Substituted benzoxazolyl amino benzoxazoles

Abstract

Substituted benzoxazolyl amino benzoxazoles, methods of making the same, and uses thereof are disclosed.

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 580,106, filed September 1, 2023, and U.S. Provisional Application No. 63 / 661,725, filed June 19, 2024, the disclosure of each of which is incorporated herein by reference in its entirety. Technical Field

[0002] This disclosure generally relates to substituted benzoxazolylaminobenzoxazoles, and more specifically to such compounds that can be used to treat hematologic conditions, inflammatory conditions, or conditions of increased oxidative stress. This disclosure relates to compounds and compositions that can be used to treat hematologic conditions, inflammatory conditions, or conditions of increased oxidative stress, as well as methods for treating hematologic conditions, inflammatory conditions, or conditions of increased oxidative stress. Background Technology

[0003] Oxidative stress, characterized by elevated levels of intracellular reactive oxygen species (ROS), is counteracted by cellular antioxidant responses to maintain homeostasis. If left uncontrolled, abnormal ROS production can lead to damage to cellular components. Excessive and prolonged intracellular oxidative stress is associated with chronic diseases, including but not limited to autoimmune diseases, lung diseases, neuroinflammatory diseases, neurodegenerative diseases, cardiovascular diseases, hematologic disorders, kidney diseases, liver diseases, metabolic diseases, bone diseases, and cancer. Therefore, therapeutic strategies to restore intracellular homeostatic oxidative states are of great significance.

[0004] The Bach1 / Nrf2 axis is a major regulator of cellular antioxidant responses and a proven clinical therapeutic target for combating diseases driven by oxidative stress (FDA-approved Nrf2 activator Tecfidera for relapsing-remitting multiple sclerosis, and Skyclarys for Friedrich ataxia). Under homeostasis, Bach1 occupies antioxidant response elements (AREs) in the promoters of various genes involved in cellular antioxidant responses, thereby inhibiting their transcription. In response to oxidative stress, Bach1 dissociates from AREs, allowing binding to the transcription factor Nrf2. This drives, but is not limited to, […]. Hmox1 It regulates the expression of antioxidant genes (HO-1 protein) and other genes. Nrf2 activation also regulates various other pathways, such as NF-κB signaling and inflammasomes.

[0005] In numerous epidemiological association studies, genetic models, and animal disease models, the pervasive activation of the Nrf2 pathway and the subsequent... Hmox1Expression / HO-1 protein induction is associated with positive outcomes. In particular, Bach1 knockout mice and Bach1 inhibitors have demonstrated protective effects in various preclinical models, especially in cases of Nrf2 activation via Bach1 inhibition. Bach1 knockout mice have shown efficacy against a variety of diseases, including models of neuroinflammatory, neurological, autoimmune, hepatic, metabolic, cardiovascular, and inflammatory conditions. In many of these models, disease protection is HO-1 dependent, as demonstrated by the use of HO-1 inhibitors. Bach1 inhibitors that inhibit the binding of Bach1 to ARE (e.g., chloromethemoglobin / heme, other porphyrins, and small molecule compounds) have shown similar protective effects in preclinical disease models of hematologic, metabolic, hepatic, ocular, bone degenerative, and autoimmune conditions.

[0006] Given the significant clinical potential of Nrf2 activators and the preclinical potential of Bach1 modulation, the development of novel Nrf2 activators that block / inhibit Bach1 for the treatment of indications in the aforementioned therapeutic areas is crucial. Hmox1 There are untapped opportunities in inducing agents.

[0007] Fetal hemoglobin (HbF, α2γ2) induction is known to improve clinical complications of sickle cell disease (SCD). Several drugs are undergoing clinical trials as HbF inducers, but hydroxyurea remains the only widely used drug therapy for SCD. Autologous transplantation of edited hematopoietic stem cells holds promise for curing SCD through HbF induction or correction of pathogenic mutations, but this therapy has limited accessibility and is not suitable for all patients. Therefore, drug therapies targeting SCD and related conditions remain needed. Summary of the Invention

[0008] In one respect, this disclosure provides compounds of formula (I): (I) Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein: R 1 R 3 R 4 and R 8 Each of these can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halogenated C1-C6 alkyl, or OR. 10 , where R 10 It is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halo-C1-C6 alkyl; R 2 Hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halogenated C1-C6 alkyl, OR10 hydroxyl C1-C6 alkyl or -C(O)NR 11 R 12 , where R 11 and R 12 Each of them is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, or hydroxy-C1-C6 alkoxy-C1-C6 alkyl; R 5 It is hydrogen, hydroxyl C1-C6 alkyl or carboxyl C1-C6 alkyl; R 6 and R 7 Independently hydrogen, hydroxyl C1-C6 alkyl, -XC(O)R 13 -YC(O)NR 14 R 15 -Z-NR 16 R 17 , heteroaryl or -S(O)2R 18 ,in X is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 13 -OH or -OR 10 ; Y is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 14 and R 15 Each of the following can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl-C3-C6 cycloalkylamino, C1-C6 amine, carboxyl-C1-C6 alkyl, -S(O)2R 19 phenyl, heteroaryl, or together with the nitrogen atoms they are attached to form 3-8 membered monocyclic heterocyclic groups, wherein R 19 It is a C1-C6 alkyl group; The phenyl group is optionally substituted with a C1-C6 alkyl group; The heteroaryl group is optionally substituted with a C1-C6 alkyl group; and The 3-8 membered monocyclic heterocyclic group is optionally substituted with C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, hydroxy-C1-C6 alkyl, or amino-C1-C6 alkyl. Z is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 16 and R 17 Each of the following can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or -(C1-C6 alkyl)-C(O)R 20 -C(O)R 21 Or, together with the nitrogen atoms they are attached to, they form 3-8 membered monocyclic heterocyclic groups, in which R 20 -OH, OR 10 or NR 22 R 23 , where R 22 and R 23 Each of them is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or hydroxy-C1-C6 alkyl-C3-C6 cycloalkylamino; R 21 It is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or C1-C6 amine; and The 3-8 membered monocyclic heterocyclic group is optionally substituted with C1-C6 alkyl, halogen, hydroxyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl or amino or mono- or di-C1-C6 alkylamino C1-C6 alkyl. R 18 It is a C1-C6 alkyl or -NH-(C1-C6 alkyl); and R 9 It is hydrogen, C1-C6 alkyl, or N-protecting group.

[0009] In another respect, this disclosure provides a pharmaceutical composition comprising a compound or salt as otherwise described herein, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0010] In another aspect, this disclosure provides a method for treating conditions of elevated blood system, inflammation, or oxidative stress, the method comprising administering to a patient in need a therapeutically effective amount of a compound or pharmaceutical composition as otherwise described herein.

[0011] Compared with prior art compounds, the compounds of this disclosure have, in some respects, improved absorption, distribution, metabolism, excretion, and pharmacokinetic (ADME-PK) properties, including improved thermodynamic stability and / or improved metabolic stability. In some respects of this disclosure, improved pharmacokinetics are achieved after intravenous (IV) and oral (PO) administration. In some respects, the compounds of this disclosure have improved pharmacodynamic (PD) effects after oral (PO) administration. In some respects, the compounds of this disclosure have improved potency as fetal hemoglobin inducers in vitro, ex vivo, or in vivo after oral (PO) administration.

[0012] Other aspects and embodiments of this disclosure will be apparent from the detailed description provided herein. Detailed Implementation

[0013] This invention relates to benzoxazole derivatives. In particular, this invention relates to compounds that can be used to treat conditions of increased blood system, inflammation, or oxidative stress, pharmaceutical compositions comprising a therapeutically effective amount of said compound, and methods of using thereof. definition

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents, patent applications, and publications mentioned herein are incorporated herein by reference, provided they are consistent with this disclosure. Unless otherwise expressly defined, terms and scope have their general meanings.

[0015] For simplicity, the chemical part is primarily defined and referred to throughout the text as a monovalent chemical part (e.g., alkyl, aryl, etc.). Nevertheless, such terms can also be used to express corresponding polyvalent parts where appropriate structures are apparent to those skilled in the art. For example, while the "alkyl" part generally refers to a monovalent group (e.g., CH3-CH2-), in some cases, a divalent linker can also be "alkyl," in which case those skilled in the art will understand alkyl as a divalent group (e.g., -CH2-CH2-), which is equivalent to the term "alkylene". Similarly, where a divalent part is required and expressed as "aryl," those skilled in the art will understand that the term "aryl" refers to the corresponding divalent part—an arylene. All atoms are understood to have their normal bonding valences (i.e., carbon 4, N 3, O 2, S 2, 4, or 6, depending on the oxidation state of S).

[0016] The term "amino" refers to -NH2.

[0017] The term "acetyl" refers to -C(O)CH3.

[0018] As used herein, the term "acyl" refers to an alkyl carbonyl or aryl carbonyl substituent, wherein the alkyl and aryl moieties are as defined herein.

[0019] As used herein, the term "alkyl" refers to a saturated straight-chain or branched aliphatic group having 1 to 12 carbon atoms. Therefore, "alkyl" includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C1 ...1, C1, C1, C1, C1, C1, C1 10 C 11 and C 12 Alkyl groups. Alkyl groups can be branched or unbranched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0020] In the definitions of X, Y, and Z, the term "C1-C6 alkyl group optionally substituted with C3-C6 cycloalkyl, halogen, hydroxyl, or amino groups" refers to groups such as:

[0021] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched aliphatic group having one or more carbon-carbon double bonds and containing 2 to 12 carbon atoms. Therefore, "alkenyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C6, C7, C8, C9, C9, C16, C16, C17, C18, C19, C19, C10, C11, C12, C13, C14, C15, C16, C17, C18 ... 10 C 11 and C 12 Groups. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0022] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched aliphatic group having one or more carbon-carbon triple bonds and containing 2 to 12 carbon atoms. Therefore, "alkynyl" includes C2, C3, C4, C5, C6, C7, C8, C9 ... 10 C 11 and C 12 Groups. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, penynyl, and hexynyl.

[0023] An "alkylene," "alkenene," or "yntynene" group is an alkyl, alkenene, or yntyl group as defined above, located between two other chemical groups and used to connect the two groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. Examples of alkenene groups include, but are not limited to, vinylene, propenene, and butenene. Examples of yntynene groups include, but are not limited to, ethynene, propynene, and butynene.

[0024] The term "alkoxy" refers to -O (C1–C6 alkyl).

[0025] As used herein, the term "cycloalkyl" refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbon atoms. Therefore, "cycloalkyl" includes C3, C4, C5, C6, C7, C8, C9, C16, C17, C18, C19, C18, C19, C19, C10, C11, C12, C13, C14, C15, C16, C17, C1 10 C 11 and C 12 Cyclic hydrocarbon groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0026] The term "C3-C6 cycloalkoxy" refers to a group of the formula -O (C3-C6 cycloalkyl).

[0027] The term "heteroalkyl" refers to an alkyl group as defined above, wherein one or more carbon atoms in the chain are independently bounded by O, S, or NR. x Replace, where R x It is hydrogen or a C1–C3 alkyl group. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.

[0028] The "aryl" group is a C6-C group containing one to three aromatic rings. 14 The aromatic component. Therefore, "aryl" includes C6, C6, C7, C8, C9 ... 10 C 13 and C 14 Cyclic hydrocarbon groups. A representative aryl group is C6-C. 10 Aryl. Specific aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, and fluorenyl. The "aryl" group also includes fused polycyclic (e.g., bicyclic) ring systems, wherein one or more fused rings are non-aromatic, provided that at least one ring is aromatic, such as indene.

[0029] An "aralkyl" or "arylalkyl" group contains an aryl group covalently linked to an alkyl group, wherein the moiety is attached to another group via the alkyl portion. A representative aralkyl group is -(C1-C6)alkyl (C6-C... 10 Aryl groups, including but not limited to benzyl, phenethyl, and naphthylmethyl. For example, aryl C1-C3 alkyl groups are aryl groups covalently linked to C1-C3 alkyl groups.

[0030] A "heterocyclic" or "heterocyclic alkyl" group is a monocyclic or bicyclic (e.g., fused) ring structure having 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently N, O or S, and the remaining ring atoms are quaternary carbons or carbonyl carbons. Examples of heterocyclic groups include, but are not limited to, epoxy groups, ethylene oxide, oxetane, azirone, acridine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, pyrrolidinyl, piperidinyl, piperazine, imidazoalkyl, thiazoalkyl, thiatanyl, dithiohexane, trithiohexane, azirone, oxothiohexane, dioxopentyl, oxazolidinyl, oxazolidinone, decahydroquinolinyl, piperidinone, 4-piperidinone, thiomorpholinyl, dimethylmorpholinyl, and morpholinyl. A heterocyclic group can be attached to a parent group (i.e., a linking point) via any ring atom (including one of the heteroatoms or one of the carbon atoms). Depending on chemical needs, a heterocycle can be attached to one or more other groups, for example, if used as a bridging group. The term "heterocyclic group" also includes fused polycyclic (e.g., bicyclic) ring systems in which one or more fused rings are aromatic or non-aromatic, provided that at least one ring is non-aromatic and contains an N, O, or S ring atom. Examples of such fused polycyclic ring systems are indolinyl, indolin-2-yl, 2,3-dihydrobenzofuran-2-yl, and 2,3,4,5-tetrahydrobenzo[d]oxazol-2-yl. These examples are all nine-membered heterocyclic groups.

[0031] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13, or 14 ring atoms; having 6, 10, or 14 π electrons shared in the ring array; and having 1 to 3 heteroatoms, each independently N, O, or S, in addition to the carbon atom. "Heteroaryl" also includes fused polycyclic (e.g., bicyclic) ring systems, wherein one or more fused rings are non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom. A heteroaryl group can be attached to a parent group (i.e., a linking point) via any ring atom (including one of the heteroatoms or one of the carbon atoms) within the heteroaryl ring group. Depending on chemical needs, a heteroaryl group can be attached to one or more other groups, for example, if used as a bridging group.

[0032] Examples of heteroaryl groups include acridinel, aziridine octyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2 H-Benzo[b][1,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophene, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazole, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolinyl, carbazole, 4aH-carbazole, carbolinyl, chromanyl, benzopyranyl, cinolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1 H -Indazole, indolenyl, indolinyl, indazinyl, indolenyl, 3 H -Indolyl, isobenzofuranyl, isochoryl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolylalkyl, oxazolyl, oxazolylalkyl, pyrimidinyl, phenanthridine, phenanthiazinyl, phenoxazinyl, phenazinyl, phenazinyl, phenanthridine, phenazinyl, phenanthridine, phthalazinyl, piperyl, pteridinyl, purine, pyranyl, pyrazinyl, pyrazinylalkyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridothiazazole, pyridinyl, pyridinyl, pyrimidinyl, pyrrolinyl, 2 H -pyrroleyl, pyrroleyl, quinazolinyl, quinolinyl, 4 H - Quinazinyl, quinoxalinyl, quininecycloyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinicyl, 1,2,3-thiadiazinicyl, 1,2,4-thiadiazinicyl, 1,2,5-thiadiazinicyl, 1,3,4-thiadiazinicyl, thianyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthonyl.

[0033] Preferred heteroaryl groups have 5-10 members. Other preferred heteroaryl groups have 5-6 members.

[0034] "Aromatic", "heteroaryl", or "heterocyclic" groups are divalent aryl, heteroaryl, or heterocyclic groups, as defined above, that are located between two other chemical groups and used to connect the two groups.

[0035] As used herein, when a part (e.g., cycloalkyl, aryl, heteroaryl, heterocyclic, urea, etc.) is described as “optionally substituted” without specifying the substituents, it means that the group may optionally have a plurality of non-hydrogen substituents, for example, one to five, or one to four, or one to three, or one or two non-hydrogen substituents.

[0036] As used in this article, the terms "halogen" or "halogenated" refer to chlorine, bromine, fluorine, or iodine.

[0037] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogen atoms have been replaced by a halogen. Representative haloalkyl groups are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0038] The term "hydroxyalkyl" refers to -alkylene-OH.

[0039] It should be understood that each individual atom present in formula (I) and the compounds within formula (I) can exist in the form of any of its naturally occurring isotopes, with the most abundant isotope being preferred. Therefore, for example, each individual hydrogen atom present in formula (I) or the general formula shown below can be in the form of any of its naturally occurring isotopes. 1 H, 2 H (deuterium; D) or 3 It exists in the form of H (tritium; T) atoms, preferably 1 H. Similarly, for example, each individual carbon atom present in formula (I) or the general formula shown below can be represented as 12 C 13 C or 14 The form of C atoms is preferred. 12 C.

[0040] As used in this article, the “effective amount” of a compound is an amount sufficient to treat an inflammatory condition.

[0041] As used herein, a "therapeuticly effective amount" of a compound is an amount sufficient to improve or alleviate, in some way, the symptoms of an inflammatory condition or to halt or reverse its progression. Such an amount may be administered as a single dose or as part of a regimen, provided it is effective.

[0042] As used in this article, “treatment” means any means of improving or otherwise beneficially altering a patient’s condition, symptoms, or pathology of a disease.

[0043] As used herein, “symptoms of an inflammatory condition improved by application of a particular compound or pharmaceutical composition” means any relief attributable to or related to the application of the composition, whether permanent or temporary, continuous or transient.

[0044] As used herein, the terms “individual,” “patient,” or “subject” are used interchangeably and refer to any animal, including mammals, preferably humans. compound

[0045] In one respect, this disclosure provides compounds of formula (I): (I) Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein: R 1 R 3 R 4 and R 8 Each of these can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halogenated C1-C6 alkyl, or OR. 10 , where R 10 It is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halo-C1-C6 alkyl; R 2 Hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halogenated C1-C6 alkyl, OR 10 hydroxyl C1-C6 alkyl or -C(O)NR 11 R 12 , where R 11 and R 12 Each of them is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, or hydroxy-C1-C6 alkoxy-C1-C6 alkyl; R 5 It is hydrogen, hydroxyl C1-C6 alkyl or carboxyl C1-C6 alkyl; R 6 and R 7 Independently hydrogen, hydroxyl C1-C6 alkyl, -XC(O)R 13 -YC(O)NR 14 R 15 -Z-NR 16 R 17 , heteroaryl or -S(O)2R 18 ,in X is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 13 -OH or -OR 10 ; Y is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 14 and R 15Each of the following can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl-C3-C6 cycloalkylamino, C1-C6 amine, carboxyl-C1-C6 alkyl, -S(O)2R 19 phenyl, heteroaryl, or together with the nitrogen atoms they are attached to form 3-8 membered monocyclic heterocyclic groups, wherein R 19 It is a C1-C6 alkyl group; The phenyl group is optionally substituted with a C1-C6 alkyl group; The heteroaryl group is optionally substituted with a C1-C6 alkyl group; and The 3-8 membered monocyclic heterocyclic group is optionally substituted with C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, hydroxy-C1-C6 alkyl, or amino-C1-C6 alkyl. Z is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 16 and R 17 Each of the following can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or -(C1-C6 alkyl)-C(O)R 20 -C(O)R 21 Or, together with the nitrogen atoms they are attached to, they form 3-8 membered monocyclic heterocyclic groups, in which R 20 -OH, OR 10 or NR 22 R 23 , where R 22 and R 23 Each of them is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or hydroxy-C1-C6 alkyl-C3-C6 cycloalkylamino; R 21 It is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or C1-C6 amine; and The 3-8 membered monocyclic heterocyclic group is optionally substituted with C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, hydroxy-C1-C6 alkyl, or amino-C1-C6 alkyl. R 18 It is a C1-C6 alkyl or -NH-(C1-C6 alkyl); and R 9 It is hydrogen, C1-C6 alkyl, or N-protecting group.

[0046] In some embodiments of formula (I) as otherwise described herein, R 1 It is hydrogen.

[0047] In some embodiments of formula (I) as otherwise described herein, R 1 It is a methyl group.

[0048] In some embodiments of formula (I) as otherwise described herein, R 1 It is fluorinated.

[0049] In some embodiments of formula (I) as otherwise described herein, R 1 OR 10 And R 10 It is a methyl group.

[0050] In some embodiments of formula (I) as otherwise described herein, R 2 It is hydrogen.

[0051] In some embodiments of formula (I) as otherwise described herein, R 2 It is a methyl group.

[0052] In some embodiments of formula (I) as otherwise described herein, R 2 It is fluorinated.

[0053] In some embodiments of formula (I) as otherwise described herein, R 2 OR 10 And R 10 It is a methyl group.

[0054] In some embodiments of formula (I) as otherwise described herein, R 2 -C(O)NR 11 R 12 And R 11 It is hydrogen, and R 12 It is a C1-C6 alkoxy-C1-C6 alkyl group.

[0055] In some embodiments of formula (I) as otherwise described herein, R 2 -C(O)NR 11 R12 And R 11 It is hydrogen, and R 12 for .

[0056] In some embodiments of formula (I) as otherwise described herein, R 3 It is hydrogen.

[0057] In some embodiments of formula (I) as otherwise described herein, R 3 It is a methyl group.

[0058] In some embodiments of formula (I) as otherwise described herein, R 3 It is either fluorinated or chlorinated.

[0059] In some embodiments of formula (I) as otherwise described herein, R 3 It is a halogenated C1-C6 alkyl group.

[0060] In some embodiments of formula (I) as otherwise described herein, R 3 It is difluoromethyl or trifluoromethyl.

[0061] In some embodiments of formula (I) as otherwise described herein, R 3 OR 10 And R 10 It is methyl or difluoromethyl.

[0062] In some embodiments of formula (I) as otherwise described herein, R 4 It is hydrogen.

[0063] In some embodiments of formula (I) as otherwise described herein, R 4 It is a methyl group.

[0064] In some embodiments of formula (I) as otherwise described herein, R 4 It is fluorinated.

[0065] In some embodiments of formula (I) as otherwise described herein, R 5 It is hydrogen.

[0066] In some embodiments of formula (I) as otherwise described herein, R 5 It is a hydroxyl C1-C6 alkyl group, preferably .

[0067] In some embodiments of formula (I) as otherwise described herein, R 5 It is a carboxyl C1-C6 alkyl group, preferably .

[0068] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 Only one of them is hydrogen.

[0069] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 Each is hydrogen.

[0070] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 One of them is hydrogen, and the other is a hydroxyl C1-C6 alkyl group, preferably. , or (Implementation Plan 1-1).

[0071] In some embodiments of formula (I) as otherwise described herein, R 6 -XC(O)R 13 , where X is the key (Scheme 1-2).

[0072] In certain embodiments and embodiments 1-2 of formula (I) as otherwise described herein, R 7 Hydrogen (Scheme 1-3).

[0073] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-2 and 1-3, R 13 It is -OH.

[0074] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-2 and 1-3, R 13 For -OR 10 And R 10 It is a methyl group.

[0075] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 One of them is -XC(O)R 13 And X is methyl or ethyl (Schemes 1-4).

[0076] In certain embodiments of formula (I) and embodiments 1-4 as otherwise described herein, R 6 -XC(O)R 13 And X is hydroxyethyl (Implementation Scheme 1-5).

[0077] In some embodiments of formula (I) as otherwise described herein, R 6 -XC(O)R 13And X is cyclopropyl (Scheme 1-6).

[0078] In certain embodiments and embodiments 1-4 to 1-6 of formula (I) as otherwise described herein, R 13 It is -OH.

[0079] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 One of them is -YC(O)NR 14 R 15 , where Y is the key (Scheme 1-7).

[0080] In certain embodiments of formula (I) and embodiments 1-7 as otherwise described herein, R 6 -YC(O)NR 14 R 15 , where Y is the key (Scheme 1-7-1).

[0081] In certain embodiments of formula (I) and embodiments 1-7 as otherwise described herein, R 7 -YC(O)NR 14 R 15 , where Y is the key (Scheme 1-7-2).

[0082] This document mentions implementation schemes 1-7, including implementation schemes 1-7-1 and 1-7-2.

[0083] In certain embodiments of formula (I) and embodiments 1-7 as otherwise described herein, R 7 Hydrogen (Scheme 1-8).

[0084] In certain embodiments of formula (I) and embodiments 1-7 as otherwise described herein, R 6 Hydrogen (Implementation Scheme 1-8-1).

[0085] This document mentions implementation schemes 1-8, including implementation scheme 1-8-1.

[0086] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 It is hydrogen.

[0087] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 It is a C1-C6 alkyl group.

[0088] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 It is a methyl group.

[0089] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 It is a C1-C6 alkoxy-C1-C6 alkyl group.

[0090] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 for .

[0091] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 It is a hydroxyl C1-C6 alkoxy C1-C6 alkyl group.

[0092] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 for or .

[0093] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 It is a halogenated C1-C6 alkyl group.

[0094] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 for .

[0095] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 It is a hydroxyl C1-C6 alkyl C3-C6 cycloalkylamino group.

[0096] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 for or .

[0097] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 It is a C1-C6 amine.

[0098] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 for or .

[0099] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 It is a heteroaryl group.

[0100] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is hydrogen, and R 15 for .

[0101] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is a C1-C6 alkyl group, and R 15 It is a C1-C6 alkyl group.

[0102] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-7 and 1-8, R 14 It is methyl, and R 15 It is a methyl group.

[0103] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 One of them is -YC(O)NR 14 R 15 , where Y is a C1-C6 alkylene group (Schemes 1-9).

[0104] In some embodiments of formula (I) as otherwise described herein, R 6 -YC(O)NR 14 R 15 , where Y is a C1-C6 alkylene group (Embodiment 1-9-1). References to Embodiments 1-9 herein include references to Embodiment 1-9-1.

[0105] In certain embodiments of formula (I) and embodiments 1-9 as otherwise described herein, R 7 Hydrogen (Implementation Scheme 1-10).

[0106] In certain embodiments of formula (I) and embodiments 1-9 as otherwise described herein, R 6 Hydrogen (Implementation Scheme 1-10-1).

[0107] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 One of them is -YC(O)NR 14 R 15 , where Y is methylene (Implementation Scheme 1-11).

[0108] In some embodiments of formula (I) as otherwise described herein, R 6 -YC(O)NR 14 R 15 , where Y is methylene (Embodiment 1-11-1). In some embodiments, embodiment 1-11 includes embodiment 1-11-1.

[0109] In certain embodiments and embodiments 1-11 of formula (I) as otherwise described herein, R 7 Hydrogen (Scheme 1-12).

[0110] In certain embodiments and embodiments 1-11 of formula (I) as otherwise described herein, R 6 Hydrogen (Implementation Scheme 1-12-1).

[0111] The implementation schemes 1-11 and 1-12 mentioned in this article include implementation schemes 1-11-1 and 1-12-1, respectively.

[0112] In certain embodiments and embodiments 1-9 to 1-12 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 It is a C1-C6 alkyl group.

[0113] In certain embodiments and embodiments 1-9 to 1-12 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 It is a methyl group.

[0114] In certain embodiments and embodiments 1-9 to 1-12 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 It is a hydroxyl C1-C6 alkyl group.

[0115] In certain embodiments and embodiments 1-9 to 1-12 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 for .

[0116] In certain embodiments and embodiments 1-9 to 1-12 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 It is a hydroxyl C1-C6 alkoxy C1-C6 alkyl group.

[0117] In certain embodiments and embodiments 1-9 to 1-12 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 for .

[0118] In certain embodiments and embodiments 1-9 to 1-12 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 It is a carboxyl C1-C6 alkyl group.

[0119] In certain embodiments and embodiments 1-9 to 1-12 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 for .

[0120] In certain embodiments and embodiments 1-9 to 1-12 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 is -S(O)2R 19 And R 19 It is a methyl group.

[0121] In certain embodiments and embodiments 1-9 to 1-12 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 The heteroaryl group is a heteroaryl group. In various embodiments, the heteroaryl group can be any heteroaryl ring system, including but not limited to isoxazole, pyrazole, and triazole.

[0122] In certain embodiments and embodiments 1-9 to 1-12 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 for , or .

[0123] In certain embodiments and embodiments 1-9 to 1-12 of formula (I) as otherwise described herein, R 14 and R 15 Together with the nitrogen to which they are attached, they form a 6-membered monocyclic heterocyclic group (Scheme 1-13).

[0124] In certain embodiments of formula (I) and embodiments 1-13 as otherwise described herein, the 6-membered monocyclic heterocyclic group is .

[0125] In certain embodiments and embodiments 1-9 to 1-12 of formula (I) as otherwise described herein, R 14 It is methyl, and R 15 It is a methyl group.

[0126] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 One of them is -YC(O)NR 14 R 15 , where Y is ethyl (Scheme 1-14).

[0127] In some embodiments of formula (I) as otherwise described herein, R 6 -YC(O)NR 14 R 15 , where Y is ethyl (Embodiment 1-14-1). In some embodiments, Embodiment 1-14 includes Embodiment 1-14-1.

