OH, -C(O)OR · -NH2, -NHR · -NR · 2 or -NO2, where each R · It is either unsubstituted or, in the case of a preceding "halogen group," substituted only with one or more halogens, and independently C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] Treatment: As used herein, the term "treat" (and "treatment" or "treating") refers to any application of a therapy that partially or completely alleviates, improves, reduces, suppresses, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms, features, and / or causes of a particular disease, condition, and / or disorder. In some embodiments, such treatment may be directed to a subject who does not exhibit signs of the relevant disease, condition, and / or disorder and / or a subject who exhibits only early signs of the disease, condition, and / or disorder. Alternatively, such treatment may be directed to a subject who exhibits one or more established signs of the relevant disease, condition, and / or disorder. In some embodiments, treatment may be directed to a subject who has been diagnosed with the relevant disease, condition, and / or disorder.

[0035] The provided compounds

[0036] This disclosure provides a compound of formula I-1:

[0037]

[0038] or a pharmaceutically acceptable salt thereof, wherein:

[0039] W is CR w Or N;

[0040] X is CR x Or N;

[0041] Y is CR y Or N;

[0042] Z is either -O- or -NR z -;

[0043] R w 、R x and R y Each independently represents hydrogen, halogen, -OR 3 、-N(R 3 )2、-SR 3 Optional substitution of C 1-6 Aliphatic or -CN;

[0044] R z C is hydrogen or optionally substituted 1-6 Aliphatic;

[0045] R 1 It is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2;

[0046] R 2 C is an optional replacement 1-6 Aliphatic;

[0047] Each R 3 Independently hydrogen or optionally substituted C 1-6 Aliphatic;

[0048] The ring A is an optionally substituted phenyl group, an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8- to 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0049] L represents a covalent bond or a divalent C. 1-3 Straight-chain or branched hydrocarbon chains;

[0050] R a For hydrogen, halogen, or optionally substituted C 1-6 Aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0051] Each R is independently hydrogen, with optional substituted C. 1-6 Aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic groups, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rs forming together, when attached to the same nitrogen atom, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0052] Each R' is independently a C that can be substituted arbitrarily. 1-6 Aliphatic or optionally substituted 3 to 7 saturated or partially unsaturated carbocyclic groups.

[0053] In some embodiments, this disclosure provides a compound of formula I-1 or a pharmaceutically acceptable salt thereof, wherein:

[0054] W is CR w Or N;

[0055] X is CR xOr N;

[0056] Y is CR y Or N;

[0057] Z is either -O- or -NR z -;

[0058] R w 、R x and R y Each independently represents hydrogen, halogen, -OR 3 、-N(R 3 )2、-SR 3 Optional substitution of C 1-6 Aliphatic or -CN;

[0059] R z C is hydrogen or optionally substituted 1-6 Aliphatic;

[0060] R 1 It is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2;

[0061] R 2 C is an optional replacement 1-6 Aliphatic;

[0062] Each R 3 Independently hydrogen or optionally substituted C 1-6 Aliphatic;

[0063] The ring A is an optionally substituted phenyl group, an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8- to 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0064] L represents a covalent bond or a divalent C. 1-3 Straight-chain or branched hydrocarbon chains;

[0065] R a For hydrogen, halogen, or optionally substituted C 1-6Aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0066] Each R is independently hydrogen, with optional substituted C. 1-6 Aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic groups, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rs together forming a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur when attached to the same nitrogen atom; and

[0067] Each R' is independently a C that can be substituted arbitrarily. 1-6 Aliphatic or optionally substituted 3 to 7 saturated or partially unsaturated carbocyclic groups.

[0068] In some embodiments, this disclosure provides compounds of formula I:

[0069]

[0070] or a pharmaceutically acceptable salt thereof, wherein:

[0071] X is CR x Or N;

[0072] Y is CR y Or N;

[0073] Z is either -O- or -NR z -;

[0074] R x and R y Each is independently hydrogen, and each of the optionally substituted C atoms is a carbon atom. 1-6 Aliphatic or -CN;

[0075] R z C is hydrogen or optionally substituted 1-6 Aliphatic;

[0076] R 1 It is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2;

[0077] R 2 C is an optional replacement 1-6Aliphatic;

[0078] The ring A is an optionally substituted phenyl group, an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8- to 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0079] L represents a covalent bond or a divalent C. 1-3 Straight-chain or branched hydrocarbon chains;

[0080] R a For hydrogen, halogen, or optionally substituted C 1-6 Aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0081] Each R is independently hydrogen, with optional substituted C. 1-6 Aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic groups, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rs together forming a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur when attached to the same nitrogen atom; and

[0082] Each R' is independently a C that can be substituted arbitrarily. 1-6 Aliphatic or optionally substituted 3 to 7 saturated or partially unsaturated carbocyclic groups.

[0083] In some embodiments, this disclosure provides compounds of formula II:

[0084]

[0085] Or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R 1 、R 2 、R a 、R x and R yAs defined above for Equation I-1 and described in both individual and combined forms in the categories and subclasses of this paper. In some implementations, rings A, L, Z, R 1 、R 2 、R a 、R x and R y As defined above for Equation I.

[0086] In some embodiments, this disclosure provides compounds of formula III:

[0087]

[0088] Or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R 1 、R 2 、R a and R y As defined above for Equation I-1 and described in both individual and combined forms in the categories and subclasses of this paper. In some implementations, rings A, L, Z, R 1 、R 2 、R a and R y As defined above for Equation I.

[0089] In some embodiments, this disclosure provides compounds of formula IV:

[0090]

[0091] Or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R 1 、R 2 、R a and R x As defined above for Equation I-1 and described in both individual and combined forms in the categories and subclasses of this paper. In some implementations, rings A, L, Z, R 1 、R 2 、R a and R x As defined above for Equation I.

[0092] In some embodiments, this disclosure provides compounds of formula I':

[0093]

[0094] Or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R 1 、R 2 、R a X and Y are as defined above for Equation I-1 and are described in both individual and combined forms in the categories and subclasses of this paper; and

[0095] R b Hydrogen, halogens, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -SO2R', -SO2N(R)2, -SO3R', and optionally substituted C 1-6 Aliphatic, optionally substituted 3 to 6 saturated or partially unsaturated carbocyclic groups, optionally substituted 3 to 6 saturated or partially unsaturated monocyclic heterocyclic groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted 5 to 6 cyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0096] In some implementations of formula I', rings A, L, Z, R 1 、R 2 、R a X and Y are as defined above for Equation I, and R b As defined above for formula I'.

[0097] In some embodiments, this disclosure provides compounds of formula II':

[0098]

[0099] Or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R 1 、R 2 、R a 、R x and R y As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined ways in the categories and subclasses of this paper. In some implementations, rings A, L, Z, R 1 、R 2 、R a 、R x and R y As defined above for equation I and R b As defined above for formula I'.

[0100] In some embodiments, this disclosure provides compounds of formula III':

[0101]

[0102] Or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R 1 、R 2 、Ra and R y As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined ways in the categories and subclasses of this paper. In some implementations, rings A, L, Z, R 1 、R 2 、R a and R y As defined above for equation I and R b As defined above for formula I'.

[0103] In some embodiments, this disclosure provides compounds of formula IV':

[0104]

[0105] Or a pharmaceutically acceptable salt thereof, wherein rings A, L, Z, R 1 、R 2 、R a and R x As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined ways in the categories and subclasses of this paper. In some implementations, rings A, L, Z, R 1 、R 2 、R a and R x As defined above for equation I and R b As defined above for formula I'.

[0106] In some embodiments, this disclosure provides compounds of formula IA:

[0107]

[0108] Or a pharmaceutically acceptable salt thereof, wherein rings A, L, X, Y, R' and R a As defined above for Equation I-1 and described in both individual and combined forms in the categories and subcategories of this paper. In some implementations, rings A, L, X, Y, R', and R a As defined above for Equation I.

[0109] In some embodiments, this disclosure provides compounds of formula II-A:

[0110]

[0111] Or a pharmaceutically acceptable salt thereof, wherein rings A, L, R', R x 、R y and R aAs defined above for Equation I-1 and described in both individual and combined forms in the categories and subcategories of this paper. In some implementations, rings A, L, R', R x 、R y and R a As defined above for Equation I.

[0112] In some embodiments, this disclosure provides compounds of formula III-A:

[0113]

[0114] Or a pharmaceutically acceptable salt thereof, wherein rings A, L, R', R y and R a As defined above for Equation I-1 and described in both individual and combined forms in the categories and subcategories of this paper. In some implementations, rings A, L, R', R y and R a As defined above for Equation I.

[0115] In some embodiments, this disclosure provides compounds of formula IV-A:

[0116]

[0117] Or a pharmaceutically acceptable salt thereof, wherein rings A, L, R', R x and R a As defined above for Equation I-1 and described in both individual and combined forms in the categories and subcategories of this paper. In some implementations, rings A, L, R', R x and R a As defined above for Equation I.

[0118] In some embodiments, this disclosure provides for compounds of formula IB:

[0119]

[0120] Or a pharmaceutically acceptable salt thereof, wherein L, X, Y, Z, R 1 、R 2 and R a As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined forms in the categories and subclasses of this paper. In some implementations, L, X, Y, Z, R 1 、R 2 and R a As defined above for equation I and R b As defined above for formula I'.

[0121] In some embodiments, this disclosure provides compounds of formula II-B:

[0122]

[0123] Or its pharmaceutically acceptable salts, wherein L, Z, R 1 、R 2 、R x 、R y and R a As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined forms in the categories and subclasses of this paper. In some implementations, L, Z, R 1 、R 2 、R x 、R y and R a As defined above for equation I and R b As defined above for formula I'.

[0124] In some embodiments, this disclosure provides compounds of formula III-B:

[0125]

[0126] Or its pharmaceutically acceptable salts, wherein L, Z, R 1 、R 2 、R y and R a As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined forms in the categories and subclasses of this paper. In some implementations, L, Z, R 1 、R 2 、R y and R a As defined above for equation I and R b As defined above for formula I'.

[0127] In some embodiments, this disclosure provides compounds of formula IV-B:

[0128]

[0129] Or its pharmaceutically acceptable salts, wherein L, Z, R 1 、R 2 、R x and R a As defined above for equation I-1 and R bAs defined above for formula I', and described in both individual and combined forms in the categories and subclasses of this paper. In some implementations, L, Z, R 1 、R 2 、R x and R a As defined above for equation I and R b As defined above for formula I'.

[0130] In some embodiments, this disclosure provides for a compound of formula IC:

[0131]

[0132] Or a pharmaceutically acceptable salt thereof, wherein L, X, Y, R' and R a As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined forms in the categories and subclasses of this document. In some implementations, L, X, Y, R', and R a As defined above for equation I and R b As defined above for formula I'.

[0133] In some embodiments, this disclosure provides compounds of formula II-C:

[0134]

[0135] Or a pharmaceutically acceptable salt thereof, wherein L, R', R x 、R y and R a As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined forms in the categories and subcategories of this paper. In some implementations, L, R', R x 、R y and R a As defined above for equation I and R b As defined above for formula I'.

[0136] In some embodiments, this disclosure provides compounds of formula III-C:

[0137]

[0138] Or a pharmaceutically acceptable salt thereof, wherein L, R', R y and R a As defined above for equation I-1 and R bAs defined above for formula I', and described in both individual and combined forms in the categories and subcategories of this paper. In some implementations, L, R', R y and R a As defined above for equation I and R b As defined above for formula I'.

[0139] In some embodiments, this disclosure provides compounds of formula IV-C:

[0140]

[0141] Or a pharmaceutically acceptable salt thereof, wherein L, R', R x and R a As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined forms in the categories and subcategories of this paper. In some implementations, L, R', R x and R a As defined above for equation I and R b As defined above for formula I'.

[0142] In some embodiments, this disclosure provides for formula ID compounds:

[0143]

[0144] Or a pharmaceutically acceptable salt thereof, wherein L, X, Y, Z, R 1 、R 2 and R a As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined forms in the categories and subclasses of this paper. In some implementations, L, X, Y, Z, R 1 、R 2 and R a As defined above for equation I and R b As defined above for formula I'.

[0145] In some embodiments, this disclosure provides compounds of formula II-D:

[0146]

[0147] Or its pharmaceutically acceptable salts, wherein L, Z, R x 、R y 、R 1 、R 2 and R a As defined above for equation I-1 and R bAs defined above for formula I', and described in both individual and combined forms in the categories and subclasses of this paper. In some implementations, L, Z, R x 、R y 、R 1 、R 2 and R a As defined above for equation I and R b As defined above for formula I'.

[0148] In some embodiments, this disclosure provides compounds of formula III-D:

[0149]

[0150] Or its pharmaceutically acceptable salts, wherein L, Z, R y 、R 1 、R 2 and R a As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined forms in the categories and subclasses of this paper. In some implementations, L, Z, R y 、R 1 、R 2 and R a As defined above for equation I and R b As defined above for formula I'.

[0151] In some embodiments, this disclosure provides compounds of formula IV-D:

[0152]

[0153] Or its pharmaceutically acceptable salts, wherein L, Z, R x 、R 1 、R 2 and R a As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined forms in the categories and subclasses of this paper. In some implementations, L, Z, R x 、R 1 、R 2 and R a As defined above for equation I and R b As defined above for formula I'.

[0154] In some embodiments, this disclosure provides IE compounds:

[0155]

[0156] Or a pharmaceutically acceptable salt thereof, wherein L, X, Y, R' and R a As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined forms in the categories and subclasses of this document. In some implementations, L, X, Y, R', and R a As defined above for equation I and R b As defined above for formula I'.

[0157] In some embodiments, this disclosure provides compounds of formula II-E:

[0158]

[0159] Or a pharmaceutically acceptable salt thereof, wherein L, R', R x 、R y and R a As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined forms in the categories and subcategories of this paper. In some implementations, L, R', R x 、R y and R a As defined above for equation I and R b As defined above for formula I'.

[0160] In some embodiments, this disclosure provides compounds of formula III-E:

[0161]

[0162] Or a pharmaceutically acceptable salt thereof, wherein L, R', R y and R a As defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined forms in the categories and subcategories of this paper. In some implementations, L, R', R y and R a As defined above for equation I and R b As defined above for formula I'.

[0163] In some embodiments, this disclosure provides compounds of formula IV-E:

[0164]

[0165] Or a pharmaceutically acceptable salt thereof, wherein L, R', R x and R aAs defined above for equation I-1 and R b As defined above for formula I', and described in both individual and combined forms in the categories and subcategories of this paper. In some implementations, L, R', R x and R a As defined above for equation I and R b As defined above for formula I'.

[0166] In some implementations of Equation I-1, W is CR w In some implementations, W is N.

[0167] In some implementations of any of Equations I-1, I, I', IA, IB, IC, ID, and IE, X is CR x In some implementations, X is N.

[0168] In some implementations of any of Equations I-1, I, I', IA, IB, IC, ID, and IE, Y is CR y In some implementations, Y is N.

[0169] In some implementations of Equation I-1, 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 Equation I-1, 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.

[0170] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IB, II-B, III-B, IV-B, ID, II-D, III-D, and IV-D, Z is -O-. In some embodiments, Z is -NR. z - In some implementations, Z is -NH-.

[0171] In some implementations of any of Equation I-1, R w For hydrogen, halogen, or optionally substituted C 1-6 Aliphatic or -CN. In some implementations, R w Hydrogen, or optionally substituted C 1-6 Aliphatic or -CN. In some implementations, R w It is hydrogen or methyl. In some embodiments, R wIt can be hydrogen, methyl, or -CN. In some embodiments, R w It is hydrogen. In some implementations, R w It is a halogen. In some implementations, R w It is fluorine. In some implementations, R w It is chlorine. In some implementations, R w It is bromine. In some implementations, R w It is iodine. In some implementations, R w For -OR 3 In some implementations, R w For -OR 3 , where R 3 C is an optional replacement 1-6 Aliphatic. In some implementations, Y is N and W is CR. w And R w For -OR 3 , where R 3 C is an optional replacement 1-6 Aliphatic. In some implementations, R w -N(R) 3 )2. In some implementation schemes, R w For -SR 3 In some implementations, R w For -SR 3 , where R 3 C is an optional replacement 1-6 Aliphatic. In some implementations, Y is N and W is CR. w And R w For -SR 3 , where R 3 C is an optional replacement 1-6 Aliphatic. In some implementations, R w C is an optional replacement 1-6 Aliphatic. In some implementations, R w For optional substitution of straight or branched C 1-6 Aliphatic (i.e., optionally substituted noncyclic C) 1-6 (Aliphatic). In some implementations, R w C is an optional replacement 1-6 Alkyl group. In some embodiments, R w C is an optional replacement 1-4 Alkyl group. In some embodiments, R w For unreplaced C 1-4 Alkyl group. In some embodiments, R w C is an optional replacement 1-2 Alkyl group. In some embodiments, R wThe methyl group is optionally substituted (e.g., a methyl group optionally substituted with one or more fluorine molecules). In some embodiments, R w It is methyl. In some embodiments, R w For -CN.

[0172] In some embodiments of any of formulas I-1, I, II, IV, I', II', IV', IA, II-A, IV-A, IB, II-B, IV-B, IC, II-C, IV-C, ID, II-D, IV-D, IE, II-E, and IV-E, R x For hydrogen, halogen, or optionally substituted C 1-6 Aliphatic or -CN. In some implementations, R x For hydrogen, halogen, -OR 3 Optional substitution of C 1-6 Aliphatic or -CN. In some implementations, R x Hydrogen, or optionally substituted C 1-6 Aliphatic or -CN. In some implementations, R x Halogen, -OR 3 、-N(R 3 )2、-SR 3 Or -CN. In some implementations, R x Halogen, -OR 3 Or -CN. In some implementations, R x It is hydrogen or methyl. In some embodiments, R x It can be hydrogen, methyl, or -CN. In some embodiments, R x It is hydrogen. In some implementations, R x It is a halogen. In some implementations, R x It is fluorine. In some implementations, R x It is chlorine. In some implementations, R x It is bromine. In some implementations, R x It is iodine. In some implementations, R x For -OR 3 In some implementations, R x For -OCH3. In some implementations, R x -N(R) 3 )2. In some implementation schemes, R x For -SR 3 In some implementations, R x C is an optional replacement 1-6 Aliphatic. In some implementations, R x For optional substitution of straight or branched C 1-6Aliphatic (i.e., optionally substituted noncyclic C) 1-6 (Aliphatic). In some implementations, R x C is an optional replacement 1-6 Alkyl group. In some embodiments, R x C is an optional replacement 1-4 Alkyl group. In some embodiments, R x For unreplaced C 1-4 Alkyl group. In some embodiments, R x C is an optional replacement 1-2 Alkyl group. In some embodiments, R x It is ethyl. In some embodiments, R x The methyl group is optionally substituted (e.g., a methyl group optionally substituted with one or more fluorine molecules, such as -CHF2). In some embodiments, R x It is methyl. In some embodiments, R x For -CN.

[0173] In some embodiments of any of formulas I-1, I, II, III, I', II', III', IA, II-A, III-A, IB, II-B, III-B, IC, II-C, III-C, ID, II-D, III-D, IE, II-E, and III-E, R y For hydrogen, halogen, or optionally substituted C 1-6 Aliphatic or -CN. In some implementations, R y Hydrogen, or optionally substituted C 1-6 Aliphatic or -CN. In some implementations, R y It is hydrogen or methyl. In some embodiments, R y It can be hydrogen, methyl, or -CN. In some embodiments, R y It is hydrogen. In some implementations, R y It is a halogen. In some implementations, R y It is fluorine. In some implementations, R y It is chlorine. In some implementations, R y It is bromine. In some implementations, R y It is iodine. In some implementations, R y For -OR 3 In some implementations, R y For -OR 3 , where R 3 C is an optional replacement 1- 6. Aliphatic. In some implementations, W represents N and Y represents CR. y And R y For -OR 3, where R 3 C is an optional replacement 1-6 Aliphatic. In some implementations, R y -N(R) 3 )2. In some implementation schemes, R y For -SR 3 In some implementations, R y For -SR 3 , where R 3 C is an optional replacement 1-6 Aliphatic. In some implementations, W is N and Y is CR. y And R y For -SR 3 , where R 3 C is an optional replacement 1-6 Aliphatic. In some implementations, R y C is an optional replacement 1-6 Aliphatic. In some implementations, R y For optional substitution of straight or branched C 1-6 Aliphatic (i.e., optionally substituted noncyclic C) 1-6 (Aliphatic). In some implementations, R y C is an optional replacement 1-6 Alkyl group. In some embodiments, R y C is an optional replacement 1-4 Alkyl group. In some embodiments, R y For unreplaced C 1-4 Alkyl group. In some embodiments, R y C is an optional replacement 1-2 Alkyl group. In some embodiments, R y The methyl group is optionally substituted (e.g., a methyl group optionally substituted with one or more fluorine molecules). In some embodiments, R y It is methyl. In some embodiments, R y For -CN.

[0174] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IB, II-B, III-B, IV-B, ID, II-D, III-D, IV-D, IE, II-E, III-E, and IV-E, R z It is hydrogen. In some implementations, R z C is an optional replacement 1-6 Aliphatic. In some implementations, R z For optional substitution of straight or branched C 1-6 Aliphatic (i.e., optionally substituted noncyclic C) 1-6(Aliphatic). In some implementations, R z C is an optional replacement 1-6 Alkyl group. In some embodiments, R z C is an optional replacement 1-4 Alkyl group. In some embodiments, R z For unreplaced C 1-4 Alkyl group. In some embodiments, R z C is an optional replacement 1-2 Alkyl group. In some embodiments, R z For unreplaced C 1-2 alkyl.

[0175] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IB, II-B, III-B, IV-B, ID, II-D, III-D, and IV-D, R 1 It is -N(R)C(O)R' or -C(O)N(R)2. In some implementations, R 1 It is -N(R)C(O)R', -C(O)N(R)2, or -N(R)C(O)N(R)2. In some embodiments, R 1 For -N(R)C(O)R'. In some implementations, R 1 It is -N(H)C(O)R'. In some implementations, R 1 -N(R)C(O) (C optionally substituted) 1-6 (Aliphatic). In some implementations, R 1 -N(H)C(O) (C optionally substituted) 1-6 (Aliphatic). In some implementations, R 1 =-N(R)C(O)R', where R' is optionally replaced by -OC 1-6 Alkyl-substituted C 1-6 Aliphatic or 3- to 7-membered saturated monocyclic heterocyclic groups having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 =-N(H)C(O)R', where R' is optionally replaced by -OC 1-6 Alkyl-substituted C 1-6 Aliphatic or 3- to 7-membered saturated monocyclic heterocyclic groups having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 -N(R)C(O)(C 1-6 (Aliphatic). In some implementations, R 1 -N(H)C(O)(C 1-6 (Aliphatic). In some implementations, R 1-N(R)C(O) (straight-chain or branched C) 1-6 (Aliphatic). In some implementations, R 1 -N(H)C(O) (straight-chain or branched C) 1-6 (Aliphatic). In some implementations, R 1 -N(R)C(O) (C optionally substituted) 1-6 Alkyl group). In some embodiments, R 1 -N(H)C(O) (C optionally substituted) 1-6 Alkyl group). In some embodiments, R 1 =-N(R)C(O)R', where R' is optionally replaced by -OC 1-6 Alkyl groups or C-membered 3- to 7-membered saturated monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-6 Alkyl group. In some embodiments, R 1 =-N(H)C(O)R', where R' is optionally replaced by -OC 1-6 Alkyl groups or C-membered 3- to 7-membered saturated monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-6 Alkyl group. In some embodiments, R 1 -N(R)C(O)(C 1-6 Alkyl group). In some embodiments, R 1 -N(H)C(O)(C 1-6 Alkyl group). In some embodiments, R 1 -N(R)C(O) (C optionally substituted) 1-4 Alkyl group). In some embodiments, R 1 -N(H)C(O) (C optionally substituted) 1-4 Alkyl group). In some embodiments, R 1 =-N(R)C(O)R', where R' is optionally replaced by -OC 1-6 Alkyl groups or C-membered 3- to 7-membered saturated monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-4 Alkyl group. In some embodiments, R 1 =-N(H)C(O)R', where R' is optionally replaced by -OC 1-6 Alkyl groups or C-membered 3- to 7-membered saturated monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-4 Alkyl group. In some embodiments, R 1 -N(R)C(O)(C 1-4 Alkyl group). In some embodiments, R 1 -N(H)C(O)(C 1-4Alkyl group). In some embodiments, R 1 -N(R)C(O) (C optionally substituted) 1-2 Alkyl group). In some embodiments, R 1 -N(H)C(O) (C optionally substituted) 1-2 Alkyl group). In some embodiments, R 1 =-N(R)C(O)R', where R' is optionally replaced by -OC 1-6 Alkyl groups or C-membered 3- to 7-membered saturated monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-2 Alkyl group. In some embodiments, R 1 =-N(H)C(O)R', where R' is optionally replaced by -OC 1-6 Alkyl groups or C-membered 3- to 7-membered saturated monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-2 Alkyl group. In some embodiments, R 1 -N(R)C(O)(C 1-2 Alkyl group). In some embodiments, R 1 -N(H)C(O)(C 1-2 Alkyl group). In some embodiments, R 1 It is -N(R)C(O)CH3. In some implementations, R 1 It is -N(H)C(O)CH3. In some implementations, R 1 -N(R)C(O) (C optionally substituted) 3-7 (Carbocyclic group). In some implementations, R 1 -N(H)C(O) (C optionally substituted) 3-7 (Carbocyclic group). In some implementations, R 1 For -N(R)C(O) (optionally substituted cyclopropyl). In some embodiments, R 1 -N(H)C(O) (optionally substituted cyclopropyl). In some embodiments, R 1 It is -N(R)C(O)CH3 or -N(R)C(O) (cyclopropyl). In some embodiments, R 1 It is -N(H)C(O)CH3 or -N(H)C(O) (cyclopropyl).

[0176] In some implementation schemes, R 1 It is -C(O)N(R)2. In some implementations, R 1 -C(O)N(R)(C 1-6 (Aliphatic). In some implementations, R 1 -C(O)N(H)(C 1-6(Aliphatic). In some implementations, R 1 -C(O)N(R) (straight or branched C) 1-6 (Aliphatic). In some implementations, R 1 -C(O)N(H) (straight-chain or branched C) 1-6 (Aliphatic). In some implementations, R 1 -C(O)N(R)(C 1-6 Alkyl group). In some embodiments, R 1 -C(O)N(H)(C 1-6 Alkyl group). In some embodiments, R 1 -C(O)N(R)(C 1-4 Alkyl group). In some embodiments, R 1 -C(O)N(H)(C 1-4 Alkyl group). In some embodiments, R 1 -C(O)N(R)(C 1-2 Alkyl group). In some embodiments, R 1 -C(O)N(H)(C 1-2 Alkyl group). In some embodiments, R 1 It is -C(O)N(R)CH3. In some implementations, R 1 It is -C(O)N(H)(R).

[0177] In some implementation schemes, R 1 It is -N(R)2. In some implementations, R 1 It is -N(H)(R).