[0128] In certain embodiments and embodiments 1-14 of formula (I) as otherwise described herein, R 7 Hydrogen (Implementation Scheme 1-15).

[0129] In certain embodiments and embodiments 1-14 of formula (I) as otherwise described herein, R 6 Hydrogen (Implementation Scheme 1-15-1).

[0130] This document mentions Implementation Plan 1-15, including Implementation Plan 1-15-1.

[0131] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 One of them is -YC(O)NR 14 R 15 , where Y is hydroxyethyl (Implementation Scheme 1-16).

[0132] In some embodiments of formula (I) as otherwise described herein, R 6 -YC(O)NR 14 R 15 , where Y is hydroxyethyl (Embodiment 1-16-1). In some embodiments, Embodiment 1-16 includes Embodiment 1-16-1.

[0133] In certain embodiments and embodiments 1-16 of formula (I) as otherwise described herein, R7 Hydrogen (Implementation Scheme 1-17).

[0134] In certain embodiments and embodiments 1-16 of formula (I) as otherwise described herein, R 6 Hydrogen (Implementation Scheme 1-17-1).

[0135] This document mentions Implementation Scheme 1-17, including Implementation Scheme 1-17-1.

[0136] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 One of them is -YC(O)NR 14 R 15 Y is a cyclopropyl group (i.e., a group having the following formula). (Implementation Plan 1-18).

[0137] In some embodiments of formula (I) as otherwise described herein, R 6 -YC(O)NR 14 R 15 Y is a cyclopropyl group (i.e., a group having the following formula).

[0138] (Implementation Scheme 1-18-1). In some implementation schemes, Implementation Scheme 1-18 includes Implementation Scheme 1-18-1.

[0139] In certain embodiments of formula (I) and embodiments 1-18 as otherwise described herein, R 7 Hydrogen (Implementation Scheme 1-19).

[0140] In certain embodiments of formula (I) and embodiments 1-18 as otherwise described herein, R 6 Hydrogen (Implementation Scheme 1-19-1).

[0141] The implementation schemes 1-18 and 1-19 mentioned in this article include implementation schemes 1-18-1 and 1-19-1, respectively.

[0142] In certain embodiments and embodiments 1-14 to 1-19 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 It is a hydroxyl C1-C6 alkoxy C1-C6 alkyl group.

[0143] In certain embodiments and embodiments 1-14 to 1-19 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 for .

[0144] In certain embodiments and embodiments 1-14 to 1-19 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 It is a C1-C6 alkyl group.

[0145] In certain embodiments and embodiments 1-14 to 1-19 of formula (I) as otherwise described herein, R 14 It is hydrogen, and R 15 It is a methyl group.

[0146] In certain embodiments and embodiments 1-14 to 1-19 of formula (I) as otherwise described herein, R 14 It is methyl, and R 15 It is a methyl group.

[0147] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 One of them is -Z-NR 16 R 17 , where Z is the key (Scheme 1-20).

[0148] In some embodiments of formula (I) as otherwise described herein, R 6 -Z-NR 16 R 17 , where Z is the key (Implementation Scheme 1-20-1). In some implementation schemes, Implementation Scheme 1-20 includes Implementation Scheme 1-20-1.

[0149] In certain embodiments and embodiments 1-20 of formula (I) as otherwise described herein, R 7 Hydrogen (Scheme 1-21).

[0150] In certain embodiments and embodiments 1-20 of formula (I) as otherwise described herein, R 6 Hydrogen (Implementation Scheme 1-21-1).

[0151] The implementation schemes 1-20 and 1-21 mentioned in this article include implementation schemes 1-20-1 and 1-21-1, respectively.

[0152] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-20 and 1-21, R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21It can be hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or C1-C6 amine.

[0153] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-20 and 1-21, R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21 It is a methyl group.

[0154] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-20 and 1-21, R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21 It is a methoxy group.

[0155] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-20 and 1-21, R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21 -NH2 or .

[0156] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 One of them is -Z-NR 16 R 17 , where Z is methyl (Implementation Scheme 1-22).

[0157] In some embodiments of formula (I) as otherwise described herein, R 6 -Z-NR 16 R 17 , where Z is methyl (Embodiment 1-22-1). In some embodiments, embodiment 1-22 includes embodiment 1-22-1.

[0158] In certain embodiments and embodiments 1-22 of formula (I) as otherwise described herein, R 7 Hydrogen (Scheme 1-23).

[0159] In certain embodiments and embodiments 1-22 of formula (I) as otherwise described herein, R 6 Hydrogen (Implementation Scheme 1-23-1).

[0160] The implementation schemes 1-22 and 1-23 mentioned in this article include implementation schemes 1-22-1 and 1-23-1, respectively.

[0161] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is hydrogen, and R 17 It is a methyl group.

[0162] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is hydrogen, and R 17 It is a C1-C6 alkoxy-C1-C6 alkyl group.

[0163] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is hydrogen, and R 17 for .

[0164] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is hydrogen, and R 17 -(C1-C6 alkyl)-C(O)R 20 And R 20 -OH, OR 10 or NR 22 R 23 And R 22 and R 23 Each of them is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or hydroxy-C1-C6 alkyl-C3-C6 cycloalkylamino.

[0165] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is hydrogen, and R 17 -(C1-C6 alkyl)-C(O)R 20 And R 20 -OH or .

[0166] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21It can be hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or C1-C6 amine.

[0167] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21 It is a methyl group.

[0168] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21 -NH2, or .

[0169] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21 for .

[0170] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is methyl, and R 17 It is a methyl group.

[0171] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is methyl, and R 17 It is a hydroxyl C1-C6 alkyl group.

[0172] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is methyl, and R 17 for .

[0173] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is methyl, and R 17 It is a halogenated C1-C6 alkyl group.

[0174] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is methyl, and R 17 for .

[0175] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 It is ethyl, and R 17 It is an ethyl group.

[0176] In certain embodiments of formula (I) as otherwise described herein, and in embodiments 1-22 and 1-23, R 16 and R 17 Together with the nitrogen to which they are attached, they form 3-8 membered monocyclic heterocyclic groups (Scheme 1-24).

[0177] In certain embodiments of formula (I) and embodiments 1-24 as otherwise described herein, the 3-8 member monocyclic heterocyclic group is , , or .

[0178] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 One of them is , , , or (Implementation Plan 1-25).

[0179] In some embodiments of formula (I) as otherwise described herein, R 6 for , , , or (Implementation Scheme 1-25-1). In some implementation schemes, Implementation Scheme 1-25 includes Implementation Scheme 1-25-1.

[0180] In certain embodiments of formula (I) and embodiments 1-25 as otherwise described herein, R 7 Hydrogen (Implementation Scheme 1-26).

[0181] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 One of them is -S(O)2R 18 , where R 18It is a C1-C6 alkyl or -NH-(C1-C6 alkyl) (Scheme 1-27).

[0182] In some embodiments of formula (I) as otherwise described herein, R 6 is -S(O)2R 18 , where R 18 It is a C1-C6 alkyl or -NH-(C1-C6 alkyl) (Embodiment 1-27-1). In some embodiments, embodiment 1-27 includes embodiment 1-27-1.

[0183] In certain embodiments of formula (I) and embodiments 1-27 as otherwise described herein, R 7 Hydrogen (Implementation Scheme 1-28).

[0184] In some embodiments of formula (I) as otherwise described herein, R 6 and R 7 One of them is -S(O)2R 18 , where R 18 It is -NH2 or -NHCH3 (Implementation Scheme 1-29).

[0185] In some embodiments of formula (I) as otherwise described herein, R 6 is -S(O)2R 18 , where R 18 It is -NH2 or -NHCH3 (Implementation Scheme 1-29-1). In some implementation schemes, Implementation Scheme 1-29 includes Implementation Scheme 1-29-1.

[0186] In certain embodiments of formula (I) and embodiments 1-29 as otherwise described herein, R 7 Hydrogen (Implementation Scheme 1-30).

[0187] In some embodiments of formula (I) as otherwise described herein, R 6 It is hydrogen, and R 7 -C(O)NR 25 R 26 , where R 25 and R 26 Each is independently hydrogen or hydroxyl C1-C3 alkoxy C1-C3 alkyl (Effective 1-31).

[0188] In some embodiments of formula (I) as otherwise described herein, R 6 It is a hydroxyl C1-C6 alkyl group, and R 7 For -OR 24 , where R 24 It is a C1-C3 alkyl group (Effective 1-32).

[0189] In some embodiments of formula (I) as otherwise described herein, R 6 -XC(O)R 13 And R 7 For -OR 24 Where X is methyl, R 13 It is -OH, and R 24 It is a C1-C3 alkyl group (Effective 1-33).

[0190] In some embodiments of formula (I) as otherwise described herein, R 6 -YC(O)NR 14 R 15 And R 7 For halogen, -OR 24 Or hydroxyl C1-C6 alkyl, wherein Y is a bond, R 14 and R 15 Each is independently hydrogen, C1-C6 alkyl, or hydroxyC1-C6 alkoxyC1-C6 alkyl, and R 24 It is a C1-C3 alkyl group (Effective Implementation 1-34).

[0191] In certain embodiments of formula (I) and embodiments 1-34 as otherwise described herein, R 14 It is hydrogen, and R 15 It is a C1-C6 alkyl group.

[0192] In certain embodiments of formula (I) and embodiments 1-34 as otherwise described herein, R 14 It is hydrogen, and R 15 It is a methyl group.

[0193] In certain embodiments of formula (I) and embodiments 1-34 as otherwise described herein, R 14 It is hydrogen, and R 15 It is a hydroxyl C1-C6 alkoxy C1-C6 alkyl group.

[0194] In certain embodiments of formula (I) and embodiments 1-34 as otherwise described herein, R 14 It is hydrogen, and R 15 for .

[0195] In certain embodiments of formula (I) and embodiments 1-34 as otherwise described herein, R 7 It is fluorinated.

[0196] In certain embodiments of formula (I) and embodiments 1-34 as otherwise described herein, R 7 It is a hydroxyl C1-C6 alkyl group, preferably or .

[0197] In some embodiments of formula (I) as otherwise described herein, R 6 -YC(O)NR 14 R 15 And R 7 For -OR 24 Or hydroxy C1-C6 alkyl, wherein Y is methyl, R 14 and R 15 Each is independently hydrogen or hydroxyl C1-C6 alkoxy C1-C6 alkyl, and R 24 It is a C1-C3 alkyl group (Effective 1-35).

[0198] In certain embodiments of formula (I) and embodiments 1-35 as otherwise described herein, R 14 It is hydrogen, and R 15 It is a hydroxyl C1-C6 alkoxy C1-C6 alkyl group.

[0199] In certain embodiments of formula (I) and embodiments 1-35 as otherwise described herein, R 14 It is hydrogen, and R 15 for .

[0200] In certain embodiments of formula (I) and embodiments 1-35 as otherwise described herein, R 7 It is a hydroxyl C1-C6 alkyl group, preferably or .

[0201] In some embodiments of formula (I) as otherwise described herein, R 6 -Z-NR 16 R 17 And R 7 For -OR 24 , where R 16 and R 17 Each is a C1-C6 alkyl group, Z is methyl, and R 24 It is a C1-C3 alkyl group (Effective 1-36).

[0202] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 16 and R 17 Each is a methyl group (Scheme 1-37).

[0203] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 8 Hydrogen (Implementation Scheme 1-37).

[0204] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 8 Methyl (Implementation Scheme 1-38).

[0205] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 8 Cyclopropyl (Implementation Scheme 1-39).

[0206] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 8 It is fluorinated or chlorinated (Implementation Scheme 1-40).

[0207] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 8 OR 10 And R 10 Methyl (Implementation Scheme 1-41).

[0208] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 9 Hydrogen (Scheme 1-42).

[0209] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 9 Methyl (Implementation Scheme 1-43).

[0210] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 9 It is an N-protecting group (Scheme 1-44).

[0211] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 1 -R 4 All are hydrogen (Implementation Scheme 1-45).

[0212] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 5 and R 8 Hydrogen (Scheme 1-46).

[0213] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 2 Halogen is preferred, preferably fluorinated (Scheme 1-47).

[0214] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R4 Halogen is preferred, preferably fluorinated (Scheme 1-48).

[0215] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 2 and R 4 Halogen is preferred, preferably fluorinated (Scheme 1-49).

[0216] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 1 and R 2 Halogen is preferred, preferably fluorinated (Scheme 1-50).

[0217] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 2 It is halogen and R 4 It is a C1-C6 alkoxy group, preferably a methoxy or ethoxy group (Examples 1-51).

[0218] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 1 and R 2 Halogen is preferred, preferably fluorinated (Scheme 1-52).

[0219] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 1 It is halogenated, preferably fluorinated, C1-C6 alkoxy, preferably methoxy or ethoxy, or C1-C6 alkyl, preferably methyl; and R 2 Halogen is preferred, preferably fluorinated (Scheme 1-53).

[0220] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 2 It is hydrogen or halogen, and R 3 It is trifluoromethyl (Scheme 1-54).

[0221] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 2 It is a halogen, trifluoromethyl, C1-C3 alkyl, or C1-C3 alkoxy; and R 1 R 3 R 4 R 5 R 7 and R 8 Hydrogen (Scheme 1-55).

[0222] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 1 -R 5 R 7 and R 8 Hydrogen (Scheme 1-56).

[0223] In certain embodiments and embodiments 1-1 to 1-36 of formula (I) as otherwise described herein, R 2 It is a halogen, trifluoromethyl, C1-C3 alkyl, or C1-C3 alkoxy; and R 1 R 3 R 4 R 5 R 6 and R 8 Hydrogen (Implementation Scheme 1-57).

[0224] In some embodiments of formula (I) as otherwise described herein, R 1 -R 6 and R 8 It is hydrogen.

[0225] In one respect, this disclosure provides compounds of formula (II): (II) Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein: R 1 R 3 R 4 and R 8 Each of these can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halogenated C1-C6 alkyl, or OR. 10 , where R 10 It is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halo-C1-C6 alkyl; R 5 It is hydrogen, hydroxyl C1-C6 alkyl or carboxyl C1-C6 alkyl; R 6 Hydrogen, hydroxyl C1-C6 alkyl, -XC(O)R 13 -YC(O)NR 14 R 15 -Z-NR 16 R 17 , heteroaryl or -S(O)2R 18 ,in X is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 13 -OH or -OR 10 ; Y is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 14 and R 15 Each of the following can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl-C3-C6 cycloalkylamino, C1-C6 amine, carboxyl-C1-C6 alkyl, -S(O)2R 19 phenyl, heteroaryl, or together with the nitrogen atoms they are attached to form 3-8 membered monocyclic heterocyclic groups, wherein R 19 It is a C1-C6 alkyl group; The phenyl group is optionally substituted with a C1-C6 alkyl group; The heteroaryl group is optionally substituted with a C1-C6 alkyl group; and The 3-8 membered monocyclic heterocyclic group is optionally substituted with C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, hydroxy-C1-C6 alkyl, or amino-C1-C6 alkyl. Z is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 16 and R 17 Each of the following can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or -(C1-C6 alkyl)-C(O)R 20 -C(O)R 21 Or, together with the nitrogen atoms they are attached to, they form 3-8 membered monocyclic heterocyclic groups, in which R 20 -OH, OR 10 or NR 22 R 23 , where R 22 and R 23Each of them is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or hydroxy-C1-C6 alkyl-C3-C6 cycloalkylamino; R 21 It is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or C1-C6 amine; and The 3-8 membered monocyclic heterocyclic group is optionally substituted with C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, hydroxy-C1-C6 alkyl, or amino-C1-C6 alkyl. R 18 It is a C1-C6 alkyl or -NH-(C1-C6 alkyl); R 7 For hydrogen, halogen, -OR 24 hydroxyl C1-C6 alkyl or -C(O)NR 25 R 26 ,in: R 24 It is a C1-C3 alkyl group, and R 25 and R 26 Each is independently hydrogen or hydroxyl C1-C3 alkoxy C1-C3 alkyl; R 9 It is hydrogen, C1-C6 alkyl, or N-protecting group.

[0226] In one embodiment, the compound of formula (I) is selected from: Table 1 Pharmaceutical Compositions and Dosage Forms

[0227] Compounds of formula (I) can be formulated into pharmaceutical compositions.

[0228] In another aspect, this disclosure provides pharmaceutical compositions comprising the benzoxazole derivatives of the present invention or salts thereof, and pharmaceutically acceptable carriers, excipients, or diluents. The compounds of the present invention can be formulated by any method known in the art and can be prepared for administration via any route, including but not limited to parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or rectal administration. In some embodiments, the compounds of the present invention are administered intravenously in a hospital setting. In some other embodiments, administration is preferably via an oral route.

[0229] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic substance that is compatible with biological systems such as cells, cell cultures, tissues, or organisms and does not interfere with the bioactivity and efficacy of the active ingredient. Therefore, compositions according to the invention may contain, in addition to inhibitors, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials known in the art. For example, the preparation of pharmaceutically acceptable formulations is described in Remington's Pharmaceutical Sciences, 18th Edition, A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0230] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the aforementioned compounds and exhibits little or no adverse toxicological effects. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. These compounds may also be administered in the form of pharmaceutically acceptable quaternary ammonium salts known to those skilled in the art, specifically including formula -NR. + Z -Quaternary ammonium salts, wherein R is hydrogen, alkyl or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methanesulfonate, sulfonate, phosphate or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandeloate, benzylate and diphenylacetate).

[0231] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to a patient without causing serious toxicity in the treated patient. For all of the above, the dose of the active compound ranges from about 0.01 to 300 mg / kg, preferably from 0.1 to 100 mg / kg daily, and more typically from 0.5 mg to about 25 mg per kilogram of recipient body weight daily. Typical topical doses in a suitable carrier range from 0.01 to 3% wt / wt. The effective dose range of a pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound to be delivered. If the derivative itself exhibits activity, the effective dose can be estimated using the weight of the derivative, or by other means known to those skilled in the art, as described above.

[0232] Pharmaceutical compositions comprising the compounds of the present invention may be used in accordance with the methods described herein.

[0233] The pharmaceutical composition may be in the form of, for example, tablets, capsules or parenteral preparations, but those skilled in the art will understand that the compound may be provided in a variety of pharmaceutical composition forms.

[0234] For example, the compounds of this disclosure may be administered orally, topically, parenterally, by inhalation or spraying, or rectally in a dosage unit formulation containing one or more pharmaceutically acceptable carriers, diluents, or excipients. As used herein, the term “parenterally” includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques. Medicinal products containing the compounds of this disclosure may be provided in any suitable formulation and dosage form described herein.

[0235] In the pharmaceutical compositions disclosed herein, one or more of the disclosed compounds may be associated with one or more pharmaceutically acceptable carriers, diluents or excipients, and (if desired) other active ingredients. Pharmaceutical compositions comprising the disclosed compounds may be in forms suitable for oral administration, such as tablets, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0236] Compositions intended for oral use can be prepared according to any suitable pharmaceutical composition manufacturing method, and such compositions may contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically refined and palatable product. Tablets contain an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated using known techniques. In some cases, such coatings can be prepared using appropriate techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used.

[0237] Oral formulations may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium such as peanut oil, liquid paraffin or olive oil.

[0238] Oral preparations may also be available in tablet form.

[0239] Aqueous suspensions contain active substances mixed with excipients suitable for preparing aqueous suspensions. Such excipients can be suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents, such as naturally occurring phospholipids, such as lecithin; or condensation products of alkyl esters and fatty acids, such as polyoxyethylene stearate; or condensation products of ethylene oxide and long-chain fatty alcohols, such as heptadecanethoxycetyl alcohol; or condensation products of ethylene oxide and esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate; or condensation products of ethylene oxide and esters derived from fatty acids and hexitol anhydrides, such as polyvinyl sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethylparaben or n-propylparaben; one or more colorants; one or more flavoring agents; and one or more sweeteners, such as sucrose or saccharin.

[0240] Oily suspensions can be formulated by suspending the active ingredients in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oils such as liquid paraffin. Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings may be added to provide palatable oral products. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0241] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide active ingredients that can be mixed with dispersants or wetting agents, suspending agents, and one or more preservatives. Examples of suitable dispersants or wetting agents or suspending agents are those already mentioned above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0242] The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or tragacanth, naturally occurring phospholipids, such as soybean lecithin, and esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate, and the condensation product of said metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings.

[0243] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not water. In other embodiments, water constitutes less than 50% of the composition. In some embodiments, the composition containing less than 50% water has at least 1%, 2%, 3%, 4%, or 5% water. In other embodiments, the water content in the composition is present in trace amounts.

[0244] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not an alcohol. In other embodiments, the alcohol constitutes less than 50% of the composition. In some embodiments, the composition containing less than 50% alcohol has at least 1%, 2%, 3%, 4%, or 5% alcohol. In other embodiments, the alcohol content in the composition is present in trace amounts.

[0245] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, glucose, or sucrose. Such formulations may also contain modifiers, preservatives, flavoring agents, and coloring agents. Pharmaceutical compositions can be in the form of sterile injectable aqueous or oily suspensions. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known techniques. Sterile injectable articles can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable carriers and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils can be used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid can be used in the preparation of injections.

[0246] The compounds disclosed herein can also be administered in suppository form, for example, for rectal administration of a drug. These compositions can be prepared by mixing the compound with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus will melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0247] The compounds disclosed herein can also be administered parenterally in sterile media. Depending on the carrier and concentration used, the drug can be suspended or dissolved in the carrier. Advantageously, adjuvants such as local anesthetics, antiseptics, and buffers can be dissolved in the carrier.

[0248] The composition can be formulated into unit dosage forms of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable for use as a single dose in human subjects and other mammals, each unit containing a predetermined amount of the active substance in combination with suitable pharmaceutical excipients, the amount of which is calculated to produce the desired therapeutic effect.

[0249] The compound may be effective over a wide dose range and is usually administered at a pharmaceutically effective amount. However, it should be understood that the actual amount of compound administered will generally be determined by the physician based on relevant circumstances, including the condition to be treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0250] To prepare solid compositions such as tablets, a major active ingredient is mixed with pharmaceutical excipients to form a solid preformation composition containing a homogeneous mixture of the compounds described herein. When these preformation compositions are referred to as homogeneous, the active ingredient is typically uniformly dispersed throughout the composition, allowing the composition to be readily subdivided into equivalent unit dosage forms, such as tablets, pills, and capsules. This solid preformation is then subdivided into unit dosage forms of the type described above, containing, for example, from 0.1 mg to about 500 mg of the active ingredient of the compounds described herein.

[0251] Tablets or pills can be coated or otherwise compounded to provide dosage forms with the advantage of prolonged action. For example, tablets or pills may contain an internal dose component and an external dose component, the latter being an encapsulation layer on top of the former. These two components can be separated by an enteric coating layer, which resists disintegration in the stomach and allows the internal component to enter the duodenum intact or with delayed release. A variety of materials can be used for such enteric coatings or coatings, including various polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0252] The amount of compound or composition administered to a patient will vary depending on the substance applied, the purpose of administration (e.g., prevention or treatment), the patient's condition, and the route of administration. In therapeutic applications, the composition may be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially stop the symptoms of the disease and its complications. The effective dose will depend on the condition being treated and the judgment of the attending physician based on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0253] The compositions administered to patients may be in the form of the pharmaceutical compositions described above. These compositions may be sterilized using conventional sterilization techniques or by sterile filtration. Aqueous solutions may be packaged for use as is or lyophilized, with the lyophilized product combined with a sterile aqueous carrier prior to administration. The pH of the compound product is typically 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It should be understood that the use of certain excipients, carriers, or stabilizers described above may result in the formation of pharmaceutical salts.

[0254] The therapeutic dose of a compound can vary depending on factors such as the specific intended use of the treatment, the route of administration, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the compound described herein in the pharmaceutical composition can vary depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compound described herein may be provided as an aqueous physiological buffer solution containing about 0.1% to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 µg / kg to about 1 g / kg body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight per day. The dosage may depend on variables such as the type and progression of the disease or condition, the overall health status of the specific patient, the relative biological efficacy of the selected compound, the formulation of excipients, and the route of administration. The effective dose can be deduced from dose-response curves obtained from in vitro or animal model testing systems.

[0255] The compounds described herein may also be formulated or administered in combination with one or more other active ingredients, which may include any pharmaceutical agent, such as antiviral agents, vaccines, antibodies, immune enhancers, immunosuppressants, anti-inflammatory agents, etc.

[0256] Those skilled in the art will be able to formulate the compounds described herein into pharmaceutical preparations. For example, based on the physicochemical properties of the compounds, those skilled in the art will recognize the pharmaceutically effective amount of the compound and the desired route of administration. How to use

[0257] On the other hand, this disclosure generally relates to methods for treating inflammatory conditions or oxidative stress. These methods include administering a therapeutically effective amount of the benzoxazole derivative according to the invention to a subject in need.

[0258] In some embodiments, the benzoxazole derivative is a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof. In certain embodiments, the benzoxazole derivative comprises compounds selected from Table 1 as described herein.

[0259] In another aspect, this disclosure provides compounds that can be obtained by or obtained by the compound preparation methods described herein (e.g., methods including one or more steps described in a general reaction scheme).

[0260] In another aspect, this disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form or tautomer thereof, and a pharmaceutically acceptable diluent or carrier.

[0261] In another aspect, this disclosure provides a method for treating inflammatory conditions or oxidative stress, the method comprising administering to a patient in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form or tautomer thereof.

[0262] The compositions and methods provided herein can be used to treat a variety of inflammatory conditions or oxidative stress. In some embodiments, the inflammatory condition or oxidative stress is a blood condition, including but not limited to sickle cell-related disease, β-thalassemia, hemoglobinopathies, or myelodysplastic syndromes.

[0263] In some other implementations, the inflammatory condition or oxidative stress is inflammatory bowel disease, arthritis, or neurodegenerative disease.

[0264] In some other implementations, the inflammatory condition or oxidative stress is an autoinflammatory syndrome.

[0265] In some other implementations, the inflammatory condition or oxidative stress is an inflammation-related condition, including but not limited to adult-onset Still's disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), macrophage activation syndrome (MAS), infantile enterocolitis autoinflammatory disease (AIFEC), bullous pemphigoid, pemphigus vulgaris, idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), systemic lupus erythematosus (SLE), multiple sclerosis, Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, and muscular atrophy. Lateral sclerosis, neurodegenerative diseases, Charcot-Marie-Tooth syndrome, traumatic brain injury (TBI), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), cryptothermal protein-associated periodic syndrome (CAPS), vitiligo, multiple self-healing palmoplantar carcinoma (MSPC), autoimmune Addison's disease, familial Mediterranean fever (FMF), autoimmune thyroiditis, stroke, type 2 diabetes (T2D), osteoarthritis, gout, atherosclerosis, hidradenitis suppurativa, psoriasis, thermoproteinosis, or sickle cell disease.

[0266] In some other implementations, the inflammatory condition or oxidative stress is an infectious disease, an autoimmune disease, cancer, a metabolic disorder, an eye disease, a liver disease, a kidney disease, a cardiovascular disease, a skin disease, a mitochondrial disease, a hematologic disorder, a muscle disease, or a nervous system disease.

[0267] In some other implementations, the inflammatory condition or oxidative stress is a fibrotic disease. More specifically, the fibrotic disease is chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, bronchitis, asthma, bronchiectasis, emphysema, or sarcoidosis. The fibrotic disease can also be liver fibrosis caused by alcoholic cirrhosis, steatosis, cholestasis, drug side effects, viral infection, or a combination thereof. Additionally, the fibrotic disease can be a cutaneous fibrotic disease, including but not limited to autoimmune diseases; and the autoimmune disease can be scleroderma or psoriasis.

[0268] In some other embodiments, the inflammatory condition or oxidative stress is a diabetic condition, including but not limited to type 1 diabetes, type 2 diabetes, gestational diabetes, prediabetes, hyperglycemia, metabolic syndrome, or secondary conditions arising therefrom. Additionally, the secondary condition may be congestive heart failure or kidney disease.

[0269] In some other implementations, the inflammatory condition or oxidative stress is a cardiovascular disease, including but not limited to hypertension, heart failure, hypercholesterolemia, atherosclerosis, arteriosclerosis, thrombosis, acute coronary thrombosis, deep vein thrombosis, peripheral vascular disease, congestive heart failure, acute coronary syndrome, dialysis fistula failure, ischemia-reperfusion injury, primary pulmonary hypertension, primary pulmonary hypertension, or secondary pulmonary hypertension.

[0270] Inflammatory conditions, as described in this article, can lead to cell death or the release of pro-inflammatory cytokines or other inflammatory mediators, caused by coronaviruses (such as SARS-CoV 2, SARS-CoV, or MERS), viruses, bacteria, fungi, parasites, or other types of infection in the subject.

[0271] In other respects, this disclosure provides methods for treating diseases and conditions that respond to fetal hemoglobin induction. The compounds of this disclosure induce fetal hemoglobin and can therefore be used to treat diseases and conditions such as sickle cell disease, β-thalassemia, and pyruvate kinase deficiency.

[0272] Details of this disclosure are set forth in the accompanying description. Illustrative methods and materials are now described; however, similar or equivalent methods and materials may be used in practice or testing of this disclosure. Other features, objects, and advantages of this disclosure will be apparent from the specification and claims. In this specification and the appended claims, the singular form also includes the plural, unless the context clearly requires otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents and publications referenced in this specification are incorporated herein by reference in their entirety. General reaction schemes and examples

[0273] The compounds of this invention can be prepared using commercially available reagents and conventional methods well known to those skilled in the art, such as the general reaction schemes and examples described herein. Those skilled in the art can adapt the reaction sequence of the schemes provided herein to suit a desired target molecule. Of course, in some cases, those skilled in the art will use different reagents to perform one or more individual steps or use certain substituents in the protected form. Furthermore, those skilled in the art will recognize that the compounds of this disclosure can be synthesized using entirely different routes. For example, those skilled in the art can modify the procedures described herein and / or other procedures familiar to those skilled in the art to prepare the compounds described herein.

[0274] Numerous common references are available, providing generally known chemical synthesis schemes and conditions that can be used to synthesize the disclosed compounds. For example, the compounds of the present invention can be prepared using the reagents and methods described in U.S. Patent Application Publication No. 2022 / 0177460 A1 and U.S. Patent Application Publication No. 2017 / 0231967 A1, the disclosures of which are incorporated herein by reference in their entirety.

[0275] The compounds described herein can be purified by any means known in the art, including chromatographic methods such as HPLC, preparative thin-layer chromatography, rapid column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal-phase and reversed-phase, as well as ionic resins. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd ed., LRSnyder and JJ Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl, Springer-Verlag, New York, 1969.

[0276] In any process used to prepare the subject compound, it may be necessary and / or desirable to protect any sensitive or reactive groups on the relevant molecule. This can be achieved by means of conventional protecting groups described in standard literature, such as JFW McOmie, "Protective Groups in Organic Chemistry," Plenum Press, London and New York 1973, and TW Greene and PGM Wuts. ,"Protective Groups in Organic Synthesis," 3rd ed., Wiley, New York 1999; "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; "Methoden der organischen Chemie," Houben-Weyl, 4th ed., Volume 15 / 1, Georg Thieme Verlag, Stuttgart 1974; H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine," Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982; and / or Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide and Derivate," Georg Thieme Verlag, Stuttgart 1974. Protecting groups can be removed at convenient subsequent stages using methods known in the art.

[0277] General Reaction Scheme 1

[0278] General Reaction Scheme 2

[0279] General Reaction Scheme 3

[0280] General Reaction Scheme 4

[0281] General Reaction Scheme 5

[0282] General Reaction Scheme 6

[0283] General Reaction Scheme 7

[0284] General Reaction Scheme 8

[0285] General Reaction Scheme 9

[0286] intermediate reaction scheme Synthesis of methyl 2-iodo-1,3-benzoxazole-5-carboxylate

[0287] Step 1: Synthesis of methyl 1,3-benzoxazole-5-carboxylate

[0288] At room temperature, methyl 3-amino-4-hydroxybenzoate (25 g, 150 mmol) solution was added to p-toluenesulfonic acid monohydrate (3.56 g, 0.13 equivalents, 18.7 mmol) and triethyl orthoformate (250 mL). The reaction mixture was stirred at 100 °C for 12 hours. The reaction progress was monitored by TLC (30% EtOAc in hexane). The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (500 mL). The organic layer was washed with water (750 mL) and saturated NaHCO3 solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the crude compound. The crude product was further purified by column chromatography using 20% ​​EtOAc in hexane as the eluent to give methyl 1,3-benzoxazole-5-carboxylate (26.1 g, 98.5%) as a grayish-white solid. LC-MS (m / z) = 178.0 [M+H] + .

[0289] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.90 (s, 1H), 8.34 (d, J = 12Hz, 1H), 8.08 (d, J = 12Hz, 1H), 8.06 (d, J = 12Hz, 1H), 3.72 (s, 3H).

[0290] Step 2: Synthesis of methyl 2-iodo-1,3-benzoxazole-5-carboxylate

[0291] Lithium bis(trimethylsilyl)imine (11.8 g, 2.5 equivalents, 70.6 mmol) was added to a tetrahydrofuran (59.5 mL, 731 mmol) solution of methyl 1,3-benzoxazole-5-carboxylate (5 g, 28.2 mmol) at -78 °C, and the mixture was stirred at the same temperature for 3 hours. A THF (15 mL) solution of iodine (6.4 g, 1.8 equivalents, 50.4 mmol) was added to the reaction mixture at -78 °C. The reaction mixture was heated to -20 °C and stirred for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (40 mL) and extracted with ethyl acetate (4 x 60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was further purified by combiflash chromatography using EtOAc / n-heptane (2:8) to give methyl 2-iodo-1,3-benzoxazole-5-carboxylate (3.5 g, 41%) as a white solid. LC-MS (m / z) = 304.0 [M+H] + .

[0292] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.34 (d, J = 12Hz, 1H), 8.08 (d, J =12Hz, 1H), 8.06 (d, J = 12Hz, 1H), 3.72 (s, 3H).

[0293] The following intermediates are synthesized in a manner similar to intermediate reaction schemes.

[0294] Example 1 Synthesis of methyl 2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,3-benzoxazol-5-carboxylate

[0295] Step 1: Synthesis of methyl 1,3-benzoxazole-5-carboxylate

[0296] At room temperature, triethyl orthoformate (250 mL) was added to a solution of methyl 3-amino-4-hydroxybenzoate (25 g, 150 mmol) in p-toluenesulfonic acid:water (1:1) (3.56 g, 18.7 mmol). The reaction mixture was heated to 100 °C and stirred for 12 hours. The reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with water and saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using 20% ​​EtOAC:hexane as the eluent to give methyl 1,3-benzoxazole-5-carboxylate (26.1 g, 98.5%) as a grayish-white solid. LCMS (ES) m / z = 178.0 [M+H] + .

[0297] Step 2: Synthesis of 5-fluoro-1,3-benzoxazole-2-amine

[0298] Cyanogen bromide (833 mg, 7.87 mmol) was added to a methanol (8 mL) solution of 0.5 g (3.93 mmol) of 2-amino-4-fluorophenol, stirred at room temperature. The reaction mixture was stirred at room temperature for 16 hours and monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was concentrated. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 25 mL). The pH of the aqueous layer was adjusted to pH ~10-12 using 1 M sodium hydroxide solution (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 5-fluoro-1,3-benzoxazol-2-amine (580 mg, 97%) as a brown solid. LCMS (ES) m / z = 153.0 [M+H] + .

[0299] Step 3: Synthesis of methyl 2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,3-benzoxazol-5-carboxylate

[0300] At 0 °C, lithium tert-butoxide (565 mg, 7.06 mmol) and iodine (466 mg, 3.67 mmol) were added to a stirred solution of methyl 1,3-benzoxazole-5-carboxylate (0.5 g, 2.82 mmol) in tetrahydrofuran (10 mL). After stirring for 10 min, 5-fluoro-1,3-benzoxazole-2-amine (429 mg, 2.82 mmol) from tetrahydrofuran (2 mL) was added, and the resulting reaction mixture was stirred at room temperature for another 16 h. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by rapid column chromatography, eluting with 50-70% ethyl acetate in n-heptane to give the compound of Example 1 (methyl 2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,3-benzoxazol-5-carboxylate) (260 mg, 28.15%) as a grayish-white solid. LCMS (ES) m / z = 328.2 [M+H] + .

[0301] Example 2 Synthesis of {2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,3-benzoxazol-5-yl}methanol

[0302] Step 1: Synthesis of {2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,3-benzoxazol-5-yl}-methanol

[0303] At 0 °C, 1 M lithium aluminum hydride (47.3 µL, 1.15 mmol) in tetrahydrofuran was added dropwise to a solution of methyl 2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,3-benzoxazol-5-carboxylate (Example 1, 250 mg, 764 μmol) in tetrahydrofuran (10 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude material was washed with diethyl ether (10 mL) and n-pentane (10 mL) to give the compound of Example 2 ({2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,3-benzoxazol-5-yl}methanol) (180 mg, 78.74%) as a brown solid. LCMS (ES) m / z = 300.1 [M+H] + .

[0304] Example 3 N Synthesis of 5-[(dimethylamino)methyl]-1,3-benzoxazol-2-yl}-5-fluoro-1,3-benzoxazol-2-amine

[0305] Step 1: N Synthesis of -[5-(chloromethyl)-1,3-benzoxazol-2-yl]-5-fluoro-1,3-benzoxazol-2-amine

[0306] At 0 °C, thionyl chloride (82.5 µL, 1.14 mmol) was added dropwise to a solution of {2-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,3-benzoxazol-5-yl}methanol (Example 2; 170 mg, 568 μmol) in dichloromethane (8 mL) and dimethylformamide (0.1 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 hours, and the reaction was monitored by TLC and LC-MS. After the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with 5% methanol (2 x 20 mL) in dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude solid in the form of a grayish-white color. N -[5-(chloromethyl)-1,3-benzoxazol-2-yl]-5-fluoro-1,3-benzoxazol-2-amine (140 mg, 77.57%). LCMS (ES) m / z = 318.1 [M+H] + .

[0307] Step 2: N Synthesis of 5-[(dimethylamino)methyl]-1,3-benzoxazol-2-yl}-5-fluoro-1,3-benzoxazol-2-amine

[0308] Stirred at room temperature NDimethylamine hydrochloride (59.6 mg, 1.32 mmol) and potassium carbonate (183 mg, 1.32 mmol) were added to a solution of 140 mg, 441 μmol, of 1,3-benzoxazol-2-yl]-5-fluoro-1,3-benzoxazol-2-amine (8 mL) in dimethylformamide. The reaction mixture was stirred in a sealed tube at 80 °C for 2 hours, and the reaction was monitored by TLC and LC-MS. After the reaction was complete, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic compounds were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was washed with diethyl ether (10 mL) and n-pentane (10 mL) to give the compound of Example 3 as a grayish-white solid. N 5-[(dimethylamino)methyl]-1,3-benzoxazol-2-yl}-5-fluoro-1,3-benzoxazol-2-amine (11 mg, 7.65%). LCMS (ES) m / z = 327.17 [M+H] + .

[0309] Example 4 5-Fluoro- N Synthesis of 5-((4-methylpiperazin-1-yl)methyl)benzo[d]oxazol-2-yl)benzo[d]oxazol-2-amine

[0310] Example 4 was synthesized in a manner similar to Example 3. LCMS (ES) m / z = 382.4 [M+H] + .

[0311] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.39 - 7.31 (m, 3H), 7.15 (d, J = 8.0Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.89 - 6.84 (m, 1H), 3.53 (s, 2H), 2.33 (s,8H), 2.26 (s, 3H).

[0312] Example 5 Synthesis of ({[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]methyl}amino)acetic acid

[0313] Step 1: Synthesis of tert-butyl acetate ({[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]methyl}amino)

[0314] This step is performed in a manner similar to step 2 of Example 3. LC-MS (m / z) = 413.3 [M+H] + .

[0315] Step 2: Synthesis of ({[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]methyl}amino)acetic acid

[0316] At 0 °C, trifluoroacetic acid (60.3 µL, 5 equivalents, 788 µmol) was added to a stirred solution of tert-butyl ({[5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]methyl}amino)acetic acid (130 mg, 158 μmol) in dichloromethane (5 mL, 78.1 mmol), and the reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give ({[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]methyl}amino)acetic acid (13 mg, 23%) as a white solid. LCMS (ES) m / z = 313.3 [M+H] + .

[0317] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.52 - 7.48 (m, 3 H), 7.27 (t, J =8.0 Hz, 2 H), 7.01 - 6.97 (m, 1 H), 4.05 (s, 2 H), 3.26 (s, 2 H).

[0318] Purification conditions Flow rate: 0.5 mL / min Column: Kinetex EVO C18 (100 mm x 2.1 mm x 2.6 µm) Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile

[0319] Example 6 Synthesis of {2-[(5-fluoro-1,3-benzoxazol-2-yl)-N-methylamino]-1,3-benzoxazol-5-yl}methanol

[0320] Step 1: Synthesis of methyl 2-(methylamino)-1,3-benzoxazole-5-carboxylate

[0321] To a stirred solution of methyl 2-iodo-1,3-benzoxazole-5-carboxylate (3 g, 9.9 mmol) in ethanol (15 mL) cooled in an ice bath, 33% methylamine (461 mg, 1.5 equivalents, 15 mL) was added. The reaction mixture was stirred at room temperature for 30 min. The reaction progress was monitored by TLC (50% EtOAc: hexane) and LCMS. When the starting material was exhausted, the reaction mixture was concentrated to give methyl 2-(methylamino)-1,3-benzoxazole-5-carboxylate (3.6 g).

[0322] Step 2: Synthesis of [2-(methylamino)-1,3-benzoxazol-5-yl]methanol

[0323] Lithium aluminum hydride (1.33 g, 2 equivalents, 17.5 mL) was added dropwise to a solution of methyl 2-(methylamino)-1,3-benzoxazole-5-carboxylate (3.6 g, 17.5 mmol) in tetrahydrofuran (20 mL, 246 mmol) under nitrogen atmosphere and stirred at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and monitored by TLC (5% MeOH: 95% DCM) and LCMS. After the starting material was exhausted, 1.4 mL of water was added and the resulting mixture was stirred for 5 min, followed by the addition of 1.4 mL of 15% NaOH and an additional 4.2 mL of water. The solids formed were removed by celite bed filtration and washed with 10% MeOH:EtOAc. The filtrate was concentrated under reduced pressure to give the crude material. The product was purified by column chromatography using 4-5% MeOH from DCM as the eluent to obtain [2-(methylamino)-1,3-benzoxazol-5-yl]methanol (2 g, 64%) as a yellow solid.

[0324] Step 3: N Synthesis of 5-methyl({[(tert-butyl)bis(methyl)siloxy]methyl}-1,3-benzoxazol-2-yl)amine

[0325] Imidazole (1.91 g, 2.5 equivalence, 28.1 mmol) was added to a solution of [2-(methylamino)-1,3-benzoxazol-5-yl]methanol (2 g, 11.2 mmol) in dimethylformamide (20 mL, 258 mmol) under nitrogen atmosphere and stirred. This was followed by the addition of (tert-butyl)(chloro)bis(methyl)silane (3.05 g, 1.8 equivalence, 20.2 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC (5% MeOH: 95% DCM) and LCMS. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The N-methyl(5-{[(tert-butyl)bis(methyl)siloxy]methyl}-1,3-benzoxazol-2-yl)amine (2 g, 60%) was purified by column chromatography using 30-40% EtOAc:n-heptane as the eluent to obtain a yellow solid.

[0326] Step 4: (5-{[(tert-butyl)bis(methyl)siloxy]methyl}-1,3-benzoxazol-2-yl)- N Synthesis of methyl(5-fluoro-1,3-benzoxazol-2-yl)amine

[0327] Towards N 2 g (6.84 mmol) of methyl(5-{[(tert-butyl)bis(methyl)siloxy]methyl}-1,3-benzoxazol-2-yl)amine, 1.69 g (1.3 equivalents, 8.89 mmol) of 2-chloro-5-fluoro-1,3-benzoxazole, 2.69 g (1.3 equivalents, 8.89 mmol) of 1,4-dioxane (20 mL, 234 mmol) was added to a solution of methyl(5-{[(tert-butyl)bis(methyl)siloxy]methyl}-1,3-benzoxazol-2-yl)amine, 2-chloro-5-fluoro-1,3-benzoxazol, 2.69 g (1.3 equivalents, 8.89 mmol), 426 mg (0.1 equivalents, 684 μmol), and 76.8 mg (0.05 equivalents, 342 µmol)palladium bis(acetic acid) were added to the solution of 2-methyl(5-{[(tert-butyl)bis(methyl)siloxy]methyl}-1,3-benzoxazol-2-yl)amine, 2-chloro-5-fluoro-1,3-benzoxazol, 2.69 g (1.3 equivalents, 8.89 mmol) of 2-benzoxazol, 2,4-dioxane (20 mL, 234 mmol), cesium carbonate (6.68 g, 3 equivalents, 20.5 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (426 mg, 0.1 equivalents, 684 μmol), and bis(acetic acid)palladium (76.8 mg, 0.05 equivalents, 342 µmol). The reaction mixture was irradiated in a microwave reactor at 120 °C for 45 min. The reaction mixture was filtered The residue was purified by column chromatography, eluting with 10-30% EtOAC in n-heptane to give a light orange solid (5-{[(tert-butyl)bis(methyl)siloxy]methyl}-1,3-benzoxazol-2-yl)- N 1-Methyl(5-fluoro-1,3-benzoxazol-2-yl)amine (1.5 g, 51%).

[0328] Step 5: {2-[(5-fluoro-1,3-benzoxazol-2-yl)- N Synthesis of [-methylamino]-1,3-benzoxazol-5-yl}methanol

[0329] At 0°C, (5-{[(tert-butyl)bis(methyl)siloxy]methyl}-1,3-benzoxazol-2-yl)- N Tetrabutylammonium fluoride (8.26 g, 9 equivalents, 31.5 mL) was added to a 15 mL solution of methyl(5-fluoro-1,3-benzoxazol-2-yl)amine (1.5 g, 3.51 mmol) in an oxopentane ring, and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After the starting material was exhausted, water was added to the reaction mixture, followed by extraction with ethyl acetate (2 x 50 mL). The organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with 0–50% EtOAC in hexane to give a grayish-white solid {2-[(5-fluoro-1,3-benzoxazol-2-yl)] -N [-methylamino]-1,3-benzoxazol-5-yl}methanol (0.5 g, 45%). LCMS (m / z) = 314.1 [M+H] + .

[0330] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.76 - 7.72 (m, 1H), 7.64 (d, J = 8 Hz,1H), 7.56 - 7.51 (m, 2H), 7.26 (dd, J = 1.6 Hz, 1.6 Hz, 1H), 7.16 - 7.11 (m,1H), 5.30 (br, 1H), 4.59 (s, 2H), 3.83 (s, 3H).

[0331] Example 7 5-((dimethylamino)methyl)- N Synthesis of -(5-fluorobenzo[d]oxazol-2-yl)-N-methylbenzo[d]oxazol-2-amine

[0332] Example 7 was synthesized in a manner similar to Example 3. LCMS (ES) m / z = 341.3 [M+H] + .

[0333] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.74 - 7.71 (m, 1 H), 7.63 (d, J =8.0 Hz, 1 H), 7.53 - 7.51 (m, 2 H), 7.23 (d, J = 8.4 Hz, 1 H), 7.15 - 7.10(m, 1 H), 3.82 (s, 3 H), 3.47 (s, 2 H), 2.16 (s, 6 H).

[0334] Example 8 N Synthesis of 5-((dimethylamino)methyl)benzo[d]oxazol-2-yl)-5-fluoro-4-methoxybenzo[d]oxazol-2-amine

[0335] Example 8 was synthesized in a manner similar to Example 3. LCMS (ES) m / z = 357.3 [M+H] + .

[0336] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.36 - 7.28 (m, 3H), 7.24 - 7.21 (m,1H), 7.00 - 6.98 (d, J = 8.0 Hz, 1H), 3.84 (s, 3H), 3.55 (s, 2H), 2.24 (s, 6H).

[0337] Example 9 Synthesis of (2-((6-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)methanol

[0338] Example 9 was synthesized in a manner similar to Example 2. LCMS (ES) m / z = 300.2 [M+H] + .

[0339] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.50 (bs, 1H), 7.51-7.56 (m, 2H),7.48 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.8 Hz, 1H), 7.12 (d, J= 2.4 Hz, 1H), 5.31 (s, 1H), 4.56 (s, 2H).

[0340] Example 10 Synthesis of 5-((dimethylamino)methyl)-N-(5-fluorobenzo[d]oxazol-2-yl)-6-methoxybenzo[d]oxazol-2-amine

[0341] Step 1: Synthesis of methyl 2,4-dihydroxybenzoate

[0342] Sulfuric acid (7 mL) was added to a methanol (35 mL) solution of 2,4-dihydroxybenzoic acid (5 g, 32.4 mmol) cooled to 0 °C. The reaction mixture was stirred at 73 °C for 16 hours, and then concentrated under reduced pressure. The residue was treated with a saturated sodium bicarbonate solution (100 mL), and the precipitated solid was collected by vacuum filtration, washed with water (300 mL) and n-heptane (100 mL), and dried under vacuum to give methyl 2,4-dihydroxybenzoate (5 g, 91%) as a grayish-white solid.

[0343] Step 2: Synthesis of methyl 2-hydroxy-4-(methoxymethoxy)benzoate

[0344] Sodium hydride (178 mg, 1.3 equivalents, 7.43 mmol) was added to a tetrahydrofuran (30 mL, 369 mmol) solution of methyl 2,4-dihydroxybenzoate (1 g, 5.95 mmol) cooled to 0 °C, and the reaction mixture was stirred at ambient temperature for 30 min. Then, chloromethoxymethane (497 µL, 1.1 equivalents, 6.54 mmol) was added dropwise to the mixture at 0 °C, and the resulting suspension was stirred at 0 °C for 0.5 h and gradually heated to 80 °C. After 2 hours, the reaction solution was treated with ice water (50 mL) and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give the product, which was used directly as the reactant for the next step (1 g, crude product) without any further purification.

[0345] Step 3: Synthesis of methyl 2-methoxy-4-(methoxymethoxy)benzoate

[0346] A mixture of methyl 2-hydroxy-4-methoxyanisate (1 g, 4.71 mmol) and anhydrous dipotassium carbonate (2.61 g, 4 equivalents, 18.9 mmol) in dimethylformamide (10 mL, 129 mmol) was stirred at 80 °C for 5 min. Iodomethane (587 µL, 2 equivalents, 9.43 mmol) was added dropwise, and the reaction mixture was stirred at 80 °C for 1 h, monitored by TLC. The reaction mixture was then cooled to room temperature, and the solids were removed by filtration. The filtrate was treated with ice water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give methyl 2-methoxy-4-(methoxymethoxy)benzoate (1 g, crude). This product was used directly as a raw material for the next step without any purification.

[0347] Step 4: Synthesis of 4-hydroxy-2-methoxybenzoic acid

[0348] To a methanol (10 mL, 247 mmol) solution of methyl 2-methoxy-4-(methoxymethoxy)benzoate (1 g, 4.42 mmol) cooled to 0 °C, 3 mL of 1 N HCl was added, and the reaction mixture was stirred at room temperature for 16 hours. The pH of the reaction mixture was adjusted to pH ~7 with saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography, eluting with ethyl acetate in n-heptane, to give 4-hydroxy-2-methoxybenzoic acid (350 mg, 43%) as a white solid.

[0349] Step 5: Synthesis of methyl 4-hydroxy-2-methoxy-5-nitrobenzoate

[0350] Nitric acid (96.2 µL, 1.2 equivalents, 2.31 mmol) was added to a chloroform (14 mL) solution of methyl 4-hydroxy-2-anisinate (350 mg, 1.92 mmol) cooled to 0 °C. The reaction mixture was stirred at ambient temperature for 30 min, treated with ice water, and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography, eluting with ethyl acetate in n-heptane, to give methyl 4-hydroxy-2-methoxy-5-nitrobenzoate (210 mg, 48%) as a white solid.

[0351] Step 6: Synthesis of methyl 5-amino-4-hydroxy-2-methoxybenzoate

[0352] Nitrogen gas was bubbled through a methanol (15 mL) solution of methyl 4-hydroxy-2-methoxy-5-nitrobenzoate (0.2 g, 880 µmol) for 5 minutes, followed by the addition of carbon-supported palladium (50% wet) (70 mg). The reaction mixture was stirred at room temperature under 60 psi of hydrogen for 16 hours. After purging with nitrogen, the reaction mixture was filtered through a celite bed, and the filtrate was concentrated to give methyl 5-amino-4-hydroxy-2-methoxybenzoate (150 mg, 86%) as a grayish-white solid.

[0353] Methyl 5-amino-4-hydroxy-2-methoxybenzoate was treated in a manner similar to that used in the synthesis of Example 3 to yield 5-((dimethylamino)methyl)-N-(5-fluorobenzo[d]oxazol-2-yl)-6-methoxybenzo[d]oxazol-2-amine. LCMS (m / z) = 357.3 [M+H] + .

[0354] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.33 (br, 2H), 7.24 (s, 1H), 7.10 (d, J = 8 Hz, 1H), 6.82 (t, J = 8.4 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 2H), 2.43 (s, 6H).

[0355] Example 11

[0356] Synthesis of 2-((5-((dimethylamino)methyl)benzo[d]oxazol-2-yl)amino)-N-(2-methoxyethyl)benzo[d]oxazol-5-carboxamide

[0357] Step 1: Synthesis of methyl 2-aminobenzo[d]oxazol-5-carboxylate

[0358] To a stirred solution of methyl 3-amino-4-hydroxybenzoate (5 g, 29.9 mmol, 1 equivalent) in methanol (100 mL), bromoformonitrile (9.5 g, 89.7 mmol, 3 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours, monitored by TLC. The reaction mixture was concentrated under reduced pressure, and the residue was treated with 80 mL of saturated aqueous Na₂CO₃ solution. The resulting solid was removed by filtration, and the filtrate was concentrated under reduced pressure to give methyl 2-amino-1,3-benzoxazole-5-carboxylate (4 g, 70% yield) as a white solid.

[0359] Step 2: Synthesis of methyl 2-((tert-butoxycarbonyl)amino)benzo[d]oxazol-5-carboxylate

[0360] Triethylamine (10.1 mL, 71.8 mmol, 3 equivalents) and DMAP (0.29 g, 2.39 mmol, 0.1 equivalents) were added to a stirred THF (60 mL) solution of methyl 2-amino-1,3-benzoxazole-5-carboxylate (4.6 g, 23.9 mmol, 1 equivalent). The reaction mixture was cooled to 0 °C, treated with tert-butyloxycarbonyloxytert-butylcarboxylate (8.25 mL, 38.9 mmol, 1.5 equivalents), stirred at room temperature for 5 h, and monitored by TLC. The reaction mixture was then concentrated under reduced pressure, diluted with water, and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography and eluted with ethyl acetate in n-heptane to give methyl 2-(tert-butoxycarbonylamino)-1,3-benzoxazole-5-carboxylate (6 g, 86% yield) as a white solid.

[0361] Step 3: Synthesis of 2-((tert-Butoxycarbonyl)amino)benzo[d]oxazol-5-carboxylic acid

[0362] Lithium hydroxide (0.059 g, 24.6 mmol, 3 equivalents) was added to a stirred solution of methyl 2-(tert-butoxycarbonylamino)-1,3-benzoxazole-5-carboxylic acid (2.4 g, 8.21 mmol, 1 equivalent) in methanol (5 mL), THF (10 mL), and water (10 mL). The reaction mixture was stirred at 60 °C for 3 h and monitored by TLC. The reaction mixture was concentrated under reduced pressure and treated with citric acid solution (30 mL). The solids were removed by filtration, and the filtrate was concentrated under reduced pressure to give crude 2-(tert-butoxycarbonylamino)-1,3-benzoxazole-5-carboxylic acid (1.5 g).

[0363] Step 4: Synthesis of tert-butyl (5-((2-methoxyethyl)carbamoyl)benzo[d]oxazol-2-yl)carbamate

[0364] To a stirred solution of 2-(tert-butoxycarbonylamino)-1,3-benzoxazol-5-carboxylic acid (2.5 g, 8.98 mmol, 1 equivalent) in DMF (25 mL), HATU (5.12 g, 13.5 mmol, 1.5 equivalent) and 2-methoxyethylamine (1.56 mL, 18 mmol, 2 equivalent) were added. The reaction mixture was cooled to 0 °C, treated with DIPEA (4.71 mL, 27 mmol, 3 equivalent), and stirred at room temperature for 5 hours. The reaction mixture was diluted with ice-cold water (30 mL), extracted with EtOAc (2 x 100 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography, eluting with ethyl acetate in n-heptane, to give a yellow gel. N -2-Methoxyethyl-2-(tert-Butoxycarbonylamino)-1,3-benzoxazole-5-carboxamide (3 g, 99% yield).