[0178] In some implementation schemes, R 1 It is -N(R)C(O)N(R)2. In some implementations, R 1 The form is -N(R)C(O)N(R)2, wherein two R groups attached to the same nitrogen atom together form a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group with 0-2 independently selected additional heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, R... 1 The form is -N(R)C(O)N(R)2, wherein two R groups attached to the same nitrogen atom together form a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally bonded by one or more halogens, C 1-6 Alkyl and -O(C) 1-6 Alkyl) substitution. In some embodiments, R 1The form is -N(R)C(O)N(R)2, wherein two R groups attached to the same nitrogen atom together form an optionally substituted 3- to 5-membered saturated monocyclic heterocyclic group with 0-1 additional heteroatoms. In some embodiments, R 1 The form is -N(R)C(O)N(R)2, wherein two R groups attached to the same nitrogen atom together form an optionally substituted 4-membered saturated monocyclic heterocyclic group with 0-1 additional heteroatoms. In some embodiments, R 1 The form is -N(R)C(O)N(R)2, wherein two R groups attached to the same nitrogen atom together form a 3- to 5-membered saturated monocyclic heterocyclic group having 0-1 additional heteroatoms, which is optionally bonded by one or more halogens, C 1-6 Alkyl and -O(C) 1-6 Alkyl) substitution. In some embodiments, R 1 The form is -N(R)C(O)N(R)2, wherein two R groups attached to the same nitrogen atom together form a 4-membered saturated monocyclic heterocyclic group having 0-1 additional heteroatoms, which is optionally bonded by one or more halogens, C 1-6 Alkyl and -O(C) 1-6 Alkyl) substitution. In some embodiments, R 1 It is -N(H)C(O)N(R)2. In some implementations, R 1 The form is -N(H)C(O)N(R)2, wherein two R groups attached to the same nitrogen atom together form a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group with 0-2 independently selected additional heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, R... 1 The form is -N(H)C(O)N(R)2, wherein two R groups attached to the same nitrogen atom together form a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally bonded by one or more halogens, C 1-6 Alkyl and -O(C) 1-6 Alkyl) substitution. In some embodiments, R 1 The form is -N(H)C(O)N(R)2, wherein two R groups attached to the same nitrogen atom together form an optionally substituted 3- to 5-membered saturated monocyclic heterocyclic group with 0-1 additional heteroatoms. In some embodiments, R... 1 The form is -N(H)C(O)N(R)2, wherein two R groups attached to the same nitrogen atom together form an optionally substituted 4-membered saturated monocyclic heterocyclic group with 0-1 additional heteroatoms. In some embodiments, R... 1 The form is -N(H)C(O)N(R)2, wherein two R groups attached to the same nitrogen atom together form a 3- to 5-membered saturated monocyclic heterocyclic group having 0-1 additional heteroatoms, which is optionally bonded by one or more halogens, C 1-6 Alkyl and -O(C)1-6 Alkyl) substitution. In some embodiments, R 1 The form is -N(H)C(O)N(R)2, wherein two R groups attached to the same nitrogen atom together form a 4-membered saturated monocyclic heterocyclic group having 0-1 additional heteroatoms, which is optionally bonded by one or more halogens, C 1-6 Alkyl and -O(C) 1-6 Alkyl) substitution. In some embodiments, R 1 for In some implementation schemes, R 1 for

[0179] In some implementation schemes, R 1 Selected from: In some implementation schemes, R 1 Selected from: In some implementation schemes, R 1 Selected from: In some implementation schemes, R 1 Selected from: In some implementation schemes, R 1 Selected from: In some implementation schemes, R 1 Selected from: In some implementation schemes, R 1 Selected from: In some implementation schemes, R 1 Selected from: In some implementation schemes, R 1 It is -C(O)N(H)CH3.

[0180] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IB, II-B, III-B, IV-B, ID, II-D, III-D, and IV-D, R 2 For optional substitution of straight or branched C 1-6 Aliphatic (i.e., optionally substituted noncyclic C) 1-6 (Aliphatic). In some implementations, R 2 C is an optional replacement 1-6 Alkyl group. In some embodiments, R 2 C is an optional replacement 1-4 Alkyl group. In some embodiments, R 2For unreplaced C 1-4 Alkyl group. In some embodiments, R 2 C is an optional replacement 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.

[0181] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, IV-A, IB, II-B, III-B, IV-B, IC, II-C, III-C, IV-C, ID, II-D, III-D, IV-D, IE, II-E, III-E, and IV-E, each R 3 Independently hydrogen or optionally substituted C 1-4 Aliphatic. In some implementations, each R 3 Independently hydrogen or optionally substituted C 1-2 Aliphatic. In some implementations, each R 3 It is hydrogen. In some implementations, each R... 3 C can be substituted independently. 1-6 Aliphatic. In some implementations, each R 3 Independently, for the optional substitution of straight or branched C 1-6 Aliphatic (i.e., optionally substituted noncyclic C) 1-6 (Aliphatic). In some implementations, each R 3 C can be substituted independently. 1-4 Aliphatic. In some implementations, each R 3 Independently, for the optional substitution of straight or branched C 1-4 Aliphatic (i.e., optionally substituted noncyclic C) 1-4 (Aliphatic). In some implementations, each R 3 C can be substituted independently. 1-2 Aliphatic. In some implementations, each R 3 For methyl. In some embodiments, each R 3 are independently hydrogen or C 1-6 Alkyl group. In some embodiments, each R 3 are independently hydrogen or C 1-4 Alkyl group. In some embodiments, each R 3 are independently hydrogen or C 1-2 alkyl.

[0182] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, ring A(i) is optionally substituted at the substituted carbon atom by one or more groups independently selected from: oxo groups, halogens, R... o -CN, -OR o -SR o 、-N(R o )2、-NO2、-C(O)R o -C(O)OR o -C(O)NR o 2. -OC(O)R o -OC(O)NR o 2. -OC(O)OR o -OS(O)2R o -OS(O)2NR o 2. -N(R) o )C(O)R o 、-N(R o )S(O)2R o -S(O)2R o (ii) the substituted nitrogen atom is optionally substituted by one or more groups selected from: and -S(O)2OR o In some embodiments, ring A(i) is optionally substituted at the substituted carbon atom by one or more groups independently selected from: oxo groups, halogens, R... o -CN, -OR o -SR o 、-N(R o )2、-NO2、-C(O)R o -C(O)OR o -C(O)NR o 2. -OC(O)R o -OC(O)NR o 2. -OC(O)OR o -OS(O)2R o -OS(O)2NR o 2. -N(R) o )C(O)R o 、-N(R o )S(O)2R o -S(O)2R o 、-SO2NR o 2 and -S(O)2OR o(ii) the substituted nitrogen atom is optionally substituted by one or more groups selected from: and In some embodiments, ring A(i) is optionally substituted with one or more groups independently selected from oxo groups, halogens, and R on the substituted carbon atom. o (ii) substitution of the substituent group on the substituted nitrogen atom, and optionally, the substituent group is selected from one or more groups selected from the substituent group on the substituted nitrogen atom. Substitution of groups.

[0183] In some implementations, ring A is optionally surrounded by one or more R b Replace (i.e., except by -LR) a (excluding replacement), where R b As defined in Formula I' above and described in the categories and subclasses herein. In some embodiments, where valence permits, ring A is affected by zero, one, two, three, four, or five R... b replace.

[0184] In some embodiments, ring A is a 5- to 6-membered monocyclic heteroaryl group having 1-4 independently selected heteroatoms selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl group having 1-4 independently selected heteroatoms selected from nitrogen, oxygen, and sulfur; an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group; an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 independently selected heteroatoms selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 independently selected heteroatoms selected from nitrogen, oxygen, and sulfur.

[0185] In some embodiments, ring A is an optionally substituted phenyl group. In some embodiments, ring A is not an optionally substituted phenyl group.

[0186] In some embodiments, ring A is a 5- to 6-membered monocyclic heteroaryl group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered monocyclic heteroaryl group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted isoxazolyl or pyrazolyl group. In some embodiments, ring A is an optionally substituted isoxazolyl, pyrazolyl, or thiazolyl group. In some embodiments, ring A is an optionally substituted isoxazolyl, pyrazolyl, imidazolyl, or thiazolyl group. In some embodiments, ring A is a 6-membered monocyclic heteroaryl group having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted pyridinyl, pyridoneyl, or pyridazinoneyl group.

[0187] In some embodiments, ring A is an 8- to 10-membered bicyclic heteroaryl group having 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 8-membered bicyclic heteroaryl group having 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 9-membered bicyclic heteroaryl group having 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 10-membered bicyclic heteroaryl group having 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur.

[0188] In some embodiments, ring A is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring A is an optionally substituted 3-membered saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring A is an optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring A is an optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring A is an optionally substituted 6-membered saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring A is an optionally substituted cyclohexyl group. In some embodiments, ring A is an optionally substituted 7-membered saturated or partially unsaturated monocyclic carbocyclic group.

[0189] In some embodiments, ring A is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 3-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 4-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0190] In some embodiments, ring A is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 7-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 8-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 9-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted tetrahydrobenzo[d]thiazolyl, tetrahydropyrazole[1,5-a]pyridyl, isoindolineone, indolineone, or tetrahydroimidazo[1,2-a]pyridyl. In some embodiments, ring A is a 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted tetrahydroisoquinoline group.

[0191] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, IV-A, IB, II-B, III-B, IV-B, IC, II-C, III-C, IV-C, ID, II-D, III-D, IV-D, IE, II-E, III-E, and IV-E, 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 A straight-chain or branched hydrocarbon chain. In some embodiments, L is methylene (-CH2-). In some embodiments, L is -CH2CH2-. In some embodiments, L is -CH2CH2CH2-. In some embodiments, L is covalently bonded or -CH2-.

[0192] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, IV-A, IB, II-B, III-B, IV-B, IC, II-C, III-C, IV-C, ID, II-D, III-D, IV-D, IE, II-E, III-E, and IV-E, R a Halogen, optional substituted C 1-6Aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl with 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group with 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group with 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0193] In some implementation schemes, R a Halogen, optional substituted C 1-4 Alkyl group, optional substituted 5-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optional substituted 3- to 6-membered saturated monocyclic carbocyclic group, optional substituted 3- to 6-membered saturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optional substituted 7-membered saturated spirocyclic bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0194] In some implementation schemes, R a C 1-4 Alkyl group, 3- to 6-membered saturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 7- to 8-membered saturated spirocyclic bicyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0195] In some implementation schemes, R a It is hydrogen. In some implementations, R a It is not hydrogen.

[0196] In some implementation schemes, R a It is a halogen. In some implementations, R a It can be fluorine, chlorine, bromine, or iodine. In some embodiments, R a It is fluorine. In some implementations, R a It is chlorine. In some implementations, R a Not halogenated. In some implementations, R a Not fluorine. In some implementations, R a It is not chlorine.

[0197] In some implementation schemes, R a C is an optional replacement 1-6 Aliphatic. In some implementations, R a For optional substitution of straight or branched C 1-6 Aliphatic (i.e., optionally substituted noncyclic C) 1-6 (Aliphatic). In some implementations, R a Optionally, it can be oxidized by one or more oxo groups, halogens, -CN, or -O(C) groups.1-6 alkyl) substituted C 1-6 Aliphatic. In some implementations, R a Optionally, it can be coated with one or more oxo groups, halogens, -CN, -OH, or -O(C) 1-6 alkyl) substituted C 1-6 Aliphatic. In some implementations, R a C is optionally substituted with one or more oxo groups, halogens, -CN or -OCH3 1-6 Aliphatic. In some implementations, R a C is a carbon atom that is optionally substituted with one or more oxo groups, halogens, -CN, -OH, or -OCH3. 1-6 Aliphatic. In some implementations, R a C is an optional replacement 1-6 Alkyl group. In some embodiments, R a C 1-6 Alkyl group. In some embodiments, R a C is optionally substituted with one or more oxo groups, halogens, -CN or -OCH3 1-6 Alkyl group. In some embodiments, R a Optionally, it can be coated with one or more oxo groups, halogens, -CN, -OH, or -O(C) 1-6 Alkyl (e.g., -OCH3) substituted C 1-6 Alkyl group. In some embodiments, R a C is an optional replacement 1-4 Alkyl group. In some embodiments, R a C 1-4 Alkyl group. In some embodiments, R a C is optionally substituted with one or more oxo groups, halogens, -CN or -OCH3 1-4 Alkyl group. In some embodiments, R a Optionally, it can be coated with one or more oxo groups, halogens, -CN, -OH, or -O(C) 1-6 Alkyl (e.g., -OCH3) substituted C 1-4 Alkyl group. In some embodiments, R a It is an optionally substituted C1 alkyl group (e.g., methyl). In some embodiments, R a It is methyl, -CF3, or -CH2OCH3. In some embodiments, R a It can be methyl, -CF3, -CH2OCH3, or -CH2CN. In some embodiments, R a It is an optionally substituted C2 alkyl group. In some embodiments, R aIt is -CH2CH2OCH3, -CH2CH2OH, or -C(O)CH3. In some embodiments, R a It can be -CH2CH2OCH3, -CH2CH2OH, -C(O)CH3-CH2CH2F, -CH2CHF2, or -CH2CH2CN. In some embodiments, R a It is an optionally substituted C3 alkyl group. In some embodiments, R a It is isopropyl or -C(CH3)2CN. In some embodiments, R a It is isopropyl, -C(CH3)2CN, or -CH2CH(OH)CH3. In some embodiments, R a It is an optionally substituted C4 alkyl group. In some embodiments, R a It is tert-butyl. In some implementations, R a It is tert-butyl or -CH2CH(CH3)CH2OH. In some embodiments, R a Not -CF3.

[0198] In some implementation schemes, R a The phenyl group is optionally substituted.

[0199] In some implementation schemes, R a It is a 5- to 6-membered monocyclic heteroaryl group with 1 to 4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 5-membered monocyclic heteroaryl group with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 5-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally bonded by one or more C atoms. 1-6 Alkyl (e.g., methyl) substitution. In some embodiments, R a The group can be optionally substituted with an imidazole, pyrazol, or oxazolyl group. In some embodiments, R a To be optionally used by one or more C 1-6 Alkyl (e.g., methyl)-substituted imidazole, pyrazol, or oxazolyl groups. In some embodiments, R a For optional replacement In some implementation schemes, R a for In some implementation schemes, R a It is a 6-membered monocyclic heteroaryl group with 1 to 4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0200] In some implementation schemes, R aIt is an optionally substituted 3 to 7-membered saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, R a For optional use by one or more -(C 1-6 Alkylene)OH, -CN, -OH or -O(C 1-6 Alkyl)-substituted 3 to 7-membered saturated or partially unsaturated monocyclic carbocyclic groups. In some embodiments, R a R is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group optionally substituted with one or more -CH2OH, -CN, -OH, or -OCH3. In some embodiments, R a C is an optional replacement 3-6 Cycloalkyl. In some embodiments, R a For optional use by one or more -(C 1-6 Alkylene)OH, -CN, -OH or -O(C 1-6 alkyl) substituted C 3-6 Cycloalkyl. In some embodiments, R a C is optionally substituted with one or more -CH2OH, -CN, -OH or -OCH3 3-6 Cycloalkyl. In some embodiments, R a It is an optionally substituted C3 cycloalkyl group. In some embodiments, R a for In some implementation schemes, R a It is an optionally substituted C4 cycloalkyl group. In some embodiments, R a for In some implementation schemes, R a for In some implementation schemes, R a It is an optionally substituted C5 cycloalkyl group. In some embodiments, R a for In some implementation schemes, R a It is an optionally substituted C6 cycloalkyl group. In some embodiments, R a for

[0201] In some implementation schemes, R a It is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It 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, optionally surrounded by one or more oxo groups, C 1-4 Alkyl, -C(O)(C 1-4 alkyl) or -O(C1-4 Alkyl) substitution. In some embodiments, R a A 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more oxo groups or one or more halogens. 1-4 Alkyl, -C(O)(C 1-4 alkyl) or -O(C 1-4 Alkyl) substitution. In some embodiments, R a It 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, optionally surrounded by one or more oxo groups, halogens, -C(O)(C 1-4 alkyl), -O(C) 1-4 Alkyl group or optionally with one or more halogens and -O (C 1-4 alkyl) substituted C 1-4 Alkyl substitution. In some embodiments, R a It 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, optionally surrounded by one or more oxo groups, C 1-2 Alkyl, -C(O)CH3, or -OCH3 substitution. In some embodiments, R a It 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, which is optionally substituted with one or more oxo groups and optionally with one or more fluorine groups. 1-2 Alkyl, -C(O)CH3, or -OCH3 substitution. In some embodiments, R a It 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, which is optionally substituted with one or more oxo groups, fluorine, -C(O)CH3, -OCH3, or optionally C substituted with one or more fluorine groups and -OCH3. 1-2 Alkyl substitution. In some embodiments, R a It is a 3- to 6-membered saturated monocyclic heterocyclic group with 1-3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 3- to 6-membered saturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally surrounded by one or more oxo groups, C 1-4 Alkyl, -C(O)(C 1-4 alkyl) or -O(C 1-4 Alkyl) substitution. In some embodiments, R aA 3- to 6-membered saturated monocyclic heterocyclic group having 1 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more oxo groups or one or more halogens. 1-4 Alkyl, -C(O)(C 1-4 alkyl) or -O(C 1-4 Alkyl) substitution. In some embodiments, R a It is a 3- to 6-membered saturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally surrounded by one or more oxo groups, halogens, -C(O)(C 1-4 alkyl), -O(C) 1-4 Alkyl group or optionally with one or more halogens and -O (C 1-4 alkyl) substituted C 1-4 Alkyl substitution. In some embodiments, R a It is a 3- to 6-membered saturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally surrounded by one or more oxo groups, C 1-2 Alkyl, -C(O)CH3, or -OCH3 substitution. In some embodiments, R a A 3- to 6-membered saturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more oxo groups or one or more fluorine groups. 1-2 Alkyl, -C(O)CH3, or -OCH3 substitution. In some embodiments, R a It is a 3- to 6-membered saturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is optionally substituted with one or more oxo groups, fluorine, -C(O)CH3, -OCH3, or optionally substituted with one or more fluorine groups and -OCH3. 1-2 Alkyl substitution. In some embodiments, R a It is a 3- to 6-membered saturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 3- to 6-membered saturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 3-membered saturated monocyclic heterocyclic group with 1-3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 3-membered saturated monocyclic heterocyclic group with one independently substituted heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 4-membered saturated monocyclic heterocyclic group with 1-3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R aIt is a 4-membered saturated monocyclic heterocyclic group with one independently substituted heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is optionally substituted with an azahexacyclic butyl or an oxacyclic butyl. In some embodiments, R a for In some implementation schemes, R a It is a 5-membered saturated monocyclic heterocyclic group with 1-3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 5-membered saturated monocyclic heterocyclic group having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is optionally substituted with pyrrolidinyl or tetrahydrofuranyl. In some embodiments, R a for In some implementation schemes, R a for In some implementation schemes, R a for In some implementation schemes, R a It is a 6-membered saturated monocyclic heterocyclic group with 1-3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 6-membered saturated monocyclic heterocyclic group with optional substitutions of 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It can be optionally substituted with piperazine, morpholino, tetrahydropyrano, or 1,4-dioxane. In some embodiments, R a It can be optionally substituted with piperidinyl, piperazine, morpholinyl, tetrahydropyranyl, or 1,4-dioxane. In some embodiments, R a for In some implementation schemes, R a for In some implementation schemes, R a for In some implementation schemes, R a Not for In some implementation schemes, R a Not for

[0202] In some implementation schemes, R a It is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R aIt is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally surrounded by one or more -C(O)(C 1-4 Alkyl) substitution. In some embodiments, R a It is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more -C(O)CH3 groups. In some embodiments, R a It is a 7- to 10-membered saturated spirocyclic bicyclic heterocyclic group with 1 to 4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 7- to 8-membered saturated spirocyclic bicyclic heterocyclic group with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 7- to 8-membered saturated spirocyclic bicyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 7- to 10-membered saturated spirocyclic bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally surrounded by one or more -C(O)(C 1-4 Alkyl) substitution. In some embodiments, R a It is a 7- to 10-membered saturated spirocyclic bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more -C(O)CH3 groups. In some embodiments, R a It is a 7-membered saturated spirocyclic bicyclic heterocyclic group with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R a It is a 7-membered saturated spirocyclic bicyclic heterocyclic group with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R a The alternative is 2-oxaspiro[3.3]heptyl or 2-azaspiro[3.3]heptyl. In some embodiments, R a The alternative is 2-oxaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, or 4-oxaspiro[2.4]heptyl. In some embodiments, R a for In some implementation schemes, R a for

[0203] In some implementation schemes, R a Choose from the following groups:

[0204]

[0205]

[0206] In some implementation schemes, R a Not fluorine, chlorine, bromine, -CF3, In some implementation schemes, R a Not chlorine, bromine or

[0207] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, IV-A, IB, II-B, III-B, IV-B, IC, II-C, III-C, IV-C, ID, II-D, III-D, IV-D, IE, II-E, III-E, and IV-E, -R a (That is, L is a covalent bond). In some implementations, For -(C 1-3 (alkylene)-R a (i.e., L is C) 1-3 (Straight-chain or branched hydrocarbon chain). In some implementations, For -(C 1-2 (alkylene)-R a (i.e., L is C) 1-2 (Straight-chain or branched hydrocarbon chain). In some implementations, -CH2-R a (i.e., L represents a C1 hydrocarbon chain). In some implementations, -CH2CH2-R a (That is, L is a C2 straight-chain hydrocarbon chain). In some implementations, -CH2CH2CH2-R a (That is, L is a C3 straight-chain hydrocarbon chain.)

[0208] In some embodiments of any of formulas I', II', III', IV', IB, II-B, III-B, IV-B, IC, II-C, III-C, IV-C, ID, II-D, III-D, IV-D, IE, II-E, III-E, and IV-E, as permitted by the valence rule, R bIt can appear up to five times, and each can independently be a halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -SO2R', -SO2N(R)2, -SO3R', or an optionally substituted C. 1-6 Aliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic groups, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 5- to 6-membered monocyclic heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b Each time it appears, it is independently hydrogen, halogen, or optionally substituted C. 1-4 Alkyl, optionally substituted C 3-4 Cycloalkyl, a 3- to 5-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-membered monocyclic heteroaryl group having 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R b Halogen, optional substituted C 1-4 Alkyl or optionally substituted C 3-4 Cycloalkyl. In some embodiments, R b C is an optional replacement 1-4 Alkyl or optionally substituted C 3-4 Cycloalkyl. In some embodiments, R b C is optionally substituted with one or more fluorine molecules. 3-4 cycloalkyl or C 1-4 alkyl.

[0209] In some implementation schemes, R b It is hydrogen.

[0210] In some implementation schemes, R b It is a halogen. In some implementations, R b It can be fluorine, chlorine, bromine, or iodine. In some embodiments, R b It is fluorine. In some implementations, R b It is chlorine. In some implementations, R b Not halogenated. In some implementations, R b Not fluorine. In some implementations, R b It is not chlorine.

[0211] In some implementation schemes, R bFor example, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -SO2R, -SO2N(R)2, or -SO3R'. In some implementations, R b For example, -CN, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -SO2R, -SO2N(R)2, or -SO3R'. In some implementations, R b Not -OR. In some implementations, R b Not for

[0212] In some implementation schemes, R b C is an optional replacement 1-6 Aliphatic. In some implementations, R b For optional substitution of straight or branched C 1-6 Aliphatic (i.e., optionally substituted noncyclic C) 1-6 (Aliphatic). In some implementations, R b C is an optional replacement 1-6 Alkyl group. In some embodiments, R b C is an optional replacement 1-4 Alkyl group. In some embodiments, R b C that is optionally substituted with one or more halogens 1-4 Alkyl group. In some embodiments, R b C is optionally replaced by one or more of halogen and -CN. 1-4 Alkyl group. In some embodiments, R b It is methyl. In some embodiments, R b For -CF3. In some implementations, R b It is tert-butyl. In some implementations, R b For -CF2CF3. In some implementations, R b It is -C(CH3)2CN.

[0213] In some implementation schemes, R b The substituted 3 to 6-membered saturated or partially unsaturated carbocyclic groups are used. In some embodiments, R b C is an optional replacement3-6 Cycloalkyl. In some embodiments, R b It is cyclopropyl. In some embodiments, R b It is cyclobutyl.

[0214] In some implementation schemes, R b It is a 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R b It is a 3- to 6-membered saturated monocyclic heterocyclic group with 1-3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R b It is a 3- to 5-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R b It is a nitrogen-containing heterocyclic butyl group.

[0215] In some implementation schemes, R b It is a 5- to 6-membered monocyclic heteroaryl group with 1 to 4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R b It is a 5-membered monocyclic heteroaryl group with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R b It is a pyrazolyl group.

[0216] In some implementation schemes, R b Not fluorine, chlorine, bromine, -OR, or -CF3. In some implementations, R b Not fluorine, chlorine, bromine, -CF3, In some implementation schemes, R b Not chlorine, bromine, or -OR. In some implementations, R b Not chlorine, bromine,

[0217]

[0218] In some embodiments of any of formulas I, II, III, IV, IA, II-A, III-A, and IV-A, the optional substitution is for

[0219] In some implementations, the optional replacement The groups may be selected from the following optional substitution groups:

[0220]

[0221] In some implementations, the optional replacement The groups may be selected from the following optional substitution groups: In some implementations, the optional replacement The groups may be selected from the following optional substitution groups: In some implementations, the optional replacement The groups may be selected from the following optional substitution groups: In some implementations, the optional replacement The groups may be selected from the following optional substitution groups: In some implementations, the optional replacement The groups may be selected from the following optional substitution groups: In some implementations, the optional replacement The groups may be selected from the following optional substitution groups: In some implementations, the optional replacement The groups may be selected from the following optional substitution groups: In some implementations, the optional replacement The groups may be selected from the following optional substitution groups: In some implementations, the optional replacement For optional replacement

[0222] In some implementation schemes, Selected from:

[0223]

[0224]

[0225] In some implementation schemes, for: In some implementation schemes, for: In some implementation schemes, for: In some implementation schemes, for: In some implementation schemes, for: In some implementation schemes, for: In some implementation schemes, for: In some implementation schemes, for: In some implementation schemes, for:

[0226] In some implementation schemes, for:

[0227] In some implementation schemes, for: In some implementation schemes, for: In some implementation schemes, for: In some implementation schemes, for: In some implementation schemes, for: In some implementation schemes, for: In some implementation schemes, for: In some implementation schemes, for: In some implementation schemes, for:

[0228] In some implementation schemes, Selected from:

[0229]

[0230]

[0231]

[0232] In some implementation schemes, for: In some implementation schemes, for:

[0233] In some implementation schemes, for:

[0234] In some implementation schemes, for: In some implementation schemes,

[0235] for:

[0236] In some implementation schemes, for:

[0237]

[0238] In some implementation schemes, for:

[0239]

[0240] In some implementation schemes, for:

[0241] In some implementation schemes, for: In some implementation schemes, for:

[0242] In some implementation schemes, for:

[0243] In some implementation schemes, Not for: In some implementation schemes, Not for:

[0244] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, IV-A, IB, II-B, III-B, IV-B, IC, II-C, III-C, IV-C, ID, II-D, III-D, IV-D, IE, II-E, III-E, and IV-E, each R is independently hydrogen or optionally substituted C.1-6 Aliphatic. In some embodiments, each R is independently hydrogen or optionally substituted C. 1-6 Alkyl group. In some embodiments, each R is independently hydrogen or C. 1-6 Alkyl group. In some embodiments, each R is independently hydrogen or optionally substituted C. 1-4 Alkyl group. In some embodiments, each R is independently hydrogen or C. 1-4 Alkyl group. In some embodiments, each R is independently hydrogen or methyl.

[0245] In some implementations, R is hydrogen.

[0246] In some implementations, R is an optional substitute for C. 1-6 Aliphatic. In some embodiments, R is an optionally substituted straight-chain or branched C. 1-6 Aliphatic (i.e., optionally substituted noncyclic C) 1-6 (Aliphatic). In some embodiments, R is an optionally substituted C. 1-6 Alkyl group. In some embodiments, R is an optionally substituted C. 1-4 Alkyl group. In some embodiments, R is an unsubstituted C. 1-4 Alkyl group. In some embodiments, R is an optionally substituted C. 1-2 Alkyl group. In some embodiments, R is an unsubstituted C. 1-2 Alkyl group. In some embodiments, R is methyl.

[0247] In some embodiments, R is an optionally substituted 3 to 7 saturated or partially unsaturated carbocyclic group.

[0248] In some embodiments, R is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur.

[0249] In some embodiments, the two R groups, when attached to the same nitrogen atom, together form a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the two R groups, when attached to the same nitrogen atom, together form a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally bonded by one or more halogens, C... 1-6 Alkyl and -O(C) 1-6Alkyl groups are substituted. In some embodiments, the two R groups, when attached to the same nitrogen, together form an optionally substituted 3- to 5-membered saturated monocyclic heterocyclic group having 0-1 additional heteroatoms. In some embodiments, the two R groups, when attached to the same nitrogen, together form an optionally substituted 4-membered saturated monocyclic heterocyclic group having 0-1 additional heteroatoms. In some embodiments, the two R groups, when attached to the same nitrogen, together form a 3- to 5-membered saturated monocyclic heterocyclic group having 0-1 additional heteroatoms, optionally substituted with one or more halogens, C... 1-6 Alkyl and -O(C) 1-6 Alkyl groups are substituted. In some embodiments, the two R groups, when attached to the same nitrogen atom, together form a 4-membered saturated monocyclic heterocyclic group having 0-1 additional heteroatoms, which is optionally substituted with one or more halogens, C... 1-6 Alkyl and -O(C) 1-6 Alkyl) substitution.

[0250] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, IV-A, IB, II-B, III-B, IV-B, IC, II-C, III-C, IV-C, ID, II-D, III-D, IV-D, IE, II-E, III-E, and IV-E, each R' is independently a optionally substituted C 1-6 Alkyl or optionally substituted C 3-6 Cycloalkyl. In some embodiments, each R' is independently a optionally substituted C. 1-2 Alkyl or optionally substituted C 3-4 Cycloalkyl. In some embodiments, each R' is independently methyl or optionally substituted C3 cycloalkyl. In some embodiments, each R' is independently C3 cycloalkyl. 1-2 Alkyl or C 3-4 Cycloalkyl. In some embodiments, each R' is independently methyl or cyclopropyl. In some embodiments, each R' is independently methyl, In some implementations, each R' is independently methyl, -CH2CH2OCH3, In some implementations, each R' is independently methyl, -CH2CH2OCH3,

[0251] In some implementations, R' is an optional substitute for C. 1-6 Aliphatic. In some embodiments, R' is an optionally substituted straight-chain or branched C. 1-6 Aliphatic (i.e., optionally substituted noncyclic C) 1-6 (Aliphatic). In some embodiments, R' is an optionally substituted C.1-6 Alkyl group. In some embodiments, R' is optionally -OC 1-6 Alkyl groups or C-membered 3- to 7-membered saturated monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-6 Alkyl group. In some embodiments, R' is an optionally substituted C. 1-4 Alkyl group. In some embodiments, R' is optionally -OC 1-6 Alkyl groups or C-membered 3- to 7-membered saturated monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-4 Alkyl group. In some embodiments, R' is an unsubstituted C. 1-4 Alkyl group. In some embodiments, R' is an optionally substituted C. 1-2 Alkyl group. In some embodiments, R' is optionally -OC 1-6 Alkyl groups or C-membered 3- to 7-membered saturated monocyclic heterocyclic groups having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-2 Alkyl group. In some embodiments, R' is an unsubstituted C. 1-2 Alkyl group. In some embodiments, R' is methyl. In some embodiments, R' is -CH2CH2OCH3. In some embodiments, R' is a C-aryl group optionally substituted with a 3- to 7-membered saturated monocyclic heterocyclic group (e.g., morpholino or tetrahydropyranyl) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1-2 alkyl.

[0252] In some implementations, R' is an optional substitute for C. 1-6 Aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic groups. In some embodiments, R' is a 3- to 7-membered saturated or partially unsaturated carbocyclic group optionally substituted with one or more halogens. In some embodiments, R' is an optionally substituted C 3-6 Cycloalkyl. In some embodiments, R' is a C-shaped compound optionally substituted with one or more halogens. 3-6 Cycloalkyl. In some embodiments, R' is an optionally substituted C3 cycloalkyl group. In some embodiments, R' is... In some implementations, R' is

[0253] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, the compound is not:

[0254]

[0255]

[0256] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, the compound is not:

[0257]

[0258] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, the compound is not:

[0259]

[0260]

[0261] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when R 1 It is -N(H)C(O)R' and R' is an optionally substituted C 1-6 Aliphatic (e.g., optionally substituted C) 1-6 Alkyl groups, such as optionally substituted C4 groups 1-2 When alkyl is present, ring A is not phenyl.

[0262] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when R 1 When the ring is -N(H)C(O)R' and R' is methyl, then ring A is not phenyl.

[0263] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when R 1 The value is -N(H)C(O)R', where R' is an optionally substituted C. 1-6 Aliphatic (e.g., optionally substituted C) 1-6 Alkyl groups, such as optionally substituted C4 groups 1-2 When alkyl and ring A is phenyl, then R a It is not fluorine.

[0264] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when R 1 The value is -N(H)C(O)R', where R' is an optionally substituted C.1-6 Aliphatic (e.g., optionally substituted C) 1-6 Alkyl groups, such as optionally substituted C4 groups 1-2 When alkyl and ring A is phenyl, then R a Not -CF3 or optionally substituted piperazine group.

[0265] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when R 1 The value is -N(H)C(O)R', where R' is an optionally substituted C. 1-6 Aliphatic (e.g., optionally substituted C) 1-6 Alkyl groups, such as optionally substituted C4 groups 1-2 When alkyl and ring A is phenyl, then R a Not -CF3 or

[0266] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when R 1 The value is -N(H)C(O)R', where R' is an optionally substituted C. 1-6 Aliphatic (e.g., optionally substituted C) 1-6 Alkyl groups, such as optionally substituted C4 groups 1-2 When alkyl and ring A is phenyl, then R b Not -CF3 or

[0267] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when R 1 It is -C(O)NH(R) and R is an optionally substituted C 1-6 Aliphatic (e.g., optionally substituted C) 1-6 Alkyl groups, such as optionally substituted C4 groups 1-2 When the alkyl group (e.g., methyl) is used, then ring A is not phenyl.

[0268] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when R 1 The denoted ... 1-6 Aliphatic (e.g., optionally substituted C) 1-6 Alkyl groups, such as optionally substituted C4 groups 1-2 When alkyl (e.g., methyl) and ring A is phenyl, then Ra and R b Neither of them are chlorine or bromine.

[0269] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when R 1 The denoted ... 1-6 Aliphatic (e.g., optionally substituted C) 1-6 Alkyl groups, such as optionally substituted C4 groups 1-2 When alkyl (e.g., methyl) and ring A is phenyl, then R a It is neither chlorine nor bromine.

[0270] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when R 1 The denoted ... 1-6 Aliphatic (e.g., optionally substituted C) 1-6 Alkyl groups, such as optionally substituted C4 groups 1-2 When alkyl (e.g., methyl) and ring A is phenyl, then R a Not for

[0271] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when R 1 The denoted ... 1-6 Aliphatic (e.g., optionally substituted C) 1-6 Alkyl groups, such as optionally substituted C4 groups 1-2 When alkyl (e.g., methyl) and ring A is phenyl, then R b Not -OR.

[0272] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when R 1 The denoted ... 1-6 Aliphatic (e.g., optionally substituted C) 1-6 Alkyl groups, such as optionally substituted C4 groups 1-2 When alkyl (e.g., methyl) and ring A is phenyl, then R b Not for

[0273] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when ring A is phenyl, R 1 It is -NHC(O)R' or -NH2, R 2 X is -CH3, X is CH, and R' is an optionally substituted C. 1-2 In the case of aliphatic, then R a and R b Not fluorine or

[0274] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when ring A is phenyl, R 1 -NHC(O)CH3, R 2 When R is -CH3 and X is N, then R a and R b Not fluorine or

[0275] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when ring A is phenyl, R 1 -NHC(O)CH3, R 2 When R is -CH3 and X is CCH3, then R a and R b Not for

[0276] In some embodiments of any of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, and IV-A, when ring A is phenyl, R 1 -C(O)NHCH3, R 2 C 1-2 When X is an alkyl group and X is CH, then R a and R b Not halogen.

[0277] In some embodiments, this disclosure provides compounds selected from Table 1:

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308] Or its pharmaceutically acceptable salt.

[0309] In some embodiments, this disclosure covers the understanding that the provided compounds exhibit certain desirable properties compared to other known compounds. For example, in some embodiments, the provided compounds are more potent and / or have one or more other properties that make them more suitable for drug development compared to other known compounds in one or more biochemical or cellular assays (e.g., the JAK2 binding assay or SET2-pSTAT5 cellular assay described herein), such as superior selectivity and / or better ADME (absorption, distribution, metabolism, and excretion) properties, including but not limited to better permeability, cytotoxicity, hepatocyte stability, solubility, and / or plasma protein binding profile (e.g., based on the assays described in the following examples). In some embodiments, the provided compounds exhibit certain desirable properties compared to other known compounds, for example, in one or more assays described herein. Without wishing to be bound by any particular theory, this disclosure covers the understanding that 6-heteroaryloxybenzimidazoles and azabenzimidazoles (e.g., the compounds described herein) exhibit certain more desirable properties (such as better properties in one or more assays described herein) compared to the corresponding 5-heteroaryloxybenzimidazoles and azabenzimidazoles.

[0310] In some embodiments, the provided compounds are provided and / or utilized in salt form (e.g., pharmaceutically acceptable salt form). Unless otherwise indicated, references to the compounds provided herein should be construed as including references to their salts. Pharmaceutically acceptable salt forms are known in the art. For example, SMBerge et al. provided a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 66:1-19 (1977).

[0311] It should be understood that throughout this disclosure, unless otherwise indicated, references to compounds of formula I-1 are also intended to include formulas I, I', II', III', IV', II, III, IV, IA, II-A, III-A, IV-A, IB, II-B, III-B, IV-B, IC, II-C, III-C, IV-C, ID, II-D, III-D, IV-D, IE, II-E, III-E and IV-E, as well as the types of compounds of such formulas disclosed herein.

[0312] Preparation of the provided compound

[0313] In some embodiments, the provided compound (e.g., compound of formula I-1, where Z is -NH-) is prepared according to the following scheme:

[0314]

[0315] Among them, rings A, L, W, X, Y, R 1 、R 2 and R a As defined above for formula I-1. Therefore, in some embodiments, intermediate A.2 is prepared by contacting intermediate A.1 with phosgene in the presence of a suitable base (e.g., NaHCO3 or triethylamine). In some embodiments, compound A-1 is prepared by contacting intermediate A.2 with intermediate A.3-1 in the presence of a suitable coupling agent (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or N,N'-diisopropylcarbodiimide).

[0316] In some embodiments, the provided compound (e.g., compound of formula I, where Z is -NH-) is prepared according to the following scheme:

[0317]

[0318] Among them, rings A, L, X, Y, and R 1 、R 2 and R a As defined above for Formula I. Therefore, in some embodiments, intermediate A.2 is prepared by contacting intermediate A.1 with phosgene in the presence of a suitable base (e.g., NaHCO3 or triethylamine). In some embodiments, compound A is prepared by contacting intermediate A.2 with intermediate A.3 in the presence of a suitable coupling agent (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or N,N'-diisopropylcarbodiimide).

[0319] In some embodiments, the provided compound (e.g., compound of formula I-1, where Z is -O-) is prepared according to the following scheme:

[0320]

[0321] Where LG is a suitable leaving group (e.g., halogen, chlorine), and the rings A, L, W, X, Y, R 1 、R 2 and R a As defined above for formula I-1. Therefore, in some embodiments, compound B-1 is prepared by contacting intermediate B.1-1 with intermediate B.2 in the presence of a suitable base (e.g., K2CO3).

[0322] In some embodiments, the provided compound (e.g., compound of formula I-1, where Z is -O-) is prepared according to the following scheme:

[0323]

[0324] Where LG is a suitable leaving group (e.g., halogen, chlorine), and the rings A, L, X, Y, R 1 、R 2 and R a As defined above for Formula I. Therefore, in some embodiments, compound B is prepared by contacting intermediate B.1 and intermediate B.2 in the presence of a suitable base (e.g., K2CO3).

[0325] In some embodiments, the provided compound is obtained by a process including the purification methods described in the Examples section. In some such embodiments, the compound is a first eluting isomer. In some such embodiments, the compound is a second eluting isomer. In some embodiments, the compound is a third eluting isomer. In some embodiments, the compound is a fourth eluting isomer. In some embodiments, the compound is a fifth, sixth, seventh, eighth, or later eluting isomer.

[0326] Composition

[0327] This disclosure also provides compositions comprising the compounds provided herein with one or more other components. In some embodiments, the provided compositions comprise and / or deliver compounds described herein (e.g., compounds of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, IV-A, IB, II-B, III-B, IV-B, IC, II-C, III-C, IV-C, ID, II-D, III-D, IV-D, IE, II-E, III-E, and IV-E).

[0328] In some embodiments, the provided composition is a pharmaceutical composition comprising and / or delivering compounds provided herein (e.g., compounds of formulas I-1, I, II, III, IV, I', II', III', IV', IA, II-A, III-A, IV-A, IB, II-B, III-B, IV-B, IC, II-C, III-C, IV-C, ID, II-D, III-D, IV-D, IE, II-E, III-E, and IV-E) and also comprising a pharmaceutically acceptable carrier. The pharmaceutical composition typically contains 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-adhesion agents, and / or antistatic agents, etc. 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 the pharmaceutical compositions are well known in the art.

[0329] In some embodiments, the provided compound is formulated in unit dosage forms for ease of administration and uniform dosage. As used herein, "unit dosage form" refers to a physically discrete unit of an active agent (such as the compound described herein) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, a unit dosage form contains the entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, multiple unit dosage forms are required or anticipated to achieve the desired effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined amount of one or more active agents, a solid pharmaceutical composition (e.g., tablets, capsules, or the like) containing a predetermined amount of one or more active agents, a sustained-release formulation containing a predetermined amount of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.

[0330] The provided composition may be applied in any amount and via any route of administration that is effective in treating or reducing the severity of any of the diseases or conditions described herein.

[0331] use

[0332] 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 medicine (e.g., as a therapy). In some embodiments, the provided compounds and compositions may be used in studies as analytical tools and / or control compounds, for example, in bioassays.

[0333] In some embodiments, this disclosure provides a method of administering the provided compound or composition to a subject in need. In some embodiments, this disclosure provides a method of administering the provided compound or composition to a subject who has or is susceptible to a JAK2-related disease, condition, or disorder.

[0334] 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 a subject, the method comprising administering the provided compound or composition. In some embodiments, this disclosure provides a method for inhibiting JAK2 in a biological sample, the method comprising contacting the sample with the provided compound or composition.

[0335] JAK (e.g., JAK2) has been involved in a variety of diseases, conditions, and disorders, such as myeloproliferative neoplasms (Vainchenker, W. et al., F1000Research 2018, 7(F1000Faculty Rev: 82), atopic dermatitis (Rodrigues, MA and Torres, TJDerm.Treat. 2019, 31(1), 33-40.), and acute respiratory syndrome, excessive inflammation, and / or cytokine 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 a subject of need, the method comprising administering the provided compound or composition to the subject. In some embodiments, the disease, condition, or disorder is associated with overexpression of JAK2.

[0336] In some embodiments, this disclosure provides a method of treating cancer, the method comprising administering the provided compound or composition to a subject in need. In some embodiments, this disclosure provides a method of treating proliferative diseases, the method comprising administering the provided compound or composition to a subject in need.

[0337] In some embodiments, this disclosure provides a method of treating a hematologic malignancy, the method comprising administering the provided compound or composition to a subject 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, the non-Hodgkin's lymphoma is B-cell lymphoma. In some embodiments, the 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 implementations, the hematologic malignancy is a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or myelofibrosis). In some implementations, the hematologic malignancy is myelodysplastic syndrome.

[0338] In some embodiments, this disclosure provides a method for treating inflammatory diseases, conditions, or disorders (e.g., acute respiratory syndrome, excessive inflammation and / or cytokine storm syndrome (including those associated with COVID-19) or atopic dermatitis), said method comprising administering the provided compound or composition to a subject in need.

[0339] 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 those situations in which a subject is simultaneously exposed to two or more treatment or preventative regimens (e.g., two or more therapeutic agents or preventative agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all "doses" of the first regimen are administered before any dose of the second regimen); in some embodiments, such agents are administered in an overlapping dosing regimen. In some embodiments, "administration" of the combination therapy may involve administering one or more agents or modalities to a subject receiving other agents or modalities in the combination. For clarity, combination therapy does not require individual agents to be administered together as a single composition (or even simultaneously), but in some embodiments, two or more agents or their active portions may be administered together as a combination composition.

[0340] For example, in some embodiments, the provided compound or composition is administered to a subject who is receiving or has received one or more additional therapies (e.g., anticancer therapy and / or therapy to address one or more side effects of such anticancer therapy, or to otherwise provide palliative care). Exemplary additional therapies include, but are not limited to, BCL2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mivebresib), proteasome inhibitors (e.g., bortezomib), LSD1 inhibitors (e.g., IMG-7289), and CXCR2 inhibitors. Useful combinations of 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 shown promising efficacy in a mouse model of myeloproliferative neoplasms (Jutzi, JS et al., HemaSphere 2018, 2(3), dx.doi.org / 10.1097 / HS9.0000000000000054). CXCR2 activity has been shown to regulate signaling pathways involved in tumor growth, angiogenesis, and / or metastasis, including the JAK-STAT3 pathway (Jaffer, T., Ma, D. Transl. Cancer Res. 2016, 5(Supplement 4), S616-S628).

[0341] Exemplary Implementation

[0342] The following numbered embodiments are non-restrictive but illustrate certain aspects of this disclosure:

[0343] A1. A compound of formula I-1:

[0344]

[0345] or a pharmaceutically acceptable salt thereof, wherein:

[0346] W is CR w Or N;

[0347] X is CR x Or N;

[0348] Y is CR y Or N;

[0349] Z is either -O- or -NR z -;

[0350] Rw 、R x and R y Each independently represents hydrogen, halogen, -OR 3 、-N(R 3 )2、-SR 3 Optional substitution of C 1-6 Aliphatic or -CN;

[0351] R z C is hydrogen or optionally substituted 1-6 Aliphatic;

[0352] R 1 It is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2;

[0353] R 2 C is an optional replacement 1-6 Aliphatic;

[0354] R 3 C is hydrogen or optionally substituted 1-6 Aliphatic;

[0355] The ring A is an optionally substituted phenyl group, an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8- to 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0356] L represents a covalent bond or a divalent C. 1-3 Straight-chain or branched hydrocarbon chains;

[0357] R a For hydrogen, halogen, or optionally substituted C 1-6 Aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0358] Each R is independently hydrogen, with optional substituted C. 1-6Aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic groups, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rs forming together, when attached to the same nitrogen atom, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0359] Each R' is independently a C that can be substituted arbitrarily. 1-6 Aliphatic or optionally substituted 3 to 7 saturated or partially unsaturated carbocyclic groups.

[0360] A2. The compound as described in embodiment A1, wherein:

[0361] W is CR w Or N;

[0362] X is CR x Or N;

[0363] Y is CR y Or N;

[0364] Z is either -O- or -NR z -;

[0365] R w 、R x and R y Each independently represents hydrogen, halogen, -OR 3 、-N(R 3 )2、-SR 3 Optional substitution of C 1-6 Aliphatic or -CN;

[0366] R z C is hydrogen or optionally substituted 1-6 Aliphatic;

[0367] R 1 It is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2;

[0368] R 2 C is an optional replacement 1-6 Aliphatic;

[0369] R 3 C is hydrogen or optionally substituted 1-6 Aliphatic;

[0370] The ring A is an optionally substituted phenyl group, an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8- to 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0371] L represents a covalent bond or a divalent C. 1-3 Straight-chain or branched hydrocarbon chains;

[0372] R a For hydrogen, halogen, or optionally substituted C 1-6 Aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0373] Each R is independently hydrogen, with optional substituted C. 1-6 Aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic groups, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rs together forming a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur when attached to the same nitrogen atom; and

[0374] Each R' is independently a C that can be substituted arbitrarily. 1-6 Aliphatic or optionally substituted 3 to 7 saturated or partially unsaturated carbocyclic groups.

[0375] A3. The compound as described in embodiment A1 or A2, wherein:

[0376] W stands for CH;

[0377] X is CR x Or N;

[0378] Y is CR y Or N;

[0379] Z is either -O- or -NR z -;

[0380] Rx and R y Each is independently hydrogen, and each of the optionally substituted C atoms is a carbon atom. 1-6 Aliphatic or -CN;

[0381] R z C is hydrogen or optionally substituted 1-6 Aliphatic;

[0382] R 1 It is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2;

[0383] R 2 C is an optional replacement 1-6 Aliphatic;

[0384] The ring A is an optionally substituted phenyl group, an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 8- to 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0385] L represents a covalent bond or a divalent C. 1-3 Straight-chain or branched hydrocarbon chains;

[0386] R a For hydrogen, halogen, or optionally substituted C 1-6 Aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0387] Each R is independently hydrogen, with optional substituted C. 1-6 Aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic groups, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rs together forming a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur when attached to the same nitrogen atom; and

[0388] Each R' is independently a C that can be substituted arbitrarily. 1-6 Aliphatic or optionally substituted 3 to 7 saturated or partially unsaturated carbocyclic groups.

[0389] A4. A compound as described in any of the foregoing embodiments, wherein said compound is not:

[0390]

[0391]

[0392] A5. The compound of any of the preceding embodiments, wherein ring A is a 5- to 6-membered monocyclic heteroaryl having 1 to 4 independently selected heteroatoms of nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1 to 4 independently selected heteroatoms of nitrogen, oxygen, and sulfur, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independently selected heteroatoms of nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 independently selected heteroatoms of nitrogen, oxygen, and sulfur.

[0393] A5. The compound of any of the foregoing embodiments, wherein ring A is a 5- to 6-membered monocyclic heteroaryl group having 1 to 4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0394] A6. The compound of any of the foregoing embodiments, wherein R a Halogen, optional substituted C 1-4 Alkyl group, optional substituted 5-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optional substituted 3- to 6-membered saturated monocyclic carbocyclic group, optional substituted 3- to 6-membered saturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optional substituted 7-membered saturated spirocyclic bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0395] A7. The compound of any of the foregoing embodiments, wherein:

[0396] for and

[0397] R bHydrogen, halogens, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -SO2R', -SO2N(R)2, -SO3R', and optionally substituted C 1-6 Aliphatic, optionally substituted 3 to 6 saturated or partially unsaturated carbocyclic groups, optionally substituted 3 to 6 saturated or partially unsaturated monocyclic heterocyclic groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted 5 to 6 cyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0398] A8. The compound as described in embodiment A7, wherein... for:

[0399]

[0400] A9. Compounds as described in embodiments A7 or A8, wherein R b Halogen, optional substituted C 1-4 Alkyl or optionally substituted C 3-4 Cycloalkyl.

[0401] A10. The compound as described in any of the foregoing embodiments, wherein R 1 It is -N(R)2.

[0402] A11. The compound as described in embodiment A10, wherein R 1 It is -N(H)(R).

[0403] A12. A compound as described in any of embodiments A1 to A9, wherein R 1 It is -N(R)C(O)R'.

[0404] A13. The compound as described in embodiment A12, wherein R 1 It is -N(H)C(O)R'.

[0405] A14. The compound as described in embodiment A13, wherein R 1 It is -N(H)C(O)CH3.

[0406] A15. A compound as described in any of embodiments A1 to A9, wherein R 1 It is -C(O)N(R)2.

[0407] A16. The compound as described in embodiment A15, wherein R1 It is -C(O)N(H)CH3.

[0408] A17. A compound as described in any of embodiments A1 to A9, wherein R 1 It is -N(R)C(O)N(R)2.

[0409] A18. The compound as described in embodiment A17, wherein R 1 It is -N(H)C(O)N(R)2.

[0410] A19. The compound of any of the foregoing embodiments, wherein R 2 C 1-4 alkyl.

[0411] A20. The compound as described in any of the foregoing embodiments, wherein X is a CR x .

[0412] A21. The compound as described in embodiment A20, wherein R x For hydrogen, halogen, -OR 3 Optional substitution of C 1-6 Aliphatic or -CN.

[0413] A22. The compound as described in embodiment A21, wherein R x It is hydrogen.

[0414] A23. A compound as described in any of embodiments A1 to A19, wherein X is N.

[0415] A24. The compound of any of the foregoing embodiments, wherein Y is CR y .

[0416] A25. The compound as described in embodiment A24, wherein R y It is hydrogen.

[0417] A26. A compound as described in any of embodiments A1 to A23, wherein Y is N.

[0418] A27. The compound of any of the foregoing embodiments, wherein Z is -NR z -

[0419] A28. The compound of embodiment 27, wherein R z It is hydrogen.

[0420] A29. A compound as described in any of embodiments A1 to A26, wherein Z is -O-.

[0421] A30. The compound of any of the foregoing embodiments, wherein the compound is a compound of formula IA:

[0422]

[0423] Or its pharmaceutically acceptable salt.

[0424] A31. The compound of any of the foregoing embodiments, wherein the compound is a compound of formula IB:

[0425]

[0426]

[0427] Or its pharmaceutically acceptable salt.

[0428] A32. The compound of any of the foregoing embodiments, wherein the compound is a compound of formula IC:

[0429]

[0430] Or its pharmaceutically acceptable salt.

[0431] A33. The compound of any of the foregoing embodiments, wherein the compound is a compound of formula ID:

[0432]

[0433] Or its pharmaceutically acceptable salt.

[0434] A34. The compound of any of the foregoing embodiments, wherein the compound is a compound of formula IE:

[0435]

[0436] Or its pharmaceutically acceptable salt.

[0437] A35. The compound of embodiment 1, wherein the compound is a compound of Table 1.

[0438] A36. A pharmaceutical composition comprising a compound as described in any of the foregoing embodiments or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0439] A37. A method for inhibiting JAK2 in a subject, the method comprising administering a compound as described in any one of embodiments A1 to A35 or a composition as described in embodiment A36.

[0440] A38. A method of treating a disease, condition, or disorder associated with JAK2, the method comprising administering to a subject in need a compound as described in any one of embodiments A1 to A35 or a composition as described in embodiment A36.

[0441] A39. A method of treating cancer, the method comprising administering to a subject in need a compound as described in any one of embodiments A1 to A35 or a composition as described in embodiment A36.

[0442] A40. A method for treating hematologic malignancies, the method comprising administering to a subject in need a compound as described in any one of embodiments A1 to A35 or a composition as described in embodiment A36.

[0443] A41. The method of implementation scheme A40, wherein the hematologic malignancy is leukemia or lymphoma.

[0444] A42. A method for treating myeloproliferative neoplasms, the method comprising administering to a subject in need a compound as described in any one of embodiments A1 to A35 or a composition as described in embodiment A36.

[0445] A43. The method of implementation scheme A42, wherein the myeloproliferative neoplasm is polycythemia vera, primary thrombocytopenia, or myelofibrosis.

[0446] B1. A compound of formula I-1 or a pharmaceutically acceptable salt thereof.

[0447]

[0448] in:

[0449] W is CR w Or N;

[0450] X is CR x Or N;

[0451] Y is CR y Or N;

[0452] Z is either -O- or -NR z -;

[0453] R w 、R x and R y Each independently represents hydrogen, halogen, -OR 3 、-N(R 3 )2、-SR 3 Optional substitution of C 1-6 Aliphatic or -CN;

[0454] R z C is hydrogen or optionally substituted 1-6 Aliphatic;

[0455] R 1It is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2;

[0456] R 2 C is an optional replacement 1-6 Aliphatic;

[0457] R 3 C is hydrogen or optionally substituted 1-6 Aliphatic;

[0458] Ring A is a 5- to 6-membered monocyclic heteroaryl group having 1 to 4 independently selected heteroatoms of nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl group having 1 to 4 independently selected heteroatoms of nitrogen, oxygen, and sulfur, an 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group having 1 to 3 independently selected heteroatoms of nitrogen, oxygen, and sulfur, or a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 independently selected heteroatoms of nitrogen, oxygen, and sulfur.

[0459] L represents a covalent bond or a divalent C. 1-3 Straight-chain or branched hydrocarbon chains;

[0460] R a For hydrogen, halogen, or optionally substituted C 1-6 Aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0461] Each R is independently hydrogen, with optional substituted C. 1-6 Aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic groups, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rs forming together, when attached to the same nitrogen atom, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0462] Each R' is independently a C that can be substituted arbitrarily. 1-6 Aliphatic or optionally substituted 3 to 7 saturated or partially unsaturated carbocyclic groups.

[0463] B2. The compound of embodiment B1, wherein ring A is a 5- to 6-membered monocyclic heteroaryl group having 1 to 4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0464] B3. The compound of embodiment B1, wherein ring A is an 8- to 10-membered bicyclic heteroaryl group having 1 to 4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0465] B4. The compound of embodiment B1, wherein ring A is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group.