[0365] Step 5: 2-Amino- N Synthesis of 5-(2-methoxyethyl)benzo[d]oxazol-5-carboxamide

[0366] To the stirring N 3 g of 2-methoxyethyl-2-(tert-butoxycarbonylamino)-1,3-benzoxazole-5-carboxamide (3 g, 8.95 mmol, 1 equivalent) was added dropwise to a DCM solution (40 mL) containing 4N HCl in 1,4-dioxane (30 mL), and the reaction mixture was stirred at 0 °C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the crude material was ground with n-pentane and diethyl ether and dried to give a white solid. N -2-Methoxyethyl-2-amino-1,3-benzoxazole-5-carboxamide (2 g, 95% yield).

[0367] Step 6: Synthesis of methyl 2-((5-((2-methoxyethyl)carbamoyl)benzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-carboxylate

[0368] Towards N To a THF (15 mL) solution of 2-methoxyethyl-2-amino-1,3-benzoxazole-5-carboxamide (1 g, 4.25 mmol, 1 equivalent), lithium 2-methyl-2-propoxide (0.68 g, 8.5 mmol, 2 equivalents) and methyl 2-iodo-1,3-benzoxazole-5-carboxylate (1.16 g, 3.83 mmol, 0.9 equivalents) were added. The reaction mixture was heated to 70 °C for 16 hours, concentrated under reduced pressure, resuspended in ethyl acetate (10 mL), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with MeOH and DCM, to give 2-[5-(N Methyl 1,3-benzoxazole-2-ylamino]-1,3-benzoxazole-5-carboxylate (0.2 g, 11% yield).

[0369] 2-[5-( was synthesized in a manner similar to that of Example 3) N Methyl 2-((5-((dimethylamino)methyl)benzo[d]oxazol-2-yl)amino)- N 5-(2-Methoxyethyl)benzo[d]oxazol-5-carboxamide. LCMS (m / z) = 410.4 [M+H] + .

[0370] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.51 - 8.43 (m, 1H), 7.85 (s, 1H),7.63 (d, J = 8.0 Hz, 1 H), 7.65 (s, 1 H), 7.46 - 7.39 (m, 3 H), 7.09 (d, J = 7.6Hz, 1H), 3.79 (bs, 2H), 3.48 - 3.34 (m, 4H), 3.26 (s, 3H), 2.40 (s, 6H).

[0371] Example 12 Synthesis of 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)urea

[0372] Step 1: Synthesis of 2-iodo-5-nitro-1,3-benzoxazole

[0373] Lithium bis(trimethylsilyl)imine (7.74 g, 2.5 equivalents, 46.3 mmol) was added to a THF (25 mL) solution of 5-nitro-1,3-benzoxazole (3 g, 18.3 mmol) cooled to -78 °C, and the reaction mixture was stirred at -78 °C for 3 h. Iodine (3.48 g, 1.5 equivalents, 27.4 mmol) was added to THF (5 mL), and the temperature was maintained at -20 °C for 1 h. The reaction mixture was then treated with a saturated ammonium chloride solution (40 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with ethyl acetate in n-heptane, to give 2-iodo-5-nitro-1,3-benzoxazole (1.1 g, 21%) as a brown solid.

[0374] Step 2: Synthesis of 2-(5-fluoro-1,3-benzoxazole-2-ylamino)-5-nitro-1,3-benzoxazole

[0375] To a THF (15 mL) solution of 5-fluoro-1,3-benzoxazol-2-ylamine (0.53 g, 3.45 mmol), lithium tert-butoxide (0.55 g, 2 equivalents, 6.9 mmol) and 2-iodo-5-nitro-1,3-benzoxazole (1 g, 3.45 mmol) were added. The reaction vessel was sealed and heated at 70 °C for 4 hours, then concentrated under reduced pressure, dissolved in ethyl acetate (40 mL), and washed with water (20 mL) and brine (20 mL). The organic layer was concentrated, and the residue was purified by column chromatography, eluting with ethyl acetate in n-heptane, to give 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-5-nitro-1,3-benzoxazole (0.55 g, 51%) as a grayish-white solid.

[0376] Step 3: Synthesis of 5-amino-2-(5-fluoro-1,3-benzoxazole-2-ylamino)-1,3-benzoxazole

[0377] Nitrogen gas was bubbled for 5 minutes through a solution of 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-5-nitro-1,3-benzoxazole (0.55 g, 1.75 mmol, 1 equivalent) in MeOH (30 mL), followed by the addition of carbon-supported palladium (10% wet; 0.3 g), and the reaction mixture was stirred at room temperature under 50 psi of hydrogen for 16 hours. The reaction mixture was filtered through a celite bed, and the filtrate was concentrated to give 5-amino-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazole (0.38 g, 76%) as a brown solid.

[0378] Step 4: Synthesis of 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)urea

[0379] Under nitrogen atmosphere, methyl dichlorocarbonate (0.10 g, 0.35 mmol) was added to a stirred THF (1 mL) solution of 5-amino-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazole (0.1 g, 0.35 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, then cooled to 0°C. Ammonia was bubbled through the reaction mixture for 15 minutes, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, diluted with water, and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with methanol in DCM to give the desired compound (0.10 g), which was further purified by preparative HPLC to give 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)urea (0.018 g, 16%) as a pale yellow solid. LCMS (m / z) = 328.1 [M+H] + .

[0380] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.70 (s, 1H), 7.80 (s, 1H), 7.53 (q, J = 4.4 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.31 (dd, J = 8.4&2 Hz, 1H), 7.13 (dd, J =8.82 Hz (1H), 5.85 (s, 2H)

[0381] Example 13 Synthesis of 3-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-1,1-dimethylurea

[0382] Example 13 was synthesized in a manner similar to Example 12. LCMS (ES) m / z = 356.3 [M+H] + .

[0383] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.41 (s, 1H), 7.75 (s, 1H), 7.53 (q, J = 4.4 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.8Hz, 1H), 7.02 (t, J = 8.4 Hz, 1H), 2.94 (s, 6H).

[0384] Example 14 Synthesis of methyl (2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)carbamate

[0385] Example 14 was synthesized in a manner similar to Example 12. LCMS (ES) m / z = 343.3 [M+H] + .

[0386] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.80 (s, 1 H), 7.79 (s, 1 H), 7.56 -7.53 (m, 1 H), 7.45 (d, J = 8.8 Hz, 1 H), 7.33 - 7.30 (dd, J = 2 Hz, 1 H), 7.24(d, J = 7.6 Hz, 1 H), 7.07 - 7.02 (m, 1 H), 3.69 (s, 3 H).

[0387] Example 15 Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)prop-2-ol

[0388] Magnesium bromide (437 mg, 5 equivalents, 3.66 mmol) was added to a stirred THF (6 mL) solution of methyl 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylate (Example 1, 240 mg, 0.732 mmol) in nitrogen. The reaction mixture was stirred at room temperature for 4 hours, treated with water (15 mL), and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude material (140 mg, 58%). 50 mg of the crude material was purified by preparative HPLC to give 2-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]-2-propanol (20 mg). LCMS (m / z) = 328.0 [M+H] + .

[0389] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.56 (s, 0.5H), 7.65 (d, J=1.2 Hz,1H), 7.56 - 7.53 (m, 1H), 7.45 (s, 1H), 7.35-7.31 (m, 2H), 7.07 - 7.01 (m,1H), 1.46 (s, 6H).

[0390] Purification conditions Column: Xbridge C-18 (250 mm x 4.6 mm x 5 µm) Mobile phase (A): 0.1% aqueous formic acid Mobile phase (B): Acetonitrile Flow rate: 1.0 mL / min

[0391] Example 16 2-(benzo[d]oxazol-2-ylamino)- N Synthesis of 5-(2-(2-hydroxyethoxy)ethyl)benzo[d]oxazol-5-carboxamide

[0392] Step 1: Synthesis of methyl 2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-carboxylate

[0393] Methyl 2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-carboxylate was prepared in a manner similar to that described in Example 1, except that 2-aminophenol was used instead of 2-amino-4-fluorophenol.

[0394] Step 2: Synthesis of 2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-carboxylic acid

[0395] Lithium hydroxide (0.083 g, 3.49 mmol, 3 equivalents) was added to a stirred solution of methyl 2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-carboxylic acid (0.36 g, 1.16 mmol, 1 equivalent) in methanol (1 mL), THF (2 mL), and water (2 mL), and the resulting mixture was heated at 70 °C for 4 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was acidified with dilute HCl solution (20 mL), and the resulting solid was filtered and dried to give crude 2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-carboxylic acid (0.25 g) as a white solid.

[0396] Step 3: 2-(benzo[d]oxazol-2-ylamino)- N Synthesis of 5-(2-(2-hydroxyethoxy)ethyl)benzo[d]oxazol-5-carboxamide

[0397] To a DMF (4 mL) solution of 2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-carboxylic acid (0.42 g, 1.42 mmol, 1 equivalent), HATU (1.08 g, 2.85 mmol, 2 equivalents) and 2-(2-aminoethoxy)ethanol (0.17 mL, 1.71 mmol, 1.2 equivalents) were added. The reaction mixture was cooled to 0 °C, treated with DIPEA (0.74 mL, 4.27 mmol, 3 equivalents), and stirred at room temperature for 4 h. The reaction mixture was diluted with ice-cold water (5 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-(benzo[d]oxazol-2-ylmethyl)-N-(2-(2-hydroxyethoxy)ethyl)benzo[d]oxazol-5-carboxamide (96 mg, 18% yield) as a white solid. LCMS (ES) m / z = 383.3 [M+H] + .

[0398] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.57 (s, 1 H), 8.54 (t, J = 5.6 Hz, 1H), 7.95 (s, 1 H), 7.72 - 7.69 (dd, J = 1.6 Hz& J= 10.0 Hz, 1 H), 7.57 - 7.50 (m, 3 H), 7.30 - 7.19 (m, 2 H), 4.62 (s, 1 H), 3.73 - 3.12 (m, 8 H).

[0399] Purification conditions Column: Xselect CSH C18(250x19)mm; 5u Flow rate: 19.0 mL / min Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile

[0400] Example 17 N , N Synthesis of 1,3-dimethyl-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxamide

[0401] Example 17 was synthesized in a manner similar to that of Example 16. LCMS (ES) m / z = 341.3 [M+H] + .

[0402] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 13.02 (s, 1H), 8.06 (d, J=1.2 Hz,1H), 7.89 - 7.87 (dd, 1H), 7.65 (s, 1H), 7.60-7.57 (m, 1H), 7.37 - 7.34 (dd,1H), 7.21 (bs, 0.5H), 7.11-7.06 (m, 1H), 6.95 (bs, 0.5H).

[0403] Purification conditions Column: Inertsil C18 (19 mm x 250 mm x 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 19 mL / min

[0404] Example 18 Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-carboxamide

[0405] Example 18 was synthesized in a manner similar to Example 16. LCMS (ES) m / z = 313.3 [M+H] + .

[0406] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.05 (s, 1 H), 7.98 (s, 1 H), 7.80 -7.78 (m, 1 H), 7.61 - 7.56 (m, 2 H), 7.42 (s, 1 H), 7.37 - 7.34 (dd, J = 2.4Hz, J = 2.8 Hz, 1 H), 7.10 - 7.05 (m, 1 H).

[0407] Purification conditions Column: X-Bridge C18 (19 mm X 250 mm X 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 19 mL / min

[0408] Example 19 2-((5-fluorobenzo[d]oxazol-2-yl)amino)- N Synthesis of 5-(2-methoxyethyl)benzo[d]oxazol-5-carboxamide

[0409] Example 19 was synthesized in a manner similar to that of Example 16. LCMS (ES) m / z = 371.3 [M+H] + .

[0410] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.61 - 8.59 (m, 1 H), 7.97 (d, J =1.2 Hz, 1 H), 7.78 - 7.75 (dd, J = 1.6 Hz, J = 1.6 Hz, 1 H), 7.63 - 7.57 (m,2 H), 7.37 - 7.35 (dd, J = 2.8 Hz, J = 2.4 Hz, 1 H), 7.11 - 7.06 (m, 1 H), 3.50 - 3.42 (m, 4 H), 3.28 (s, 3 H).

[0411] Purification conditions Column: Xselect CSH C18(250x19)mm; 5u Flow rate: 19.0 mL / min Mobile phase: EtOAc:hexane (7:3).

[0412] Example 20 N -[2-(2-hydroxyethoxy)ethyl]- N Synthesis of methyl-2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxamide

[0413] Example 20 was synthesized in a manner similar to that of Example 16. LCMS (ES) m / z = 397.4 [M+H] + .

[0414] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.58 - 7.54 (m, 3H), 7.51 (s, 1H), 7.33 - 7.23 (m, 3H), 4.60 (bs, 1H), 3.64 - 3.35(m, 8H), 3.00 (s, 3H).

[0415] Purification conditions Column: SUNFIRE C18 (19 mm x 250 mm x 5 mic) Mobile phase (A): 5 mM ammonium bicarbonate aqueous solution Mobile phase (B): Acetonitrile Flow rate: 19 mL / min The desired product RT is 12.49 min.

[0416] Example 21 N Synthesis of -[2-(2-hydroxy-2-methylpropoxy)ethyl]-2-(1,3-benzoxazole-2-ylamino)-1,3-benzoxazole-5-carboxamide

[0417] Example 21 was synthesized in a manner similar to that of Example 16. LCMS (ES) m / z = 411.4 [M+H] + .

[0418] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.51 (t, J = 8.0 Hz, 1H), 7.97 (s, 1H),7.73 - 7.71 (dd, J = 1.2 Hz, J = 0.8 Hz, 1H), 7.60 - 7.53 (m, 3H), 7.31 (t, J =8.0 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 4.33 (s, 1H), 4.57 (t, J = 8.0 Hz, 2H), 3.47 - 3.43 (m, 2H), 3.20 (s, 2H), 1.07 (s, 6H).

[0419] Example 22 2-(benzo[d]oxazol-2-ylamino)- N Synthesis of 1-(1-(2-hydroxyethyl)piperidin-4-yl)benzo[d]oxazol-5-carboxamide

[0420] Example 22 was synthesized in a manner similar to that of Example 16. LCMS (ES) m / z = 422.5 [M+H] + .

[0421] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.27 (d, J = 7.2 Hz, 1 H), 7.86 (s, 1H), 7.62 (d, J = 2.8 Hz, J = 8.0 Hz, 1 H), 7.47 - 7.40 (m, 3 H), 7.22 - 7.09 (m,2 H), 4.71 (s, 1 H), 3.85 (d, J = 6.0 Hz, 1 H), 3.59 - 3.57 (m, 2 H), 3.10 (d, J = 10.4 Hz, 2 H), 2.67 - 2.66 (m, 2 H), 2.50 - 2.32 (m, 2 H), 1.88 - 1.67 (m, 4 H).

[0422] Example 23 Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-(2-hydroxyethoxy)ethyl)benzo[d]oxazol-6-carboxamide

[0423] Step 1: Synthesis of methyl 1,3-benzoxazole-6-carboxylate

[0424] At room temperature, p-toluenesulfonic acid monohydrate (1.14 g, 0.13 equivalents, 5.98 mmol) was added to a solution of methyl 4-amino-3-hydroxybenzoate (8 g, 47.9 mmol) in triethyl orthoformate (80 mL). The reaction mixture was heated and stirred at 100 °C for 16 h. The reaction progress was monitored by TLC (30% ethyl acetate in heptane). After the starting material was exhausted, the reaction mixture was concentrated under reduced pressure, and the resulting residue was resuspended in ethyl acetate (200 mL). The organic layer was washed with water and a saturated aqueous solution of NaHCO3, and concentrated under reduced pressure to give a crude product. This substance was further ground with n-pentane to give the title compound (7.2 g, 64.54%) as a brown solid.

[0425] Step 2: Synthesis of methyl 2-iodo-1,3-benzoxazole-6-carboxylate

[0426] To a solution of methyl 1,3-benzoxazole-6-carboxylate (5 g, 28.2 mmol) in tetrahydrofuran (0.1 L), lithium bis(trimethylsilyl)imine (5.9 g, 1.3 equivalents, 35.3 mmol, 1 N solution in THF, 35.3 mL) was added, and the reaction mixture was stirred at -78 °C for 3 h. Then, a solution of iodine (7.16 g, 2 equivalents, 56.4 mmol) in THF (20 mL) was added at -78 °C, and the reaction mixture was gradually heated to -20 °C and stirred for 1 h. The reaction progress was monitored by TLC (30% ethyl acetate in heptane). After the starting material was exhausted, the reaction mixture was treated with a saturated ammonium chloride solution (35 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The substance was purified by rapid chromatography using 10%-20% EtOAc in n-heptane as the mobile phase to give methyl 2-iodo-1,3-benzoxazole-6-carboxylate (2.8 g, 21.28%) as a white solid. LC-MS (m / z) = 303.9 [M+H] + .

[0427] Step 3: Synthesis of methyl 2-(1,3-benzoxazole-2-ylamino)-1,3-benzoxazole-6-carboxylate

[0428] To a solution of 1,3-benzoxazol-2-ylamine (1.23 g, 9.17 mmol) in tetrahydrofuran (17.6 mL, 216 mmol), lithium 2-methyl-2-propoxide (1.47 g, 2 equivalents, 18.3 mmol) and methyl 2-iodo-1,3-benzoxazol-6-carboxylate (2.5 g, 0.9 equivalents, 8.25 mmol) were added, and the reaction mixture was stirred at 70 °C for 16 h. The reaction progress was monitored by TLC (40% ethyl acetate in heptane). After the starting material was exhausted, the reaction mixture was concentrated, and the residue was resuspended in water (50 mL). The resulting solid was filtered and dried under vacuum to give a crude product. The product was further washed with DCM (50 mL) to give methyl 2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-6-carboxylate (2.2 g, 78% yield) as a grayish-white solid. LC-MS (m / z) = 310.0 [M + H] + .

[0429] Step 4: Synthesis of 2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-6-carboxylic acid

[0430] Lithium hydroxide (852 mg, 5 equivalents, 35.6 mmol) was added to a stirred solution of methyl 2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-6-carboxylic acid (2.2 g, 7.11 mmol) in methanol (8 mL, 197 mmol), tetrahydrofuran (15 mL, 184 mmol), and water (15 mL, 833 mmol). The reaction mixture was stirred at 70 °C for 5 h, and the reaction progress was monitored by TLC (30% ethyl acetate in heptane). After the starting material was exhausted, the reaction mixture was concentrated under reduced pressure to give a crude residue. The residue was treated with 1N HCl solution (20 mL), and the resulting solid was filtered and dried to give crude 2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-6-carboxylic acid (1.9 g, yield: 90%) as a purple solid. LC-MS (m / z) = 295.9 [M + H] + .

[0431] Step 5: Synthesis of 2-(benzo[d]oxazol-2-ylamino)-N-(2-(2-hydroxyethoxy)ethyl)benzo[d]oxazol-6-carboxamide

[0432] T3P (1.29 g, 2 equivalents, 3.39 mmol) and 2-(2-aminoethoxy)ethanol (257 µL, 1.5 equivalents, 2.54 mmol) were added to a stirred solution of 2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-6-carboxylic acid (0.5 g, 1.69 mmol) in dimethylformamide (20 mL), and the reaction mixture was stirred for 10 min. The reaction mixture was then cooled to 0 °C, and ethylbis(propyl-2-yl)amine (885 µL, 3 equivalents, 5.08 mmol) was added, and the reaction mixture was stirred for 5 min. The reaction mixture was then warmed to room temperature and stirred for 2 h. The reaction progress was monitored by TLC (5% methanol in DCM). After the starting material was exhausted, the reaction mixture was diluted with ice-cold water (5 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The substance was dissolved in DCM (30 mL) and then treated dropwise with pentane at 0 °C. The resulting solid was filtered to give 2-(benzo[d]oxazol-2-ylamino)-N-(2-(2-hydroxyethoxy)ethyl)benzo[d]oxazol-6-carboxamide (64 mg, yield: 9.59%) as a pale pink solid. LC-MS (m / z) = 383.4 [M+H] + .

[0433] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.70 (s, 1H), 8.51 (s, 1H), 7.99 (s,1H), 7.83 (m, 1H), 7.57 - 7.55 (m, 3H), 7.32 - 7.25 (m, 2H), 4.60 (s, 1H),3.54 - 3.45 (m, 8H).

[0434] Example 24 N Synthesis of 2-[2-(2-hydroxyethoxy)ethyl]2-[2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionamide

[0435] Step 1: Synthesis of methyl 2-(4-((tert-butyldimethylsilyl)oxy)phenyl)acetate

[0436] Imidazole (6.15 g, 90.3 mmol, 3 equivalents) was added to a stirred solution of methyl p-hydroxyphenyl)acetate (5 g, 30.1 mmol, 1 equivalent) in DMF (50 mL). The reaction mixture was cooled to 0 °C, and (tert-butyl)(chloro)bis(methyl)silane (9.07 g, 60.2 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice-cold water (20 mL), extracted with ethyl acetate (2 x 50 mL), and concentrated under reduced pressure to give a crude product. The crude product was purified by rapid column chromatography, eluting with 5% EtOAc-heptane, to give a colorless liquid of methyl p-[(tert-butyl)bis(methyl)siloxy]phenyl}acetate (7 g, 83% yield). LCMS m / z = 281.2 [M+H] + .

[0437] Step 2: Synthesis of methyl 2-(4-((tert-butyldimethylsilyl)oxy)phenyl)propionate

[0438] A solution of methyl p-[(tert-butyl)bis(methyl)siloxy]phenyl}acetate (7 g, 25 mmol) in THF (70 mL) was cooled to -78 °C, and then lithium bis(isopropyl)imine (18.7 mL, 37.4 mmol, 1.5 equivalents) was added at the same temperature. The reaction mixture was stirred at the same temperature for 1 hour. Iodomethane (3.11 mL, 49.9 mmol, 2 equivalents) was added to the mixture, and the reaction mixture was slowly heated to -20 °C and stirred again for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL), and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was further purified by rapid column chromatography using 2.5% EtOAc-heptane to give methyl 2-{p-[(tert-butyl)bis(methyl)siloxy]phenyl}propionate (7.1 g, 96% yield) as a colorless liquid. LCMS m / z = 295.2 [M+H] + .

[0439] Step 3: Synthesis of methyl 2-(4-hydroxyphenyl)propionate

[0440] A solution of methyl 2-{p-[(tert-butyl)bis(methyl)siloxy]phenyl}propionate (3 g, 10.2 mmol, 1 equivalent) in THF (30 mL) was cooled to 0 °C, and then TBAF (10.2 mL, 10.2 mmol, 1 equivalent) was added at the same temperature. The reaction mixture was heated to room temperature and stirred for 3 hours. The reaction mixture was quenched with H₂O (30 mL), extracted with ethyl acetate (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated to give crude methyl 2-(p-hydroxyphenyl)propionate (1.8 g). LCMS m / z = 181.1 [M+H] + .

[0441] Step 4: Synthesis of methyl 2-(4-hydroxy-3-nitrophenyl)propionate

[0442] A solution of methyl 2-(p-hydroxyphenyl)propionate (2.6 g, 14.4 mmol, 1 equivalent) in acetic acid (10 mL) was cooled to 0 °C. Nitric acid (602 µL, 14.4 mmol) in acetic acid was added dropwise to the reaction mixture, and the mixture was stirred for 10 min at the same temperature, followed by stirring at room temperature for 1 h. The reaction was monitored by TLC and LCMS. Water (30 mL) was added to the reaction mixture at 0 °C, and the mixture was extracted with EtOAc (50 mL) and washed with brine. The organic layer was dried over sodium sulfate and concentrated to give a crude product, which was purified by rapid column chromatography, eluting with 8% EtOAc-heptane to give methyl 2-(4-hydroxy-3-nitrophenyl)propionate (2 g, 62%) as a yellow liquid. LCMS m / z = 224.0 [MH].

[0443] Step 5: Synthesis of methyl 2-(3-amino-4-hydroxyphenyl)propionate

[0444] Iron (496 mg, 2 equivalents, 8.88 mmol) and ammonium chloride (713 mg, 3 equivalents, 13.3 mmol) were added to a solution of methyl 2-(4-hydroxy-3-nitrophenyl)propionate (1 g, 4.44 mmol, 1 equivalent) in ethanol (10 mL) and water (8 mL), and the mixture was stirred at 70 °C for 16 h. The reaction progress was monitored by TLC. The reaction mixture was filtered through a celite bed, the filtrate was diluted with water (10 mL), and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over NaSO4 and concentrated to give methyl 2-(3-amino-4-hydroxyphenyl)propionate (0.6 g, yield: 70%) as a brown solid. LCMS m / z = 196.1 [M+H] + .

[0445] Step 6: Synthesis of methyl 2-(2-aminobenzo[d]oxazol-5-yl)propionate

[0446] To a stirred solution of methyl 2-(3-amino-4-hydroxyphenyl)propionate (2 g, 10.2 mmol, 1 equivalent) in methanol (20 mL), bromoformonitrile (1.3 g, 12.3 mmol, 1.2 equivalent) was added. The reaction mixture was then stirred at room temperature for 16 hours. The reaction progress was monitored by TLC after completion. The reaction mixture was concentrated under reduced pressure to give a crude residue. The residue was alkalized with saturated aqueous Na₂CO₃ solution (30 mL), and the resulting solid was filtered and dried to give methyl 2-(2-amino-1,3-benzoxazol-5-yl)propionate (2.1 g, 93% yield) as a brown solid. LCMS m / z = 221.2 [M+H] + .

[0447] Step 7: Synthesis of methyl 2-[2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionate

[0448] To a DMF (55 mL) solution of methyl 2-(2-amino-1,3-benzoxazole-5-yl)propionate (5.5 g, 25 mmol), 2-(methylthio)-1,3-benzoxazole (4.95 g, 30 mmol, 1.2 equivalents) and dicesium carbonate (20.3 g, 62.4 mmol) were added, and the reaction mixture was heated at 85 °C for 16 h. The reaction progress was monitored by TLC and LCMS. Once the reaction was complete, the reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography using 50%–60% ethyl acetate in n-heptane as the eluent to give the title compound (3 g, 35.61%). LCMS m / z = 338.0 [M+H] + .

[0449] Step 8: Synthesis of 2-[2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionic acid

[0450] Lithium hydroxide (1.06 g, 44.5 mmol) was added to a stirred solution of methyl 2-[2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionate (3 g, 8.89 mmol) in a mixture of methanol (25.3 mL), THF (25.3 mL), and water (25.3 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a crude residue. The residue was acidified with dilute HCl (10 mL), and the resulting solid was filtered and dried under vacuum to give the title compound (1.5 g, 52.17%). LCMS m / z = 324 [M+H] + .

[0451] Step 9: N Synthesis of 2-[2-(2-hydroxyethoxy)ethyl]2-[2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionamide

[0452] Add 2-(2-aminoethoxy)ethanol (0.976 g, 9.28 mmol) and 2,4,6-tripropyl-1,3,5,2λ to a DCM solution of 2-[2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionic acid (1.5 g, 4.64 mmol) in 15.8 mL. 5 ,4λ 5 ,6λ 5 - Trioxane-2,4,6-trione (5.52 mL, 9.28 mmol). Triethylamine (1.94 mL, 13.9 mmol) was added to the above mixture at 0 °C, and the reaction mixture was stirred at room temperature for 5 hours. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude product. The crude product was further purified under the preparation conditions described below, and the collected fractions were concentrated to give N-[2-(2-hydroxyethoxy)ethyl]2-[2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionamide (0.9 g, 47.26% yield) as a white solid. Note: The two isomers were collected and concentrated together to give the racemic compound. LCMS m / z = 411.4 [M+H] + .

[0453] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.05 ( t, J = 5.6 Hz, 1 H), 7.55 – 7.51(m,3 H), 7.45 – 7.43 (m,1 H), 7.31 – 7.28 (m, 1 H), 7.25 – 7.21 (m, 1 H),7.19 – 7.16 (m, 1 H), 3.74 – 3.69 (m, 1 H), 3.47 – 3.37 (m, 8 H), 1.36 ( d , J =6.8 Hz, 3 H).

[0454] Purification conditions Column: CHIRALCEL OJ H (250 mm x 4.6 mm x 5 µm) Mobile phase: n-hexane: ethanol containing 0.1% FA (70:30) Flow rate: 1.0 mL / min

[0455] Examples 25 and 26 N -[2-(2-hydroxyethoxy)ethyl]( R )-2-[2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionamide and N -[2-(2-hydroxyethoxy)ethyl]( S Synthesis of 2-[2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionamide

[0456] Chiral purification in Example 24

[0457] Purification conditions Column: CHIRALCEL OJ H (250 mm x 4.6 mm x 5 µm) Mobile phase: n-hexane: ethanol containing 0.1% FA (70:30) Flow rate: 1.0 mL / min

[0458] After chiral purification, the fraction containing the compound (peak 1) was concentrated under reduced pressure to obtain... N -[2-(2-hydroxyethoxy)ethyl](R)-2-[2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionamide (0.195 g, 21.67%). LCMS m / z = 411.4 [M+H]+ .

[0459] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.07 - 8.04 (m, 1H), 7.55 - 7.51 (m,3H), 7.46 - 7.44 (m, 1H), 7.32 - 7.11 (m, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 3.79 (s, 1H), 2.33 (s, 6H), 1.43 (d, J = 6.4 Hz, 3H).

[0460] After chiral purification, the fraction containing the compound (peak 1) was concentrated under reduced pressure to obtain... N -[2-(2-hydroxyethoxy)ethyl]( S 2-[2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionamide (0.220 g, 24.44%). LCMS m / z = 411.4 [M+H] + .

[0461] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.07 - 8.04 (m, 1H), 7.55 - 7.51 (m,3H), 7.46 - 7.44 (m, 1H), 7.32 - 7.11 (m, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 3.79 (s, 1H), 2.33 (s, 6H), 1.43 (d, J = 6.4 Hz, 3H).

[0462] Example 27 2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)- N -(2-(2-hydroxyethoxy)ethyl)- N Synthesis of methylpropionamide

[0463] Example 27 was synthesized following step 9 of Example 24. Note: Both isomers were collected and concentrated together to obtain the racemic compound. LCMS (ES) m / z = 425 [M+H] + .

[0464] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 – 7.52 (m, 2 H), 7.47 – 7.44 (m, 2 H), 7.31 – 7.28 (m, 1 H), 7.25 – 7.21 (m, 1H), 7.17 – 7.13 (m, 1 H), 4.25– 4.14 (m, 1 H), 3.65 – 3.60 (m, 1 H), 3.47 – 3.43 (m, 8 H), 2.92 – 2.85(m, 3 H), 1.31 ( t , J = 6.4 Hz, 3 H).

[0465] Purification conditions Column: CHIRALCEL OJ H (250 mm x 4.6 mm x 5 µm) Mobile phase A: Hexane: Ethanol containing 0.1% DEA (50:50) Flow rate: 1.0 mL / min

[0466] Examples 28 and 29 ( R )-2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)- N -(2-(2-hydroxyethoxy)ethyl)- N -Methylpropionamide and (S)-2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)- N -(2-(2-hydroxyethoxy)ethyl)- N Synthesis of methylpropionamide

[0467] Chiral purification in Example 27

[0468] Purification conditions Column: CHIRALCEL OJ H (250 mm x 4.6 mm x 5 µm) Mobile phase: n-hexane: ethanol containing 0.1% DEA (50:50) Flow rate: 1.0 mL / min

[0469] After chiral purification, the fraction containing the compound (peak 1) was concentrated under reduced pressure to give 2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)- N -(2-(2-hydroxyethoxy)ethyl)- N 1,3-methylpropionamide (0.06 g, 7.5%). LCMS (ES) m / z = 425 [M+H] + .

[0470] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 – 7.52 (m, 2 H), 7.47 – 7.44 (m, 2 H), 7.31 – 7.28 (m, 1 H), 7.25 – 7.21 (m, 1H), 7.17 – 7.13 (m, 1 H), 4.25– 4.14 (m, 1 H), 3.65 – 3.60 (m, 1 H), 3.47 – 3.43 (m, 8 H), 2.92 – 2.85(m, 3 H), 1.31 ( t , J = 6.4 Hz, 3 H).

[0471] After chiral purification, the fraction containing the compound (peak 1) was concentrated under reduced pressure to give 2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)- N -(2-(2-hydroxyethoxy)ethyl)- N 1,3-methylpropionamide (0.220 g, 27.5%). LCMS (ES) m / z = 425 [M+H] + .

[0472] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 – 7.52 (m, 2 H), 7.47 – 7.44 (m, 2 H), 7.31 – 7.28 (m, 1 H), 7.25 – 7.21 (m, 1H), 7.17 – 7.13 (m, 1 H), 4.25– 4.14 (m, 1 H), 3.65 – 3.60 (m, 1 H), 3.47 – 3.43 (m, 8 H), 2.92 – 2.85(m, 3 H), 1.31 ( t , J = 6.4 Hz, 3 H).

[0473] Example 30 Synthesis of 2-{5-[(diethylamino)methyl]-1,3-benzoxazole-2-ylamino}-5-fluoro-1,3-benzoxazole

[0474] Step 1: Synthesis of 5-fluoro-1,3-benzoxazol-2-ylamine

[0475] Cyanogen bromide (31.2 g, 295 mmol) was added to a stirred methanol (300 mL) solution of 15 g (118 mmol) of 2-amino-4-fluorophenol at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC (40% ethyl acetate / n-hexane) and LC-MS. The reaction mixture was evaporated under reduced pressure to give a brown solid residue. The residue was resuspended in water (100 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give a crude product. The crude product was further purified by column chromatography using 40% ethyl acetate in n-heptane as the eluent to give a brown solid of 5-fluoro-1,3-benzoxazol-2-amine (12 g, 66.85%). LCMS(ES) m / z = 153 [M+H] + .

[0476] Step 2: Synthesis of methyl 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylate

[0477] Methyl 2-iodo-1,3-benzoxazole-2-ylamine (0.8 g, 5.26 mmol) was added to a THF (10 mL) solution of 5-fluoro-1,3-benzoxazole-5-carboxylate (1.59 g, 5.26 mmol), and the mixture was heated at 70 °C for 4 hours. The reaction mixture was concentrated, the residue was quenched with water (20 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give a crude product. The crude product was further resuspended in DCM (20 mL), and the resulting precipitate was filtered and dried under vacuum to give methyl 2-(5-fluoro-1,3-benzoxazole-2-ylamino)-1,3-benzoxazole-5-carboxylate (1 g, 41%) as a brown solid. LCMS (ES) m / z = 328.2 [M+H] + .

[0478] Step 3: Synthesis of [2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]methanol

[0479] LiAlH4 (162 mg, 2 equivalents, 4.28 mmol) was added to a tetrahydrofuran (10 mL, 123 mmol) solution of methyl 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylate (1 g, 2.14 mmol) stirred under inert conditions at 0–5 °C. The reaction mixture was stirred at 0–5 °C for 2 h. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the reactants were quenched with 10 mL of aqueous NH4Cl solution and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude substance was purified by MPLC using 75% EtOAc in n-heptane to give [2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]methanol (450 mg, 70%) as a light brown solid. LCMS (ES) m / z = 300.2 [M+H] + .

[0480] Step 4: Synthesis of [5-(chloromethyl)-1,3-benzoxazol-2-yl](5-fluoro-1,3-benzoxazol-2-yl)amine

[0481] At 0 °C, thionyl dichloride (0.13 mL, 1.75 mmol) was added to a stirred solution of [2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]methanol (350 mg, 1.17 mmol) in 10 mL of dichloromethane. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reactants were concentrated under reduced pressure under nitrogen to give a crude residue. This crude product was used directly for the next step. LCMS (ES) m / z = 318.1 [M+H] + .

[0482] Step 5: Synthesis of 2-{5-[(diethylamino)methyl]-1,3-benzoxazole-2-ylamino}-5-fluoro-1,3-benzoxazole

[0483] At room temperature, dipotassium carbonate (261 mg, 1.89 mmol) and diethylamine (0.130 mL, 1.26 mmol) were added to a stirred solution of [5-(chloromethyl)-1,3-benzoxazol-2-yl](5-fluoro-1,3-benzoxazol-2-yl)amine (0.2 g, 0.630 mmol) in dimethylformamide (5 mL). The reaction mixture was stirred at 60 °C for 2 h. The reaction progress was monitored by TLC [70% EA in heptane] and LCMS. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the crude compound. The crude product was further purified by preparative HPLC under the conditions described below to obtain 2-{5-[(diethylamino)methyl]-1,3-benzoxazol-2-ylamino}-5-fluoro-1,3-benzoxazole (89 mg, 39.9%) as a pale yellow liquid. LCMS (ES) m / z = 355.29 [M+H] + .

[0484] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.38 - 7.34 (m, 3H) 7.130 (d, J =7.2Hz, 1H), 7.074 (d, J = 7.2Hz, 1H), 6.84 (t, J = 8.0Hz, 1H), 3.81 (s, 2H), 2.67(s, 4H), 1.09 - 1.05 (t, J = 7.2Hz, 6H).

[0485] Preparative HPLC conditions Column: Xselect C18 (250x19) mm; 5u Flow rate: 19.0 mL / min Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile The desired product was obtained in 12.57 min.

[0486] Example 31 Synthesis of 2-(((2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)methyl)(methyl)amino)ethanol-1-ol

[0487] Example 31 was synthesized according to step 5 of Example 30. LCMS (ES) m / z = 357.25 [M+H] + .

[0488] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.57 - 7.53 (m, 1H) 7.50 (t, J = 4.0Hz, 2H), 7.33 (d, J = 2.8Hz, 1H), 7.19 (m, 1H), 7.05 (m, 1H), 3.79 (s, 2H), 3.29(m, 2H), 2.34 (s, 2H).

[0489] Purification conditions Column: Xbridge C18 (250x19)mm; 5u Flow rate: 19.0 mL / min Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile

[0490] Example 32 5-Fluoro- N Synthesis of -(5-((methyl(2,2,2-trifluoroethyl)amino)methyl)benzo[d]oxazol-2-yl)benzo[d]oxazol-2-amine

[0491] Example 32 was synthesized according to step 5 of Example 30. LCMS (ES) m / z = 395.2 [M+H] + .

[0492] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.57 - 7.55 (t, 1H), 7.51 (d, J =8.8Hz, 2H), 7.32 (d, J = 2.8Hz, 2H), 7.20 (s, 1H), 3.79 (s, 2H), 3.33 - 3.26(m, 2H) 2.34 (s, 3H).

[0493] Purification conditions Column: Xbridge C18 (19 mm X 250 mm X 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 19 mL / min

[0494] Example 33 5-Fluoro- N Synthesis of 5-(morpholinylmethyl)benzo[d]oxazol-2-yl)benzo[d]oxazol-2-amine

[0495] Example 33 was synthesized according to step 5 of Example 30. LCMS (ES) m / z = 369.3 [M+H] + .

[0496] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.16 - 7.13 (m, 3 H), 6.97 - 6.94 (dd, J = 2.4 Hz, 2.4 Hz, 1 H), 6.84 - 6.82 (dd, J = 1.2 Hz, 1.2 Hz, 1 H), 6.82 (m, 1 H), 3.58 (t, J = 8.0 Hz, 4 H), 3.46 (s, 2 H), 2.36 - 2.33 (m, 4H).

[0497] Purification conditions Column: Xterra RP C18 (19 mm X 250 mm X 10 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 19 mL / min

[0498] Example 34 5-(azacyclobutane-1-ylmethyl)- N Synthesis of -(5-fluorobenzo[d]oxazol-2-yl)benzo[d]oxazol-2-amine

[0499] Example 34 was synthesized according to step 5 of Example 30. LCMS (ES) m / z = 339.3 [M+H] + .

[0500] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.30 - 7.25 (m, 3 H), 7.06 - 7.03(dd, J = 2.4 Hz, 2.8 Hz 1 H), 6.99 - 6.97 (dd, J = 1.6 Hz, 1.6 Hz 1 H), 6.78- 6.73 (m, 1 H), 3.99 (s, 2 H), 3.64 (t, J = 8.0 Hz, 4 H), 2.22 - 2.07 (s, 2H).

[0501] Purification conditions Column: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile

[0502] Example 35 5-Fluoro- N Synthesis of 5-((4-methylpiperazin-1-yl)methyl)benzo[d]oxazol-2-yl)benzo[d]oxazol-2-amine

[0503] Example 35 was synthesized according to step 5 of Example 30. LCMS (ES) m / z = 382.4 [M+H] + .

[0504] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.39 - 7.31 (m, 3H), 7.15 (d, J = 8.0Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.89 - 6.84 (m, 1H), 3.53 (s, 2H), 2.33 (s,8H), 2.26 (s, 3H).

[0505] Purification conditions Column: X-Select CSH C18 (250x19)mm; 5u Flow rate: 19.0 mL / min Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile

[0506] Example 36 5-Fluoro-N Synthesis of 5-(((2-methoxyethyl)amino)methyl)benzo[d]oxazol-2-yl)benzo[d]oxazol-2-amine

[0507] Example 36 was synthesized according to step 5 of Example 30. LCMS (ES) m / z = 357.35 [M+H] + .

[0508] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.20 - 7.14 (m, 3H), 6.97 (dd, J =2.4Hz, 2.4Hz, 1H), 6.66 - 6.61 (m, 1H), 3.81 (s, 2H), 3.44 (t, J = 5.2Hz, 2H),3.25 (s, 3H), 2.75 (t, J = 5.2Hz, 2H).

[0509] Purification conditions Column: X-Select CSH C18(250x19)mm; 5u Flow rate: 19.0 mL / min Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile

[0510] Example 37 5-Fluoro- N Synthesis of 5-((methylamino)methyl)benzo[d]oxazol-2-yl)benzo[d]oxazol-2-amine

[0511] Example 37 was synthesized according to step 5 of Example 30. LCMS (ES) m / z = 313.3 [M+H] + .

[0512] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.27 (s, 2H), 7.185 (m, 1H), 6.97 (t,J = 7.6Hz, 2H), 6.66 (t,J = 9.6Hz, 1H), 4.08 (s, 2H), 2.54 (s, 3H).

[0513] Purification conditions Column: X-Select CSH C18(250x19)mm; 5u Flow rate: 19.0 mL / min Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile

[0514] Example 38 5-Fluoro- N Synthesis of -(5-(((2,2,2-trifluoroethyl)amino)methyl)benzo[d]oxazol-2-yl)benzo[d]oxazol-2-amine

[0515] Example 38 was synthesized according to step 5 of Example 30. LCMS (ES) m / z = 379.2 [M+H] + .

[0516] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 - 7.46 (m, 1H), 7.47 (d, J =8.0Hz, 1H), 7.06 - 6.78 (m, 5H), 3.54 (s, 2H), 2.67 (s, 2H).

[0517] Purification conditions Column: Sunfire C18 (250x19)mm; 5u Flow rate: 19.0 mL / min Mobile phase A: 5 mM ammonium acetate aqueous solution Mobile phase B: Acetonitrile

[0518] Example 39 Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-carboxylic acid

[0519] Lithium hydroxide monohydrate (641 mg, 15.3 mmol) was added to a stirred solution of methyl 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylic acid (1 g, 3.06 mmol) in THF (10 mL), MeOH (10 mL), and water (10 mL), and the mixture was stirred at room temperature for 12 hours. The progress of the reaction mixture was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was acidified with dilute HCl (15 mL) and filtered. The resulting solid was first washed with heptane (3 mL), then washed with DCM (3 mL), decanted, and dried to give 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylic acid (250 mg, 26%) as a light brown solid. LCMS (ES) m / z = 314.1 [M+H] + .

[0520] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 13.02 (s, 1H), 8.06 (d, J=1.2 Hz,1H), 7.89 - 7.87 (dd, 1H), 7.65 (s, 1H), 7.60-7.57 (m, 1H), 7.37 - 7.34 (dd,1H), 7.21 (bs, 0.5H), 7.11-7.06 (m, 1H), 6.95 (bs, 0.5H).

[0521] Purification conditions Column: Inertsil C18 (19 mm x 250 mm x 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 19 mL / min

[0522] Example 40 2-((5-fluorobenzo[d]oxazol-2-yl)amino)- N Synthesis of 5-methylbenzo[d]oxazol-5-carboxamide

[0523] Example 40 was synthesized in a manner similar to that of Example 16. LCMS (ES) m / z = 327.3 [M+H] + .

[0524] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.5 (s, 1 H), 7.95 (d, J = 1.2 Hz, 1H), 7.74 - 7.72 (dd, J = 1.6 Hz, J = 1.6 Hz, 1 H), 7.62 - 7.56 (m, 2 H), 7.37 -7.34 (dd, J = 2.4 Hz, J = 2.4 Hz, 1 H), 7.10 - 7.05 (m, 1 H), 2.81 - 2.80 (m, 3H).

[0525] Purification conditions Column: Xselect CSH C18 (250x19)mm; 5u Flow rate: 19.0 mL / min Mobile phase: EtOAc:hexane (7:3).

[0526] Example 41 N Synthesis of 2-(dimethylamino)ethyl)-2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-carboxamide

[0527] Example 41 was synthesized in a manner similar to that of Example 16. LCMS (ES) m / z = 356.3 [M+H] + .

[0528] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.50 (t, J = 8.0 Hz, 1 H), 7.92 (bs,2 H), 7.75 (s, 1 H), 7.54 - 7.47 (dd, J = 1.2 Hz, 1.6 Hz, 1 H), 7.30 (d, J =8.0 Hz, 1 H), 7.21 - 7.17 (m, 1 H), 7.04 - 7.01 (dd, J = 2.4 Hz, 2.4 Hz, 1H), 6.71 - 6.65 (m, 1 H), 3.56 - 3.51 (m, 2 H), 3.07 (t, J = 8.0 Hz, 2H).

[0529] Purification conditions Column: Sunfire C18 (19 mm x 250 mm x 5 mic) Mobile phase (A): 5 mM ammonium acetate aqueous solution Mobile phase (B): Acetonitrile Flow rate: 19 mL / min

[0530] Example 42 2-((5-fluorobenzo[d]oxazol-2-yl)amino)- N Synthesis of 2,2,2-trifluoroethyl)benzo[d]oxazol-5-carboxamide

[0531] Example 42 was synthesized in a manner similar to that of Example 16. LCMS (ES) m / z = 395.3 [M+H] + .

[0532] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.18 (t, J = 8.0 Hz, 1 H), 8.01 (d, J = 1.2 Hz, 1 H), 7.82 - 7.79 (dd, J = 1.6 Hz, 2.0 Hz, 1 H), 7.66 (d, J = 8.0Hz, 1 H), 7.60 - 7.57 (m, 1 H), 7.37 - 7.34 (dd, J = 2.4 Hz, 2.8 Hz, 1 H), 7.11 - 7.06 (m, 1 H), 4.16 - 4.07 (m, 2 H).

[0533] Purification conditions Column: X-Select CSH C18 (250x19)mm; 5u Flow rate: 19.0 mL / min Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile

[0534] Example 43 N Synthesis of -(2-aminoethyl)-2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-carboxamide

[0535] Example 43 was synthesized in a manner similar to that of Example 16. LCMS (ES) m / z = 384.1 [M+H]+ .

[0536] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 10.52 (bs, 1 H), 8.48 (t, J = 8.0 Hz, 1 H), 7.78 (s, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.32 - 7.29 (m, 1 H), 7.09 (d, J = 8.0 Hz, 1 H), 6.81 (t, J = 8.0 Hz, 1H), 3.52 - 3.48 (m, 2 H), 2.91 - 2.86 (m, 2 H), 2.58 (s, 6 H).

[0537] Purification conditions Column: Sunfire C18 (250 mm x 4.6 mm x 5 µm) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 1.0 mL / min

[0538] Example 44 2-((5-fluorobenzo[d]oxazol-2-yl)amino)- N Synthesis of -(isoxazo-4-yl)benzo[d]oxazol-5-carboxamide

[0539] Example 44 was synthesized in a manner similar to that of Example 16. LCMS (ES) m / z = 380.3 [M+H] + .

[0540] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 10.81 (s, 1 H), 9.28 (s, 1 H), 8.75 (s, 1 H), 8.06 (s, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H),7.58 - 7.55 (m, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.07 (t, J = 2.4 Hz, 1 H).

[0541] Purification conditions Column: Sunfire C18 (250 mm x 4.6 mm x 5 µm) Mobile phase: MEOH:DCM (1:9)

[0542] Example 45 N Synthesis of 2-(2-(2-hydroxyethoxy)ethyl)-2-((6-methylbenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-carboxamide

[0543] To a solution of 2-(6-methyl-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylic acid (0.9 g, 2.91 mmol) cooled to 0 °C, N-ethylbis(isopropyl)amine (1.52 mL, 3 equivalents, 8.73 mmol), 2,4,6-T3P (3.46 mL, 2 equivalents, 5.82 mmol), and 2-(2-aminoethoxy)ethanol (367 mg, 1.2 equivalents, 3.49 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC and LCMS data. Subsequently, the reaction mixture was quenched with water (80 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude substance was purified by preparative HPLC to obtain N-[2-(2-hydroxyethoxy)ethyl]-2-(6-methyl-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxamide (210 mg, 18% yield) as a grayish-white solid. LCMS (ES) m / z = 397.4 [M+H] + .

[0544] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.55(t, J = 5.2 Hz, 1H), 7.98(s, 1H),7.73(dd, J = 1.2Hz, 1H), 7.58(d, J = 8.4Hz, 1H), 7.43 - 7.39(m, 2H), 7.13(d, J =8Hz, 1H), 4.61(s, 1H), 3.57-3.35(m, 8H), 2.40(s,3H).

[0545] Purification conditions Column: X-Bridge C18 (250 mm x 4.6 mm x 5 µm) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 1.0 mL / min

[0546] Example 46 2-((6-fluorobenzo[d]oxazol-2-yl)amino)- N Synthesis of 5-(2-(2-hydroxyethoxy)ethyl)benzo[d]oxazol-5-carboxamide

[0547] Example 46 was synthesized in a manner similar to that of Example 45. LCMS (ES) m / z = 401.4 [M+H] + .

[0548] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.56(t, J = 5.6 Hz, 1H), 7.96 (s, 1H), 7.74 (dd, J = 8.4Hz, 1H), 7.61 - 7.51 (m, 3H), 7.19 - 7.14 (m, 1H), 4.60 (s, 1H), 3.57 - 3.42 (m, 8H).

[0549] Purification conditions Column: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 1.0 mL / min

[0550] Example 47 2-((6-chlorobenzo[d]oxazol-2-yl)amino)- N Synthesis of 5-(2-(2-hydroxyethoxy)ethyl)benzo[d]oxazol-5-carboxamide

[0551] Example 47 was synthesized in a manner similar to that of Example 45. LCMS (ES) m / z = 417.4 [M+H] + .

[0552] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.56 - 8.55 (m, 1 H), 7.94 (s, 1 H),7.73 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 4.60 (s, 1 H), 3.71 - 3.32 (m, 8 H).

[0553] Purification conditions Column: Kinetex EVO C18 (100 mm x 2.1 mm x 2.6 µm) Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile Flow rate: 0.5 mL / min

[0554] Example 48 N Synthesis of 2-(2-(2-hydroxyethoxy)ethyl)-2-((6-methoxybenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-carboxamide

[0555] Example 48 was synthesized in a manner similar to that of Example 45. LCMS (ES) m / z = 413.4 [M+H] + .

[0556] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.32 (s, 1H), 7.64 (d, J = 8.00 Hz,1H), 7.57 (d, J = 8.40 Hz, 1H), 7.44 (s, 1H), 7.21 (s, 1H), 6.81 (d, J = 8.40Hz, 1H), 6.60-6.57 (m, 1H), 4.54 (t, J = 5.60 Hz, 1H), 3.71 (s, 3H), 3.45-3.36 (m, 8H).

[0557] Purification conditions Column: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 1.0 mL / min

[0558] Example 49 Synthesis of 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)ethanol-1-ol

[0559] Step 1: Synthesis of 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylic acid

[0560] Lithium hydroxide monohydrate (641 mg, 5 equivalents, 15.3 mmol) was added to a stirred solution of methyl 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylic acid (1 g, 3.06 mmol) in THF (10 mL), MeOH (10 mL), and water (10 mL), and stirred at room temperature for 12 hours. The progress of the reaction mixture was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was acidified with dilute HCl (15 mL) and filtered. The resulting solid was first washed with heptane (5 mL), then washed with DCM (5 mL), decanted, and dried to give 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylic acid (0.9 g, 94%) as a light brown solid. LCMS (ES) m / z = 314.1 [M+H] + .

[0561] Step 2: Synthesis of N-methoxy-N-methyl-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxamide

[0562] At 0 °C, N-ethylbis(isopropyl)amine (334 µL, 3 equivalents, 1.92 mmol) and 2,4,6-tripropyl-1,3,5,2λ were added to a DCM (7 mL) solution of 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylic acid (0.2 g, 638 µmol). 5 ,4λ 5 ,6λ 5- Trioxane-2,4,6-trione (406 mg, 2 equivalents, 1.28 mmol). After stirring for 30 minutes, N-methyl-O-methylhydroxylamine (81 mg, 1.3 equivalents, 830 µmol) was added to the mixture at 0 °C. After the reaction was complete, RM was quenched with water (25 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure using a rotary evaporator to give the crude product. The crude product was purified by column chromatography using 80% EtOAc:hexane as the eluent to give the pure product N-methoxy-N-methyl-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxamide (80 mg, 35%) as a brown solid. LCMS (ES) m / z = 357.1 [M+H] + .

[0563] Step 3: Synthesis of 1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]-1-ethylone

[0564] Lithium methanide (60.1 mg, 3 equivalents, 2.74 mmol) was added to a THF (7 mL) solution of N-methoxy-N-methyl-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxamide (325 mg, 912 µmol) at -78 °C under nitrogen atmosphere. The reaction mixture was then stirred at -78 °C for 5 h. The reaction was then stirred at room temperature for 10 h. After 15 h, the reaction was quenched with a saturated ammonium chloride solution (15 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure using a rotary evaporator to give 1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]-1-ethyl ketone (0.2 g, 70.44%) as a brown solid. LCMS (ES)m / z = 312.1 [M+H] + .

[0565] Step 4: Synthesis of 1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]-1-ethanol

[0566] Sodium boranuide (72.9 mg, 3 equivalents, 1.93 mmol) was added to a stirred solution of 1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]-1-ethylone (0.2 g, 0.643 mmol) in MeOH (6 mL) at 0 °C, and the mixture was stirred for 5 hours at room temperature. After the reaction was complete, the reaction mixture was concentrated. The residue was quenched with water (10 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by combiflash chromatography (MPLC), and the product was eluted in 3% MeOH:DCM to give 1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]-1-ethanol (160 mg, 79%). The product was then further purified by preparative HPLC to obtain a pure compound (15 mg). LCMS (ES) m / z = 314.2 [M+H] + .

[0567] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.41 (bs, 0.5H), 7.56 - 7.52 (m,1H), 7.51 (s, 1H), 7.47 (s, 1H), 7.34 - 7.31 (dd, 1H), 7.22 - 7.20 (dd, 1H), 7.07 - 7.01 (m, 1H), 5.26 (s, 1H), 4.83 - 4.78 (m, 1H), 1.35 (d, J=6.4 Hz, 3H).

[0568] Purification conditions Column: Xselect CSH-C18 (19 mm X 250 mm X 5 mic) Mobile phase (A): 5 mM ammonium acetate aqueous solution Mobile phase (B): Acetonitrile Flow rate: 19 mL / min Chiral HPLC: Racemic mixture (44.76% + 55.24%) Optical rotation: 0.00

[0569] Example 50 5-(1-(dimethylamino)ethyl)- N Synthesis of -(5-fluorobenzo[d]oxazol-2-yl)benzo[d]oxazol-2-amine

[0570] Step 1: Synthesis of [5-(1-chloroethyl)-1,3-benzoxazol-2-yl](5-fluoro-1,3-benzoxazol-2-yl)amine

[0571] At 0 °C, thionyl dichloride (69.5 µL, 1.5 equivalents, 958 µmol) was added to a stirred solution of 1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]-1-ethanol (0.2 g, 638 µmol) in dichloromethane (5 mL, 78.1 mmol). The reaction mixture was stirred at room temperature for 30 min. After 30 min, the RM was concentrated under reduced pressure under nitrogen to give a crude residue. This crude product was used directly for the next step. LCMS (ES) m / z = 331.9 [M+H] + .

[0572] Step 2: Synthesis of 2-{5-[1-(dimethylamino)ethyl]-1,3-benzoxazole-2-ylamino}-5-fluoro-1,3-benzoxazole

[0573] At room temperature, triethylamine (254 µL, 3 equivalents, 1.81 mmol) and dimethylamine (32.6 mg, 1.2 equivalents, 723 µmol) were added to a stirred solution of [5-(1-chloroethyl)-1,3-benzoxazol-2-yl](5-fluoro-1,3-benzoxazol-2-yl)amine (0.2 g, 603 µmol) in dimethylformamide (5 mL, 64.6 mmol). The reaction mixture was stirred at 90 °C for 12 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was concentrated under reduced pressure to give a crude product (350 mg). This crude product was purified by preparative HPLC to give 2-{5-[1-(dimethylamino)ethyl]-1,3-benzoxazol-2-ylamino}-5-fluoro-1,3-benzoxazole (9 mg, 4.39%). LCMS (ES) m / z = 339.3 [M+H] + .