[0466] B5. The compound of embodiment B1, wherein ring A is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0467] B6. The compound of embodiment B1, wherein ring A is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0468] B7. The compound of any of the foregoing embodiments, wherein R a Halogen, optional substituted C 1-4 Alkyl group, optional substituted 5-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optional substituted 3- to 6-membered saturated monocyclic carbocyclic group, optional substituted 3- to 6-membered saturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optional substituted 7-membered saturated spirocyclic bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0469] B8. The compound of any of the foregoing embodiments, wherein R a Optionally, it can be coated with one or more oxo groups, halogens, -CN, -OH, or -O(C) 1-6 alkyl) substituted C 1-4 alkyl.

[0470] B9. A compound as described in any of embodiments B1 to B7, wherein R a For optional use by one or more -(C 1-6 Alkylene)OH, -CN, -OH or -O(C 1-6 Alkyl)-substituted 3 to 6-membered saturated monocyclic carbocyclic groups.

[0471] B10. A compound as described in any of embodiments B1 to B7, wherein R a It is a 3- to 6-membered saturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally surrounded by one or more oxo groups, halogens, -C(O)(C1-4 alkyl), -O(C) 1-4 Alkyl group or optionally with one or more halogens and -O (C 1-4 alkyl) substituted C 1-4 Alkyl substitution.

[0472] B11. A compound as described in any of embodiments B1 to B7, wherein R a It is a 7- to 8-membered saturated spirocyclic bicyclic heterocyclic group with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0473] B12. The compound of any of the foregoing embodiments, wherein R a C 1-4 Alkyl group, 3- to 6-membered saturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 7- to 8-membered saturated spirocyclic bicyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0474] B13. The compound of any of the foregoing embodiments, wherein:

[0475] for and

[0476] R b Hydrogen, halogens, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -SO2R', -SO2N(R)2, -SO3R', and optionally substituted C 1-6 Aliphatic, optionally substituted 3 to 6 saturated or partially unsaturated carbocyclic groups, optionally substituted 3 to 6 saturated or partially unsaturated monocyclic heterocyclic groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted 5 to 6 cyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0477] B14. The compound as described in embodiment B13, wherein... for:

[0478] B15. The compound as described in embodiments B13 or B14, wherein... for:

[0479] B16. A compound as described in any of embodiments B13 to B15, wherein R bFor hydrogen, halogen, or optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Cycloalkyl, a 3- to 5-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 independently selected heteroatoms chosen from nitrogen, oxygen and sulfur, or a 5-membered monocyclic heteroaryl group having 1 to 4 independently selected heteroatoms chosen from nitrogen, oxygen and sulfur.

[0480] B17. A compound as described in any of embodiments B13 to B16, wherein R b Halogen, optional substituted C 1-4 Alkyl or optionally substituted C 3-4 Cycloalkyl.

[0481] B18. A compound as described in any of embodiments B13 to B16, wherein R b C is optionally substituted with one or more fluorine molecules. 3-4 cycloalkyl or C 1-4 alkyl.

[0482] B19. The compound of any of the foregoing embodiments, wherein the compound is a compound of formula IB:

[0483]

[0484] Or its pharmaceutically acceptable salt.

[0485] B20. The compound of any of the foregoing embodiments, wherein the compound is a compound of formula IC:

[0486]

[0487] Or its pharmaceutically acceptable salt.

[0488] B21. The compound of any of the foregoing embodiments, wherein the compound is a compound of formula ID:

[0489]

[0490] Or its pharmaceutically acceptable salt.

[0491] B22. The compound of any of the foregoing embodiments, wherein the compound is a compound of formula IE:

[0492]

[0493] Or its pharmaceutically acceptable salt.

[0494] B23. A compound of formula I-1:

[0495]

[0496] or a pharmaceutically acceptable salt thereof, wherein:

[0497] W is CR w Or N;

[0498] X is CR x Or N;

[0499] Y is CR y Or N;

[0500] Z is either -O- or -NR z -;

[0501] R w 、R x and R y Each independently represents hydrogen, halogen, -OR 3 、-N(R 3 )2、-SR 3 Optional substitution of C 1-6 Aliphatic or -CN;

[0502] R z C is hydrogen or optionally substituted 1-6 Aliphatic;

[0503] R 1 It is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2;

[0504] R 2 C is an optional replacement 1-6 Aliphatic;

[0505] R 3 C is hydrogen or optionally substituted 1-6 Aliphatic;

[0506] Ring A is an optionally substituted phenyl group;

[0507] L represents a covalent bond or a divalent C. 1-3 Straight-chain or branched hydrocarbon chains;

[0508] R a For hydrogen, halogen, or optionally substituted C 1-6 Aliphatic, optionally substituted phenyl, optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0509] Each R is independently hydrogen, with optional substituted C. 1-6 Aliphatic, optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic groups, or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rs forming together, when attached to the same nitrogen atom, an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0510] Each R' is independently a C that can be substituted arbitrarily. 1-6 Aliphatic or optionally substituted 3 to 7 saturated or partially unsaturated carbocyclic groups.

[0511] B22. The compound of embodiment B21, wherein the compound is not:

[0512]

[0513]

[0514] B24. The compound as described in embodiments B22 or B23, wherein:

[0515] (i) If R 1 It is -NHC(O)R' or -NH2, R 2 X is -CH3, X is CH, and R' is an optionally substituted C. 1-2 Aliphatic, then R a and R b Not fluorine or

[0516] (ii) If R 1 -NHC(O)CH3, R 2 If R is -CH3 and X is N, then R a and R b Not fluorine or

[0517] (iii) If R 1 -NHC(O)CH3, R 2 If R is -CH3 and X is CCH3, then R a and R b Not for and

[0518] (iv) If R 1 -C(O)NHCH3, R 2 C 1-2 Alkyl group, and X is CH, then R a and Rb Not halogen.

[0519] B25. A compound as described in any of embodiments B22 to B24, wherein R a Halogen, optional substituted C 1-4 Alkyl group, optional substituted 5-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optional substituted 3- to 6-membered saturated monocyclic carbocyclic group, optional substituted 3- to 6-membered saturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or optional substituted 7-membered saturated spirocyclic bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0520] B26. A compound as described in any of embodiments B22 to B25, wherein R a Optionally, it can be coated with one or more oxo groups, halogens, -CN, -OH, or -O(C) 1-6 alkyl) substituted C 1-4 alkyl.

[0521] B27. A compound as described in any of embodiments B22 to B25, wherein R a It is a 5-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally bonded by one or more C atoms. 1-6 Alkyl substitution.

[0522] B28. A compound as described in any of embodiments B22 to B25, wherein R a It 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, optionally surrounded by one or more oxo groups, halogens, -C(O)(C 1-4 alkyl), -O(C) 1-4 Alkyl group or optionally with one or more halogens and -O (C 1-4 alkyl) substituted C 1-4 Alkyl substitution.

[0523] B29. A compound as described in any of embodiments B22 to B28, wherein:

[0524] for and

[0525] R bHydrogen, halogens, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -SO2R', -SO2N(R)2, -SO3R', and optionally substituted C 1-6 Aliphatic, optionally substituted 3 to 6 saturated or partially unsaturated carbocyclic groups, optionally substituted 3 to 6 saturated or partially unsaturated monocyclic heterocyclic groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted 5 to 6 cyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0526] B30. A compound as described in any of embodiments B22 to B29, wherein... for:

[0527] B31. The compound as described in embodiments B29 or B30, wherein R b Halogen, optional substituted C 1-4 Alkyl or optionally substituted C 3-4 Cycloalkyl.

[0528] B32. The compound of any of the foregoing embodiments, wherein L is a covalent bond or -CH2-.

[0529] B33. The compound of any of the foregoing embodiments, wherein R 1 It is -N(R)2.

[0530] B34. A compound as described in any of embodiments B1 to B32, wherein R 1 It is -N(H)(R).

[0531] B35. A compound as described in any of embodiments B1 to B32, wherein R 1 It is -N(R)C(O)R'.

[0532] B36. A compound as described in any of embodiments B1 to B32, wherein R 1 It is -N(H)C(O)R'.

[0533] B37. A compound as described in any of embodiments B1 to B32, wherein R 1 -N(H)C(O) (C optionally substituted) 1-4 alkyl).

[0534] B38. A compound as described in any of embodiments B1 to B32, wherein R1 It is -N(H)C(O)CH3 or -N(H)C(O) (cyclopropyl).

[0535] B39. A compound as described in any of embodiments B1 to B32, wherein R 1 It is -C(O)N(R)2.

[0536] B40. A compound as described in any of embodiments B1 to B32, wherein R 1 It is -C(O)N(H)CH3.

[0537] B41. A compound as described in any of embodiments B1 to B32, wherein R 1 It is -N(R)C(O)N(R)2.

[0538] B42. A compound as described in any of embodiments B1 to B32, wherein R 1 It is -N(H)C(O)N(R)2.

[0539] B43. A compound as described in any of embodiments B1 to B32, wherein R 1 The form is -N(R)C(O)N(R)2, wherein two R groups attached to the same nitrogen atom together form a 3- to 5-membered saturated monocyclic heterocyclic group having 0-1 additional heteroatoms, which is optionally bonded by one or more halogens, C 1-6 Alkyl and -O(C) 1-6 Alkyl) substitution.

[0540] B44. The compound of any of the foregoing embodiments, wherein R 2 C 1-4 alkyl.

[0541] B45. The compound as described in any of the foregoing embodiments, wherein R 2 It is a methyl group.

[0542] B46. The compound of any of the foregoing embodiments, wherein X is a CR x .

[0543] B47. The compound as described in embodiment B46, wherein R x For hydrogen, halogen, -OR 3 Optional substitution of C 1-6 Aliphatic or -CN.

[0544] B48. The compound as described in embodiment B46, wherein R x Halogen, -OR 3 Or -CN.

[0545] B49. The compound as described in embodiment B46, wherein R xHalogen, -OR 3 、-N(R 3 )2、-SR 3 Or -CN.

[0546] B50. A compound as described in any of embodiments B1 to B45, wherein X is N.

[0547] B51. The compound of any of the foregoing embodiments, wherein Y is CR y .

[0548] B52. The compound as described in embodiment B51, wherein R y It is hydrogen.

[0549] B53. A compound as described in any of embodiments B1 to B50, wherein Y is N.

[0550] B54. The compound of any of the foregoing embodiments, wherein W is CR w .

[0551] B55. The compound as described in embodiment B54, wherein R w It is hydrogen.

[0552] B56. A compound as described in any of embodiments B1 to B53, wherein W is N.

[0553] B57. The compound of any of the foregoing embodiments, wherein Z is -NR z -

[0554] B58. The compound as described in embodiment B57, wherein R z It is hydrogen.

[0555] B59. A compound as described in any of embodiments B1 to B56, wherein Z is -O-.

[0556] B60. A compound as described in any of the foregoing embodiments, wherein each R is independently hydrogen and optionally substituted C. 1-6 Aliphatic, optionally substituted 3 to 7 saturated or partially unsaturated carbocyclic groups or optionally substituted 3 to 7 saturated or partially unsaturated monocyclic heterocyclic groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two Rs together forming a 3 to 7 saturated or partially unsaturated monocyclic heterocyclic group having 0 to 2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur when attached to the same nitrogen atom.

[0557] B61. A compound as described in any of the foregoing embodiments, wherein each R is independently hydrogen or optionally substituted C. 1-6 Aliphatic.

[0558] B62. The compound of any of the foregoing embodiments, wherein each R' is independently an optionally substituted C. 1-2 Alkyl or optionally substituted C 3-4 Cycloalkyl.

[0559] B63. The compound as described in any of the foregoing embodiments, wherein:

[0560] W stands for CH;

[0561] R x and R y Each is independently hydrogen, and each of the optionally substituted C atoms is a carbon atom. 1-6 Aliphatic or -CN;

[0562] Each R is independently hydrogen, with optional substituted C. 1-6 Aliphatic, optionally substituted 3 to 7 saturated or partially unsaturated carbocyclic groups or optionally substituted 3 to 7 saturated or partially unsaturated monocyclic heterocyclic groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two Rs together forming a 3 to 7 saturated or partially unsaturated monocyclic heterocyclic group having 0 to 2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur when attached to the same nitrogen atom.

[0563] B64. The compound of any of the foregoing embodiments, wherein the compound is a compound of formula IA:

[0564]

[0565] Or its pharmaceutically acceptable salt.

[0566] B65. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

[0567] B66. A pharmaceutical composition comprising a compound as described in any of the foregoing embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0568] B67. A method for inhibiting JAK2 in a subject, the method comprising administering a compound as described in any one of embodiments B1 to B63 or a composition as described in embodiment B64.

[0569] B68. The method of embodiment B67, wherein the applied compound or composition is characterized as a type II JAK2 inhibitor.

[0570] B69. A method of treating a disease, condition, or disorder associated with JAK2, the method comprising administering to a subject in need a compound as described in any one of embodiments B1 to B65 or a composition as described in embodiment B66.

[0571] B70. A method of treating cancer, the method comprising administering to a subject in need a compound as described in any one of embodiments B1 to B65 or a composition as described in embodiment B66.

[0572] B71. A method for treating hematologic malignancies, the method comprising administering to a subject in need a compound as described in any one of embodiments B1 to B65 or a composition as described in embodiment B66.

[0573] B72. The method of implementation scheme B71, wherein the hematologic malignancy is leukemia or lymphoma.

[0574] B73. A method for treating myeloproliferative neoplasms, the method comprising administering to a subject in need a compound as described in any one of embodiments B1 to B65 or a composition as described in embodiment B66.

[0575] B74. The method of implementation scheme B73, wherein the myeloproliferative neoplasm is polycythemia vera, primary thrombocytopenia, or myelofibrosis.

[0576] Example

[0577] As described in the examples below, in some exemplary embodiments, compounds are prepared according to the following general procedure. It should be understood that although the general method depicts the synthesis of certain compounds of this disclosure, the following general method and other methods known to those skilled in the art are applicable to all compounds as described herein and their respective subclasses and species.

[0578] Preparation of intermediates

[0579] Preparation of intermediate Int-1: N-(4-hydroxypyridin-2-yl)acetamide

[0580]

[0581] Synthesis of compound Int-1.2. Sodium hydride (12.61 g, 315.38 mmol, 1.0 equivalent) was added in small portions 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 (Int-1.1, 25 g, 157.69 mmol, 1.0 equivalent) was added in multiple portions. The reaction mixture was stirred at 0 °C for 2 hours. It was poured onto ice, stirred, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 10% ethyl acetate in hexane as the eluent to give Int-1.2. MS (ES): m / z 220.13 [M+H] + .

[0582] Synthesis of compound Int-1.3. A solution of compound Int-1.2 (20 g, 91.05 mmol, 1.0 equivalent) in 200 mL THF was degassed by bubbling through it with argon for 10 min. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (4.34 g, 9.105 mmol, 0.1 equivalent) and tris(dibenzylacetone)dipalladium (4.17 g, 4.55 mmol, 0.05 equivalent) were added under argon atmosphere, and the mixture was degassed again 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 it was stirred at 60 °C for 1 h. The reaction mixture was cooled to room temperature, 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. Rapid column chromatography on silica gel ( The residue was purified using 3% methanol in dichloromethane as the eluent to give Int-1.3. MS (ES): m / z 201.2 [M+H] + .

[0583] Synthesis of compound Int-1.4. Acetic anhydride (6.34 mL, 67.11 mmol, 1.2 equivalence) was slowly added to a solution of compound Int-1.3 (11.2 g, 55.93 mmol, 1.0 equivalence) in dichloromethane (110 mL) and pyridine (6.3 mL, 78.30 mmol, 1.4 equivalence) at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured onto ice, stirred, and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 1% methanol in dichloromethane as the eluent to give Int-1.4. MS (ES): m / z 243.21 [M+H] + .

[0584] Synthesis of compound Int-1. A round-bottom flask containing compound Int-1.4 (6.1 g, 25.18 mmol, 1.0 equivalent), 10% carbon-supported palladium (2 g), and methanol (60 mL) was evacuated and purged three times with hydrogen. The reaction mixture was stirred at room temperature for 1 hour under 1 atm hydrogen. The flask was then evacuated and purged with nitrogen, and then left open to air. The reaction mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure and subjected to rapid column chromatography on silica gel. The residue was purified using 5% methanol in dichloromethane as the eluent to give Int-1. MS (ES): m / z 153.2 [M+H] + .

[0585] Preparation of intermediate Int-2: N-(4-(4-amino-3-(methylamino)phenoxy)pyridin-2-yl)acetamide

[0586]

[0587] Synthesis of compound Int-2.2. A solution of methylamine (33% in ethanol, 1.18 mL, 12.58 mmol, 2.0 equivalent) was added dropwise to a solution of 2,4-difluoro-1-nitrobenzene (Int-2.1, 1.0 g, 6.29 mmol, 1.0 equivalent) in 10 mL of THF at 0 °C. The reaction mixture was stirred at room temperature for 2 h. It was poured onto ice and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give Int-2.2. MS (ES): m / z 171.2 [M+H] + .

[0588] Synthesis of compound Int-2.3. A mixture of Int-2.2 (0.170 g, 0.99 mmol, 1.0 equivalent), Int-1 (0.152 g, 0.99 mmol, 1.0 equivalent), and potassium carbonate (0.273 g, 1.98 mmol, 2.0 equivalent) in N-methyl-2-pyrrolidone (1.7 mL) was stirred at 130 °C for 12 hours under nitrogen. The mixture was cooled to room temperature, poured onto ice, 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 solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 2.5% methanol in dichloromethane as the eluent to give Int-2.3. MS (ES): m / z 303.3 [M+H] + .

[0589] Synthesis of compound Int-2. A round-bottom flask packed with Int-2.3 (0.180 g, 0.59 mmol, 1.0 equivalent), 10% carbon-supported palladium (0.1 g), and methanol (2 mL) was evacuated and purged with hydrogen. The reaction mixture was stirred at room temperature for 2 hours under 1 atm hydrogen. The flask was then evacuated and purged with nitrogen, and then left open to air. The mixture was filtered through a filter and washed with methanol. The filtrate was concentrated under reduced pressure and passed through a rapid column chromatography on silica gel. The residue was purified using 5% methanol in dichloromethane as the eluent to give Int-2. MS (ES): m / z 273.3 [M+H] + .

[0590] Preparation of intermediate Int-3: N-(4-(4-amino-2-methyl-3-(methylamino)phenoxy)pyridin-2-yl)acetamide

[0591]

[0592] Synthesis of compound Int-3.2. Int-3.2 was prepared from 1,3-difluoro-2-methyl-4-nitrobenzene (Int-3.1) following the procedure described in the synthesis of compound Int-2.2. MS (ES): m / z 185.2 [M+H] + .

[0593] Synthesis of compound Int-3.3. Int-3.3 was prepared from Int-3.2 following the procedure described in the synthesis of compound Int-2.3. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 2.5% methanol in dichloromethane as the eluent. MS (ES): m / z 317.03 [M+H] + .

[0594] Synthesis of compound Int-3. Int-3 was prepared from Int-3.3 following the procedure described in the synthesis of compound Int-2. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 5% methanol in dichloromethane as the eluent. MS (ES): m / z 287.3 [M+H] + .

[0595] Preparation of intermediate Int-4: N-(4-(4-amino-2-cyano-3-(methylamino)phenoxy)pyridin-2-yl)acetamide

[0596]

[0597] Synthesis of compound Int-4.2: Concentrated nitric acid (6 mL) was slowly added to a solution of 2,6-difluorobenzonitrile (Int-4.1, 5.0 g, 35.94 mmol, 1.0 equivalent) in 15 mL of concentrated sulfuric acid at -10 °C. The reaction mixture was stirred at room temperature for 15 min. It was poured onto crushed ice. The precipitate was collected by filtration, washed with a small amount of water, and air-dried to give Int-4.2. MS (ES): m / z 185.1 [M+H] + .

[0598] Synthesis of compound Int-4.3. A solution of methylamine (40% in water, 2.19 mL, 28.24 mmol, 2.0 equivalent) was added dropwise to a solution of Int-4.2 (2.6 g, 14.12 mmol, 1.0 equivalent) in 25 mL of THF at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. 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 solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 6% ethyl acetate in hexane as the eluent, yielding Int-4.3. MS (ES): m / z 196.2 [M+H] + .

[0599] Synthesis of compound Int-4.4. Int-4.4 was prepared from Int-4.3 following the procedure described in the synthesis of compound Int-2.3. The synthesis was achieved by rapid column chromatography on silica gel (…). The residue was purified using 2.5% methanol in dichloromethane as the eluent. MS (ES): m / z 328.3 [M+H] + .

[0600] Synthesis of compound Int-4. A mixture of compound Int-4.4 (0.860 g, 2.63 mmol, 1.0 equivalent), ammonium chloride (1.406 g, 26.3 mmol, 10 equivalent), and iron powder (1.472 g, 26.3 mmol, 10 equivalent) in ethanol (9 mL) and water (3 mL) was stirred at 80 °C for 3 hours under nitrogen. [The synthesis was achieved via...] The mixture was filtered through a filter pad. The filtrate 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 solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 3.5% methanol in dichloromethane as the eluent to give Int-4. MS (ES): m / z 298.3 [M+H] + .

[0601] Preparation of intermediate Int-5: N-(4-((5-amino-6-(methylamino)pyridin-2-yl)oxy)pyridin-2-yl)acetamide

[0602]

[0603] Synthesis of compound Int-5.2. A solution of methylamine (33% in ethanol, 4.9 mL, 51.82 mmol, 2.0 equivalent) was added dropwise to a solution of 2,6-dichloro-3-nitropyridine (Int-5.1, 5.0 g, 25.91 mmol, 1.0 equivalent) in ethanol (30 mL) at 0 °C, followed by the addition of sodium carbonate (4.10 g, 38.7 mmol, 1.5 equivalent). The reaction mixture was stirred at room temperature for 16 hours. 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-5.2. MS (ES): m / z 188.5 [M+H] + .

[0604] Synthesis of compound Int-5.3. A mixture of Int-5.2 (0.500 g, 2.67 mmol, 1.0 equivalent), Int-1 (0.405 g, 2.67 mmol, 1.0 equivalent), and sodium carbonate (0.311 g, 2.93 mmol, 1.1 equivalent) in DMF (5 mL) was stirred at 90 °C for 12 hours under nitrogen. The mixture was cooled to room temperature, poured onto an ice-water plate, 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 solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 25% ethyl acetate in hexane as the eluent, yielding 1.3. MS (ES): m / z 304.3 [M+H] + .

[0605] Synthesis of compound Int-5. Int-5 was prepared from Int-5.3 following the procedure described in the synthesis of compound Int-2. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 5% methanol in dichloromethane as the eluent. MS (ES): m / z 274.3 [M+H] + .

[0606] Preparation of compounds

[0607] Example 1: N-(4-((2-((5-(tert-butyl)isoxazo-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0608]

[0609] Synthesis of compound 1.2. Sulfophosgene (0.52 mL, 6.85 mmol, 1.2 equivalent) was added dropwise to a solution of 1.1 (0.8 g, 5.71 mmol, 1.0 equivalent) and triethylamine (2.38 mL, 17.13 mmol, 3.0 equivalent) in 8 mL of THF at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 10% ethyl acetate in hexane as the eluent, yielding 1.2. MS (ES): m / z 183.2 [M+H] + .

[0610] Synthesis of compound I-1. N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.141 g, 0.74 mmol, 2.0 equivalent) was added to a solution of Int-2 (0.100 g, 0.37 mmol, 1.0 equivalent) in THF (2 mL). The reaction mixture was stirred at 50 °C for 4 hours. It was cooled to room temperature, 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. The solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 4% methanol in dichloromethane as the eluent to give I⁻. MS (ES): m / z: 421.6 [M+H] + ; 1 H NMR(DMSO-d6,400M Hz): δ10.14(bs,2H),8.15-8.14(d,J=5.6Hz,1H),7.65(s,1H),7.42-7.40(d,J=8.4Hz,1H),7.13(s, 1H), 6.86-6.84 (d, J = 8.0Hz, 1H), 6.63-6.62 (d, J = 3.6Hz, 1H), 3.56 (s, 3H), 2.06 (s, 3H), 1.34 (s, 9H).

[0611] Example 2: N-(4-((2-((5-(tert-butyl)isoxazo-3-yl)amino)-1,7-dimethyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0612]

[0613] Synthesis of I-2. N,N′-diisopropylcarbodiimide (0.087 mL, 1.04 mmol, 2.0 equivalent) was added to a solution of Int-3 (0.150 g, 0.52 mmol, 1.0 equivalent) and 1.2 (0.124 g, 0.68 mmol, 1.3 equivalent) in THF (3 mL). The reaction mixture was stirred at 70 °C for 5 hours. It was then cooled to room temperature, 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. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 8% methanol in dichloromethane as the eluent to give I⁻². MS (ES): m / z: 435.1 [M+H] + ; 1 H NMR (DMSO-d6, 400MHz): δ10.50(s,1H),10.10(s,1H),8.14-8.13(d,J=5.2Hz,1H),7.58(s,1H),7.31-7.29(d,J= 8.4Hz,1H),6.84-6.80(t,1H),6.73(bs,1H),6.55(bs,1H),3.77(s,3H),2.39(s,3H),2.02(s,3H),1.30(s,9H).

[0614] Example 3: N-(4-((2-((5-(tert-butyl)isoxazo-3-yl)amino)-7-cyano-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0615]

[0616] Synthesis of compound I-3. Compound I-3 was prepared by Int-4 and 1.2 following the procedure described in the synthesis of compound I-2. The synthesis was carried out by rapid column chromatography on silica gel (…). The product was purified using 5% methanol in dichloromethane as the eluent. MS (ES): m / z: 446.45 [M+H] + ; 1 H NMR (DMSO-d6, 400MHz): δ10.24 (s, 1H), 8.22-8.21 (d, J = 5.6Hz, 1H), 7.70 (bs, 2H), 7. 01(s,1H),6.69(bs,2H),3.95(bs,3H),3.78(bs,1H),2.07-2.06(d,3H),1.27(s,9H).

[0617] Example 4: N-(4-((2-((4-chloro-3-(trifluoromethyl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0618]

[0619] Synthesis of Compound 4.2. Compound 4.2 was prepared from 4-chloro-3-(trifluoromethyl)aniline (4.1) following the procedure described in the synthesis of Compound 1.2. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 8% ethyl acetate in hexane as the eluent. MS (ES): m / z 238.5 [M+H] + .

[0620] Synthesis of I-4. Compound I-4 was prepared from 4.2 and Int-2 following the procedure described in the synthesis of compound I-1. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 5% methanol in dichloromethane as the eluent. MS (ES): m / z: 476.6 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.48(s,1H),9.49(s,1H),8.41(s,1H),8.33-8.31(d,J=8.8Hz,1H),8.16-8.14(d,J=5.6Hz,1H),7.70-7.65 (m,2H),7.49-7.47(d,J=8.8Hz,1H),7.29(s,1H),6.90-6.88(d,J=8.4Hz,1H),6.63-6.61(t,J=3.6Hz,1H),3.77(s,3H),2.03(s,3H).

[0621] Example 5: N-(4-((2-((4-chloro-3-(trifluoromethyl)phenyl)amino)-1,7-dimethyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0622]

[0623] Synthesis of compound I-5. Compound I-5 was prepared from Int-3 and 4.2 following the procedure described in the synthesis of compound I-2. The synthesis was carried out by rapid column chromatography on silica gel (…). The product was purified using 4% methanol in dichloromethane as the eluent. MS (ES): m / z: 490.71 [M+H] + , 1H NMR (DMSO-d6, 400MHz): δ10.48(s,1H),9.43(s,1H),8.35(s,1H),8.26-8.24(d,J=8.4Hz,1H),8.14-8.13(d,J=5.6Hz,1H),7.68-7.66(d,J=8.8 Hz,1H),7.59(s,1H),7.34-7.32(d,J=8.4Hz,1H),6.85-6.83(d,J=7.6H z, 1H), 6.55-6.54 (d, J = 4Hz, 1H), 3.97 (s, 3H), 2.50 (s, 3H), 2.02 (s, 3H).

[0624] Example 6: N-(4-((2-((2,4-difluorophenyl)amino)-1,7-dimethyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0625]

[0626] Synthesis of Compound 6.2. Compound 6.2 was prepared from 2,4-difluoroaniline (6.1) following the procedure described in the synthesis of Compound 1.2. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 10% ethyl acetate in hexane as the eluent. MS (ES): m / z 172.2 [M+H] + .