[0574] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.37 (s, 3H), 7.15 - 7.14 (m, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 3.79 (s, 1H), 2.33 (s, 6H), 1.43 (d,J = 6.4 Hz, 3H).

[0575] Purification conditions Column: X-Bridge C18 (250 mm x 4.6 mm x 5µm) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 1.0 mL / min Chiral HPLC: Racemic mixture (59.89% + 40.11%) Optical rotation: 0.00

[0576] Example 51 Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)acetic acid

[0577] Step 1: Preparation of 5-fluoro-2,3-dihydro-1,3-benzoxazolidine-2-thione

[0578] Potassium dicarbonate (1.09 g, 7.87 mmol) dissolved in water (2 mL, 111 mmol) was added to a solution of 2-amino-4-fluorophenol (1 g, 7.87 mmol) in ethanol (15 mL, 257 mmol), followed by the addition of methanedithion (475 µL, 7.87 mmol), and the reaction was refluxed at 50 °C for 2 h. The reaction mixture was stirred at 50 °C for 2 h. The reaction progress was monitored by TLC. Once the reaction was complete, the reaction mixture was quenched with water, and the aqueous solution was neutralized with acetic acid (3.0 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with water and brine, dried over Na₂SO₄, and concentrated under reduced pressure to give a crude residue. The crude sample was loaded onto a rapid column for MPLC, using 10%-12% EtOAc in heptane as the eluent, to obtain 5-fluoro-2,3-dihydro-1,3-benzoxazolidine-2-thione as a brown solid (0.6 g, yield: 45%).

[0579] Step 2: Preparation of 2-chloro-5-fluoro-1,3-benzoxazole

[0580] A stirred solution of 5-fluoro-2,3-dihydro-1,3-benzoxazolidine-2-thione-methane (1 / 1) (0.3 g, 1.62 mmol) in thionyl dichloride (5 mL) was refluxed at 70 °C for 2 h. The reaction progress was monitored by TLC and mass spectrometry. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give 2-chloro-5-fluoro-1,3-benzoxazole (265 mg, yield: 26%) as a purple gel. The crude product was used in the next step without further purification. LCMS (ES) m / z = 172.0 [M+H] + .

[0581] Step 3: Preparation of methyl (3-amino-4-hydroxyphenyl)acetate

[0582] Palladium (0.8 g, 1.1 equivalent, 7.52 mmol) was added to a methanol (15 mL, 370 mmol) solution of methyl (4-hydroxy-3-nitrophenyl)acetate (1.5 g, 7.1 mmol) at room temperature and under a nitrogen atmosphere, and the reaction was stirred at room temperature for 6 h under a hydrogen atmosphere at 60 PSI. The reaction progress was monitored by TLC. Once the reaction was complete, the reaction mixture was filtered through a celite bed with ethyl acetate, and the filtrate was concentrated under reduced pressure to give methyl (3-amino-4-hydroxyphenyl)acetate (1.3 g, yield: 98%, purity: 97%) as a brown solid. LCMS (ES) m / z = 182.0 [M+H] + .

[0583] Step 4: Preparation of (2-amino-1,3-benzoxazol-5-yl)methyl acetate

[0584] At 0 °C, bromoformonitrile (1.75 g, 3 equivalents, 16.6 mmol) was added to a stirred methanol (15 mL) solution of (3-amino-4-hydroxyphenyl)acetic acid (1 g, 5.52 mmol). The reaction mixture was then stirred at room temperature for 16 hours, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude residue. The residue was alkalized with a saturated aqueous solution of Na₂CO₃ (40 mL), and the resulting solid was filtered and dried to give (0.9 g, 79% yield) methyl (2-amino-1,3-benzoxazol-5-yl)acetic acid as a brown solid.

[0585] Step 5: Preparation of methyl [2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]acetate

[0586] To a THF (2.0 mL) solution of methyl (2-amino-1,3-benzoxazol-5-yl)acetate (90 mg, 436 µmol), lithium 2-methyl-2-propoxide (69.9 mg, 2 equivalents, 873 µmol) and 2-chloro-5-fluoro-1,3-benzoxazole (250 mg, 436 μmol) were added, and the mixture was heated at 70 °C for 4 hours. Once the reaction was complete, the reaction mixture was concentrated. The residue was dissolved in water (8.0 mL) and extracted with ethyl acetate (3 x 5.0 mL). The combined organic extracts were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give the crude product. The crude product was loaded onto a rapid column for MPLC, using EtOAc in heptane as the mobile phase (the compound eluted in 100% EtOAc due to solubility issues), yielding methyl [2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]acetate (40 mg, yield: 27%) as a brown solid.

[0587] Step 6: Preparation of [2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]acetic acid

[0588] Lithium hydroxide (8.42 mg, 3 equivalents, 352 µmol) was added to a stirred solution of [2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]acetate (40 mg, 117 µmol) in tetrahydrofuran (134 µL, 1.65 mmol), methanol (67.2 µL, 1.66 mmol), and water (134 µL, 7.46 mmol), and the reaction was stirred at room temperature for 3 h. The progress of the reaction mixture was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was acidified with dilute HCl (1.0 mL) and extracted with EtOAc (2 x 4.0 mL). The combined organic extracts were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a crude product. The crude product was purified by the preparative HPLC method described below to obtain the desired product, [2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]acetic acid (9 mg, yield: 23.4%), as a grayish-white solid. LCMS (ES) m / z = 328.2 [M+H] + .

[0589] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.40 (bs, 1H), 7.52- 7.55 (m, 1H),7.46 (d, J= 8.0 Hz, 1H), 7.41 (s, 1H), 7.30- 7.33 (dd, J = 2.0 Hz, 10.8 Hz, 1H),7.12 (d, J = 7.6 Hz, 1H), 7.00- 7.06 (m, 1H), 3.67 (s, 2H).

[0590] Purification conditions Column: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Methanol Flow rate: 1.0 mL / min B's percentage: 0 / 2, 1 / 2, 18 / 98, 25 / 98, 27 / 2, 30 / 2

[0591] Example 52 Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-4-yl)acetic acid

[0592] Example 52 was synthesized in a manner similar to that of Example 51. LCMS (ES) m / z = 328.3 [M+H] + .

[0593] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.53 - 7.50 (m,1 H), 7.42 - 7.41(d, J =4 Hz, 1 H), 7.32 - 7.29 (d, J = 12 Hz, 1 H), 7.16 (s, 2 H), 7.03- 6.99 (m, 1H), 3.95 (s, 2 H).

[0594] Purification conditions Column: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 1.0 mL / min B's percentage: 0 / 2, 1 / 2, 18 / 98, 25 / 98, 27 / 2, 30 / 2

[0595] Example 53 Synthesis of 2-(2-((6-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)acetic acid

[0596] Example 53 was synthesized in a manner similar to that of Example 51. LCMS (ES) m / z = 328.3 [M+H] + .

[0597] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.4 (s, 1H), 7.54-7.41 (m, 4H), 7.15-7.10 (m, 2H), 3.66 (s, 2H).

[0598] Purification conditions Column: Xterra C18 (250x19)mm; 10u Flow rate: 19.0 mL / min Mobile phase A: 0.1% aqueous solution of formic acid Mobile phase B: Acetonitrile

[0599] Example 54 2-(2-((6-methylbenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)acetic acid

[0600] Example 54 was synthesized in a manner similar to Example 51. The crude material was acidified with 1N HCl to pH (2-3), and the resulting solid was filtered using a sintering funnel to obtain the desired product. LCMS (ES) m / z = 324.3 [M+H] + .

[0601] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.44 (s, 1H), 7.46-7.37 (m, 4H), 7.11 (d, J = 8.00 Hz, 2H), 3.67 (s, 2H), 2.40 (s, 3H).

[0602] Example 55 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- N , N Synthesis of dimethylacetamide

[0603] At 0 °C, 1,1,3,3-tetramethyl-2-(3H-1,2,3,4-tetraazaindene-3-yl)-3-isoureon hexafluorophosphate (1-) (279 mg, 0.733 mmol) and dimethylamine (0.05 mL, 2 equivalents, 0.733 mmol) were added to a DMF (5.0 mL) solution of [2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]acetic acid (120 mg, 0.367 mmol). After stirring for 5 min, N-ethylbis(isopropyl)amine (0.192 mL, 3 equivalents, 1.1 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (2 x 8.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by the preparative HPLC method described below to give N,N-dimethyl[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]acetamide (8 mg, yield: 6%) as a grayish-white solid. LCMS(ES) m / z = 355.4 [M+H] + .

[0604] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.53- 7.56 (m, 1 H), 7.46 (d, J = 8.0Hz, 1 H), 7.37 (s, 1 H), 7.31- 7.34 (dd, J = 2.0 Hz, 10.8 Hz, 1 H), 7.02- 7.11(m, 2 H), 3.78 (s, 2 H), 3.03 (s, 3 H), 2.85 (s, 3 H).

[0605] Purification conditions Column: X-Bridge C18 (250 mm x 4.6 mm x 5 μm) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Gradient % B: 0 / 2, 2 / 2, 18 / 98, 25 / 98, 27 / 2, 30 / 2 Flow rate: 1.0 mL / min

[0606] Example 56 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- N Synthesis of methylacetamide

[0607] Example 56 was synthesized in a manner similar to that of Example 55. LCMS (ES) m / z = 341.3 [M+H] + .

[0608] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.99 (d, J = 3.6 Hz, 1 H), 7.53- 7.62(m, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 7.42 (s, 1 H), 7.33 (d, J = 8.4 Hz, 1 H),7.03- 7.07 (m, 1 H), 3.47 (s, 2 H), 2.58 (d, J = 4.8Hz, 3 H).

[0609] Purification conditions Column: X-Bridge C18 (250 mm x 4.6 mm x 5 μm) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Gradient % B: 0 / 2, 2 / 2, 20 / 98, 25 / 98, 28 / 2, 30 / 2 Flow rate: 1.0 mL / min

[0610] Example 57 2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)- N -Methylacetamide

[0611] Example 57 was synthesized in a manner similar to that of Example 55. LCMS (ES) m / z = 323.3 [M+H] + .

[0612] 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.48(bs, 1 H), 7.97- 7.96 (m, 1 H),7.55- 7.52 (m, 2 H), 7.45- 7.43 (m, 2 H)7.29 (t, J = 7.4 Hz, 1 H), 7.25- 7.21(m, 1 H), 7.10 (d, J = 9.6 Hz, 1 H), 3.47 (s, 2 H), 2.58 (d, J = 4.4 Hz, 3 H).

[0613] Purification conditions Column: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 1.0 mL / min B's percentage: 0 / 2, 15 / 50, 25 / 98, 27 / 2, 30 / 2

[0614] Example 58 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- N -(1-methyl-1 H Synthesis of pyrazole-4-yl)acetamide

[0615] Example 58 was synthesized in a manner similar to that of Example 55. LCMS (ES) m / z = 407.1 [M+H] + .

[0616] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 10.20 (s, 1 H), 7.85 (s, 1 H), 7.41-7.53 (m, 4 H), 7.32 (d, J = 6.0 Hz, 1 H), 7.17 (d, J = 6.8 Hz, 1 H), 7.04 (s, 1H), 3.77 (s, 2 H), 3.65 (s, 3 H).

[0617] Purification conditions Column: X-Terra C18 (250x19)mm; 10u Flow rate: 19.0 mL / min Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile

[0618] Example 59 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- N -(2-methyl-2 H Synthesis of -1,2,3-triazol-4-yl)acetamide

[0619] Example 59 was synthesized in a manner similar to that of Example 55. LCMS (ES) m / z = 408.1 [M+H] + .

[0620] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 11.08 (s, 1H), 7.79 (s, 1H), 7.55 -7.52 (m, 1H), 7.49- 7.47(d, J = 8 Hz, 2H), 7.33-7.30 (d, J =12,1H), 7.06 - 7.05(d, J = 4Hz, 1H), 7.04 -7.01 (m, 1H), 4.05 (s, 3H), 3.74 (s, 2H).

[0621] Purification conditions Column: X-Select C18 (19 mm X 250 mm X 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 19 mL / min %B / T:0 / 5,1 / 5,12 / 50,13 / 100,17 / 100

[0622] Example 60 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- N Synthesis of -(isoxazo-4-yl)acetamide

[0623] Example 60 was synthesized in a manner similar to that of Example 55. LCMS (ES) m / z = 394.3 [M+H] + .

[0624] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.58(s, 1H), 10.50(s, 1H),9.33 (s,1H), 9.10 (s, 1H), 7.55-7.52 (m,1H), 7.50- 7.45 (m, 2H),7.33 -7.30 (dd, J =4Hz, J = 4 Hz, 1H), 7.18 -7.16 (d, J =8 Hz,1H), 7.06 - 7.01 (m, 1H), 3.73 (s, 2H).

[0625] Purification conditions Column: Kinetex EVO C18 (100 mm x 2.1 mm x 2.6 µm) Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile Flow rate: 0.5 mL / min %B / T:0.10 / 10,06 / 80,08 / 98,8.01 / 10,10 / 10

[0626] Example 61 2-(2-((6-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- N Synthesis of methylacetamide

[0627] Example 61 was synthesized in a manner similar to Example 55. The crude product was purified by combi-flash MPLC using 5% MeOH in DCM as the mobile phase. LCMS (ES) m / z = 341.3 [M+H] + .

[0628] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.98 (d, J= 3.2 Hz, 1H), 7.55-7.50 (m,2H), 7.45-7.41 (m, 2H), 7.16-7.10 (m, 2H), 3.47 (s, 2H), 2.58 (d, J = 4.4 Hz, 3H).

[0629] Example 62 Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-1-morpholinylethane-1-one

[0630] Example 62 was synthesized in a manner similar to that of Example 55. LCMS (ES) m / z = 371.34 [M+H] + .

[0631] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.54-7.56 (m, 1 H), 7.48-7.46 (m, 1H), 7.37 (s, 1 H), 7.32-7.33 (d, J=6.8, 1 H), 7.0-7.1 (m, 2 H), 3.81 (s, 2H), 3.47-3.55 (m, 8H).

[0632] Purification conditions Column: X-select CSH C-18 (250 mm X 4.6 mm X 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 1.0 mL / min

[0633] Example 63 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- N Synthesis of 2-hydroxyethyl)acetamide

[0634] Example 63 was synthesized in a manner similar to that of Example 55. LCMS (ES) m / z = 371.4 [M+H] + .

[0635] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.05 (s,1H), 7.421-7.421 (m, 1 H), 7.339-7.37 (m, 2 H), 7.221-7.241 (d, J=8.0 1 H), 7.024-7.044 (d, J=8, 1 H), 6.908-6.951 (m, 1 H), 4.686 (s, 1 H), 3.473 (s, 2 H), 3.328-3.387 (m, 2H), 3.103-3.147 (m, 2H).

[0636] Purification conditions Column: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic) Mobile phase (A): 0.1% aqueous formic acid Mobile phase (B): Acetonitrile Flow rate: 1.0 mL / min

[0637] Example 64 Synthesis of (2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)acetyl)glycine

[0638] Example 64 was synthesized in a manner similar to Example 55. The crude material was acidified with dilute HCl (3.0 mL), and the resulting solid was filtered through a sintering funnel and washed with water to obtain the desired product. LCMS (ES) m / z = 385.4 [M+H] + .

[0639] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.542 (s,1H), 8.41 (t, 1H),7.538-7.571 (m, 1H), 7.438-7.483 (m, 2H), 7.324-7.353 (dd, J1=2.8, J2=2.8, 1H), 7.142-7.166 (dd, J1=1.2, J2=1.2, 1H), 7.028-7.081 (m, 1H), 3.764-3.779 (d, J=6, 2H), 3.577 (s, 2H).

[0640] Example 65 NSynthesis of methyl-2-(2-((6-methylbenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)acetamide

[0641] Example 65 was synthesized in a manner similar to that of Example 55. LCMS (ES) m / z = 337.3 [M+H] + .

[0642] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.97 (d, J = 3.60 Hz, 1H), 7.45-7.40(m, 3H), 7.37 (s, 1H), 7.12-7.09 (m, 2H), 3.47 (s, 2H), 2.59 (d, J = 4.40 Hz, 3H), 2.40 (s, 3H).

[0643] Purification conditions Column: Xbridge C18 (19 mm X 250 mm X 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 19 mL / min

[0644] Example 66 N , N Synthesis of 2-(2-((6-methylbenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)acetamide

[0645] Example 66 was synthesized in a manner similar to that of Example 55. LCMS (ES) m / z = 351.4 [M+H] + .

[0646] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.45-7.37 (m, 4H), 7.12-7.06 (m, 2H), 3.78 (s, 2H), 3.03 (s, 3H), 2.85 (s, 3H), 2.40 (s, 3H).

[0647] Purification conditions Column: X-Select CSH C18 (19 mm X 250 mm X 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 19 mL / min %B / T:0 / 5,1 / 5,12 / 35,13 / 100,18 / 100,19 / 5

[0648] Example 67 2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)- N Synthesis of 2-(2-hydroxyethoxy)ethyl)acetamide

[0649] Example 67 was synthesized in a manner similar to that of Example 55. LCMS (ES) m / z = 426.3 [M+H] + .

[0650] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.14 (s, 1H), 7.53 (t, J = 4.8 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.11(t, J = 8.0 Hz, 1H), 3.49 (d, J = 5.6 Hz, 4H), 3.42 (d, J = 3.2 Hz, 4H), 3.22 (d, J = 5.6 Hz, 2H).

[0651] Purification conditions Column: Xterra; Flow rate: 19.0 mL / min Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile The desired product rt is 8.56 min.

[0652] Example 68 2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)- N , NSynthesis of dimethylacetamide

[0653] Example 68 was synthesized in a manner similar to that of Example 55. LCMS (ES) m / z = 337.3 [M+H] + .

[0654] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.52 (d, J =7.6 Hz, 2 H), 7.44 (d, J =8.0Hz, 1 H), 7.37 (s, 1 H), 7.20 -7.30 (m, 2 H), 7.07 (d, J =8.0 Hz, 1 H), 3.78 (s, 2 H), 3.03 (s, 3 H), 2.84 (s, 3 H).

[0655] Purification conditions Column: Kinetex EVO C18 (100 mm x 2.1 mm x 1.7 μm) Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile %B / T:0.10 / 10,06 / 98,08 / 98,8.01 / 10,10 / 10

[0656] Example 69 2-(2-(benzo[d]oxazol-2-ylamino)benzo[d]oxazol-5-yl)- N -(2-(2-hydroxyethoxy)ethyl)- N Synthesis of methylacetamide

[0657] At 0 °C, 2-methyl-2,6,8-triaza-6,7-decadiene-hydrochloride (1 / 1) (242 mg, 2 equivalents, 1.26 mmol), 1H-1,2,3-benzotriazol-4-ol (128 mg, 1.5 equivalents, 946 µmol), and 2-[2-(methylamino)ethoxy]ethanol (225 mg, 3 equivalents, 1.89 mmol) were added to the mixture at the same temperature. Then, N-ethylbis(isopropyl)amine (329 µL, 3 equivalents, 1.89 mmol) was added to the mixture, and the mixture was stirred at 100 °C for 12 hours. The reaction progress was monitored by TLC (10% MeOH in DCM) and LCMS data. After the reaction was complete, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 8 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column MPLC using (1.5%–2.0%) MeOH in DCM as the eluent to obtain the desired compound (0.34 g) with a purity of 42% in LCMS. It was then further purified by the preparative HPLC method mentioned below to give N-[2-(2-hydroxyethoxy)ethyl]-N-methyl[2-(1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]acetamide (49 mg, yield: 19%) as a brown gel-like liquid. LC-MS (m / z) = 411.4 [M+H] + .

[0658] Purification conditions Flow rate: 0.5 mL / min Column: Kinetex EVO C18 (100 mm x 2.1 mm x 1.7 μm) Mobile phase A: 0.1% aqueous solution of formic acid Mobile phase B: Acetonitrile %B / T:0.10 / 10,06 / 98,08 / 98,8.01 / 10,10 / 10

[0659] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.46-7.48 (m, 2 H), 7.38 (s, 2 H),7.19- 7.26 (m, 2 H), 7.06 (d, J= 8.0 Hz, 1 H), 3.78 (s, 2 H), 3.45- 3.54 (m, 11 H).

[0660] Example 70 N Synthesis of 5-((dimethylamino)methyl)benzo[d]oxazol-2-yl)-5,7-difluorobenzo[d]oxazol-2-amine

[0661] Step 1: Synthesis of 2-amino-4,6-difluorophenol

[0662] Ammonium chloride (917 mg, 3 equivalents, 17.1 mmol) dissolved in water (15 mL, 833 mmol) was added to a stirred solution of 2,4-difluoro-6-nitrophenol (1 g, 5.71 mmol) in tetrahydrofuran (70 mL), and the mixture was stirred for 5 minutes. Zinc (1.87 g, 5 equivalents, 28.6 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC [50% EA in heptane] and LCMS. The reaction mixture was first filtered through a celite bed setup, and the filtrate was diluted with water. The aqueous layer was extracted with ethyl acetate (25 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the crude compound. The crude compound was further purified by MPLC using 42% EA in heptane as the mobile phase to give 2-amino-4,6-difluorophenol (580 mg, 70%) as a white solid.

[0663] Step 2: Synthesis of 5,7-difluoro-1,3-benzoxazol-2-ylamine

[0664] At room temperature, bromoformonitrile (1.09 g, 2.5 equivalents, 10.3 mmol) was added to a stirred methanol (60 mL) solution of 0.6 g (4.13 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC (40% ethyl acetate / n-hexane) and LC-MS. The reaction mixture was evaporated under reduced pressure to give a crude brown solid, which was purified by MPLC using 40% ethyl acetate in n-heptane as the eluent to give 5,7-difluoro-1,3-benzoxazol-2-ylamine (70 mg, 10%) as a light brown solid.

[0665] Step 3: Synthesis of methyl 2-(5,7-difluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylate

[0666] To a solution of 5,7-difluoro-1,3-benzoxazole-2-ylamine (0.4 g, 2.35 mmol) in tetrahydrofuran (18 mL), lithium 2-methyl-2-propoxide (376 mg, 2 equivalents, 4.7 mmol) and methyl 2-iodo-1,3-benzoxazole-5-carboxylate (641 mg, 0.9 equivalents, 2.12 mmol) were added, and the mixture was heated at 70 °C for 9 h. The reaction was monitored by TLC and LCMS. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate (100 mL) and washed with water (40 mL). The organic layer was concentrated and purified by rapid MPLC using 5% MeOH in DCM as the mobile phase to give methyl 2-(5,7-difluoro-1,3-benzoxazole-2-ylamino)-1,3-benzoxazole-5-carboxylate (347 mg, 42%) as a pure brown solid.

[0667] Step 4: Synthesis of [2-(5,7-difluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]methanol

[0668] To a solution of methyl 2-(5,7-difluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylate (0.1 g, 0.290 mmol) in tetrahydrofuran (4.93 mL) stirred at 0–5 °C under inert conditions, lithium aluminate (1+) (22 mg, 2 equivalents, 0.6 mmol) was added dropwise to the reaction mixture at 0–5 °C. The reaction mixture was stirred at 0–5 °C for 1 hour. The reaction progress was monitored by TLC (50% EtOAc in heptane) and LCMS. After the reaction was complete, the reaction mixture was quenched with an aqueous solution of ammonium chloride and extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give [2-(5,7-difluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]methanol (55 mg) as a crude brown solid.

[0669] Step 5: Synthesis of [5-(chloromethyl)-1,3-benzoxazol-2-yl](5,7-difluoro-1,3-benzoxazol-2-yl)amine

[0670] At 0 °C, thionyl dichloride (0.025 mL, 2 equivalents, 0.347 mmol) and 2 drops of N,N-dimethylformamide were added to a stirred solution of [2-(5,7-difluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]methanol (55 mg, 0.173 mmol) in dichloromethane (4 mL, 62.5 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC [70% EA in heptane] and LCMS. The reaction mixture was evaporated under reduced pressure to give a crude residue. The residue was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried with sodium sulfate, filtered, and evaporated under reduced pressure to obtain [5-(chloromethyl)-1,3-benzoxazol-2-yl](5,7-difluoro-1,3-benzoxazol-2-yl)amine (54 mg) as a brown powder.

[0671] Step 6: Synthesis of 2-{5-[(dimethylamino)methyl]-1,3-benzoxazole-2-ylamino}-5,7-difluoro-1,3-benzoxazole

[0672] To a stirred solution of [5-(chloromethyl)-1,3-benzoxazol-2-yl](5,7-difluoro-1,3-benzoxazol-2-yl)amine (75 mg, 0.223 mmol) in dimethylformamide (3.87 mL, 49.9 mmol), potassium carbonate (124 mg, 4 equivalents, 0.894 mmol) and dimethylamine (50.4 mg, 5 equivalents, 1.12 mmol) were added. The reaction mixture was stirred at 70 °C for 4 hours. The reaction progress was monitored by TLC [10% MeOH in DCM] and LCMS. The reaction mixture was evaporated under reduced pressure to give a crude residue. The residue was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, evaporated under reduced pressure, and purified by HPLC to obtain 2-{5-[(dimethylamino)methyl]-1,3-benzoxazole-2-ylamino}-5,7-difluoro-1,3-benzoxazole (15 mg, 19.5%) as a grayish-white powder. LC-MS (m / z) = 355.29 [M+H] + .

[0673] Purification conditions Column: X-Bridge C18 (250 mm x 4.6 mm x 5µm) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Gradient % B: 0 / 02, 2 / 02, 18 / 98, 25 / 98, 27 / 02, 30 / 02 Flow rate: 1.0 mL / min

[0674] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.29 (s, 2H), 6.96 (d, J = 7.6Hz, 1H),6.91 (s, 2H), 6.78 (t, J = 9.6Hz, 1H), 3.83 (s, 2H), 2.43 (s, 6H).

[0675] Examples 71-77 The following compounds were synthesized in a manner similar to that of Example 70:

[0676] Examples 78-82 The following compounds were synthesized in a manner similar to that of Example 70, using the RHS intermediate synthesized in the intermediate reaction scheme.

[0677] Example 83 6-Fluoro-2-((5-Fluorobenzo[d]oxazol-2-yl)amino)- N Synthesis of 5-methylbenzo[d]oxazol-5-carboxamide

[0678] Step 1: Synthesis of methyl 2-fluoro-4-hydroxy-5-nitrobenzoate

[0679] Potassium nitrate (3.09 g, 1.3 equivalents, 30.6 mmol) was added to a 40 mL solution of methyl 2-fluoro-4-hydroxybenzoate (4 g, 23.5 mmol) in sulfuric acid. The reaction mixture was stirred at 0 °C and stirred at room temperature for 12 hours. The reaction solution was then quenched by pouring it into ice water. After stirring for 5 minutes and extraction with EtOAc and water, the combined organic layers were dried over sodium sulfate and concentrated to give a crude product. This crude product was purified by rapid silica gel chromatography (dry loading) with an elution gradient of 0 to 30% EtOAc in heptane. The purified fraction was concentrated to give methyl 2-fluoro-4-hydroxy-5-nitrobenzene (2.34 g, 10.9 mmol) as a pale yellow solid. LC-MS (m / z) = 214.6 [MH] - .

[0680] Step 2: Synthesis of methyl 5-amino-2-fluoro-4-hydroxybenzoate

[0681] To a stirred solution of methyl 2-fluoro-4-hydroxy-5-nitrobenzene (2.34 g, 10.9 mmol) in 1,4-dioxane (30 mL, 352 mmol) and water (10 mL, 555 mmol), zinc (5.69 g, 8 equivalents, 87 mmol) and ammonium chloride (4.65 g, 8 equivalents, 87 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC and LCMS. Once the reaction was complete, the mixture was filtered and diluted with EtOAc (5 mL), washed with water (3 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure to give crude methyl 5-amino-2-fluoro-4-hydroxybenzoate (2 g, 10.8 mmol) as a brown solid. LC-MS (m / z) = 186.0 [M+1H] + .

[0682] Step 3: Synthesis of methyl 6-fluorobenzo[d]oxazol-5-carboxylate

[0683] p-Toluenesulfonic acid (309 mg, 0.15 equivalents, 1.79 mmol) was added to a solution of methyl 5-amino-2-fluoro-4-hydroxybenzoate (2 g, 0.9 equivalents, 10.8 mmol) in diethoxymethoxyethane (20 mL) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. The reaction progress was monitored by TLC. The reaction mixture was evaporated under reduced pressure to give the crude compound. The crude product was loaded onto a rapid column and MPLC was performed using EtOAc in heptane as the mobile phase (the compound elutes with 30% EtOAc in hexane) to give methyl 6-fluoro-1,3-benzoxazole-5-carboxylate (1.26 g, 6.46 mmol, white solid). LC-MS (m / z) = 196.0 [M+1H] + .

[0684] Step 4: Synthesis of methyl 6-fluoro-2-iodobenzo[d]oxazol-5-carboxylate

[0685] Then, lithium bis(trimethylsilyl)imine (2.04 g, 2 equivalents, 12.2 mmol) was added to a THF (25 mL) solution of methyl 6-fluoro-1,3-benzoxazole-5-carboxylate (1.19 g, 6.1 mmol) cooled to -78 °C, and the mixture was stirred at the same temperature for 2 hours. Iodine (1.16 g, 1.5 equivalents, 9.15 mmol) was added to THF (5.0 mL), and the temperature was gradually cooled to -78 °C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by rapid silica gel chromatography (dry loading) with an elution gradient of 0 to 30% EtOAc in heptane. The purified fraction was concentrated to give methyl 6-fluoro-2-iodo-1,3-benzoxazole-5-carboxylate (0.9 g, 2.8 mmol) as a grayish-white solid. LC-MS (m / z) = 322.0 [M+H] + .

[0686] Step 5: Synthesis of methyl 6-fluoro-2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-carboxylate

[0687] To a solution of 5-fluoro-1,3-benzoxazole-2-ylamine (330 mg, 2.17 mmol) in tetrahydrofuran (9.9 mL, 122 mmol), lithium 2-methyl-2-propoxide (347 mg, 2 equivalents, 4.34 mmol) and methyl 6-fluoro-2-iodo-1,3-benzoxazole-5-carboxylate (696 mg, 2.17 mmol) were added, and the mixture was heated at 70 °C for 4 hours.

[0688] The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (15 mL) and washed with water (6 mL). The organic layer was concentrated to give the crude product. This crude product was purified by rapid silica gel chromatography (dry loading) with an elution gradient of 0 to 60% EtOAc in heptane. The fraction was concentrated, and dichloromethane (5 mL) was added, precipitating a solid. The precipitate was filtered, washed with dichloromethane (10 mL), and dried under vacuum to give methyl 6-fluoro-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylate (190 mg, 550 µmol) as a light brown solid. LC-MS (m / z) = 346.0 [M+H] + .

[0689] Step 6: Synthesis of 6-fluoro-2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-carboxylic acid

[0690] Lithium hydroxide (36.5 mg, 4 equivalents, 1.52 mmol) was added to a stirred solution of methyl 6-fluoro-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylic acid (190 mg, 1.4 equivalents, 550 µmol) in tetrahydrofuran (2 mL, 24.6 mmol), methanol (2 mL, 49.4 mmol), and water (1 mL, 55.5 mmol), and the reaction was stirred at room temperature for 3 hours. The progress of the reaction mixture was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was acidified with 1N HCl to pH (2–3), and the solid was filtered through a sintered funnel to give the desired product, 6-fluoro-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylic acid (140 mg, 423 µmol), as a brown solid. The crude product can be used in the next step without further purification. LC-MS (m / z) = 332.0 [M+H] + .

[0691] Step 7: Synthesis of 6-fluoro-2-((5-fluorobenzo[d]oxazol-2-yl)amino)-N-methylbenzo[d]oxazol-5-carboxamide

[0692] Add 2,4,6-tripropyl-1,3,5,2λ to a solution of 6-fluoro-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylic acid (140 mg, 423 µmol) in dichloromethane (6 mL, 93.7 mmol). 5 ,4λ 5 ,6λ 5- Trioxane-2,4,6-trione 50% v / v (498 µL, 2 equivalents, 845 µmol) and methylamine (39.4 mg, 3 equivalents, 1.27 mmol). N-ethylbis(isopropyl)amine (221 µL, 3 equivalents, 1.27 mmol) was added to the above mixture at 0 °C, and the reaction mixture was stirred at room temperature for 12 h. The reaction progress was monitored by TLC and LCMS data. After the reaction was complete, the reaction mixture was quenched with water (3.0 mL) and extracted with ethyl acetate (2 x 5.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by rapid silica gel chromatography (dry loading) with an elution gradient of 0 to 15% MeOH in DCM, and the fraction was concentrated under reduced pressure to give an impure product (140 mg) as a brown solid. The crude substance was purified by the preparative HPLC method described below to give N-methyl-6-fluoro-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxamide (21.8 mg, 63.3 µmol, yield: 14.98%) as a white solid. LC-MS (m / z) = 345.3 [M+H] + .

[0693] Purification conditions Column: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 1.0 mL / min

[0694] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.07 (s, 1H), 7.50 (d, J = 6.40 Hz, 1H), 7.28 (d, J = 10.00 Hz, 1H), 7.23-7.20 (m, 1H), 7.09 (d, J = 8.40 Hz, 1H),6.73-6.69 (m, 1H), 2.78 (d, J = 4.40 Hz, 3H).

[0695] Example 84 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxy- N Synthesis of 5-methylbenzo[d]oxazol-5-carboxamide

[0696] Step 1: Synthesis of methyl 2,4-dihydroxybenzoate

[0697] Sulfuric acid (7 mL) was added to a methanol (35 mL) solution of 2,4-dihydroxybenzoic acid (5 g, 32.4 mmol) cooled to 0 °C, and the mixture was stirred at 73 °C for 16 hours. The reaction mixture was concentrated. The residue was alkalized with a saturated sodium bicarbonate solution (100 mL), precipitating a solid. The solid was filtered through a sintered funnel, washed with water (300 mL), then washed with n-heptane (100 mL), and dried under vacuum to give methyl 2,4-dihydroxybenzoate (5 g, 91%) as a grayish-white solid. LC-MS (m / z) = 169.0 [M+1H] + .

[0698] Step 2: Synthesis of methyl 2,4-dihydroxy-5-nitrobenzoate

[0699] To a chloroform (40 mL, 502 mmol) solution of methyl 2,4-dihydroxybenzoate (4 g, 23.8 mmol) cooled to 0 °C, nitric acid (1.29 mL, 1.3 equivalents, 30.9 mmol) was added to the reaction mixture, and the mixture was stirred at 0 °C for 30 h. After the reaction time, the reaction mixture was quenched with ice-cold water and extracted with DCM (2 x 50 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by combi-flash using ethyl acetate in n-heptane (1-20% of the product eluted at 12%) to give methyl 2,4-dihydroxy-5-nitrobenzene (1.1 g, 22%) as a white solid (desired product) and methyl 2,4-dihydroxy-3-nitrobenzene (1.4 g, 27%) as a yellow solid (undesirable product). LC-MS (m / z) = 211.9 [MH] - .

[0700] Step 3: Synthesis of methyl 5-amino-2,4-dihydroxybenzoate

[0701] To a stirred solution of methyl 2,4-dihydroxy-5-nitrobenzoate (1 g, 4.69 mmol) in 1,4-dioxane (15 mL, 176 mmol) and water (5 mL, 278 mmol), zinc (2.45 g, 8 equivalents, 37.5 mmol) and ammonium chloride (2.01 g, 8 equivalents, 37.5 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC and LCMS. Once the reaction was complete, the mixture was filtered and diluted with EtOAc (5 mL), washed with water (3 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure to give crude methyl 5-amino-2,4-dihydroxybenzoate (620 mg, 3.38 mmol) as a black solid. LC-MS (m / z) = 184.1 [M+H] + .

[0702] Step 4: Synthesis of methyl 6-hydroxybenzo[d]oxazol-5-carboxylate

[0703] At room temperature, p-toluenesulfonic acid (87.4 mg, 0.15 equivalents, 508 µmol) was added to a solution of methyl 5-amino-2,4-dihydroxybenzoate (620 mg, 3.38 mmol) in diethoxymethoxyethane (10 mL). The reaction mixture was stirred at 100 °C for 16 h. The reaction progress was monitored by TLC. The reaction mixture was evaporated under reduced pressure to give the crude compound. The crude product was loaded onto a Flash column and MPLC was performed using EtOAc in heptane as the mobile phase (the compound eluted with 50% EtOAc in hexane) to give methyl 6-hydroxy-1,3-benzoxazole-5-carboxylate (240 mg, 1.24 mmol) as a light brown solid. LC-MS (m / z) = 194.1 [M+H] + .

[0704] Step 5: Synthesis of methyl 6-methoxybenzo[d]oxazol-5-carboxylate

[0705] Then, at 0 °C, potassium dicarbonate (687 mg, 4 equivalents, 4.97 mmol) and iodomethane (155 µL, 2 equivalents, 2.49 mmol) were added to a solution of methyl 6-hydroxy-1,3-benzoxazole-5-carboxylate (240 mg, 1.24 mmol) in dimethylformamide (3 mL, 38.7 mmol), and the reaction mixture was stirred at 100 °C for 12 hours. The reaction mixture was concentrated and diluted with ethyl acetate (10 mL), washed with water (5 mL) and brine (5 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by rapid silica gel chromatography (dry loading) with an elution gradient of 0 to 40% EtOAc in heptane. The purified fraction was concentrated to give methyl 6-methoxy-1,3-benzoxazole-5-carboxylate (160 mg, 772 µmol) as a white solid. LC-MS (m / z) = 208.1 [M+H] + .

[0706] Step 6: Synthesis of methyl 2-iodo-6-methoxybenzo[d]oxazol-5-carboxylate

[0707] Then, lithium bis(trimethylsilyl)imine (258 mg, 2 equivalents, 1.54 mmol) was added to a THF (3.0 mL) solution of methyl 6-methoxy-1,3-benzoxazole-5-carboxylate (160 mg, 772 µmol) cooled to -78 °C, and the mixture was stirred at the same temperature for 2 hours. Iodine (147 mg, 1.5 equivalents, 1.16 mmol) was added to THF (1.0 mL), and the temperature was gradually cooled to -78 °C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (5.0 mL), extracted with ethyl acetate (2 x 10 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by rapid silica gel chromatography (dry loading) with an elution gradient of 0 to 40% EtOAc in heptane. The purified fraction was concentrated to give methyl 2-iodo-6-methoxy-1,3-benzoxazole-5-carboxylate (153 mg, 459 µmol) as a white solid. LC-MS (m / z) = 334.0 [M+H] + .

[0708] Step 7: Synthesis of methyl 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxybenzo[d]oxazol-5-carboxylate

[0709] To a solution of 5-fluoro-1,3-benzoxazol-2-ylamine (70 mg, 460 µmol) in tetrahydrofuran (3 mL, 36.9 mmol), lithium 2-methyl-2-propoxide (73.7 mg, 2 equivalents, 920 µmol) and methyl 2-iodo-6-methoxy-1,3-benzoxazol-5-carboxylate (153 mg, 460 µmol) were added, and the mixture was heated at 70 °C for 4 hours. The reaction mixture was monitored by TLC. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (10 mL) and washed with water (5 mL). The combined organic layers were dried over sodium sulfate and concentrated to give a crude substance, methyl 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-6-methoxy-1,3-benzoxazol-5-carboxylate (140 mg, 392 µmol), as a light brown solid.

[0710] Step 8: Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxybenzo[d]oxazol-5-carboxylic acid

[0711] Lithium hydroxide (37.5 mg, 4 equivalents, 1.57 mmol) was added to a stirred solution of methyl 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-6-methoxy-1,3-benzoxazol-5-carboxylate (140 mg, 392 µmol) in tetrahydrofuran (2 mL, 24.6 mmol), methanol (2 mL, 49.4 mmol), and water (1 mL, 55.5 mmol), and the reaction was stirred at room temperature for 3 hours. The progress of the reaction mixture was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was acidified with 1N HCl to pH (2-3), and the solid was filtered through a sintered funnel to give the desired product, 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-6-methoxy-1,3-benzoxazol-5-carboxylic acid (60 mg, 175 µmol), as a light brown solid, and 82 mg of impurities as a black solid. The crude product was used in the next step without further purification. LC-MS (m / z) = 344.1 [M+H] + .

[0712] Step 9: Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxy-N-methylbenzo[d]oxazol-5-carboxamide

[0713] Add 2,4,6-tripropyl-1,3,5,2λ to a solution of 2-(5-fluoro-1,3-benzoxazol-2-ylamino)-6-methoxy-1,3-benzoxazol-5-carboxylic acid (82 mg, 239 µmol) in dichloromethane (6 mL, 93.7 mmol). 5,4λ 5 ,6λ 5 - Trioxane-2,4,6-trione 50% v / v (282 µL, 2 equivalents, 478 µmol) and methylamine (22.3 mg, 3 equivalents, 717 µmol). N-ethylbis(isopropyl)amine (125 µL, 3 equivalents, 717 µmol) was added to the above mixture at 0 °C, and the reaction mixture was stirred at room temperature for 12 h. The reaction progress was monitored by TLC and LCMS data. After the reaction was complete, the reaction mixture was quenched with water (3.0 mL) and extracted with ethyl acetate (2 x 5.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product (94 mg). The crude substance was purified by the preparative HPLC method described below to obtain N-methyl-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-6-methoxy-1,3-benzoxazol-5-carboxamide (25 mg, 70.2 µmol, yield: 29.37%) as a grayish-white solid. LC-MS (m / z) = 357.1 [M+H] + .

[0714] Purification conditions Column: Xterra C18 (250x19) mm; 10u Flow rate: 19.0 mL / min Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile The desired product RT is 8.90 min.

[0715] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.12 (d, J = 4.40 Hz, 1H), 7.77 (s,1H), 7.19-7.15 (m, 2H), 7.07-7.05 (m, 1H), 6.69-6.65 (m, 1H), 3.89 (s, 3H), 2.81 (d, J = 4.80 Hz, 3H).

[0716] Example 85 7-Cyclopropyl-2-((5-Fluorobenzo[d]oxazol-2-yl)amino)- N Synthesis of 5-methylbenzo[d]oxazol-5-carboxamide

[0717] Step 1: Synthesis of methyl 4-(benzyloxy)-3-bromobenzoate

[0718] Potassium dicarbonate (8.97 g, 3 equivalents, 64.9 mmol) was added to a stirred solution of methyl 3-bromo-4-hydroxybenzoate (5 g, 21.6 mmol) in acetonitrile (70 mL), followed by the dropwise addition of (bromomethyl)benzene (3.86 mL, 1.5 equivalents, 32.5 mmol). The reaction mixture was stirred at 80 °C for 5 hours, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. The reactants were quenched with water (100 mL), extracted with ethyl acetate (100 mL), and the combined organic layers were concentrated under reduced pressure to give methyl 4-(benzyloxy)-3-bromobenzoate (6.7 g, 80.97%) as a grayish-white solid. LC-MS (m / z) = 322 [M+H] + .

[0719] Step 2: Synthesis of methyl 4-(benzyloxy)-3-cyclopropylbenzoate

[0720] Cyclopropylboranediol (2.72 g, 1.5 equivalents, 31.7 mmol) was added to a stirred solution of methyl 4-(benzyloxy)-3-bromobenzoate (6.78 g, 21.1 mmol) in toluene (60 mL) and water (15 mL). Tripotassium phosphate (13.4 g, 3 equivalents, 63.3 mmol) was added, and the reaction mixture was purged with nitrogen for 5 min. Then palladium-triphenylphosphine (1 / 4) (2.44 g, 0.1 equivalents, 2.11 mmol) was added, and the reaction mixture was stirred at 100 °C for 12 h. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (2 x 50 mL), and the combined organic layers were dried under reduced pressure to give the crude product. The crude product was purified by combi flash using 10-20% EtOAc:hexane as the eluent to give methyl 4-(benzyloxy)-3-cyclopropylbenzoate (4.2 g, 59.19%) as a grayish-white solid. LC-MS (m / z) = 283 [M+H] + .

[0721] Step 3: Synthesis of methyl 3-cyclopropyl-4-hydroxybenzoate

[0722] Palladium (1.14 g, 0.74 equivalent, 10.7 mmol) was added to a solution of methyl 4-(benzyloxy)-3-cyclopropylbenzoate (4.2 g, 1 equivalent, 14.9 mmol) in methanol (0.1 L) and ethyl acetate (0.1 L) under a nitrogen atmosphere and at room temperature. The reaction was stirred at room temperature for 12 h under a hydrogen atmosphere of 60 Psi. The reaction progress was monitored by TLC. Once the reaction was complete, the reaction mixture was filtered through a celite bed with methanol, and the filtrate was concentrated under reduced pressure to give methyl 3-cyclopropyl-4-hydroxybenzoate (2.7 g, 93.1%) as a grayish-white solid. LC-MS (m / z) = 193.3 [M+H] + .

[0723] Step 4: Synthesis of methyl 3-cyclopropyl-4-hydroxy-5-nitrobenzene

[0724] To a solution of methyl 3-cyclopropyl-4-hydroxybenzoate (2.7 g, 14 mmol) cooled to 0 °C in 10 mL of acetic acid, 0.5 mL of nitric acid (586 µL, 14 mmol) in acetic acid was added dropwise to the reaction mixture, and the mixture was stirred at the same temperature for 10 min, followed by stirring at room temperature to thicken the precipitate for 1 h. The reaction was monitored by TLC and LCMS. Water (10 mL) was added to the reaction mixture at 0 °C, and the mixture was stirred for 15 min. The precipitate was filtered, washed with water, and dried under high vacuum to give a crude yellow solid of methyl 3-cyclopropyl-4-hydroxy-5-nitrobenzene (3.2 g, 57.62%). LC-MS (m / z) = 237 [M+ H] + .

[0725] Step 5: Synthesis of methyl 3-amino-5-cyclopropyl-4-hydroxybenzoate

[0726] Palladium (1.06 g, 0.74 equivalent, 9.99 mmol) was added to a solution of methyl 3-cyclopropyl-4-hydroxy-5-nitrobenzene (3.2 g, 13.5 mmol) in methanol (0.1 L) and ethyl acetate (50 mL) under a nitrogen atmosphere and at room temperature. The reaction was stirred at room temperature for 12 h under a hydrogen atmosphere of 60 Psi. The reaction progress was monitored by TLC. Once the reaction was complete, the reaction mixture was filtered through a celite bed with methanol, and the filtrate was concentrated under reduced pressure to give methyl 3-amino-5-cyclopropyl-4-hydroxybenzoate (2.7 g, 59.88%) as a grayish-white solid. LC-MS (m / z) = 208 [M+H] + .

[0727] Step 6: Synthesis of methyl 7-cyclopropylbenzo[d]oxazol-5-carboxylate

[0728] Triethyl orthoformate (30 mL) was added to methyl 3-amino-5-cyclopropyl-4-hydroxybenzoate (2.4 g, 11.6 mmol), and the reaction was heated at 100 °C for 2 hours. The reaction mixture was cooled to room temperature. The reaction mixture was concentrated and diluted with EtOAc (20 mL x 3), and washed with 10 mL of water. The combined organic layers were concentrated under reduced pressure, and the crude residue was purified by rapid column chromatography using 20–30% ethyl acetate in n-heptane to give methyl 7-cyclopropylbenzo[d]oxazol-5-carboxylate (1.7 g, 58.11%) as a grayish-white solid. LC-MS (m / z) = 218 [M+H] + .

[0729] Step 7: Synthesis of methyl 7-cyclopropyl-2-iodobenzo[d]oxazol-5-carboxylate

[0730] At -78 °C, LiHMDS (3.27 g, 2.5 equivalents, 19.6 mL) in THF was added to a stirred solution of methyl 7-cyclopropylbenzo[d]oxazol-5-carboxylate (1.7 g, 7.83 mmol) in tetrahydrofuran (72 mL), and the mixture was stirred for 2 hours at the same temperature. Then, iodine (1.49 g, 1.5 equivalents, 11.7 mmol) dissolved in THF (5 mL) was added at -78 °C, and the reaction mixture was gradually heated to -20 °C for 2 hours. The reaction progress was monitored by TLC (20% EtOAc: hexane) and LCMS. The reaction mixture was quenched with NH4Cl, extracted with EtOAc, and washed with water. The organic layer was dried over sodium sulfate and concentrated. The crude compound was purified by Combi flash column chromatography using 0-10% EtOAC:heptane as the eluent to give methyl 7-cyclopropyl-2-iodobenzo[d]oxazol-5-carboxylate (1.1 g, 38.51%) as a grayish-white solid. LC-MS (m / z) = 344 [M+H] + .

[0731] Step 8: Synthesis of methyl 7-cyclopropyl-2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-carboxylate

[0732] To a solution of methyl 7-cyclopropyl-2-iodobenzo[d]oxazol-5-carboxylate (1 g, 2.91 mmol) in tetrahydrofuran (20 mL), 5-fluoro-1,3-benzoxazol-2-ylamine (443 mg, 2.91 mmol) and lithium 2-methyl-2-propoxide (467 mg, 2 equivalents, 5.83 mmol) were added, and the mixture was heated at 70 °C for 3 h. The reaction progress was monitored by LCMS and TLC. The reaction mixture was concentrated, diluted with EtOAc (50 mL), and washed with water (50 mL). The organic layer was dried over sodium sulfate and concentrated. The crude compound was purified by combi flash column chromatography using EtOAC:petroleum ether (30-50%) to give methyl 7-cyclopropyl-2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-carboxylate (470 mg, 31.61%) as a brown solid. LC-MS (m / z) = 368 [M+H] + .

[0733] Step 9: Synthesis of 7-cyclopropyl-2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-carboxylic acid

[0734] Lithium hydroxide monohydrate (215 mg, 4 equivalents, 5.12 mmol) was added to a stirred solution of methyl 7-cyclopropyl-2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-carboxylic acid (470 mg, 1.28 mmol) in tetrahydrofuran (5 mL, 61.4 mmol), methanol (5 mL, 123 mmol), and water (5 mL, 278 mmol), and the reaction was stirred at room temperature for 12 hours. The progress of the reaction mixture was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was acidified with dilute HCl (3.0 mL), and the solid was filtered through a sintered funnel to give the desired 7-cyclopropyl-2-(5-fluoro-1,3-benzooxazol-2-ylamino)-1,3-benzooxazol-5-carboxylic acid (0.4 g, 85.83%). LC-MS (m / z) = 354 [M+H] + .

[0735] Step 10: Synthesis of 7-cyclopropyl-2-((5-fluorobenzo[d]oxazol-2-yl)amino)-N-methylbenzo[d]oxazol-5-carboxamide

[0736] To a solution of 7-cyclopropyl-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-carboxylic acid (350 mg, 991 μmol) in dichloromethane (10 mL), methylamine (36.9 mg, 1.2 equivalents, 0.5 mL) and N-ethylbis(isopropyl)amine (518 µL, 3 equivalents, 2.97 mmol) at 0°C were added, followed by the addition of 2,4,6-tripropyl-1,3,5,2λ. 5 ,4λ 5 ,6λ 5 -trioxatriphosphonane-2,4,6-trione (1.18 mL, 2 equivalents, 1.98 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC and LCMS data. The reaction mixture was diluted with DCM (10 mL), water (5 mL) was added, the extracted organic layer was washed with a brine solution (10 mL), dried over sodium sulfate, and concentrated. The crude compound was absorbed into a saturated NaHCO3 solution and stirred for 15 min. The solid was filtered, washed with water (20 mL), and dried under vacuum to give 7-cyclopropyl-2-((5-fluorobenzo[d]oxazol-2-yl)amino)-N-methylbenzo[d]oxazol-5-carboxamide (170 mg, 45.8%) as a grayish-white solid. LC-MS (m / z) = 367 [M+H] + .

[0737] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.32 (s, 1H), 7.60 (s, 1H),7.42 (s,1H),7.21 -7.15 (m, 2H), 6.90 (m,1H), 2.75(s, 3H), 2.19 -2.12 (m ,1H), 1.07 -1.04 (2H),0.94 - 0.93 (m, 2H).

[0738] Example 86 N Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)acetamide

[0739] Step-1: N Synthesis of 2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzoxazol-5-yl)acetamide

[0740] Triethylamine (0.15 mL, 2.5 equivalence, 1.06 mmol) was added to an 8 mL solution of 5-amino-2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazole (0.12 g, 0.42 mmol) in DCM (stirred at 0 °C under inert conditions). Acetic anhydride (0.047 mL, 1.1 equivalence, 0.46 mmol) was then added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred for 2 hours. The reaction progress was monitored by TLC (5% MeOH: 95% DCM) and LCMS. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 15 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using 10–12% methanol in the DCM to obtain the desired compound (80 mg). Further preparative HPLC purification yielded a pale yellow solid. N -[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]acetamide (0.023 g, 17%). LC-MS (m / z) = 327.3 [M+H] + .

[0741] Purification conditions Column: Xbridge C18 (19 mm X 250 mm X 5 mic) Mobile phase (A): 0.1% HCl aqueous solution Mobile phase (B): Acetonitrile Flow rate: 18 mL / min RT: 19.43 min

[0742] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 10.5 (s, 1H), 7.92 (s, 1H), 7.48 (s,1H), 7.41-7.39 (m, 1H), 7.29-7.27 (m, 2H), 6.98 (m, 1H), 2.07 (s, 3H).

[0743] Example 87 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- N Synthesis of -(methylsulfonyl)acetamide

[0744] Step-1: 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- N Synthesis of -(methylsulfonyl)acetamide

[0745] To a stirred solution of [2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]acetic acid (0.2 g, 0.611 mmol, 1 equivalent), methanesulfonamide (0.069 g, 0.733 mmol, 1.2 equivalent) in DCM (10 mL), DMAP (0.003 g, 0.030 mmol, 0.05 equivalent) and 2-chloro-1-methyl-1-pyridinium iodide (0.187 g, 0.733 mmol, 1.2 equivalent) were added dropwise. The reaction mixture was stirred for 5 minutes, followed by dropwise addition of triethylamine (0.256 mL, 1.83 mmol, 3 equivalent) at room temperature. The reaction mixture was then stirred at room temperature for 12 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude residue. The obtained residue was diluted in ethyl acetate and then treated with 1N... The product was washed with HCl aqueous solution, the organic layer was separated, dried, and concentrated under reduced pressure to obtain the crude product. Further purification was performed using preparative HPLC with the following analytical method: LC-MS (m / z) = 405.3 [M+H] + .

[0746] Purification conditions Column: X-Bridge C-18 (250 mm X 4.6 mm X 5 mic) Mobile phase (A): 5 mM ammonium acetate aqueous solution Mobile phase (B): Acetonitrile Flow rate: 1.0 mL / min B's percentage: 0 / 2, 2 / 02, 18 / 98, 25 / 98, 27 / 2, 30 / 2

[0747] After preparative HPLC purification, the sample containing fractions was concentrated under reduced pressure to obtain the desired product with a recovery rate of (0.017 g, 6.88%), which was a grayish-white solid.

[0748] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.08 (bs, 1 H), 7.57 - 7.54 (m, 1H), 7.50 (d, J = 8.4 Hz, 1 H), 7.43 (s, 1H), 7.35 -7.32 (m, 1H), 5.14 (d , J =8.4 Hz, 1 H), 7.08 -7.03 (m, 1 H), 3.71 (s, 2 H), 3.24 (s, 3 H).

[0749] Example 88 N -(5-(1 H Synthesis of pyrazol-4-yl)benzo[d]oxazol-2-yl)-5-fluorobenzo[d]oxazol-2-amine

[0750] Step 1: Synthesis of 5-bromo-1,3-benzoxazol-2-ylamine

[0751] At room temperature, cyanogen bromide (1.35 g, 1.2 equivalents, 12.8 mmol) was added to a stirred solution of 2-amino-4-bromophenol (2 g, 10.6 mmol) in methanol (20 mL, 494 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with saturated Na₂CO₃ (70 mL). MeOH was evaporated under reduced pressure and quenched with ethyl acetate (100 mL). 2) Extraction of the residue. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 5-bromo-1,3-benzoxazol-2-ylamine (1.9 g, 72%) as a brown solid. LC-MS (m / z) = 214.9 [M+H] + .