[0627] Synthesis of compound I-6. Compound I-6 was prepared from Int-3 and 6.2 following the procedure described in the synthesis of compound I-2. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 2% methanol in dichloromethane as the eluent. MS (ES): m / z: 424.0 [M+H] + ; 1 H NMR (DMSO-d6, 400MHz): δ10.53(s,1H),8.68(s,1H),8.18-8.16(d,J=5.2Hz,1H),7.86(s,1H),7.63(s,1H),7.37(b s,1H),7.23(s,1H),7.14(s,1H),6.84-6.82(d,J=7.6Hz,1H),6.57(bs,1H),3.94(s,3H),2.46(s,3H),2.07(s,3H).

[0628] Example 7: N-(4-((2-((3-(3-methoxyazacyclobutane-1-yl)-5-(trifluoromethyl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0629]

[0630] Synthesis of Compound 7.2. A mixture of 3-bromo-5-(trifluoromethyl)aniline (7.1 g, 0.7 g, 2.92 mmol, 1.0 equivalent), 3-methoxyazinobutane hydrochloride (0.72 g, 5.83 mmol, 2.0 equivalent), and cesium carbonate (2.37 g, 7.3 mmol, 2.5 equivalent) in 1,4-dioxane (20 mL) was degassed by bubbling through argon for 10 minutes. BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (0.363 g, 0.584 mmol, 0.2 equivalent) and Pd2(dba)3 (0.267 g, 0.292 mmol, 0.1 equivalent) were added, and degassed for 5 minutes. The reaction mixture was stirred at 110 °C for 5 hours under argon. It was then cooled to room temperature and... Filter the solution using a filter pad. Decant the filtrate onto water and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Perform rapid column chromatography on silica gel (…). The residue was purified using 10%-15% ethyl acetate in hexane as the eluent, yielding a concentration of 7.2. MS (ES): m / z 247.2 [M+H] + .

[0631] Synthesis of compound 7.3. Compound 7.3 was prepared from 7.2 following the procedure described in the synthesis of compound 1.2. MS (ES): m / z 289.3 [M+H] + .

[0632] Synthesis of I-7. Compound I-7 was prepared from 7.3 and Int-2 following the procedure described in the synthesis of compound I-2. The product was purified by grinding with methanol and drying under vacuum. MS (ES): m / z: 527.49 [MH] + , 1H NMR (DMSO-d6, 400MHz): δ10.49(s,1H),9.16(s,1H),8.15-8.14(d,J=5.6Hz,1H),7.68(s,1H),7.65(s,1H),7.46-7.44(d,J=8.4Hz,1H),7.26-7. 22(m,2H),6.87-6.85(d,J=8.0Hz,1H),6.62-6.61(t,1H),6.30(s,1H), 4.36(bs,1H),4.15-4.11(t,2H),3.69(s,5H),3.27(s,3H),1.99(s,3H).

[0633] Example 8: N-(4-((2-((4-(2-cyanopropyl-2-yl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0634]

[0635] Synthesis of Compound 8.2. Compound 8.2 was prepared from 2-(4-aminophenyl)-2-methylpropionitrile (8.1) following the procedure described in the synthesis of Compound 1.2. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 8% ethyl acetate in hexane as the eluent. MS (ES): m / z 203.2 [M+H] + .

[0636] Synthesis of I-8. Compound I-8 was prepared from 8.2 and Int-2 following the procedure described in the synthesis of compound I-1. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 10% methanol in dichloromethane as the eluent. MS (ES): m / z: 441.29 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.49(s,1H),9.12(s,1H),8.15-8.14(d,J=5.2Hz,1H),7.67(s,1H),7.91-7.89(d,J=8Hz,1H),7.65(s,1H),7. 49-7.47(m,2H),7.43-7.41(d,J=8Hz,1H),7.24(s,1H),6.87-6.85(d,J=8Hz,1H),6.62(bs,1H),3.70(s,3H),2.03(s,3H),1.69(s,6H).

[0637] Example 9: N-(4-((1-methyl-2-((4-((1-methyl-1H-imidazol-5-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0638]

[0639] Synthesis of compound 9.3. Butyllithium (2.5 M in hexane, 7.3 mL, 18.26 mmol, 2.0 equivalent) was added dropwise to a solution of 5-iodo-1-methyl-1H-imidazole (9.2 g, 1.9 g, 9.13 mmol, 1.0 equivalent) in 20 mL of THF at -78 °C for 5 minutes. A solution of 4-nitro-2-(trifluoromethyl)benzaldehyde (9.1 g, 2.00 g, 9.13 mmol, 1.0 equivalent) in 5 mL of THF was added to the reaction mixture, and the mixture was stirred at -78 °C for 10 minutes. The mixture was poured over a saturated ammonium chloride 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 solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 4% methanol in dichloromethane as the eluent, yielding a concentration of 9.3. MS (ES): m / z 302.2 [M+H] + .

[0640] Synthesis of compound 9.4. Phosphorus tribromide (0.44 mL, 4.59 mmol, 3.0 equivalent) was added to a solution of compound 9.3 (0.460 g, 1.53 mmol, 1.0 equivalent) in THF (10 mL), and the reaction mixture was stirred at 80 °C for 2 hours. 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 1% methanol in dichloromethane as the eluent, yielding a concentration of 9.4. MS (ES): m / z 286.2 [M+H] + .

[0641] Synthesis of compound 9.5. A mixture of compound 9.4 (0.210 g, 0.736 mmol, 1.0 equivalent) and 10% carbon-supported palladium (0.1 g) in methanol (10 mL) was stirred at room temperature for 2 hours under 1 atm hydrogen. [The rest of the text appears to be a continuation of the previous sentence and can be omitted.] The mixture was filtered through a filter and washed with methanol. The filtrate was concentrated under reduced pressure and subjected to rapid column chromatography on silica gel. The residue was purified using 3% methanol in dichloromethane as the eluent, yielding a 9.5 μmol / L MS (ES): m / z 256.3 [M+H]. + .

[0642] Synthesis of compound 9.6. Compound 9.6 was prepared from 9.4 following the procedure described in the synthesis of compound 1.2. MS (ES): m / z 298.3 [M+H] + .

[0643] Synthesis of I-9. Compound I-9 was prepared from 9.6 and Int-2 following the procedure described in the synthesis of compound I-1. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 3.5% methanol in dichloromethane as the eluent. MS (ES): m / z: 534.15 [MH] + , 1 H NMR (DMSO-d6, 400MHz): δ10.48(s,1H),9.32(s,1H),8.32(s,1H),8.15-8.08(m,2H),7.65(s,1H),7.46-7.42(d,J=8.4Hz,1H),7.26 (s,1H),7.12(s,1H),7.01-6.99(m,1H),6.87-6.82(m,2H),6.62-6.61(m,1H),4.14(s,2H),3.70(s,3H),3.51(s,3H),1.99(s,3H).

[0644] Example 10: N-(4-((2-((4-((1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0645]

[0646] Synthesis of compound 10.2. Sodium hydride (1.48 g, 30.93 mmol, 1.2 equivalent) was added in small amounts to a solution of 4-iodo-1H-pyrazole (10.1 g, 5.0 g, 25.78 mmol, 1.0 equivalent) in DMF (50 mL) at 0 °C. After addition, the mixture was stirred for 15 min, followed by the addition of 4-methoxybenzyl chloride (4.85 g, 30.93 mmol, 1.2 equivalent) and stirring at room temperature for 2 h. The mixture was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 6% ethyl acetate in hexane as the eluent, yielding 10.2. MS (ES): m / z 315.13 [M+H] + .

[0647] Synthesis of compound 10.4. A solution of isopropyl magnesium chloride-lithium chloride complex (1.3 M in THF, 12.25 mL, 15.92 mmol, 2.5 equivalence) was added to a solution of 10.2 (2.06 g, 6.37 mmol, 1.0 equivalence) in 20 mL of THF at -10 °C. The reaction mixture was stirred at -10 °C for 30 min, and a solution of 4-nitro-2-(trifluoromethyl)benzaldehyde (10.3 g, 1.12 g, 5.09 mmol, 0.8 equivalence) in 10 mL of THF was added and stirred for 5 min. The mixture was poured onto ice, stirred, acidified with 1 N 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. The solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 25% ethyl acetate in hexane as the eluent, yielding 10.4. MS (ES): m / z 408.4 [M+H] + .

[0648] Synthesis of compound 10.5. Triethylsilane (3.5 mL) was added to a solution of 10.4 (0.700 g, 1.72 mmol, 1.0 equivalent) in dichloromethane (10 mL) and trifluoroacetic acid (7 mL) at 0 °C. The solution was heated to 50 °C and stirred for 1 hour. The mixture was carefully poured onto a cold, saturated sodium bicarbonate solution, 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 solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 15% ethyl acetate in hexane as the eluent, yielding 10.5. MS (ES): m / z 392.4 [M+H] + .

[0649] Synthesis of compound 10.6. Compound 10.6 was prepared from 10.5 following the procedure described in the synthesis of compound 9.5. MS (ES): m / z 362.4 [M+H] + .

[0650] Synthesis of compound 10.7. Compound 10.7 was prepared from 10.6 following the procedure described in the synthesis of compound 1.2. MS (ES): m / z 404.4 [M+H] + .

[0651] Synthesis of compound 10.8. Compound 10.8 was prepared from 10.7 and Int-2 following the procedure described in the synthesis of compound I-1. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 2.6% methanol in dichloromethane as the eluent. MS (ES): m / z 626.6 [M+H] + .

[0652] Synthesis of I-10. A mixture of 10.8 (0.162 g, 0.258 mmol, 1.0 equivalent) and palladium hydroxide (0.200 g) in ethanol (8 mL) and cyclohexene (4 mL) was stirred at 80 °C for 16 hours. (The rest of the text appears to be a continuation of the previous sentence and is not directly related to the synthesis of I-10.) The reaction mixture was filtered and washed with ethanol. The filtrate was concentrated under reduced pressure and subjected to rapid column chromatography on silica gel. The residue was purified using 3.5% methanol in dichloromethane as the eluent to give I-10. MS (ES): m / z: 522.7 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.49(s,1H),9.28(s,1H),8.24(s,1H),8.15-8.14(d,J=5.6Hz,1H),7.65(s,1H),7.45-7.39(m ,4H),7.26(s,1H),7.06(bs,2H),6.87-6.81(m,1H),6.62-6.61(d,J=3.6Hz,1H),3.90(bs,2H),3.70(s,3H),2.02(s,3H).

[0653] Example 11: N-(4-((2-((3-methoxy-4-(methoxymethyl)-5-(trifluoromethyl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0654]

[0655] Synthesis of compound 11.2. Sodium borohydride (4.84 g, 127.59 mmol, 3.0 equivalent) was added aliquots of 4-nitro-2-(trifluoromethyl)benzoic acid (11.1, 10 g, 42.53 mmol, 1.0 equivalent) in THF (200 mL) at 0 °C, followed by the slow addition of boron trifluoride ether (15.7 mL, 127.59 mmol, 3.0 equivalent) over a 30-minute period. The reaction mixture was stirred at room temperature for 16 hours. It was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 9% ethyl acetate in hexane as the eluent, yielding 11.2. MS (ES): m / z 222.1 [M+H] + .

[0656] Synthesis of compound 11.3. Silver oxide (47 g, 203.5 mmol, 5.0 equivalents), water (9 mL), and then iodomethane (25 mL, 407 mmol, 10 equivalents) were added to a solution of 11.2 (9.0 g, 40.7 mmol, 1.0 equivalents) in dichloromethane (90 mL). The reaction mixture was stirred in the dark at room temperature for 16 hours. (via...) The reaction mixture was filtered through a filter pad, and the filtrate was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 4% ethyl acetate in hexane as the eluent, yielding 11.3. MS (ES): m / z 236.2 [M+H] + .

[0657] Synthesis of compound 11.4. 1,3-Dibromo-5,5-dimethylhydantoin (5.59 g, 19.56 mmol, 1.0 equivalent) was added to a solution of 11.3 (4.6 g, 19.56 mmol, 1.0 equivalent) in sulfuric acid (46 mL). The reaction mixture was stirred at room temperature for 16 hours. It was poured onto ice-water and stirred. The precipitate was collected by filtration, washed with water, and dried under vacuum. MS (ES): m / z 315.1 [M+H] + .

[0658] Synthesis of compound 11.5. Potassium hydroxide (0.602 g, 10.75 mmol, 2.25 equivalences) was added to a solution of 11.4 (1.5 g, 4.78 mmol, 1.0 equivalences) in 1,4-dioxane (12 mL) and water (12 mL). The reaction mixture was degassed by bubbling with argon for 10 min. 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.052 g, 0.123 mmol, 0.18 equivalences) and tris(dibenzylideneacetone)dipalladium(0) (0.131 g, 0.143 mmol, 0.03 equivalences) were added, followed by further degassed for 5 min. The reaction mixture was stirred at 80 °C for 1 h under argon. It was then cooled to room temperature and subjected to... Filter the solution using a filter pad. Decant the filtrate onto water and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Perform rapid column chromatography on silica gel (…). The residue was purified using 9% ethyl acetate in hexane as the eluent, yielding 11.5. MS (ES): m / z 252.2 [M+H] + .

[0659] Synthesis of compound 11.6. Iodimethane (0.381 g, 2.68 mmol, 1.5 equivalent) was added to a mixture of 11.5 (0.45 g, 1.79 mmol, 1.0 equivalent) and potassium carbonate (0.494 g, 3.58 mmol, 2.0 equivalent) in DMF (4 mL). The reaction mixture was stirred at 70 °C for 1 hour under argon. It was poured onto 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 5% ethyl acetate in hexane as the eluent, yielding 11.6. MS (ES): m / z 266.2 [M+H] + .

[0660] Synthesis of compound 11.7. Compound 11.7 was prepared from 11.6 following the procedure described in the synthesis of compound 9.5. MS (ES): m / z 236.3 [M+H] + .

[0661] Synthesis of compound 11.8. A solution of sodium bicarbonate (0.214 g, 2.55 mmol, 5.0 equivalent) in water (1 mL) was added to a solution of 11.7 (0.120 g, 0.510 mmol, 1.0 equivalent) in dichloromethane (3 mL) at 0 °C, followed by the addition of phosgene (0.146 g, 1.27 mmol, 2.5 equivalent). The reaction mixture was stirred at room temperature for 1 hour. 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 11.8. MS (ES): m / z 278.3 [M+H] + .

[0662] Synthesis of I-11. Compound I-11 was prepared from 11.8 and Int-2 following the procedure described in the synthesis of compound I-1. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 2.7% methanol in dichloromethane as the eluent. MS (ES): m / z: 516.5 [M+H] + , 1H NMR (DMSO-d6, 400MHz): δ10.49(s,1H),9.41(s,1H),8.16-8.15(d,J=5.6Hz,1H),8.01(s,1H),7.65(s,1H),7.48-7.46(d,J=8.4Hz,1H),7 .29(s,1H),7.07(s,1H),6.89-6.81(m,1H),6.63-6.62(d,J=3.6Hz,1H),4.43(s,2H),3.90(s,3H),3.72(s,3H),3.28(s,3H),2.02(s,3H).

[0663] Example 12: (R)-N-(4-((1-methyl-2-((3-(1-methyl-5-oxopyrrolidone-3-yl)-5-(trifluoromethyl)phenyl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide and (S)-N-(4-((1-methyl-2-((3-(1-methyl-5-oxopyrrolidone-3-yl)-5-(trifluoromethyl)phenyl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0664]

[0665] Synthesis of compound 12.2. Nitric acid (2.5 mL) was slowly added to a mixture of 3-(trifluoromethyl)benzaldehyde (12.1, 10 g, 57.43 mmol, 1.0 equivalent) in concentrated sulfuric acid (98%, 20 mL) at 0 °C. The reaction mixture was stirred at 50 °C for 8 hours. It was poured onto crushed ice, stirred, and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 10% ethyl acetate in hexane as the eluent, yielding a concentration of 12.2. MS (ES): m / z 220.2 [M+H] + .

[0666] Synthesis of compound 12.3. Sodium hydride (1.18 g, 24.64 mmol, 1.2 equivalents) was added to a solution of ethyl diethylphosphinoacetate (4.74 g, 22.59 mmol, 1.1 equivalents) in THF (50 mL) at 0 °C and stirred for 30 min. Compound 12.2 (4.5 g, 20.54 mmol, 1.2 equivalents) was added to the solution, and the mixture was stirred at room temperature for 3 h. It was poured into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 20% ​​ethyl acetate in hexane as the eluent, yielding 12.3. MS (ES): m / z 290.2 [M+H] + .

[0667] Synthesis of compound (±)-12.4. A solution of compound 12.3 (4.0 g, 13.83 mmol, 1.0 equivalent) and tetramethylguanidine (0.6 mL) in nitromethane (40 mL) was stirred at 80 °C for 2 h. The solution was poured into ice-water, stirred, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 12% ethyl acetate in hexane as the eluent, yielding (±)-12.4. MS (ES): m / z 351.3 [M+H] + .

[0668] Synthesis of compound (±)-12.5. Zinc dust (3.9 g, 61.23 mmol, 19.5 equivalents) was added aliquots of (±)-12.4 (1.1 g, 3.14 mmol, 1.0 equivalent) in isopropanol (60 mL) and 1 N hydrochloric acid aqueous solution (30 mL) at 0 °C. After addition, the reaction mixture was heated to room temperature and stirred for 2 hours. It was then slowly poured into a saturated aqueous solution of sodium bicarbonate while stirring, and 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 solution was then analyzed by rapid column chromatography on silica gel. The residue was purified to obtain an amine by elution in dichloromethane (10% methanol as eluent), which was dissolved in ethanol (20 mL), triethylamine (2 mL) was added, and the mixture was heated to reflux for 16 hours. The reaction 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 amine was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 4.1% methanol in dichloromethane as the eluent, yielding (±)-12.5. MS (ES): m / z 245.2 [M+H] + .

[0669] Synthesis of compound (±)-12.6. Phthalic anhydride (0.485 g, 3.28 mmol, 2.0 equivalent) was added to a solution of 12.5 (0.4 g, 1.64 mmol, 1.0 equivalent) in acetic acid (5 mL) and stirred at 80 °C for 4 h. The solution 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 10% methanol in dichloromethane as the eluent, yielding (±)-12.6. MS (ES): m / z 375.3 [M+H] + .

[0670] Synthesis of compound (±)-12.7. A mixture of (±)-12.6 (0.271 g, 0.723 mmol, 1.0 equivalent) and potassium carbonate (0.209 g, 1.51 mmol, 2.1 equivalent) in DMF (3 mL) was stirred for 15 min and iodomethane (0.123 g, 0.867 mmol, 1.2 equivalent) was added. The reaction mixture was stirred at 85 °C for 3 h. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was analyzed by rapid column chromatography on silica gel (…). The residue was purified using 4.7% methanol in dichloromethane as the eluent, yielding (±)-12.7. MS (ES): m / z 389.4 [M+H] + .

[0671] Synthesis of compound (±)-12.8. Hydrazine (99%, 1 mL) was added to a solution of (±)-12.7 (0.190 g, 0.489 mmol, 1.0 equivalent) in methanol (10 mL), and the mixture was heated to reflux for 2 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 to give (±)-12.8. MS (ES): m / z 259.2 [M+H] + .

[0672] Synthesis of compound (±)-12.9. Compound (±)-12.9 was prepared from compound (±)-12.8 following the procedure described in the synthesis of 11.8. MS (ES): m / z 301.3 [M+H] + .

[0673] Synthesis of compound (±)-I-12. Compound (±)-I-12 was prepared from (±)-12.9 and Int-2 following the procedure described in the synthesis of compound I-1. The synthesis was performed by rapid column chromatography on silica gel (…). The residue was purified using 4.8% methanol in dichloromethane as the eluent. MS (ES): m / z 539.5 [M+H] + .

[0674] I-12-a and I-12-b. The enantiomers of (±)-I-12 were separated by HPLC (CHIRALPAK IH (250 mm × 21 mm, 5 μm); mobile phase: (A) 0.1% diethylamine / n-hexane (B) 0.1% diethylamine / isopropanol:acetonitrile (70:30); flow rate: 20 mL / min), yielding a first elution fraction (I-12-a) and a second elution fraction (I-12-b). (*Absolute stereochemistry not determined.)

[0675] I-12-a:MS(ES):m / z:539.8[M+H] + ; 1 H NMR(DMSO-d6,400MHz): δ10.50(s,1H),9.37(s,1H),8.34(s,1H),8.16-8.14(d,J=5.6H z,1H),8.01(s,1H),7.65(s,1H),7.48-7.46(d,J=8.4Hz,1H),7.29(s,1H),7.25(s,1H) ,6.89-6.87(m,1H),6.63-6.62(m,1H),3.82-3.80(m,1H),3.72(s,3H),3.69-3.65(m,1 H),3.40-3.35(m,1H),2.81(s,3H),2.79-2.72(m,1H),2.42-2.33(m,1H),2.02(s,3H).

[0676] I-12-b:MS(ES):m / z:539.4[M+H] + ; 1 H NMR(DMSO-d6,400MHz): δ10.50(s,1H),9.37(s,1H),8.34(s,1H),8.16-8.14(d,J=5.6H z,1H),8.01(s,1H),7.65(s,1H),7.48-7.46(d,J=8.4Hz,1H),7.29(s,1H),7.25(s,1H) ,6.89-6.86(m,1H),6.63-6.61(m,1H),3.82-3.80(m,1H),3.72(s,3H),3.69-3.65(m,1 H),3.40-3.35(m,1H),2.81(s,3H),2.79-2.72(m,1H),2.42-2.33(m,1H),2.02(s,3H).

[0677] Example 13: N-(4-((1-methyl-2-((6-morpholinopyridin-2-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0678]

[0679] Synthesis of compound 13.2. A mixture of 6-bromopyridin-2-amine (13.1, 1.5 g, 8.67 mmol, 1.0 equivalent) and morpholine (7.47 mL, 86.7 mmol, 10 equivalent) was stirred at 150 °C for 4 h in a microwave reactor. The mixture was cooled to room temperature, 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. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 40% ethyl acetate in hexane as the eluent, yielding 13.2. MS (ES): m / z 180.3 [M+H] + .

[0680] Synthesis of compound 13.3. Compound 13.3 was prepared from 13.2 following the procedure described in the synthesis of compound 1.2. The synthesis was carried out by rapid column chromatography on silica gel (…). The residue was purified using 15% ethyl acetate in hexane as the eluent. MS (ES): m / z 222.3 [M+H] + .

[0681] Synthesis of I-13. Compound I-12 was prepared from 13.3 and Int-2 following the procedure described in the synthesis of compound I-1. The synthesis was performed by rapid column chromatography on silica gel (…). The residue was purified using 8% methanol in dichloromethane as the eluent. MS (ES): m / z: 460.45 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.49(s,1H),9.13(s,1H),8.15-8.14(d,J=5.6Hz,1H),7.65(s,1H),7.57-7.46(m,3H),7.29(s,1H) ,6.90-6.88(d,J=8.4Hz,1H),6.63-6.62(d,J=3.6Hz,1H),6.40-6.38(d,J=8Hz,1H),3.69(bs,8H),3.55(s,3H),2.02(s,3H).

[0682] Example 14: N-(4-((2-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)cyclopropaneformamide

[0683]

[0684] Synthesis of compound 14.2. Sodium hydride (12.61 g, 315.38 mmol, 2 equivalents) was added to a solution of benzyl alcohol (17.05 g, 157.69 mmol, 1.0 equivalent) in THF (250 mL) at 0 °C and stirred for 1 h. 2-Chloro-4-nitropyridine (14.1 g, 25 g, 157.69 mmol, 1.0 equivalent) was added, and the reaction mixture was stirred at 0 °C for 2 h. It was poured onto 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 10% ethyl acetate in hexane as the eluent, yielding 1.1. MS (ES): m / z 220.13 [M+H] + .

[0685] Synthesis of compound 14.3. A solution of 14.2 (20 g, 91.05 mmol, 1.0 equivalent) in THF (200 mL) was degassed by argon bubbling for 10 min. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (4.34 g, 9.105 mmol, 0.1 equivalent) and tris(dibenzylacetone)dipalladium(0) (4.17 g, 4.55 mmol, 0.05 equivalent) were added, and degassed 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 the reaction mixture was stirred at 60 °C for 1 h under argon. The mixture was cooled to room temperature, 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. The solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 3% methanol in dichloromethane as the eluent, yielding 14.3. MS (ES): m / z 201.2 [M+H] + .

[0686] Synthesis of compound 14.4. Triethylamine (1.67 mL, 12.0 mmol, 3.0 equivalence) was added to a solution of 14.3 (0.8 g, 4.0 mmol, 1.0 equivalence) in dichloromethane (10 mL) at room temperature, followed by the addition of cyclopropylcarbonyl chloride (0.49 g, 4.8 mmol, 1.2 equivalence) and stirring for 1 hour. The mixture was poured onto ice, stirred, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 1.2% methanol in dichloromethane as the eluent, yielding 14.4. MS (ES): m / z 269.3 [M+H] + .

[0687] Synthesis of compound 14.5. Compound 14.5 was prepared from 14.4 following the procedure described in the synthesis in Int-1. The synthesis was carried out by rapid column chromatography on silica gel (…). The product was purified using 5% methanol in dichloromethane as the eluent. MS (ES): m / z 179.2 [M+H] + .

[0688] Synthesis of compound 14.7. Tetrafluoroboronic acid O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylureonium (18.4 g, 58.5 mmol, 1.2 equivalence) was added to a solution of 4-amino-2-(trifluoromethyl)benzoic acid (14.6 g, 10 g, 48.75 mmol, 1.0 equivalence) in DMF (30 mL) at 0 °C. The reaction mixture was stirred for 30 min, and 1-ethylpiperazine (6.67 g, 58.5 mmol, 1.2 equivalence) was added, followed by N,N-diisopropylethylamine (24 mL, 146.25 mmol, 3.0 equivalence). The mixture was stirred at room temperature for 3 h. It was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was analyzed by rapid column chromatography on silica gel (…). The residue was purified using 1.5% methanol in dichloromethane as the eluent, yielding a concentration of 14.7. MS (ES): m / z 302.3 [M+H] + .

[0689] Synthesis of compound 14.8. A solution of lithium aluminum hydride (1 M in THF, 19.9 mL, 19.92 mmol, 3.0 equivalent) was added to a solution of 14.7 (2 g, 6.64 mmol, 1.0 equivalent) in 20 mL of THF at 0 °C. The reaction mixture was heated to reflux for 3 hours. It was then cooled to room temperature, carefully 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 14.8. MS (ES): m / z 288.3 [M+H] + .

[0690] Synthesis of compound 14.9. Compound 14.9 was prepared from 14.8 following the procedure described in the synthesis of compound 1.2. The synthesis was carried out by rapid column chromatography on silica gel (…). The product was purified using 3.0% methanol in dichloromethane as the eluent. MS (ES): m / z 330.3 [M+H] + .

[0691] Synthesis of compound 14.11. A solution of methylamine (33% in ethanol, 1.18 mL, 12.58 mmol, 2.0 equivalent) was added dropwise to a solution of 2,4-difluoro-1-nitrobenzene (14.10, 1.0 g, 6.29 mmol, 1.0 equivalent) in 10 mL of THF at 0 °C. The reaction mixture was stirred at room temperature for 2 h. It was poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 14.11. MS (ES): m / z 171.2 [M+H] + .

[0692] Synthesis of compound 14.12. Compound 14.12 was prepared from 14.11 and 14.5 following the procedure described in the synthesis of compound Int-2.3. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 2.5% methanol in dichloromethane as the eluent. MS (ES): m / z 329.3 [M+H] + .

[0693] Synthesis of compound 14.13. Compound 14.13 was prepared from 14.12 following the procedure described in the synthesis of compound Int-2. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 5% methanol in dichloromethane as the eluent. MS (ES): m / z 299.3 [M+H] + .

[0694] Synthesis of I-14. Compound I-14 was prepared from 14.9 and 14.13 following the procedure described in the synthesis of compound I-2. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 10% methanol in dichloromethane as the eluent. MS (ES): m / z: 594.30 [M+H] + , 1 H NMR(DMSO-d6,400MHz): δ10.79(s,1H),9.31(s,1H),8.24(s,1H),8.19-8.15(m ,2H),7.68-7.66(d,J=8.4Hz,1H),7.62(s,1H),7.45-7.43(d,J=7.6Hz,1H),7. 26(s,1H),6.87-6.85(d,J=10.4Hz,1H),6.66-6.65(d,J=3.2Hz,1H),3.70(s,3 H),3.55(s,2H),2.33(bs,10H),1.95(bs,1H),1.01-0.97(t,3H),0.75(bs,4H).

[0695] Example 15: 4-((2-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)-N-methylpyridineamide

[0696]

[0697] Synthesis of compound 15.2. A mixture of compound 15.1 (0.5 g, 2.93 mmol, 1.0 equivalent) and 1 M hydrochloric acid (5 mL) was stirred at 150 °C for 2 h in a microwave reactor. The mixture was poured onto a saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 3% methanol in dichloromethane as the eluent, yielding a concentration of 15.2. MS (ES): m / z 153.2 [M+H] + .

[0698] Synthesis of compound 15.3. Compound 15.3 was prepared from Int-2.2 and 15.2 following the procedure described in the synthesis of compound Int-2.3. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 2.0% methanol in dichloromethane as the eluent. MS (ES): m / z 303.3 [M+H] + .

[0699] Synthesis of compound 15.4. Compound 15.4 was prepared from 15.3 following the procedure described in the synthesis of compound Int-2. The synthesis was carried out by rapid column chromatography on silica gel (…). The product was purified using 5% methanol in dichloromethane as the eluent. MS (ES): m / z 273.3 [M+H] + .

[0700] Synthesis of I-15. Compound I-15 was prepared from 15.4 and 14.9 following the procedure described in the synthesis of compound I-2. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 10% methanol in dichloromethane as the eluent. MS (ES): m / z: 568.9 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ9.35 (s, 1H), 8.80-8.78 (d, J = 4.8Hz, 1H), 8.50-8.49 (d, J = 5.6Hz, 1 H),8.25(s,1H),8.21-8.19(d,J=8.0Hz,1H),7.69-7.67(d,J=8.4Hz,1H),7.50-7.48(d,J=8. 4Hz,1H),7.37-7.36(d,J=2.4Hz,1H),7.33(s,1H),7.17-7.15(m,1H),6.93-6.90(t,J=8.4Hz ,1H),3.71(s,3H),3.55(s,2H),2.76(s,3H),2.42(bs,6H),2.33(bs,4H),1.01-0.97(t,3H).

[0701] Example 16: 4-((2-((5-(tert-butyl)isoxazo-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)-N-methylpyridine amide

[0702]

[0703] Synthesis of I-16. Compound I-16 was prepared from compounds 15.4 and 1.2 following the procedure described in the synthesis of compound I-2. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 3% methanol in dichloromethane as the eluent. MS (ES): m / z: 421.46 [M+H] + , 1H NMR (DMSO-d6, 400MHz): δ 8.49-8.48 (d, 2H), 7.46 (bs, 2H), 7.17-7.11 (m, 2H), 6.89-6.87 (d, J = 7.2Hz, 1H), 3.56 (bs, 3H), 2.84 (s, 3H), 1.35 (s, 9H).

[0704] Example 17: N-(4-((2-((3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0705]

[0706] Synthesis of compound 17.2. Compound 17.2 was prepared by following the procedure described in the synthesis of compound 1.2 in section 17.1. The synthesis was carried out by rapid column chromatography on silica gel (…). The product was purified using 12% ethyl acetate in hexane as the eluent. MS (ES): m / z 196.3 [M+H] + .

[0707] Synthesis of I-17. Compound I-17 was prepared from 17.2 and Int-2 following the procedure described in the synthesis of compound I-1. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 3% methanol in dichloromethane as the eluent. MS (ES): m / z: 434.4 [M+H] + , 1 H NMR(DMSO-d6,400MHz): δ10.56-10.50(m,2H),8.18-8.16(d,J=5.6Hz,1H),7.67(s,1H),7.35-7.16(m,2H),6 .84-6.78(t,J=7.6Hz,1H),6.64(bs,1H),5.92(s,1H),3.61(bs,3H),3.42(s,3H),2.04(s,3H),1.27(s,9H).

[0708] Example 18: N-(4-((2-((3-(tert-butyl)-1-methyl-1H-pyrazole-5-yl)amino)-1,7-dimethyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0709]

[0710] Synthesis of I-18. Compound I-18 was prepared from 17.2 and Int-3 following the procedure described in the synthesis of compound I-2. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 3% methanol in dichloromethane as the eluent. MS (ES): m / z: 448.4 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.53-10.48(t,1H),8.76(s,1H),8.15-8.12(m,1H),7.58(s,1H),7.07-7.05(d,J=8.0Hz,1H),6.7 8-6.74(t,1H),6.56-6.55(d,J=5.6Hz,1H),6.07(s,1H),3.72(s,3H),3.61(bs,3H),2.37(s,3H),2.03(s,3H),1.26(s,9H).

[0711] Example 19: (S)-N-(4-((2-((3-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-5-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0712]

[0713] Synthesis of Compound 19.1. A round-bottom flask equipped with a Dean-Stark apparatus and condenser was charged with 5-(tert-butyl)-1H-pyrazole-3-amine (17.1 g, 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 (catalytic). The reaction mixture was heated to reflux for 3 hours. It was then cooled to room temperature and concentrated under reduced pressure. The solution was analyzed by rapid column chromatography on silica gel. The residue was purified using 12% ethyl acetate in hexane as the eluent, yielding a concentration of 19.1. MS (ES): m / z 218.3 [M+H] + .

[0714] Synthesis of compounds 19.3 and 19.4. A mixture of 19.1 (2.5 g, 11.50 mmol, 1.0 equivalent), 19.2 (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 under nitrogen. 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 results were analyzed by rapid column chromatography on silica gel. The residue was purified using 2% ethyl acetate in hexane as the eluent, yielding a concentration of 19.3. MS (ES): m / z 287.4 [M+H] + and 19.4. MS(ES):m / z 248.3[M+H] + .

[0715] Compound 19.5 was synthesized by stirring a solution of 19.3 (0.100 g, 0.347 mmol, 1.0 equivalent) and hydroxylamine hydrochloride (0.239 g, 3.47 mmol, 10 equivalent) in ethanol-water (2 / 1, v / v, 3 mL) at 120 °C for 1 h in a microwave reactor. The solution was poured into ice-water, and the pH was adjusted to approximately 10 by adding 2N sodium hydroxide aqueous solution. The mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 19.5. MS (ES): m / z 210.3 [M+H] + .

[0716] Synthesis of compound 19.6. Compound 19.6 was prepared from 19.5 following the procedure described in the synthesis of compound 1.2. MS (ES): m / z 252.3 [M+H] + .

[0717] Synthesis of I-19. Compound I-19 was prepared from 19.6 and Int-2 following the procedure described in the synthesis of compound I-2. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 1.4% methanol in dichloromethane as the eluent. MS (ES): m / z: 490.85 [M+H] + , 1 H NMR(CDCl3,400M Hz): δ8.14-8.12(d,J=5.6Hz,1H),7.99(bs,1H),7.82(bs,1H),7.17-7.15(d,J=7.6Hz,1H),6.86-6.84(d,J=8.0Hz,1H),6.64(bs, 1H),5.27(bs,1H),4.39(bs,1H),4.25(bs,1H),4.14(bs,2H),4.02(bs,1H),3.49(s,3H),2.54(bs,2H),2.20(s,3H),1.35(s,9H).

[0718] Example 20: (S)-N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0719]

[0720] Synthesis of compound 20.1. Compound 20.1 was prepared from compound 19.4 following the procedure described in the synthesis of compound 19.5. MS (ES): m / z 210.3 [M+H] + .

[0721] Synthesis of compound 20.2. Compound 20.2 was prepared from compound 20.1 following the procedure described in the synthesis section 11.8. The crude product was used without further purification. MS (ES): m / z 252.3 [M+H] + .

[0722] Synthesis of compound I-20. Compound I-20 was prepared from 20.2 and Int-2 following the procedure described in the synthesis of compound I-1. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 1.5% methanol in dichloromethane as the eluent. MS (ES): m / z: 490.25 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.48 (s, 1H), 9.51 (s, 1H), 8.14-8.13 (d, J = 6.0Hz, 1H), 7. 64(s,1H),7.36-7.34(d,J=8.0Hz,1H),7.16(s,1H),7.08-7.06(d,J=8Hz,1H),6.81 -6.79(m,1H),6.61-6.60(d,J=3.6Hz,1H),5.22(bs,1H),4.08-4.07(m,2H),3.99-3 .95(m,1H),3.85-3.82(m,2H),3.62(s,3H),2.24(bs,1H),2.02(s,3H),1.39(s,9H).

[0723] Example 21: (S)-N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-cyano-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0724]

[0725] Synthesis of I-21. Compound I-21 was prepared from 20.2 and Int-4 following the procedure described in the synthesis of compound I-1. The product was purified by preparative HPLC. MS (ES): m / z: 515.8 [M+H] + ,1 H NMR(DMSO-d6,400MHz): δ10.60(s,1H),9.88(s,1H),8.22-8.20(d,J=5.6H z,1H),7.68(s,1H),7.65(s,1H),7.02-7.00(d,J=8.4Hz,1H),6.70-6.68(m ,1H),6.51(s,1H),5.25(bs,1H),4.10-4.07(m,2H),3.91(s,3H),3.87-3. 81(m,2H),2.37-2.34(m,1H),2.24-2.20(m,1H),2.04(s,3H),1.39(s,9H).

[0726] Example 22: (S)-N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

[0727]

[0728] Synthesis of I-22. Compound I-22 was prepared from 20.2 and Int-5 following the procedure described in the synthesis of compound I-1. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 3.2% methanol in dichloromethane as the eluent. MS (ES): m / z: 491.45 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.54 (s, 1H), 9.81 (s, 1H), 8.19-8.18 (d, J = 5.6Hz, 1H),7.79-7.77(d,J=8Hz,1H),7.75(s,1H),6.84-6.82(d,J=8Hz,1H),6.71- 6.70(d,J=4Hz,1H),6.56(s,1H),5.24(bs,1H),4.08(bs,2H),3.87-3.81(m, 2H),3.59(s,3H),2.33(bs,1H),2.25-2.22(m,1H),2.04(s,3H),1.39(s,9H).

[0729] Example 23: (R)-N-(4-((2-((3-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-5-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0730]

[0731] Synthesis of compounds 23.2 and 23.3. Compounds 23.2 and 23.3 were prepared from compounds 19.1 and 23.1 following the procedure described in the synthesis of compounds 19.3 and 19.4. Isomers were separated by rapid column chromatography on silica gel. (2% ethyl acetate in hexane as eluent) yielded 23.2. MS (ES): m / z 287.4 [M+H] + and 23.3. MS(ES):m / z 248.3[M+H] + .

[0732] Synthesis of I-23. Compound I-23 was prepared by following the procedure described in each step of the synthesis of compound I-19 in section 23.2. The synthesis was carried out by rapid column chromatography on silica gel (…). The product was purified using 1.5% methanol in dichloromethane as the eluent. MS (ES): m / z: 490.80 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.58 (s, 1H), 10.51 (s, 1H), 8.16-8.15 (d, J = 5.2Hz ,1H),7.65(bs,1H),7.17-7.15(d,J=8.4Hz,1H),7.07(s,1H),6.80-6.78(d, J=8.0Hz,1H),6.63(bs,1H),5.21(bs,1H),4.01-3.99(m,2H),3.83-3.77(m, 2H),3.65(bs,1H),3.39(s,3H),2.22-2.20(m,2H),2.03(s,3H),1.26(s,9H).

[0733] Example 24: (R)-N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0734]

[0735] Synthesis of compound I-24. Compound I-24 was prepared by following the procedure described in each step of the synthesis of compound I-20 in section 23.3. The synthesis was carried out by rapid column chromatography on silica gel (…). The product was purified using 1.5% methanol in dichloromethane as the eluent. MS (ES): m / z: 490.37 [M+H] + , 1H NMR (DMSO-d6, 400MHz): δ10.48 (s, 1H), 9.56 (s, 1H), 8.16-8.14 (d, J = 5.6Hz, 1H), 7. 65(s,1H),7.38-7.36(d,J=8.4Hz,1H),7.19(s,1H),7.10-7.04(d,J=8Hz,1H),6.84 -6.82(m,1H),6.62-6.61(d,J=3.6Hz,1H),5.24(bs,1H),4.10-4.07(m,2H),4.01-3 .96(m,1H),3.89-3.83(m,2H),3.63(s,3H),2.24(bs,1H),2.03(s,3H),1.39(s,9H).

[0736] Example 25: (R)-N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-cyano-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0737]

[0738] Synthesis of compound I-25. Compound I-25 was prepared by Int-4 and 24.2 following the procedure described in the synthesis of compound I-1. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 1.8% methanol in dichloromethane as the eluent. MS (ES): m / z: 515.36 [M+H] + , 1 H NMR(DMSO-d6,400MHz): δ10.60(s,1H),9.88(s,1H),8.22-8.20(d,J=5.6H z,1H),7.68(s,1H),7.66(s,1H),7.02-7.00(d,J=8.4Hz,1H),6.70-6.68(m ,1H),6.51(s,1H),5.25(bs,1H),4.10-4.07(m,2H),3.91(s,3H),3.88-3. 84(m,2H),2.37-2.34(m,1H),2.23-2.22(m,1H),2.04(s,3H),1.39(s,9H).

[0739] Example 26: (R)-N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

[0740]

[0741] Synthesis of compound I-26. Compound I-26 was prepared by Int-5 and 24.2 following the procedure described in the synthesis of I-1. The synthesis was carried out by rapid column chromatography on silica gel (…). The product was purified using 3.1% methanol in dichloromethane as the eluent. MS (ES): m / z: 491.40 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.54 (s, 1H), 9.81 (s, 1H), 8.19-8.18 (d, J = 5.6Hz, 1H),7.79-7.77(d,J=8Hz,1H),7.75(s,1H),6.84-6.82(d,J=8Hz,1H),6.71- 6.70(d,J=4Hz,1H),6.56(s,1H),5.24(bs,1H),4.08(bs,2H),3.85-3.81(m, 2H),3.59(s,3H),2.33(bs,1H),2.25-2.20(m,1H),2.04(s,3H),1.39(s,9H).

[0742] Example 27: N-(4-((2-((5-(tert-butyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0743]

[0744] Synthesis of compound 27.2. Methanesulfonyl chloride (3.61 mL, 46.99 mmol, 1.2 equivalents) was slowly added to a solution of tetrahydro-2H-pyran-4-ol (27.1 g, 4.0 g, 39.16 mmol, 1.0 equivalents) in dichloromethane (40 mL) and triethylamine (13.64 mL, 97.9 mmol, 2.5 equivalents) at 0 °C. The reaction mixture was heated to room temperature and stirred for 6 hours. It was poured onto 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 solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 20% ​​ethyl acetate in hexane as the eluent, yielding a concentration of 27.2. MS (ES): m / z 181.2 [M+H] + .

[0745] Synthesis of compounds 27.3 and 27.4. Compounds 27.3 and 27.4 were prepared from 27.2 and 19.1 following the procedure described in the synthesis of compounds 19.3 and 19.4. Isomers were separated by rapid column chromatography on silica gel. (8%-12% ethyl acetate in hexane as eluent) yielded 27.3. MS (ES): m / z 302.4 [M+H] + and 27.4. MS(ES):m / z 302.3[M+H] + .

[0746] Synthesis of compound I-27. Compound I-27 was prepared from compound 27.4 following the procedure described in each step of the synthesis of I-20. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 2.5% methanol in dichloromethane as the eluent. MS (ES): m / z: 503.85 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.49 (s, 1H), 9.48 (s, 1H), 8.16-8.14 (d, J = 5.6Hz, 1H), 7. 65(s,1H),7.37-7.35(d,J=8.4Hz,1H),7.17(s,1H),6.82-6.80(d,J=8.4Hz,1H),6.6 2-6.61(d,J=3.6Hz,1H),6.51(s,1H),4.50(bs,1H),3.98-3.96(m,2H),3.64(s,3H) ,3.59-3.53(m,2H),2.21-2.16(m,2H),2.04(s,3H),1.79-1.76(m,2H),1.40(s,9H).

[0747] Example 28: N-(4-((2-((5-(tert-butyl)-1-(((1s,3s)-3-hydroxycyclobutyl)methyl)-1H-pyrazole-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0748]

[0749] Synthesis of compound 28.2. Sodium borohydride (2.21 g, 58.53 mmol, 1.5 equivalent) was added in small amounts to a solution of 28.4 (5 g, 39.02 mmol, 1.0 equivalent) in methanol (25 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred for 2 hours. It was poured onto an ice-water mixture, stirred, and the pH was adjusted to 4–5 by adding 1 N 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 28.2. The crude product was used in the next step without further purification. MS (ES): m / z 131.2 [M+H] + .

[0750] Synthesis of compound 28.3. Imidazole (2.82 g, 41.49 mmol, 1.5 equivalence) was added to a solution of 28.2 (3.6 g, 27.66 mmol, 1.0 equivalence) in dichloromethane (36 mL), followed by the addition of tert-butyldimethylchlorosilane (6.22 g, 41.49 mmol, 1.5 equivalence) and stirring at room temperature for 12 hours. The mixture was poured over 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified by eluting with 10% ethyl acetate in hexane to give 28.3. 1 H NMR (CDCl3, 400MHz): δ4.19-4.14(m,1H),3.69(s,3H),2.57-2.46(m,3H),2.25-2.17(m,2H),0.89(s,9H),0.05(s,6H).

[0751] Synthesis of compound 28.4. A solution of lithium aluminum hydride (1M in THF, 20.1 mL, 20.13 mmol, 1.2 equivalent) was added to a solution of 28.3 (4.1 g, 16.78 mmol, 1.0 equivalent) in diethyl ether (40 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (4 mL) and 15% sodium hydroxide (12 mL) were added and stirred for 30 minutes. The reaction 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified by eluting with 30% ethyl acetate in hexane to give 28.4. 1H NMR (CDCl3, 400MHz): δ4.22-4.15(m,1H),3.66-3.62(m,2H),2.41-2.35(m,2H),2 .15-2.11(m,1H),2.02-1.94(m,1H),1.73-1.66(m,2H),0.91(s,9H),0.06(s,6H).

[0752] Synthesis of compound 28.5. Triethylamine (4.44 mL, 31.89 mmol, 3.0 equivalent) was added to a solution of 28.4 (2.3 g, 10.63 mmol, 1.0 equivalent) in dichloromethane (25 mL) at 0 °C, followed by the addition of methanesulfonyl chloride (2.45 mL, 31.89 mmol, 3.0 equivalent), and the mixture was stirred at room temperature for 3 hours. The mixture was poured onto ice, stirred, and extracted with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate solution, followed by brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified by eluting with 12% ethyl acetate in hexane to give 28.5. 1 H NMR (CDCl3, 400MHz): δ4.24-4.16(m,3H),3.03(s,3H),2.45-2.39(m,1H),2.20-2.14(m,1H),1.78-1.69(m,3H),0.89(s,9H),0.05(s,6H).

[0753] Synthesis of compounds 28.6 and 28.7. Cesium carbonate (5.98 g, 18.40 mmol, 2.0 equivalent) was added to solutions of 19.1 (2.0 g, 9.20 mmol, 1.0 equivalent) in DMF (7 mL), and the reaction mixture was stirred at 80 °C for 16 h. The mixture was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The results were analyzed by rapid column chromatography on silica gel (…). The residue was purified using 6%-8% ethyl acetate in hexane as the eluent, yielding a concentration of 28.6. MS (ES): m / z 416.7 [M+H] + And 28.7 (0.500 g, yield: 13.07%). MS (ES): m / z 416.6 [M+H] + .

[0754] Synthesis of compound 28.8. A solution of 28.7 (0.500 g, 1.2 mmol, 1.0 equivalent) and hydroxylamine hydrochloride (0.828 g, 12 mmol, 10 equivalent) in ethanol:water (2:1, 10 mL) was stirred at 120 °C for 1 h in a microwave reactor. The solution was poured over ice-water, neutralized with 2N sodium hydroxide, 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 a chiral mixture, which was separated by preparative HPLC to obtain 28.8. MS (ES): m / z 224.3 [M+H] + and 28.9. MS(ES):m / z 224.2[M+H] + .

[0755] Synthesis of compound 28.9. Compound 28.9 was prepared from 28.8 following the procedure described in the synthesis section 1.2. The crude product was used in the next step without purification. MS (ES): m / z 266.4 [M+H] + .

[0756] Synthesis of I-28. Compound I-28 was prepared from compound 28.9 following the procedure described in each step of the synthesis of I-1. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 2.5% methanol in dichloromethane as the eluent. MS (ES): m / z: 504.9 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.48 (s, 1H), 9.39 (s, 1H), 8.14-8.13 (d, J = 5.2Hz, 1H), 7.64 (s, 1H),7.35-7.33(d,J=8.4Hz,1H),7.16(s,1H),6.81-6.78(d,J=8.4Hz,1H),6.61-6.60(d, J=4Hz,1H),6.50(s,1H),5.02-5.01(d,J=6.4Hz,1H),4.08-4.07(d,J=5.2Hz,2H),3.93-3 .91(m,1H),3.62(s,3H),2.32-2.29(m,3H),2.02(s,3H),1.70-1.68(m,2H),1.37(s,9H).

[0757] Example 29: N-(4-((2-((5-(tert-butyl)-1-((1r,3r)-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0758]

[0759] The synthesis of compound 29.2 was performed by adding methanesulfonyl chloride (1.7 mL, 21.87 mmol, 1.3 equivalents) to a solution of 29.1 (3.0 g, 16.83 mmol, 1.0 equivalents) in dichloromethane (30 mL) and triethylamine (3.0 mL, 21.87 mmol, 1.3 equivalents) at 0 °C. The reaction mixture was heated to room temperature and stirred for 12 hours. It was poured onto an ice-water mixture, 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 solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 20% ​​ethyl acetate in hexane as the eluent, yielding a concentration of 29.2. MS (ES): m / z 257.3 [M+H] + .

[0760] Synthesis of compounds 29.3, 29.4, 29.5, and 29.6. Compounds 29.3, 29.4, 29.5, and 29.6 were prepared from compounds 19.1 and 29.2 following the procedure described in the synthesis of compounds 19.3 and 19.4. Isomers were separated by rapid column chromatography on silica gel. (8%-12% ethyl acetate in hexane as eluent). MS (ES): m / z 378.5 [M+H] + .

[0761] Synthesis of compound 29.9. Compound 29.9 was prepared from 29.5 following the procedure described in each step of the synthesis of compound I-20. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 2.2% methanol in dichloromethane as the eluent. MS (ES): m / z 580.7 [M+H] + .

[0762] Synthesis of I-29. A mixture of compound 29.9 (0.070 g, 0.120 mmol, 1.0 equivalent) and 20% carbon-supported palladium hydroxide (0.150 g) in methanol (5 mL) was stirred at room temperature for 12 hours under 1 atm hydrogen. (via...) The reaction mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure and subjected to rapid column chromatography on silica gel. The residue was purified using 5% methanol in dichloromethane as the eluent to give I-29. MS (ES): m / z: 490.51 [M+H] + , 1H NMR (DMSO-d6, 400MHz): δ10.49 (s, 1H), 9.53 (s, 1H), 8.16-8.14 (d, J = 5.2Hz, 1H),7.65(s,1H),7.38-7.36(d,J=8.0Hz,1H),7.19(s,1H),6.83-6.81(d,J=7 .6Hz,1H),6.62-6.61(d,J=3.6Hz,1H),6.50(s,1H),5.19-5.18(m,2H),4.46 (bs,1H),3.64(s,3H),2.74(bs,2H),2.33(bs,2H),2.03(s,3H),1.36(s,9H).

[0763] Example 30: N-(4-((2-((5-(tert-butyl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazole-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0764]

[0765] Synthesis of compound I-30. Compound I-30 was prepared from 29.6 in the same manner as in the synthesis of I-29. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 5% methanol in dichloromethane as the eluent. MS (ES): m / z: 490.46 [M+H] + , 1 H NMR(DMSO-d6,400MHz): δ10.48(s,1H),9.53(s,1H),8.15-8.13(d,J=5.6Hz,1H ),7.64(s,1H),7.36-7.34(d,J=8.4Hz,1H),7.17(s,1H),6.82-6.80(d,J=7.6Hz ,1H),6.61-6.60(d,J=3.6Hz,1H),6.48(s,1H),5.20-5.19(m,2H),4.03-4.01( m,1H),3.63(s,3H),3.50-3.48(m,2H),2.62(bs,2H),2.02(s,3H),1.35(s,9H).

[0766] Example 31: N-(4-((2-((5-(tert-butyl)-1-(oxecyclobutane-3-ylmethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0767]

[0768] Synthesis of compounds 31.2 and 31.3. Sodium hydride (0.165 g, 3.45 mmol, 1.3 equivalent) was added to a solution of 31.1 (0.4 g, 2.65 mmol, 1.0 equivalent) in DMF (5 mL) at 0 °C and stirred for 30 min. 17.1 (0.0368 g, 2.65 mmol, 1.0 equivalent) was added to the solution. The reaction mixture was stirred at room temperature for 16 h. It was poured onto 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 preparative HPLC to give 31.2. MS (ES): m / z 210.3 [M+H] + and 31.3. MS(ES):m / z 210.3[M+H] + .

[0769] Synthesis of compound 31.4. Compound 31.4 was prepared from 31.2 following the procedure described in the synthesis in section 11.8. MS (ES): m / z 252.3 [M+H] + .

[0770] Synthesis of I-31. Compound 31.4 was prepared from 31.4 and Int-2 following the procedure described in the synthesis of compound I-1. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 3%-4% methanol in dichloromethane as the eluent. MS (ES): m / z 489.8 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.49 (s, 1H), 9.41 (s, 1H), 8.15-8.13 (d, J = 5.6Hz, 1H),7.64(s,1H),7.36-7.34(d,J=8.4Hz,1H),7.17(s,1H),6.82-6.80(d,J=7 .6Hz,1H),6.60(s,1H),6.48(s,1H),4.71-4.67(m,2H),4.56-4.54(m,2H),4 .42-4.40(m,2H),3.60(bs,3H),3.50-3.47(m,1H),2.02(s,3H),1.37(s,9H).

[0771] Example 32: N-(4-((2-((5-(tert-butyl)-1-(oxecyclobutane-3-ylmethyl)-1H-pyrazol-3-yl)amino)-7-cyano-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0772]

[0773] Synthesis of I-32. Compound I-32 was prepared from 31.4 and Int-4 following the procedure described in the synthesis of compound I-1. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 2.0% methanol in dichloromethane as the eluent. MS (ES): m / z: 515.15 [M+H] + , 1 H NMR(DMSO-d6,400MHz): δ10.61(s,1H),9.79(s,1H),8.22(bs,1H),7.68-7.58(m,2H),7.04(bs,1H),6.70(bs,1H), 6.51-6.48(m,1H),4.69(bs,2H),4.54(bs,2H),4.29(bs,2H),3.90(s,3H),3.77(s,1H),2.04(s,3H),1.38(s,9H).

[0774] Example 33: N-(4-((1-methyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0775]

[0776] Synthesis of compound 33.1. Trifluoroacetic anhydride (52 g, 246.57 mmol, 2.0 equivalent) was added to a solution of 1,1,1-triethoxyethane (20 g, 123.28 mmol, 1.0 equivalent) and pyridine (21 mL, 258.8 mmol, 2.1 equivalent) in dichloromethane (200 mL) at 0 °C. The reaction solution was heated to room temperature and stirred for 16 hours. The solution was poured onto 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 to give 33.1. MS (ES): m / z 213.2 [M+H] + .

[0777] Synthesis of compound 33.2. Ammonia solution (28 mL) was added to a solution of 33.1 (14.2 g, 66.93 mmol, 1.0 equivalent) in acetonitrile (150 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred for 24 hours. It was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude extract, which was ground with n-pentane to give 33.2. MS (ES): m / z 184.2 [M+H] + .

[0778] Synthesis of compound 33.3. Triethylamine (5.3 mL, 38.22 mmol, 1.0 equivalent) was added to a solution of 33.2 (7.0 g, 38.22 mmol, 1.0 equivalent) in ethanol (70 mL), followed by the addition of hydrazine hydrochloride (2.61 g, 38.22 mmol, 1.0 equivalent). The reaction mixture was heated to reflux for 12 hours. It was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 30% ethyl acetate in hexane as the eluent, yielding 33.3. MS (ES): m / z 152.1 [M+H] + .

[0779] Synthesis of compounds 33.4 and 33.5. Sodium hydride (0.288 g, 6.019 mmol, 1.3 equivalent) was added to a solution of 4-(bromomethyl)tetrahydro-2H-pyran (0.7 g, 4.63 mmol, 1.0 equivalent) in DMF (8 mL) at 0 °C and stirred for 30 min. 33.3 (0.829 g, 4.63 mmol, 1.0 equivalent) was added to the solution. The reaction mixture was heated to room temperature and stirred for 16 h. It was poured onto 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 preparative HPLC to give 33.4. MS (ES): m / z 250.4 [M+H] + and 33.5. MS(ES):m / z 250.4[M+H] + .

[0780] Synthesis of compound 33.6. Compound 33.6 was prepared from 33.4 following the procedure described in the synthesis in section 11.8. The crude product was used without further purification. MS (ES): m / z 292.3 [M+H] + .

[0781] Synthesis of I-33. Compound I-33 was prepared from 33.6 and Int-2 following the procedure described in the synthesis of I-1. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 10% methanol in dichloromethane as the eluent. MS (ES): m / z: 530.49 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.48 (s, 1H), 10.07 (s, 1H), 8.15-8.13 (d, J = 6.0Hz, 1H), 7. 64(s,1H),7.43-7.41(d,J=8.4Hz,1H),7.32(s,1H),7.23(s,1H),6.85-6.83(d,J=6. 8Hz,1H),6.61-6.60(d,J=3.2Hz,1H),4.04-4.02(m,2H),3.87-3.84(m,2H),3.67(s, 3H),2.20(bs,1H),2.02(s,3H),1.56(bs,1H),1.48-1.45(m,2H),1.35-1.23(m,3H).

[0782] Example 34: N-(4-((7-cyano-1-methyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0783]

[0784] Synthesis of I-34. Compound I-34 was prepared from 33.6 and Int-4 following the procedure described in the synthesis of I-1. The synthesis was achieved by rapid column chromatography on silica gel (…). The residue was purified using 1.8% methanol in dichloromethane as the eluent. MS (ES): m / z: 555.42 [M+H] + , 1H NMR (DMSO-d6, 400MHz): δ10.61 (s, 1H), 10.41 (s, 1H), 8.22-8.21 (d, J = 5.6Hz, 1H) ,7.75-7.73(d,J=8.4Hz,1H),7.68(s,1H),7.30(s,1H),7.07-7.05(d,J=8.4Hz,1H ),6.71-6.70(d,J=4Hz,1H),4.06-4.04(m,2H),3.94(s,3H),3.87-3.85(m,2H),3. 27-3.24(m,2H),2.20(bs,1H),2.04(s,3H),1.48-1.45(m,2H),1.35-1.27(m,2H).

[0785] Example 35: N-(4-((2-((1-(((1s,4s)-4-hydroxycyclohexyl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0786]

[0787] Synthesis of compound 35.2. Tert-butyldimethylchlorosilane (11.5 g, 76.29 mmol, 2.2 equivalents) was added to a solution of 35.1 (5.0 g, 34.68 mmol, 1.0 equivalent) and triethylamine (10.6 mL, 76.29 mmol, 2.2 equivalents) in DMF (30 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was poured over ice-water, acidified to pH 4 with 1 M hydrochloric acid, and extracted with diethyl ether. The organic layers were separated, washed with brine, and concentrated under reduced pressure to give a crude product. The crude product was dissolved in a mixture of methanol and THF (1:1, 20 mL), and 5 M aqueous sodium hydroxide solution (10 mL) was added at room temperature. The mixture was stirred for 3 hours and concentrated to half its volume. It was then acidified to pH 4 with 2 M hydrochloric acid and extracted with diethyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 35.2. MS(ES): m / z 259.4 [M+H] + .

[0788] Synthesis of compound 35.3. A solution of lithium aluminum hydride (1 M in THF, 23.2 mL, 23.2 mmol, 2.0 equivalent) was added to a solution of 35.2 (3.0 g, 11.61 mmol, 1.0 equivalent) in 30 mL of THF at 0 °C. The reaction mixture was heated to room temperature and stirred for 3 hours. It was carefully poured over ice-water, neutralized with 1 M 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 35.3. MS (ES): m / z 245.5 [M+H] + .

[0789] Synthesis of compound 35.4. Methanesulfonyl chloride (1.6 mL, 20.85 mmol, 1.3 equivalent) was added to a solution of 35.3 (1.7 g, 6.95 mmol, 1.0 equivalent) and triethylamine (1.25 mL, 9.035 mmol, 1.3 equivalent) in dichloromethane (25 mL) at 0 °C. The reaction solution was heated to room temperature and stirred for 12 hours. The solution was poured onto ice, stirred, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 5% ethyl acetate in hexane as the eluent, yielding a concentration of 35.4. MS (ES): m / z 323.5 [M+H] + .

[0790] Synthesis of compounds 35.5 and 35.6. Sodium hydride (0.247 g, 5.161 mmol, 1.3 equivalent) was added to a solution of 33.3 (0.6 g, 3.97 mmol, 1.0 equivalent) in DMF (8 mL) at 0 °C and stirred for 30 min. 35.4 (1.28 g, 3.97 mmol, 1.0 equivalent) was added to the mixture. The reaction mixture was stirred at room temperature for 16 h. It was poured onto 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 preparative HPLC to give 35.5. MS (ES): m / z 378.5 [M+H] + And 35.6. MS(ES): m / z 378.5 [M+H] + .

[0791] Synthesis of compound 35.7. Compound 35.7 was prepared from 35.5 following the procedure described in the synthesis in section 11.8. The crude product was used in the next step without further purification. MS (ES): m / z 420.5 [M+H] + .

[0792] Synthesis of compound 35.8. Compound 35.8 was prepared from 35.5 and Int-2 following the procedure described in the synthesis in I-1. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 2% methanol in dichloromethane as the eluent. MS (ES): m / z 658.8 [M+H] + .

[0793] Synthesis of I-35. Tetrabutylammonium fluoride solution (1M in THF, 5mL) was added to a solution of 35.8 (0.062 g, 0.094 mmol, 1.0 equivalent) in 2 mL THF. The reaction mixture was stirred at 50 °C for 3 hours. It was cooled to room temperature, poured onto an ice-water plate, 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 5% methanol in dichloromethane as the eluent to give I-35. MS (ES): m / z: 544.57 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.49 (s, 1H), 10.06 (s, 1H), 8.15-8.13 (d, J = 5.6Hz, 1H), 7.64 (s, 1H) ),7.43-7.41(d,J=8.4Hz,1H),7.30(s,1H),7.23(s,1H),6.85-6.83(d,J=7.2Hz,1H),6.62-6 .60(d,J=5.2Hz,1H),4.57-4.56(d,1H),4.02-3.95(m,2H),3.67(s,3H),3.03(bs,1H),2.02( s,3H),1.85-1.82(m,2H),1.55(bs,2H),1.34-1.30(m,1H),1.30(bs,2H),1.11-1.03(m,2H).

[0794] Example 36: (S)-N-(4-((1-methyl-2-((1-((tetrahydro-2H-pyran-3-yl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide and (R)-N-(4-((1-methyl-2-((1-((tetrahydro-2H-pyran-3-yl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide)

[0795]

[0796] Synthesis of compounds (±)-36.2 and (±)-36.3. Sodium hydride (0.206 g, 4.303 mmol, 1.3 equivalent) was added to a solution of 33.3 (0.5 g, 3.31 mmol, 1.0 equivalent) in DMF (8 mL) at 0 °C and stirred for 30 min. 3-(bromomethyl)tetrahydro-2H-pyran ((±)-36.1, 0.592 g, 3.31 mmol, 1.0 equivalent) was added to the mixture. The reaction mixture was stirred at room temperature for 16 h. It was poured onto 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 preparative HPLC to give (±)-36.2. MS (ES): m / z 250.3 [M+H] + and (±)-36.3. MS(ES):m / z 250.3[M+H] + .

[0797] Synthesis of compound (±)-36.4. Compound (±)-36.4 was prepared from (±)-36.2 following the procedure described in the synthesis section 11.8. The crude product was used in the next step without further purification. MS (ES): m / z 292.3 [M+H] + .

[0798] Synthesis of compound (±)-I-36. Compound (±)-I-36 was prepared by (±)-36.4 and Int-2 following the procedure described in the synthesis of I-1. MS (ES): m / z 530.5 [M+H] + .

[0799] I-36-a and I-36-b. The enantiomers of (±)-I-36 were separated on an SFC column (CHIRALCEL OJ-H (250 mm × 4.6 mm, 5 μm); eluent: 0.1% DEA in methanol; flow rate: 4 mL / min) to give a first elution fraction (I-36-a) and a second elution fraction (I-36-b). (*Absolute stereochemistry not determined.)

[0800] I-36-a.MS(ES):m / z:530.44[M+H] + , 1H NMR (DMSO-d6, 400MHz): δ10.48 (s, 1H), 10.06 (s, 1H), 8.15-8.13 (d, J = 6Hz, 1H), 7.64 (s,1H),7.43-7.41(m,1H),7.32(s,1H),7.23(s,1H),6.86-6.83(d,J=10.4Hz,1H),6. 62-6.60(d,J=6.4Hz,1H),4.07-4.01(m,2H),3.71(bs,1H),3.67(s,3H),3.27-3.23(m ,2H),2.19(bs,1H),2.02(s,3H),1.69-1.60(m,3H),1.49(bs,1H),1.34-1.23(m,1H).

[0801] I-36-b.MS(ES):m / z:530.49[M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.49 (s, 1H), 10.08 (s, 1H), 8.16-8.14 (d, J = 6Hz, 1H), 7.65 (s ,1H),7.44-7.42(d,J=8.4Hz,1H),7.33(s,1H),7.23(s,1H),6.86-6.84(d,J=8.4Hz,1H) ,6.62-6.61(d,J=5.6Hz,1H),4.11-4.00(m,2H),3.71(bs,1H),3.68(s,3H),3.28-3.23 (m,2H),2.20(bs,1H),2.03(s,3H),1.70-1.61(m,3H),1.50(bs,1H),1.34-1.24(m,1H).

[0802] Example 37: N-(4-((2-((1-(2-oxaspiro[3.3]hept-6-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0803]

[0804] Synthesis of compound 37.2. Sodium borohydride (0.203 g, 5.35 mmol, 1.0 equivalent) was added in small amounts to a solution of 37.1 (0.600 g, 5.35 mmol, 1.0 equivalent) in 10 mL of methanol at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. It was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 37.2. MS (ES): m / z 115.2 [M+H] + .

[0805] Synthesis of compound 37.3. Methanesulfonyl chloride (0.71 mL, 9.46 mmol, 2.0 equivalent) was added to a solution of 37.2 (0.540 g, 4.73 mmol, 1.0 equivalent) and triethylamine (1.64 mL, 11.82 mmol, 2.5 equivalent) in dichloromethane (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. It was poured over ice-water, stirred, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 40% ethyl acetate in hexane as the eluent, yielding a concentration of 37.3. MS (ES): m / z 193.2 [M+H] + .

[0806] Synthesis of compounds 37.4 and 37.5. Cesium carbonate (1.352 g, 4.16 mmol, 2.0 equivalent) was added to solutions of 37.3 (0.4 g, 2.08 mmol, 1.0 equivalent) in DMF (7 mL), and the reaction mixture was stirred at 80 °C for 5 h. The mixture was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 37.4. MS (ES): m / z 248.2 [M+H] + and 37.5. MS(ES):m / z 248.3[M+H] + .

[0807] Synthesis of compound 37.6. Compound 37.6 was prepared from 37.4 following the procedure described in the synthesis in section 11.8. The crude product was used in the next step without further purification. MS (ES): m / z 290.2 [M+H] + .

[0808] Synthesis of I-37. Compound I-37 was prepared from 37.6 following the procedure described in the synthesis of I-1. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 1.5% methanol in dichloromethane as the eluent. MS (ES): m / z: 527.8 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.49(s,1H),10.10(s,1H),8.15-8.13(d,J=6.0Hz,1H),7.64(s,1H),7.42-7.40(d,J=8.4Hz,1H),7.32(s,1H),7.23-7.2 2(d,J=1.6Hz,1H),6.85-6.83(m,1H),6.62-6.60(m,1H),4.70(s,2H),4.5 8(s,2H),3.67(s,3H),3.41-3.39(m,1H),2.80-2.78(m,4H),2.02(s,3H).

[0809] Example 38: N-(4-((2-((1-((((1r,4r)-4-hydroxycyclohexyl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0810]

[0811] Synthesis of compound 38.2. Tert-butyldimethylchlorosilane (5.2 g, 34.83 mmol, 1.2 equivalents) was added to a solution of 38.1 (5.0 g, 29.03 mmol, 1.0 equivalent) and imidazole (5.0 g, 72.57 mmol, 1.2 equivalent) in DMF (25 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was poured over 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 10% ethyl acetate in hexane as the eluent, yielding a concentration of 38.2. MS (ES): m / z 287.5 [M+H] + .

[0812] Synthesis of compound 38.3. A solution of lithium aluminum hydride (1 M in THF, 16.1 mL, 16.12 mmol, 1.1 equivalent) was added to a solution of 38.2 (4.2 g, 14.66 mmol, 1.0 equivalent) in diethyl ether (42 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred for 4 hours. It was carefully poured onto 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 38.3. MS (ES): m / z 245.5 [M+H] + .

[0813] Synthesis of compound 38.4. Compound 38.4 was prepared from 38.3 following the procedure described in the synthesis of 35.4. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 12% ethyl acetate in hexane as the eluent. MS (ES): m / z 323.5 [M+H] + .

[0814] Synthesis of compounds 38.5 and 38.6. Compounds 38.5 and 38.6 were prepared from 38.4 and 33.3 following the procedure described in the synthesis of 35.5 and 35.6. Isomer 38.5 was obtained by separation of the isomers by preparative HPLC. MS (ES): m / z 378.5 [M+H] + and 38.6. MS(ES):m / z 378.5[M+H] + .

[0815] Synthesis of compound 38.7. Compound 38.7 was prepared from 38.5 following the procedure described in the synthesis of 11.8. The crude product was used in the next step without further purification. MS (ES): m / z 420.5 [M+H] + .

[0816] Synthesis of compound 38.8. Compound 38.8 was prepared from 38.7 and Int-2 following the procedure described in the synthesis of I-2. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 2% methanol in dichloromethane as the eluent. MS (ES): m / z 658.8 [M+H] + .

[0817] Synthesis of compound I-38. Compound I-38 was prepared from 38.8 following the procedure described in the synthesis of I-35. The synthesis was achieved by rapid column chromatography on silica gel (…). The product was purified using 5% methanol in dichloromethane as the eluent. MS (ES): m / z: 544.49 [M+H] + , 1H NMR (DMSO-d6, 400MHz): δ10.48 (s, 1H), 10.05 (s, 1H), 8.15-8.13 (d, J = 5.6Hz, 1H), 7.64 (s ,1H),7.43-7.41(d,J=8.4Hz,1H),7.30(s,1H),7.22(s,1H),6.85-6.83(d,J=7.2Hz,1H), 6.62-6.60(d,J=5.2Hz,1H),4.56-4.55(d,1H),4.04-4.02(m,2H),3.67(s,3H),2.02(s,3 H),1.85-1.82(m,2H),1.55(bs,2H),1.34-1.30(m,1H),1.30(bs,2H),1.11-1.03(m,2H).

[0818] Example 39: N-(4-((2-((1-(2-acetyl-2-azaspiro[3.3]hept-6-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0819]

[0820] Synthesis of compound 39.2. Sodium borohydride (1.439 g, 37.88 mmol, 4.0 equivalent) was added in small amounts to a solution of 39.1 (2.0 g, 9.47 mmol, 1.0 equivalent) in methanol (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. It was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 39.2. MS (ES): m / z 214.3 [M+H] + .

[0821] Synthesis of compound 39.3. Methanesulfonyl chloride (0.75 mL, 9.75 mmol, 1.0 equivalent) was added to a solution of 39.2 (1.6 g, 7.5 mmol, 1.0 equivalent) and triethylamine (1.35 mL, 9.75 mmol, 1.3 equivalent) in dichloromethane (20 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. It was poured over ice-water, stirred, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 39.3. MS (ES): m / z 292.3 [M+H] + .

[0822] Synthesis of compounds 39.4 and 39.5. Compounds 39.4 and 39.5 were prepared from 39.3 and 17.1 following the procedure described in the synthesis of 37.4 and 37.5. The isomers were separated by preparative HPLC, yielding 39.4, MS (ES): m / z 347.3 [M+H]. + and 39.5, MS(ES):m / z 347.3[M+H] + .

[0823] Synthesis of compound 39.6. Compound 39.6 was prepared from 39.4 following the procedure described in the synthesis in section 11.8. The crude product was used in the next step without further purification. MS (ES): m / z 389.4 [M+H] + .

[0824] Synthesis of compound 39.7. Compound 39.7 was prepared from 39.6 following the procedure described in the synthesis in I-2. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 1.5% methanol in dichloromethane as the eluent. MS (ES): m / z: 627.6 [M+H] + .

[0825] Synthesis of compound 39.8. Trifluoroacetic acid (0.199 g, 1.75 mmol, 10.0 equivalent) was added to a solution of 39.7 (0.110 g, 0.175 mmol, 1.0 equivalent) in dichloromethane (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. It was poured onto an ice-cold saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 39.8. MS (ES): m / z 526.5 [M+H] + .

[0826] Synthesis of I-39. Acetic anhydride (0.014 g, 0.140 mmol, 1.0 equivalent) was added dropwise to a solution of 39.8 (0.074 g, 0.140 mmol, 1.0 equivalent) and triethylamine (0.058 mL, 0.42 mmol, 1.5 equivalent) in dichloromethane (3 mL) at 0 °C. The reaction mixture was stirred for 15 min. It was poured onto ice-water, stirred, and extracted with dichloromethane. Further purification was performed by rapid column chromatography on silica gel. I-39 was obtained by eluing with 0.5% methanol in dichloromethane. MS (ES): m / z: 569.5 [M+H] + , 1H NMR (DMSO-d6, 400MHz): δ10.50 (s, 1H), 10.14 (s, 1H), 8.15-8.14 (d, J = 5.6Hz, 1H), 7 .64-7.40(m,2H),7.32(s,1H),7.23(s,1H),6.86-6.83(d,J=8.8Hz,1H),6.62-6.61 (d,J=4.4Hz,1H),4.94-4.85(m,1H),4.25(s,1H),4.14(s,1H),4.05-3.97(m,1H),3 .87(s,1H),3.67(s,3H),2.82(s,3H),2.74(bs,1H),2.02(s,3H),1.75-1.74(m,3H).

[0827] Example 40: N-(4-((2-((4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0828]

[0829] Synthesis of compound 40.2. Bis(trimethylsilyl)aminolithium (1M in THF, 219 mL, 219.7 mmol, 2.2 equivalences) was added to a solution of 40.1 (10 g, 99.88 mmol, 1.0 equivalence) and iodomethane (24.8 mL, 399.52 mmol, 4.0 equivalences) in 200 mL of THF at -78 °C. The reaction mixture was stirred at room temperature for 16 hours. 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 10% ethyl acetate in hexane as the eluent, yielding a concentration of 40.2. MS (ES): m / z 129.2 [M+H] + .

[0830] Synthesis of compound 40.3. A solution of n-butyllithium (2.5 M in hexane, 24.2 mL, 60.46 mmol, 1.25 equivalence) was slowly added to a solution of diisopropylamine (4.88 g, 48.37 mmol, 1.0 equivalence) in THF (100 mL) at -78 °C. The reaction mixture was stirred for 5 min, followed by the addition of acetonitrile (2.5 mL, 48.37 mmol, 1.0 equivalence). The reaction mixture was stirred for 10 min, and compound 40.3 (6.20 g, 48.37 mmol, 1.0 equivalence) was added to THF (30 mL). The reaction mixture was stirred at 5 °C for 6 h. It was poured onto a cold saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 20% ​​ethyl acetate in hexane as the eluent, yielding a concentration of 40.3. MS (ES): m / z 170.2 [M+H] + .

[0831] Synthesis of compound 40.4. Hydrazine hydrochloride (2.35 g, 34.57 mmol, 1.5 equivalents) was added to a solution of 40.3 (3.9 g, 23.05 mmol, 1.0 equivalents) in ethanol (40 mL), followed by potassium carbonate (4.77 g, 34.57 mmol, 1.5 equivalents). The reaction mixture was heated to reflux for 16 hours. It was then concentrated under reduced pressure. The concentrate was obtained by rapid column chromatography on silica gel (…). The residue was purified using 3%-4% methanol in dichloromethane as the eluent, yielding 40.4. MS (ES): m / z 184.26 [M+H] + .

[0832] Synthesis of compound 40.5. A solution of 40.4 (1.1 g, 6.0 mmol, 1.0 equivalent) in THF (20 mL) was added with thionyl chloride (2.15 mL, 30 mmol, 5.0 equivalent). The reaction mixture was stirred at room temperature for 2 hours. It was poured onto 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 2% methanol in dichloromethane as the eluent, yielding 40.5 mg / z. MS (ES): m / z 166.24 [M+H] + .

[0833] Synthesis of compound 40.6. Compound 40.6 was prepared from 40.5 following the procedure described in the synthesis section 1.2. The crude product was used in the next step without further purification. MS (ES): m / z 208.3 [M+H] + .

[0834] Synthesis of compound I-40. Compound I-40 was prepared by following the procedure described in the synthesis of I-1. The product was purified by preparative HPLC. MS (ES): m / z: 446.41 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.48(s,1H),9.48(s,1H),8.15-8.14(d,J=5.6Hz,1H),7.65(s,1H),7.38-7.36(d,J=8Hz,1H),7.1 6(s,1H),6.82-6.80(d,J=7.6Hz,1H),6.61-6.56(m,2H),3.94(bs,2H),3.62(s,3H),2.03(s,6H),1.68(s,3H),1.25(bs,4H).

[0835] Example 41: N-(4-((7-cyano-2-((4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0836]

[0837] Synthesis of I-41. Compound I-41 was prepared from 40.6 and Int-4 following the procedure described in the synthesis of I-1. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 5%-7% methanol in dichloromethane as the eluent. MS (ES): m / z: 470.83 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.59 (s, 1H), 9.85 (s, 1H), 8.22-8.20 (d, J = 5.6Hz, 1H), 7.68 (bs, 2H), 7.03-7.01 (d,J=8.4Hz,1H),6.69(bs,1H),6.55(s,1H),4.02-3.90(m,4H),2.04(s,6H),1.67(bs,2H),1.30(bs,6H).

[0838] Example 42: N-(4-((2-((4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

[0839]

[0840] Synthesis of I-42. Compound I-42 was prepared from 40.6 and Int-5 following the procedure described in the synthesis of I-1. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 5%-6% methanol in dichloromethane as the eluent. MS (ES): m / z: 447.45 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.53(s,1H),9.79(s,1H),8.19-8.17(d,J=5.6Hz,1H),7.81-7.75(m,2H),6.84-6.82(d,J=8Hz,1 H),6.71-6.70(t,1H),6.58(s,1H),5.76(s,1H),3.95-3.93(m,2H),3.58(s,3H),2.04(bs,4H),1.67(bs,2H),1.30(bs,6H).

[0841] Example 43: N-(4-((2-((5,5-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)amino)-1,7-dimethyl-1H-benzo[d]imidazolyl-6-yl)oxy)pyridin-2-yl)acetamide

[0842]

[0843] Synthesis of compound 43.2. Thiourea (10.86 g, 142 mmol, 3.0 equivalent) was added to a solution of 3,3-dimethylcyclohexane-1-one (43.1, 6.0 g, 47.54 mmol, 1.0 equivalent) in ethanol (60 mL), followed by the addition of iodine (12.02 g, 47.54 mmol, 1.0 equivalent). The reaction mixture was heated to reflux for 8 hours. 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 25% ethyl acetate in hexane as the eluent, yielding a concentration of 43.2. MS (ES): m / z 183.3 [M+H] + .

[0844] Synthesis of compound 43.3. A solution of 43.2 (0.200 g, 1.1 mmol, 1.0 equivalent) in acetonitrile (4 mL) was added to a solution of thiocarbonyl diimidazole (0.214 g, 1.208 mmol, 1.1 equivalent). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the precipitated solid was filtered off and thoroughly dried to give 43.3. MS (ES): m / z 293.4 [M+H] + .

[0845] Synthesis of I-43. N,N-diisopropylethylamine (0.2 mL, 1.047 mmol, 3.0 equivalent) was added to a solution of 43.3 (0.100 g, 0.349 mmol, 1.0 equivalent) and Int-3 (0.122 g, 0.417 mmol, 1.2 equivalent) in DMF (2 mL). The reaction mixture was stirred at 70 °C for 6 hours. It was cooled to room temperature, 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. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 5% methanol in dichloromethane as the eluent to give I-43. MS (ES): m / z: 477.81 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ11.83(s,1H),10.47(s,1H),8.13-8.11(d,J=5.2Hz,1H),7.59(s,1H),7.28(s,1H),6.79(s,1H),6 .53(s,1H),3.87(s,3H),2.43-2.42(m,2H),2.27(s,3H),2.03-2.02(d,3H),1.55(bs,2H),1.00(s,6H),0.99-0.84(m,2H).

[0846] Example 44: N-(4-((2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazolyl-2-yl)amino)-1,7-dimethyl-1H-benzo[d]imidazolyl-6-yl)oxy)pyridin-2-yl)acetamide

[0847]

[0848] Synthesis of compound 44.2. Compound 44.2 was prepared from 4,4-dimethylcyclohexane-1-one (44.1) following the procedure described in the synthesis of 43.2. The synthesis was performed by rapid column chromatography on silica gel (…). The residue was purified using 30% ethyl acetate in hexane as the eluent. MS (ES): m / z 183.3 [M+H]+ .

[0849] Synthesis of compound 44.3. Compound 44.3 was prepared from 44.2 following the procedure described in the synthesis of 43.3. The crude product was used in the next step without further purification. MS (ES): m / z 293.4 [M+H] + .

[0850] Synthesis of I-44. A solution of 44.3 (0.100 g, 0.349 mmol, 1.0 equivalent), Int-3 (0.113 g, 0.384 mmol, 1.1 equivalent), and N,N-diisopropylethylamine (0.2 mL, 1.047 mmol, 3.0 equivalent) in DMF (2 mL) was stirred at 70 °C for 12 h under nitrogen. The 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 preparative HPLC to obtain I-44. MS (ES): m / z: 477.81 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ11.88(s,1H),10.49(s,1H),8.14-8.13(d,J=5.6Hz,1H),7.60(s,1H),7.28(s,1H),6.81-6.79( d,J=8.4Hz,1H),6.55-6.53(m,1H),3.88(s,3H),2.43(bs,4H),2.34(s,3H),2.03(s,3H),1.58-1.55(m,2H),1.01(s,6H).

[0851] Example 45: (R)-N-(4-((1-methyl-2-((2-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)amino)-1H-benzo[d]imidazo-6-yl)oxy)pyridin-2-yl)acetamide and (S)-N-(4-((1-methyl-2-((2-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)amino)-1H-benzo[d]imidazo-6-yl)oxy)pyridin-2-yl)acetamide)

[0852]

[0853] Synthesis of compound 45.2. 1-Chloroprop-2-one (5.05 g, 54.54 mmol, 1.5 equivalents) was added to a solution of 45.1 (8.0 g, 36.36 mmol, 1.0 equivalent) in ethanol (50 mL). The reaction mixture was heated to reflux for 24 hours. It was then concentrated under reduced pressure. The residue was absorbed into water and alkalized to pH 8 with saturated sodium carbonate solution. The aqueous solution was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 50% ethyl acetate in hexane as the eluent, yielding a concentration of 45.2. MS (ES): m / z 259.2 [M+H] + .

[0854] Synthesis of compound 45.3. A solution of 45.2 (4.8 g, 18.16 mmol, 1.0 equivalent) in acetonitrile (100 mL) was added with (diacetoxyiodine)benzene (11.69 g, 36.32 mmol, 2.0 equivalent) and cesium fluoride (11.04 g, 72.64 mmol, 4.0 equivalent), followed by the addition of trifluoromethyltrimethylsilane (10.314 g, 72.64 mmol, 4.0 equivalent) and stirring at room temperature for 4 hours. The solution was filtered through a silica gel filter and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The solution was then subjected to rapid column chromatography on silica gel. The residue was purified using 12% ethyl acetate in hexane as the eluent, yielding a concentration of 45.3. MS (ES): m / z 327.2 [M+H] + .

[0855] Synthesis of compound 45.4. A mixture of 45.3 (1.7 g, 5.21 mmol, 1.0 equivalent), benzophenone imine (1.037 g, 5.73 mmol, 1.1 equivalent), and cesium carbonate (3.39 g, 10.42 mmol, 2.0 equivalent) in DMF (20 mL) was degassed by argon bubbling for 10 min. 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (0.090 g, 0.156 mmol, 0.03 equivalent) and tris(dibenzylideneacetone)dipalladium (0, 0.071 g, 0.078 mmol, 0.015 equivalent) were added, and degassed for 5 min. The reaction mixture was stirred at 80 °C for 4 h. It was then cooled to room temperature and... Filter the solution using a filter pad. Decant the filtrate onto water and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Perform rapid column chromatography on silica gel (…). The residue was purified using 15% ethyl acetate in hexane as the eluent, yielding a concentration of 45.4. MS (ES): m / z 380.4 [M+H] + .

[0856] Synthesis of compound 45.5. A solution of 45.4 (1.62 g, 4.27 mmol, 1.0 equivalent) in THF (16 mL) was added with 1 N hydrochloric acid (16 mL, 10 v) and stirred at room temperature for 30 min. The solution was poured over ice-water, stirred, and extracted with ethyl acetate. The aqueous layer was separated, neutralized with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 45.5. MS (ES): m / z 216.2 [M+H] + .

[0857] Synthesis of compound 45.6. A mixture of compound 45.5 (0.500 g, 2.32 mmol, 1.0 equivalent) and 10% carbon-supported palladium (0.500 g) in methanol (10 mL) was stirred at 90 °C for 12 hours under 280 psi hydrogen. After the reaction was complete, the mixture was... The reaction mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to give 45.6 mg / z. MS (ES): m / z 220.2 [M+H] + .

[0858] Synthesis of compound (±)-45.7. Compound (±)-45.7 was prepared from 45.6 following the procedure described in the synthesis in 11.8. The crude product was used in the next step without further purification. MS (ES): m / z 262.3 [M+H] + .

[0859] Synthesis of compound (±)-I-45. Compound (±)-I-45 was prepared from (±)-45.6 following the procedure described in the synthesis of I-1. The synthesis was carried out by rapid column chromatography on silica gel (…). The product was purified using 3.0% methanol in dichloromethane as the eluent. MS (ES): m / z: 500.5 [M+H] + .

[0860] I-45-a and I-45-b. The enantiomers of I-45 were separated by SFC (CHIRALPAK AD-H (250 mm × 4.6 mm, 5 μm), eluent: 0.1% DEA in MEOH; flow rate: 4 mL / min), yielding a first elution fraction (I-45-a) and a second elution fraction (I-45-b). (*Absolute stereochemistry not determined.)

[0861] I-45-a:MS(ES):m / z:500.8[M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.47 (s, 1H), 8.13-8.12 (d, J = 5.6Hz, 1H), 7.62 (s, 1H) ,7.29-7.27(d,J=8.4Hz,1H),7.11(s,1H),6.90-6.88(d,J=6.4Hz,1H),6.78-6. 75(m,1H),6.59-6.58(m,1H),4.43(bs,1H),4.37-4.33(m,1H),4.06-3.97(m,2H ),3.51(s,3H),2.99-2.85(m,2H),2.22(bs,3H),2.15-2.10(m,1H),2.02(s,3H).

[0862] I-45-b:MS(ES):m / z:500.77[M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.46 (s, 1H), 8.13-8.12 (d, J = 5.6Hz, 1H), 7.62 (s, 1H) ,7.29-7.27(d,J=8.4Hz,1H),7.11(s,1H),6.89-6.88(d,J=6.4Hz,1H),6.78-6. 76(m,1H),6.59-6.58(m,1H),4.43(bs,1H),4.37-4.33(m,1H),4.04-3.97(m,2H ),3.51(s,3H),2.99-2.89(m,2H),2.22(bs,3H),2.13-2.12(m,1H),2.02(s,3H).

[0863] Example 46: N-(4-((2-((2-acetyl-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0864]

[0865] The synthesis of compound 46.2 involved adding potassium nitrate (4.17 g, 41.35 mmol, 1.1 equivalent) to a solution of 46.1 (5.0 g, 35.94 mmol, 1.0 equivalent) in concentrated sulfuric acid (20 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. It was poured onto crushed ice, neutralized with an aqueous solution of ammonium hydroxide, 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 3%-4% methanol in dichloromethane as the eluent, yielding a concentration of 46.2. MS (ES): m / z 179.2 [M+H] + .

[0866] Synthesis of compound 46.3. N-iodosuccinimide (1.97 g, 8.76 mmol, 1.2 equivalent) was added to a solution of 46.2 (1.3 g, 7.30 mmol, 1.0 equivalent) in trifluoromethanesulfonic acid (2.5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. It was poured onto a cold saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 3% methanol in dichloromethane as the eluent, yielding a concentration of 46.3. MS (ES): m / z 305.1 [M+H] + .

[0867] Synthesis of compound 46.4. Triethylamine (1.23 mL, 8.88 mmol, 3.0 equivalence) was added to a solution of 46.3 (0.9 g, 2.96 mmol, 1.0 equivalence) in 20 mL of THF at 0 °C, followed by the addition of acetyl chloride (0.25 mL, 3.55 mmol, 1.2 equivalence), and the mixture was stirred at room temperature for 4 hours. The mixture was then cooled to room temperature, poured onto 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 solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 60% ethyl acetate in hexane as the eluent, yielding a concentration of 46.4. MS (ES): m / z 347.12 [M+H] + .

[0868] Synthesis of compound 46.5. A mixture of 46.4 (0.350 g, 1.01 mmol, 1.0 equivalent), copper(II) chloride (0.027 g, 0.202 mmol, 0.2 equivalent), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.582 g, 3.03 mmol, 3.0 equivalent) in N,N-dimethylformamide (10 mL) was heated at 120 °C for 2 h using a microwave reactor. The reaction mixture was 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 final product was obtained by rapid column chromatography on silica gel. The residue was purified using 30% ethyl acetate in hexane as the eluent. MS (ES): m / z 289.23 [M+H] + .

[0869] Synthesis of compound 46.6. A mixture of compound 46.5 (0.155 g, 0.537 mmol, 1.0 equivalent) and 10% carbon-supported palladium (0.050 g) in ethanol (10 mL) was evacuated and purged three times with hydrogen. The reaction mixture was stirred at room temperature for 2 hours under 1 atm hydrogen. The mixture was filtered through a filter and washed with methanol. The filtrate was concentrated under reduced pressure and subjected to rapid column chromatography on silica gel. The residue was purified using 5% methanol in dichloromethane as the eluent, yielding a concentration of 46.6. MS (ES): m / z 259.24 [M+H] + .

[0870] Synthesis of compound 46.7. Compound 46.7 was prepared from 46.6 following the procedure described in the synthesis in section 11.8. The crude product was used in the next step without further purification. MS (ES): m / z 301.3 [M+H] + .

[0871] Synthesis of I-46. Compound I-46 was prepared from 46.7 following the procedure described in the synthesis of I-1. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 5% methanol in dichloromethane as the eluent. MS (ES): m / z: 539.57 [M+H] + , 1H NMR (DMSO-d6, 400MHz): δ10.49(s,1H),9.29(s,1H),8.16(bs,2H),8.10(s,1H),7.66(s,1H),7.50-7.48(d,J=7.6Hz,1H),7.27(s,1H) ,6.89-6.87(d,J=8Hz,1H),6.63(s,1H),4.77-4.70(m,2H),3.71(bs,5H),2.96(bs,1H),2.83(bs,1H),2.14-2.11(d,3H),2.00(s,3H).

[0872] Example 47: N-(4-((2-((1-(2-methoxyethyl)-3,3-dimethyl-2-oxo-4-(trifluoromethyl)indoline-6-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0873]

[0874] Synthesis of compound 47.2. A solution of N-iodosuccinimide (1.32 g, 5.88 mmol, 1.2 equivalents) was added to a solution of 47.1 (10 g, 4.90 mmol, 1.0 equivalent) in sulfuric acid (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. It was carefully poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 47.2. MS (ES): m / z 332.2 [M+H] + .

[0875] Synthesis of compound 47.3. Dimethyl oxalate (4.27 g, 36.25 mmol, 1.0 equivalent) was added to a 21% sodium methoxide solution in methanol (9.3 mL, 36.25 mmol, 1.0 equivalent) at room temperature and stirred for 1.5 h. A solution of 47.2 (12 g, 36.25 mmol, 1.0 equivalent) in methanol (10 mL) was added to the mixture and stirred for 12 h at room temperature. It was then added to ice-cold 2.5 M hydrochloric acid until the pH reached 4–5, 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 10% ethyl acetate in hexane as the eluent, yielding a concentration of 47.3. MS (ES): m / z 418.2 [M+H] + .

[0876] Synthesis of compound 47.4. Perchloric acid (10 mL) was added to a solution of 47.3 (10 g, 23.98 mmol, 1.0 equivalent) in acetic acid (20 mL) at room temperature. The mixture was heated at 80 °C for 1 hour. It was then cooled to room temperature and a 30% hydrogen peroxide solution (59 mL, 527 mmol, 22 equivalent) was added. The reaction mixture was stirred at 60 °C for 5 hours. It was poured onto a saturated aqueous sodium sulfite solution, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine and 2N sodium hydroxide solution. The aqueous layer was acidified to pH 3 using concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried under vacuum to give 47.4. MS (ES): m / z 376.1 [M+H] + .

[0877] Synthesis of compound 47.5. Oxaloyl chloride (3.75 mL, 43.7 mmol, 6.5 equivalents) was added to a solution of 47.4 (2.5 g, 6.67 mmol, 1.0 equivalent) in methanol (25 mL). The reaction mixture was stirred at 70 °C for 4 hours. It was poured onto 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 20% ​​ethyl acetate in hexane as the eluent, yielding a concentration of 47.5. MS (ES): m / z 390.1 [M+H] + .

[0878] Synthesis of compound 47.6. A commercially available 15% titanium(III) chloride solution (9.8 g, 63.73 mmol, 12.4 equivalents) was added to a solution of 47.5 (2.0 g, 5.14 mmol, 1.0 equivalent) in methanol (20 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. It was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 10% ethyl acetate in hexane as the eluent, yielding a concentration of 47.6. MS (ES): m / z 328.2 [M+H] + .

[0879] Synthesis of compound 47.7. Potassium tert-butoxide (2.39 g, 21.4 mmol, 5.0 equivalent) was added to a solution of 47.6 (1.4 g, 4.28 mmol, 1.0 equivalent) in 15 mL of THF at 0 °C, followed by the addition of copper(I) dimethyl sulfide complex (0.087 g, 0.428 mmol, 0.1 equivalent). Iodimethane (1.27 g, 8.98 mmol, 2.1 equivalent) was slowly added at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. It was poured onto 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 solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 8% ethyl acetate in hexane as the eluent, yielding a concentration of 47.7. MS (ES): m / z 356.1 [M+H] + .

[0880] Synthesis of compound 47.8. Cesium carbonate (1.14 g, 3.52 mmol, 2.5 equivalents) was added to a solution of 47.7 (0.5 g, 1.41 mmol, 1.0 equivalents) and 2-methoxyethyl methanesulfonate (0.260 g, 1.69 mmol, 1.2 equivalents) in DMF (5 mL). The reaction mixture was stirred at 80 °C for 16 h. It was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 5%-8% ethyl acetate in hexane as the eluent, yielding a concentration of 47.8. MS (ES): m / z 414.5 [M+H] + .

[0881] Synthesis of compound 47.9. L-proline (0.020 g, 0.179 mmol, 0.2 equivalence), copper iodide (0.068 g, 0.358 mmol, 0.4 equivalence), and potassium carbonate (0.432 g, 3.13 mmol, 3.5 equivalence) were added to a solution of 47.8 (0.370 g, 0.895 mmol, 1.0 equivalence) in dimethyl sulfoxide (4 mL), followed by the addition of ammonium hydroxide solution (0.13 mL). The reaction mixture was stirred at 90 °C for 16 hours. After cooling to room temperature, the mixture was poured over 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 solution was then analyzed by rapid column chromatography on silica gel. The residue was purified using 25% ethyl acetate in hexane as the eluent, yielding a concentration of 47.9. MS (ES): m / z 303.3 [M+H] + .

[0882] Synthesis of compound 47.10. Compound 47.10 was prepared from 47.9 following the procedure described in the synthesis in section 11.8. The crude product was used in the next step without further purification. MS (ES): m / z 345.4 [M+H] + .

[0883] Synthesis of I-47. Compound I-47 was prepared from 47.10 and Int-2 following the procedure described in the synthesis of I-1. The synthesis was performed by rapid column chromatography on silica gel (…). The product was purified using 3%-5% methanol in dichloromethane as the eluent. MS (ES): m / z: 583.9 [M+H] + , 1 H NMR(DMSO-d6,400MHz): δ10.48(s,1H),9.42(s,1H),8.16-8.15(d,J=6.0Hz,1 H),8.01(s,1H),7.97(s,1H),7.65(s,1H),7.45-7.43(d,J=8.4Hz,1H),7.28( s,1H),6.89-6.87(d,J=7.2Hz,1H),6.63-6.62(d,J=3.6Hz,1H),3.90-3.89(m ,2H),3.72(s,3H),3.65-3.62(m,2H),3.24(s,3H),2.03(s,3H),1.36(s,6H).

[0884] Example 48: N-(4-((2-((1-(2-hydroxyethyl)-3,3-dimethyl-2-oxo-4-(trifluoromethyl)indoline-6-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0885]

[0886] Synthesis of compound 48.2. Methanesulfonyl chloride (0.76 mL, 9.85 mmol, 1.5 equivalent) was added to a solution of 48.1 (1.0 g, 6.57 mmol, 1.0 equivalent) and triethylamine (2.74 mL, 19.71 mmol, 3.0 equivalent) in dichloromethane (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. It was poured over ice-water, stirred, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 48.2. MS (ES): m / z 231.3 [M+H] + .

[0887] Synthesis of compound 48.3. Compound 48.3 was prepared from 48.1 and 47.7 following the procedure described in the synthesis of 47.8. The synthesis was achieved by rapid column chromatography on silica gel (…). The residue was purified using 10%-12% ethyl acetate in hexane as the eluent. MS (ES): m / z 490.3 [M+H] + .

[0888] Synthesis of compound 48.4. Compound 48.4 was prepared from 48.3 following the procedure described in the synthesis of 47.9. The synthesis was carried out by rapid column chromatography on silica gel (…). The residue was purified using 20%-22% ethyl acetate in hexane as the eluent. MS (ES): m / z 379.4 [M+H] + .

[0889] Synthesis of compound 48.5. Compound 48.5 was prepared from 48.4 following the procedure described in the synthesis in section 11.8. The crude product was used in the next step without further purification. MS (ES): m / z 421.5 [M+H] + .

[0890] Synthesis of compound 48.6. Compound 48.6 was prepared from 48.5 following the procedure described in the synthesis in I-1. The synthesis was carried out by rapid column chromatography on silica gel (…). The product was purified using 3%-4% methanol in dichloromethane as the eluent. MS (ES): m / z: 659.6 [M+H] + .

[0891] Synthesis of compound I-48. Trifluoromethanesulfonic acid (0.5 mL) was added to a solution of compound 48.6 (0.100 g, 0.151 mmol, 1.0 equivalent) in dichloromethane (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. It was poured onto a saturated sodium bicarbonate solution 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 grinding with methanol to give I-48. MS (ES): m / z: 569.9 [M+H] + , 1H NMR(DMSO-d6,400MHz): δ10.50(s,1H),9.42(s,1H),8.16-8.15(d,J=5.6Hz,1H ),8.03(s,1H),7.92(s,1H),7.65(s,1H),7.47-7.45(d,J=8.4Hz,1H),7.29(s, 1H),6.89-6.87(d,J=8.4Hz,1H),6.64-6.63(d,J=3.6Hz,1H),4.99-4.97(m,1H ),3.79-3.78(m,2H),3.72(s,3H),3.70-3.67(m,2H),2.02(s,3H),1.37(s,6H).

[0892] Example 49: N-(4-((1-methyl-2-((1,1,2-trimethyl-3-oxo-7-(trifluoromethyl)isoindoline-5-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

[0893]

[0894] Synthesis of compound 49.2. Nitric acid (2.08 mL, 49 mmol, 10 equivalents) and bromine (0.86 g, 5.39 mmol, 1.1 equivalents) were added to a solution of 49.1 (1.0 g, 4.90 mmol, 1.0 equivalents) in 20 mL of 0.2 M aqueous acetic acid solution, followed by the addition of 2.5 M aqueous silver nitrate solution (2.5 mL, 6.37 mmol, 1.3 equivalents) over a 30-minute period. The reaction mixture was stirred at room temperature for 48 hours. It was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 49.2. MS (ES): m / z 284.1 [M+H] + .

[0895] Synthesis of compound 49.3. A solution of 49.2 (1.6 g, 5.65 mmol, 1.0 equivalent) in methanol (20 mL) was added to a solution of thionyl chloride (0.82 mL, 11.3 mmol, 2.0 equivalent) at 0 °C. The reaction mixture was heated to reflux for 4–5 hours. It was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 49.3. MS (ES): m / z 298.1 [M+H] + .

[0896] Synthesis of compound 49.4. N-bromosuccinimide (0.425 g, 2.39 mmol, 1.0 equivalent) was added to a solution of 49.3 (0.710 g, 2.39 mmol, 1.0 equivalent) in carbon tetrachloride (10 mL), followed by the addition of azobisisobutyronitrile (0.078 g, 0.478 mmol, 0.2 equivalent). The reaction mixture was heated to reflux for 1 hour. It was poured over ice-water, stirred, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 49.4. MS (ES): m / z 362.9 [M+H] + .

[0897] Synthesis of compound 49.5. An aqueous solution of ammonium hydroxide (2.5 mL) was added to a solution of 49.4 (0.480 g, 1.33 mmol, 1.0 equivalence) in methanol (5 mL) and THF (5 mL). The reaction mixture was stirred at 50 °C and heated to reflux for 4 hours. It was poured over ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 3.0% methanol in dichloromethane as the eluent, yielding 49.5. MS (ES): m / z 281.1 [M+H] + .

[0898] Synthesis of compound 49.6. Sodium hydride (0.175 g, 3.66 mmol, 5.0 equivalent) was added in small amounts to a solution of 49.5 (0.205 g, 0.732 mmol, 1.0 equivalent) in 3 mL of THF at 0 °C and stirred for 20 min. Iodimethane (0.620 g, 4.39 mmol, 6.0 equivalent) was added to the mixture. The reaction mixture was stirred at room temperature for 24 h. It was poured onto 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 solution was then analyzed by rapid column chromatography on silica gel (…). The residue was purified using 17% ethyl acetate in hexane as the eluent, yielding a concentration of 49.6. MS (ES): m / z 323.2 [M+H] + .

[0899] Synthesis of compound 49.7. Compound 49.7 was prepared from 49.6 following the procedure described in the synthesis of 47.9. The synthesis was achieved by rapid column chromatography on silica gel (…). The residue was purified using 30% ethyl acetate in hexane as the eluent, yielding a concentration of 49.7. MS (ES): m / z 259.3 [M+H] + .

[0900] Synthesis of compound 49.8. Compound 49.8 was prepared from 49.7 following the procedure described in the synthesis of 11.8. The crude product was used in the next step without further purification. MS (ES): m / z 301.3 [M+H] + .

[0901] Synthesis of compound I-49. Compound I-49 was prepared from 49.8 following the procedure described in the synthesis of I-1. The synthesis was performed by rapid column chromatography on silica gel (…). The residue was purified using 4.2% methanol in dichloromethane as the eluent. MS (ES): m / z: 539.5 [M+H] + , 1 H NMR (DMSO-d6, 400MHz): δ10.51(s,1H),9.60(s,1H),8.71(s,1H),8.44(s,1H),8.16-8.15(d,J=5.6Hz,1H),7.66(s,1H),7.55-7.53(d,J =8.4Hz,1H),7.31(s,1H),6.91-6.89(d,J=6.4Hz,1H),6.63-6.62(d,J=3.6Hz,1H),3.74(s,3H),2.99(s,3H),2.02(s,3H),1.52(s,6H).

[0902] Example 50: (R)-N-(4-((2-((5-(tert-butyl)isoxazo-3-yl)amino)-1-methyl-1H-benzo[d]imidazo-6-yl)oxy)pyridin-2-yl)-2,2-difluorocyclopropane-1-carboxamide and (S)-N-(4-((2-((5-(tert-butyl)isoxazo-3-yl)amino)-1-methyl-1H-benzo[d]imidazo-6-yl)oxy)pyridin-2-yl)-2,2-difluorocyclopropane-1-carboxamide)

[0903]

[0904] Synthesis of compound (±)-50.1. N,N-diisopropylethylamine (2.17 mL, 12.48 mmol, 2.5 equivalence) was added to a solution of Int-1.3 (1.0 g, 4.99 mmol, 1.0 equivalence) and 2,2-difluorocyclopropane-1-carboxylic acid (0.913 g, 7.485 mmol, 1.5 equivalence) in THF (10 mL), and the mixture was stirred at room temperature for 30 min. Propylphosphonic anhydride (approximately 50% in ethyl acetate, 2.38 g, 7.485 mmol, 1.5 equivalence) was added to the mixture at 0 °C. The reaction mixture was stirred at room temperature for 2 h. It was poured over ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was analyzed by rapid column chromatography on silica gel. The residue was purified using 20%-25% ethyl acetate in hexane as the eluent, yielding (±)-50.1. MS (ES): m / z 305.3 [M+H] + .

[0905] Synthesis of compound (±)-50.2. A mixture of compound (±)-50.1 (0.75 g, 2.46 mmol, 1.0 equivalent) and 10% carbon-supported palladium (0.3 g) in methanol (15 mL) was added under vacuum and purged three times with hydrogen. The reaction mixture was stirred at room temperature for 2 hours at 1 atm hydrogen. (via...) The mixture was filtered through a filter and washed with methanol. The filtrate was concentrated under reduced pressure and subjected to rapid column chromatography on silica gel. The residue was purified using 30%-35% ethyl acetate in hexane as the eluent, yielding (±)-50.2. MS (ES): m / z 215.2 [M+H] + .

[0906] Synthesis of compound (±)-50.3. Compound (±)-50.3 was prepared from (±)-50.2 and Int-2.2 following the procedure described in the synthesis of Int-2.3. The syn...

Claims

1. A compound of formula III or IV: Or its pharmaceutically acceptable salt, wherein: Z is either -O- or -NR z -; R x and R y Each independently represents hydrogen, halogen, -OR 3 -N(R) 3 )2、-SR 3 C 1-6 Alkyl or -CN; R z It is hydrogen or C 1-6 alkyl; R 1 It is -N(R)2, -N(R)C(O)R', -C(O)N(R)2 or -N(R)C(O)N(R)2; R 2 C 1-6 alkyl; R 3 It is hydrogen or C 1-6 alkyl; for: R b The C-type carbon can be hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)SO2R', -SO2R', -SO2N(R)2, -SO3R', or C-type carbon optionally substituted with one or more of halogens and -CN. 1-4 Alkyl groups, 3 to 6-membered saturated or partially unsaturated carbocyclic groups, 3 to 6-membered saturated or partially unsaturated monocyclic heterocyclic groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5 to 6-membered monocyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. L represents a covalent bond or a divalent C. 1-3 Straight-chain or branched hydrocarbon chains; R a For hydrogen, halogen, C 1-6 Alkyl, phenyl, 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen, C 1-6 Alkyl groups, 3- to 7-membered saturated or partially unsaturated carbocyclic groups, or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic groups having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups forming a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 0 to 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur when attached to the same nitrogen atom; and Each R' is independently C 1-6 Alkyl or 3 to 7 saturated or partially unsaturated carbocyclic groups.

2. The compound as described in claim 1, wherein R a Halogen, C 1-4 Alkyl groups, 5-membered monocyclic heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 3- to 6-membered saturated monocyclic carbocyclic groups, 3- to 6-membered saturated monocyclic heterocyclic groups having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 7-membered saturated spirocyclic bicyclic heterocyclic groups having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

3. The compound as claimed in any one of the preceding claims, wherein R a C 1-4 alkyl.

4. The compound according to any one of claims 1-2, wherein R a It consists of 3 to 6-membered saturated monocyclic carbon cyclic groups.

5. The compound according to any one of claims 1-2, wherein R a It is a 3- to 6-membered saturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

6. The compound of claim 1, wherein R a It is a 7- to 8-membered saturated spirocyclic bicyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

7. The compound of claim 1, wherein R a C 1-4 Alkyl group, 3- to 6-membered saturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 7- to 8-membered saturated spirocyclic bicyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

8. The compound of claim 1, wherein... for:

9. The compound of claim 1, wherein R b C is a carbon that is optionally substituted with one or more of hydrogen, halogen, halogenated carbon, and -CN. 1-4 Alkyl, C 3-4 Cycloalkyl, a 3- to 5-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

10. The compound of claim 9, wherein R b C 3-4 Cycloalkyl or C substituted with one or more fluorine molecules 1-4 alkyl.

11. The compound as claimed in any of the preceding claims, wherein L is a covalent bond or -CH2-.

12. The compound according to any one of claims 1-11, wherein R 1 It is -N(H)C(O)R'.

13. The compound as claimed in any of the preceding claims, wherein R 1 -N(H)C(O)(C 1-4 alkyl).

14. The compound according to any one of claims 1-12, wherein R 1 It is -N(H)C(O)CH3 or -N(H)C(O) (cyclopropyl).

15. The compound according to any one of claims 1-11, wherein R 1 It is -C(O)N(H)CH3.

16. The compound according to any one of claims 1-11, wherein R 1 It is -N(H)C(O)N(R)2.

17. The compound as claimed in any of the preceding claims, wherein R 2 C 1-4 alkyl.

18. The compound as claimed in any of the preceding claims, wherein R 2 It is a methyl group.

19. The compound as claimed in any one of the preceding claims, wherein R x For hydrogen, halogen, -OR 3 C 1-6 Alkyl or -CN.

20. The compound as claimed in any one of the preceding claims, wherein R y For hydrogen.

21. The compound as claimed in any of the preceding claims, wherein Z is -NR z - 22. The compound of claim 21, wherein R z For hydrogen.

23. The compound according to any one of claims 1-20, wherein Z is -O-.

24. The compound as claimed in any one of the preceding claims, wherein each R is independently hydrogen or C. 1-6 alkyl.

25. The compound as claimed in any of the preceding claims, wherein each R' is independently C. 1-2 Alkyl or C 3-4 Cycloalkyl.

26. The compound of claim 1 above, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

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

28. Use of the compound of any one of claims 1-26 or the composition of claim 27 in the preparation of a pharmaceutical product for treating a disease, condition or ailment related to JAK2.

29. The use as claimed in claim 28, wherein the disease, symptom, or ailment is cancer.

30. The use according to claim 28, wherein the disease, symptom, or ailment is a hematologic malignancy.

31. The use as described in claim 30, wherein the hematologic malignancy is leukemia or lymphoma.

32. The use of claim 28, wherein the disease, symptom, or ailment is myeloproliferative neoplasm.

33. The use as described in claim 32, wherein the myeloproliferative neoplasm is polycythemia vera, primary thrombocytopenia, or myelofibrosis.

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

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