[0752] Step 2: Synthesis of 5-(4-pyrazolyl)-1,3-benzoxazol-2-ylamine

[0753] A solution of 5-bromo-1,3-benzoxazol-2-ylamine (1 g, 4.69 mmol) and 4,4,5,5-tetramethyl-2-(4-pyrazolyl)-1,3,2-dioxoboronyl pentane (911 mg, 4.69 mmol) in 1,2-dimethoxyethane (30 mL) was degassed in a microwave flask for 5 min. A solution of cesium carbonate (4.59 g, 3 equivalents, 14.1 mmol) in water (14 mL, 777 mmol) and [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) complexed with dichloromethane (383 mg, 0.1 equivalents, 469 µmol) were added, and the mixture was heated in a microwave reactor at 110 °C for 1 h. Monitoring was performed by TLC and LCMS. The reaction mixture was quenched with water (50 mL) and thawed with ethyl acetate (70 mL). 2) Extraction. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography using MeOH and DCM (0–7%). The fraction was concentrated under reduced pressure to give 5-(4-pyrazolyl)-1,3-benzoxazol-2-ylamine (280 mg, 25%) as a brown solid. LC-MS (m / z) = 201.1 [M+H] + .

[0754] Step 3: Synthesis of (5-fluoro-1,3-benzoxazol-2-yl)[5-(4-pyrazolyl)-1,3-benzoxazol-2-yl]amine

[0755] To a solution of 0.2 g (999 μmol) of 5-(4-pyrazolyl)-1,3-benzoxazol-2-ylamine in tetrahydrofuran (5.15 mL, 63.3 mmol), lithium 2-methyl-2-propoxide (160 mg, 2 equivalents, 2 mmol) and 2-chloro-5-fluoro-1,3-benzoxazole (245 mg, 999 μmol) were added, and the mixture was heated at 70 °C for 2 hours. The reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain a crude product. The crude product was loaded onto a Flash column and subjected to MPLC using MeOH in DCM as the mobile phase (the compound eluted at 5%–7%). Preparative HPLC purification was then performed. Mobile phase (A): 0.1% ammonia; mobile phase (B): acetonitrile. The fractions were concentrated under reduced pressure to give (5-fluoro-1,3-benzoxazol-2-yl)[5-(4-pyrazolyl)-1,3-benzoxazol-2-yl]amine (72 mg, 21%) as a white solid. LC-MS (m / z) = 336.3 [M+H] + .

[0756] Purification conditions Column: Xselect C18 (19 mm x 250 mm x 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 19 mL / min

[0757] 1H NMR (400 MHz, DMSO-d6) δ ppm: 1H NMR (400 MHz, DMSO d6) δ ppm -12.97(s,1H), 8.17(s, 1H), 8.13(s, 1H), 7.6-7.7 (s,1H) 7.4-7.7 (m,3H) ,7.34(d, j=8.8, 1H), 7.0-7.1 (t,1H).

[0758] MP: 297.7℃

[0759] Examples 89-92 The following compounds were synthesized in a manner similar to that of Example 88:

[0760] Example 93 Synthesis of 3-((2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)methyl)-1,1-dimethylurea

[0761] Step 1: Synthesis of 2-{5-[(3,3-dimethylureido)methyl]-1,3-benzoxazole-2-ylamino}-5-fluoro-1,3-benzoxazole

[0762] At room temperature, 1,1-dimethylurea (208 mg, 5 equivalents, 2.36 mmol) was added to a stirred solution of [5-(chloromethyl)-1,3-benzoxazol-2-yl](5-fluoro-1,3-benzoxazol-2-yl)amine (150 mg, 472 μmol) in dimethylformamide (20 mL, 258 mmol). The reaction mixture was stirred for 5 min and cooled to 0 °C. Sodium hydride (34 mg, 3 equivalents, 1.42 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC [10% MeOH in DCM] and LCMS. The reaction mixture was evaporated under reduced pressure to give a crude residue. The residue was purified by HPLC to give 2-{5-[(3,3-dimethylureido)methyl]-1,3-benzoxazol-2-ylamino}-5-fluoro-1,3-benzoxazole (32 mg, 86.6 μmol) as a grayish-white solid (yield: 18%). LC-MS (m / z) = 370.3 [M+H] + .

[0763] Purification conditions Column: Xselect C18 (19 mm x 250 mm x 5 mic) Mobile phase (A): 0.1% aqueous formic acid Mobile phase (B): Acetonitrile Flow rate: 19 mL / min Required product RT: 14.13 min

[0764] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.56 - 7.54 (m, 1H), 7.47 (s, 1H)7.32 (d, J = 8.4Hz, 1H), 7.12 (d, J = 8.0Hz, 1H), 7.06 (t, 1H), 6.97(s, 1H) 4.29(d, J = 5.2Hz, 2H), 2.83 (s, 6H).

[0765] Example 94 Synthesis of 1-((2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)methyl)urea

[0766] Example 94 was synthesized in a manner similar to Example 93. LC-MS (m / z) = 342.3 [M+H ]+ .

[0767] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.19 - 7.16 (m, 3 H), 7.01 (d, J =8.8 Hz, 1 H), 6.83 (d, J = 7.6 Hz, 1 H), 6.68 - 6.64 (t, J = 8.4 Hz, 1 H),6.35 - 6.32 (t, J = 5.6 Hz, 1 H), 5.47 (s, 2 H), 4.18 (d, J = 5.6 Hz, 2 H).

[0768] Purification conditions Column: Inertsil ODS C18 (250x19)mm; 5u Flow rate: 19.0 mL / min Mobile phase A: 0.1% aqueous solution of formic acid Mobile phase B: Acetonitrile

[0769] Example 95 Synthesis of 1-((2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)methyl)-3-methylurea

[0770] Triethylamine (193 µL, 3 equivalents, 1.38 mmol) and DPPA (298 µL, 3 equivalents, 1.38 mmol) were added to a toluene (2 mL) solution of [2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]acetic acid (150 mg, 458 μmol). After stirring at 110 °C for 5 hours, methylamine (71.2 mg, 5 equivalents, 2.29 mmol) (1.15 mL of 2.0 M THF solution) was added at 0 °C. After stirring at room temperature for 18 hours, saturated NaHCO3 was added. The mixture was extracted with CHCl3, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography, eluting with 5–10% MeOH in CHCl3, to give the title compound (11 mg, 6.62%) as a grayish-white solid. LC-MS (m / z) = 356.5 [M+H] + .

[0771] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.54 (d, J = 4.4 Hz, 1H), 7.48- 7.42(m, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 8 Hz, 1H), 7.07-7.02 (t, J = 8.4Hz, 1H), 6.47 (s, 1H), 5.86 (s, 1H), 4.26 (d, J = 5.2 Hz, 2H), 2.58 (d, J = 4Hz, 3H).

[0772] Example 96 N Synthesis of -((2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)methyl)acetamide

[0773] Step 1: Synthesis of 2-[5-(aminomethyl)-1,3-benzoxazole-2-ylamino]-5-fluoro-1,3-benzoxazole

[0774] The reaction mixture was added to a stirred solution of [5-(chloromethyl)-1,3-benzoxazol-2-yl](5-fluoro-1,3-benzoxazol-2-yl)amine (0.6 g, 1.89 mmol) in dimethylformamide (30 mL, 387 mmol). After 5 minutes, the reaction mixture was purged with ammonia (3 g, 93 equivalents, 176 mmol) for 10 minutes. The reaction mixture was stirred at room temperature for 8 hours. The reaction progress was monitored by LC-MS. The reaction mixture was evaporated under reduced pressure to give a crude residue as a brown, viscous liquid of 2-[5-(aminomethyl)-1,3-benzoxazol-2-ylamino]-5-fluoro-1,3-benzoxazole (0.6 g, 1.75 mmol) (yield: 92%). LC-MS (m / z) = 299.9 [M+H] + .

[0775] Step 2: Synthesis of N-{[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]methyl}acetamide

[0776] Triethylamine (471 µL, 5 equivalents, 3.35 mmol) and acetyl acetate (228 µL, 3 equivalents, 2.01 mmol) were added to a solution of 2-[5-(aminomethyl)-1,3-benzoxazol-2-ylamino]-5-fluoro-1,3-benzoxazole (0.2 g, 671 μmol) in dichloromethane (20 mL, 312 mmol) and stirred at room temperature for 5 min. The reaction mixture was stirred at room temperature for 8 h. The reaction progress was monitored by TLC (10% MeOH in DCM) and LCMS. The reaction mixture was evaporated under reduced pressure to give a crude residue. The residue was purified by HPLC and then evaporated under reduced pressure to give N-{[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]methyl}acetamide (42 mg, 123 μmol) as a grayish-white powder (yield: 18.41%). LC-MS (m / z) = 341.4 [M+H] + .

[0777] Purification conditions Column: Sunfire C18 (250x19)mm; 5u Flow rate: 19.0 mL / min Mobile phase A: 0.1% aqueous solution of formic acid Mobile phase B: Acetonitrile Gradient %B: 0 / 20, 1 / 30, 14 / 57, 15 / 100, 20 / 100, 21 / 20, 22 / 20 The desired product RT is 12.0 min.

[0778] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.43 (s, 1H), 7.54(m, 1H) 7.48 (d, J =8.0Hz, 1H), 7.41 (s, 1H) 7.32 (d, J = 8.8Hz, 1H), 7.13 (d, J = 8.0Hz, 1H), 7.13(t, J = 9.2Hz, 1H), 4.31 (d, J = 5.6Hz, 2H) 1.89 (s, 3H).

[0779] Example 97 Synthesis of (2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxybenzo[d]oxazol-5-yl)methanol

[0780] Step 1: Synthesis of methyl 2,4-dihydroxybenzoate

[0781] Sulfuric acid (7 mL) was added to a methanol (35 mL) solution of 2,4-dihydroxybenzoic acid (5 g, 32.4 mmol) cooled to 0 °C, and the mixture was stirred at 73 °C for 16 hours. The reaction mixture was concentrated. The residue was alkalized with a saturated sodium bicarbonate solution (100 mL), precipitating a solid. The solid was filtered through a sintered funnel, washed with water (300 mL), then washed with n-heptane (100 mL), and dried under vacuum to give methyl 2,4-dihydroxybenzoate (5 g, 91%) as a grayish-white solid. LC-MS (m / z) = 169.0 [M+H] + .

[0782] Step 2: Synthesis of methyl 2-hydroxy-4-(methoxymethoxy)benzoate

[0783] Sodium hydride (178 mg, 1.3 equivalents, 7.43 mmol) was added to a tetrahydrofuran (30 mL, 369 mmol) solution of methyl 2,4-dihydroxybenzoate (1 g, 5.95 mmol) cooled to 0 °C, and the mixture was stirred at room temperature for 30 min. Then, chloromethoxymethane (497 µL, 1.1 equivalents, 6.54 mmol) was added dropwise to the mixture at 0 °C. The suspension was stirred at 0 °C for 0.5 h, the temperature was gradually increased to 80 °C, and the reaction was allowed to proceed for 2 h until completion. The reaction solution was quenched with ice water (50 mL) and extracted three times with ethyl acetate. The combined organic layers were then washed with brine, dried over anhydrous Na₂SO₄, and evaporated under vacuum to give the product, which was used directly as the reactant for the next step (1 g, crude product) without any further purification. LC-MS (m / z) = 213.1 [MH] + .

[0784] Step 3: Synthesis of methyl 2-methoxy-4-(methoxymethoxy)benzoate

[0785] A mixture of methyl 2-hydroxy-4-methoxyanisate (1 g, 4.71 mmol) and anhydrous dipotassium carbonate (2.61 g, 4 equivalents, 18.9 mmol) in dimethylformamide (10 mL, 129 mmol) was stirred at 80 °C for 5 min. Iodomethane (587 µL, 2 equivalents, 9.43 mmol) was added dropwise, and the reaction mixture was stirred at 80 °C for 1 h. TLC monitoring showed the reaction was complete. The reaction mixture was cooled to room temperature, the solids were filtered off, quenched with ice water (50 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were then washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give methyl 2-methoxy-4-(methoxymethoxy)benzoate (1 g, crude). This product was used directly as a starting material for the next step without any purification. LC-MS (m / z) = 227 [M+H] + .

[0786] Step 4: Synthesis of 4-hydroxy-2-methoxybenzoic acid

[0787] To a methanol (10 mL, 247 mmol) solution of methyl 2-methoxy-4-(methoxymethoxy)benzoate (1 g, 4.42 mmol) cooled to 0 °C, 1 N HCl (3 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with saturated sodium carbonate solution, adjusted to pH ~7, and extracted with ethyl acetate (3 x 20 mL). The reaction mixture was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by combiflash chromatography using ethyl acetate in n-heptane as the eluent on a 12 g column. The product eluted with 20–29% ethyl acetate in n-heptane to give 4-hydroxy-2-methoxybenzoic acid (350 mg, 43%) as a white solid. LC-MS (m / z) = 183.1 [M+H] + .

[0788] Step 5: Synthesis of methyl 4-hydroxy-2-methoxy-5-nitrobenzoate

[0789] Nitric acid (96.2 µL, 1.2 equivalents, 2.31 mmol) was added to a chloroform (14 mL) solution of methyl 4-hydroxy-2-anisinate (350 mg, 1.92 mmol) cooled to 0 °C, and the mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with ice water and extracted with DCM (2 x 50 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by combiflash using ethyl acetate (1–30%) in n-heptane to give methyl 4-hydroxy-2-methoxy-5-nitrobenzeneate (210 mg, 48%) as a white solid. LC-MS (m / z) = 225.9 [MH] - .

[0790] Step 6: Synthesis of methyl 5-amino-4-hydroxy-2-methoxybenzoate

[0791] The solution of methyl 4-hydroxy-2-methoxy-5-nitrobenzoate (0.2 g, 880 µmol) in a methanol mixture (15 mL) was then purged with N2 for 5 minutes. Carbon-supported palladium (50% wet) (70 mg) was added, and the mixture was stirred at 60 psi for 16 hours at room temperature. The reaction mixture was filtered through a celite bed, and the filtrate was concentrated to give methyl 5-amino-4-hydroxy-2-methoxybenzoate (150 mg, 86%) as a grayish-white solid. LC-MS (m / z) = 198.1 [M+H] + .

[0792] Step 7: Synthesis of methyl 6-methoxybenzo[d]oxazol-5-carboxylate

[0793] At room temperature, p-toluenesulfonic acid (19.6 mg, 0.15 equivalents, 114 µmol) was added to a solution of methyl 5-amino-4-hydroxy-2-methoxybenzoate (150 mg, 761 µmol) in diethoxymethoxyethane (5 mL). The reaction mixture was stirred at 100 °C for 12 h. The reaction progress was monitored by TLC. The reaction mixture was evaporated under reduced pressure to give the crude compound. The crude compound was purified by combiflash using ethyl acetate in n-heptane (1-40%, product eluted at 28%) to give methyl 6-methoxybenzo[d]oxazol-5-carboxylate (130 mg, 82%) as a grayish-white solid. LC-MS (m / z) = 208.1 [M+H] + .

[0794] Step 8: Synthesis of methyl 2-iodo-6-methoxybenzo[d]oxazol-5-carboxylate

[0795] Then, lithium bis(trimethylsilyl)imine (262 mg, 2.5 equivalents, 1.57 mmol) was added to a THF (8 mL) solution of methyl 6-methoxybenzo[d]oxazol-5-carboxylate (130 mg, 627 µmol) cooled to -78 °C, and the mixture was stirred at the same temperature for 2 h. Iodine (119 mg, 1.5 equivalents, 941 μmol) was added to THF (2 mL), and the temperature was gradually cooled to -20 °C for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (4 x 30 mL), dried over sodium sulfate, filtered, and concentrated. The crude material was purified by combiflash chromatography, and the product was eluted in n-heptane at 10%–35% EtOAc to give methyl 2-iodo-6-methoxybenzo[d]oxazol-5-carboxylate (0.1 g, impure) as a grayish-white solid. LC-MS (m / z) = 334.0 [M+H] + .

[0796] Step 9: Synthesis of methyl 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxybenzo[d]oxazol-5-carboxylate

[0797] To a THF (10 mL) solution of 5-fluoro-1,3-benzoxazol-2-ylamine (45 mg, 296 μmol), lithium 2-methyl-2-propoxide (47.4 mg, 2 equivalents, 592 μmol) and methyl 2-iodo-6-methoxybenzo[d]oxazol-5-carboxylate (98.5 mg, 296 μmol) were added, and the mixture was heated at 70 °C for 16 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate (50 mL), washed with water (20 mL), dried over sodium sulfate, filtered, and concentrated. Dichloromethane (40 mL) was added to the reaction mixture, precipitating a solid. The solid was filtered and dried under vacuum to give methyl 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxybenzo[d]oxazol-5-carboxylate (65 mg, 61%) as a brown solid. LC-MS (m / z) = 358.1 [M+H] + .

[0798] Step 10: Synthesis of (2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxybenzo[d]oxazol-5-yl)methanol

[0799] To a solution of methyl 2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxybenzo[d]oxazol-5-carboxylate (65 mg, 196 μmol) in tetrahydrofuran (5 mL, 61.4 mmol), stirred under inert conditions at 0–5 °C, lithium alumanuide (14.9 mg, 2 equivalents, 392 μmol) was added, and the reaction mixture was stirred at 0–5 °C for 2 hours. The reaction progress was monitored by TLC (5% MeOH: 95% DCM) and LCMS. After the reaction was complete, the reaction mixture was quenched with an aqueous solution of ammonium chloride (3 mL) and extracted with ethyl acetate (3 x 15 mL). The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give a colloidal (2-((5-fluorobenzo[d]oxazol-2-yl)amino)-6-methoxybenzo[d]oxazol-5-yl)methanol (0.050 g, crude). LC-MS (m / z) = 330.3 [M+H] + .

[0800] The crude compound was purified by preparative HPLC under the following analytical conditions: Column: X-Bridge C18 (19 mm X 250 mm X 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 19 mL / min

[0801] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.55 - 7.51 (m, 2 H), 7.33 - 7.30 (m,2 H), 7.06 - 7.00 (m, 1 H), 5.18 (s, 1 H), 4.53 (s, 2 H), 3.82 (s, 3 H).

[0802] Example 98 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- N Synthesis of 1-methylcyclopropane-1-carboxamide

[0803] Step 1: Synthesis of 1-(4-methoxyphenyl)cyclopropane-1-carboxynitrile

[0804] Under an inert atmosphere and at 0°C, dimethyl sulfoxide (75 mL, 1.05 mol) was added dropwise to sodium hydride (4.35 g, 3.2 equivalents, 109 mmol) with vigorous stirring. A solution of (p-methoxyphenyl)acetonitrile (5 g, 34 mmol) and 1,2-dibromoethane (3.24 mL, 1.1 equivalents, 37.4 mmol) in diethyl ether (37.5 mL, 361 mmol) was added at 0°C. The mixture was then heated to room temperature and stirred for 2 hours. The reaction progress was monitored by TLC. The mixture was cooled to 0°C and quenched with water. The solution was diluted with EtOAc and washed with water and brine. The solution was dried over sodium sulfate, filtered, and concentrated. The crude substance was purified by Combi flash column chromatography using EtOAc:n-heptane (10-20%) as the eluent to obtain 1-(4-methoxyphenyl)cyclopropane-1-carboxynitrile (1.5 g, 24.22%) as a colorless liquid. LC-MS (m / z) = 173 [M+H] + .

[0805] Step 2: Synthesis of 1-(4-methoxyphenyl)cyclopropane-1-carboxylic acid

[0806] A solution of 1-(4-methoxyphenyl)cyclopropane-1-carboxynitrile (2.25 g, 13 mmol) in concentrated HCl (20 mL) was heated at 100 °C for 12 h. The reaction progress was monitored by TLC. The precipitated reaction mixture was filtered through a sintered funnel, washed with water (200 mL), and dried to give crude 1-(4-methoxyphenyl)cyclopropane-1-carboxylic acid (1.6 g, 53.19%) as a grayish-white solid. LC-MS (m / z) = 193 [M+H] + .

[0807] Step 3: Synthesis of 1-(4-methoxyphenyl)-N-methylcyclopropane-1-carboxamide

[0808] To a solution of 1-(4-methoxyphenyl)cyclopropane-1-carboxylic acid (1 g, 4.71 mmol) in dichloromethane (12.5 mL, 195 mmol), methylamine (322 mg, 2.2 equivalents, 10.4 mmol, 4.15 mL) and N-ethylbis(isopropyl)amine (2.46 mL, 3 equivalents, 14.1 mmol) were added at 0 °C, followed by propylphosphonic anhydride (5.61 mL, 2 equivalents, 9.42 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC and LCMS data. The reaction mixture was diluted with DCM (20 mL) and water (10 mL). The extracted organic layer was washed with a saline solution (10 mL), dried over sodium sulfate, filtered, and concentrated. The crude compound was purified by combi flash chromatography using 20-50% EtOAc:n-heptane to give 1-(4-methoxyphenyl)-N-methylcyclopropane-1-carboxamide (870 mg, 89.05%) as a grayish-white solid. LC-MS (m / z) = 206 [M+H] + .

[0809] Step 4: Synthesis of 1-(4-hydroxyphenyl)-N-methylcyclopropane-1-carboxamide

[0810] At 0 °C, tribromoborane (0.7 mL, 4 equivalents, 16.9 mmol) was added to a solution of 1-(4-methoxyphenyl)-N-methylcyclopropane-1-carboxamide (870 mg, 1 equivalent, 4.24 mmol) in dichloromethane (32 mL, 0.5 mol). The reaction mixture was stirred slowly at room temperature for 3 hours. The reaction mixture was quenched with methanol and concentrated to give a crude residue, which was purified by column chromatography using EtOAc:n-heptane (0-60%) to give 1-(4-hydroxyphenyl)-N-methylcyclopropane-1-carboxamide (0.4 g, 49%) as a grayish-white solid. LC-MS (m / z) = 192 [M + H]+ .

[0811] Step 5: Synthesis of 1-(4-hydroxy-3-nitrophenyl)-N-methylcyclopropane-1-carboxamide

[0812] To a solution of 1-(4-hydroxyphenyl)-N-methylcyclopropane-1-carboxamide (0.4 g, 2.09 mmol) cooled to 0 °C in acetic acid (2 mL, 34.9 mmol), 0.5 mL of fuming nitric acid (87.3 µL, 2.09 mmol) in acetic acid was added dropwise. The mixture was stirred at the same temperature for 10 min and then continued stirring at room temperature for 1 h. The reaction was monitored by TLC and LCMS. Water (10 mL) was added to the reaction mixture at 0 °C, and the mixture was extracted with EtOAc (50 mL), NaHCO3 (50 mL), and brine (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the crude compound. The crude compound was purified by Combi flash column chromatography using EtOAc:n-heptane (40–50%) as the eluent to give 1-(4-hydroxy-3-nitrophenyl)-N-methylcyclopropane-1-carboxamide (370 mg, 52.42%) as a yellow solid. LC-MS (m / z) = 237 [M+H] + .

[0813] Step 6: Synthesis of 1-(3-amino-4-hydroxyphenyl)-N-methylcyclopropane-1-carboxamide

[0814] Under a nitrogen atmosphere and at room temperature, carbon-supported palladium (123 mg, 0.74 equivalents, 1.16 mmol) was added to a solution of 1-(4-hydroxy-3-nitrophenyl)-N-methylcyclopropane-1-carboxamide (370 mg, 1.57 mmol) in methanol (12 mL) and ethyl acetate (6 mL), and the reaction was stirred at room temperature for 12 h at 60 psi under a hydrogen atmosphere. The reaction progress was monitored by TLC. Once the reaction was complete, the reaction mixture was filtered through a celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to give 1-(3-amino-4-hydroxyphenyl)-N-methylcyclopropane-1-carboxamide (270 mg, 77.73%) as a grayish-white solid. LC-MS (m / z) = 207 [M+H] + .

[0815] Step 7: Synthesis of 1-(benzo[d]oxazol-5-yl)-N-methylcyclopropane-1-carboxamide

[0816] Triethyl orthoformate (3.64 mL, 31 equivalents, 21.9 mmol) was added to 1-(3-amino-4-hydroxyphenyl)-N-methylcyclopropane-1-carboxamide (145 mg, 703 μmol), and the reaction was heated at 100 °C for 12 h. The reaction was monitored by LC-MS and TLC. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by combiflash chromatography using methanol:DCM (0–5%) as eluent to give 1-(benzo[d]oxazol-5-yl)-N-methylcyclopropane-1-carboxamide (150 mg, 57.23%) as a yellow solid. LC-MS (m / z) = 217 [M+H + .

[0817] Step 8: Synthesis of 1-(2-iodobenzo[d]oxazol-5-yl)-N-methylcyclopropane-1-carboxamide

[0818] Then, LiHMDS (1.62 mL, 2.5 equivalence, 1.62 mmol) was added to a THF (6 mL) solution of N-methyl-1-(1,3-benzoxazol-5-yl)cyclopropane-1-carboxamide (140 mg, 647 μmol) cooled to -78 °C, and the mixture was stirred at the same temperature for 2 hours. Iodine (123 mg, 1.5 equivalence, 971 μmol) was then added to THF (2.0 mL), and the mixture was slowly heated to 0 °C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (2 x 50 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by combiflash chromatography-MPLC, and the product was eluted in dichloromethane with 6%–8% methanol to give 0.1 g (impure) of 1-(2-iodobenzo[d]oxazol-5-yl)-N-methylcyclopropane-1-carboxamide as a grayish-white solid. LC-MS (m / z) = 343.1 [M+H] + .

[0819] Step 9: Synthesis of 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-N-methylcyclopropane-1-carboxamide

[0820] Then, 5-fluoro-1,3-benzoxazol-2-ylamine (31.1 mg, 0.7 equivalents, 205 μmol) and lithium 2-methyl-2-propoxide (46.8 mg, 2 equivalents, 585 μmol) were added to a solution of 1-(2-iodobenzo[d]oxazol-5-yl)-N-methylcyclopropane-1-carboxamide (0.1 g, 292 µmol) in tetrahydrofuran (6 mL, 73.7 mmol), and the mixture was stirred at 70 °C for 12 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate (30 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Methanol from the DCM was used as the eluent, and the residue was purified by column chromatography (4 g column) to give N-methyl-1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]cyclopropaneformamide (26 mg, impure). This impure fraction was subjected to preparative HPLC to give N-methyl-1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]cyclopropaneformamide (15 mg, 14%) as a grayish-white solid. LC-MS (m / z) = 367.4 [M+H] + .

[0821] Purification conditions Column: Xselect C18 (19 mm x 250 mm x 5 mic) Mobile phase (A): 0.1% ammonia Mobile phase (B): Acetonitrile Flow rate: 19 mL / min %B / T:0 / 20,15 / 70,16 / 98,19 / 98,20 / 20 The desired product was obtained in 12.74 min.

[0822] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.58 (br, 1H), 7.53 - 7.46 (m, 2H),7.41 (s, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.20 - 7.17 (dd, J = 1.2 Hz& J = 1.2 Hz,1H), 7.04 - 6.99 (m, 1H), 6.69 (d, J = 4.4 Hz, 1H), 2.50 (s, 3H), 1.36 (d, J=3.6 Hz, 2H), 0.98 (d, J = 3.6 Hz, 2H).

[0823] Example 99 Synthesis of 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)cyclopropane-1-carboxylic acid

[0824] Step 1: Synthesis of 1-(4-hydroxyphenyl)cyclopropane-1-carboxylic acid

[0825] Potassium hydroxide (550 mg, 2.5 equivalence, 9.8 mmol) was added to a solution of methyl 1-(p-bromophenyl)cyclopropanecarboxylate (1 g, 3.92 mmol) in 1,4-dioxane (10 mL, 117 mmol) and water (10 mL, 555 mmol), and the reaction mixture was purged with nitrogen for 5 min. Then, (1E,4E)-1,5-diphenyl-1,4-pentadien-3-one-1,5-diphenyl-1,4-pentadien-3-one-palladium (1 / 2 / 2) (179 mg, 0.05 equivalence, 196 μmol) and bis(tert-butyl)[2',4',6'-tris(isopropyl)-2-biphenyl]phosphine (83.2 mg, 0.05 equivalence, 196 μmol) were added, and the reaction mixture was stirred at 100 °C for 12 h. The reaction progress was monitored by TLC. After the reaction was complete, the crude product was filtered through a celite bed, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was acidified with 1N HCl (pH: 3-4), filtered, and then dried under vacuum to give crude 1-(p-hydroxyphenyl)cyclopropanecarboxylic acid (1.62 g, 9.09 mmol) as a pale yellow solid. LC-MS (m / z) = 179.1 [M+H] + .

[0826] Step 2: Preparation of methyl 1-(4-hydroxyphenyl)cyclopropane-1-carboxylate

[0827] Sulfuric acid (1.5 mL) was added to a methanol (30 mL, 741 mmol) solution of 1-(p-hydroxyphenyl)cyclopropanecarboxylic acid (1.6 g, 8.98 mmol) cooled to 0 °C, and the mixture was stirred at 73 °C for 16 h. The reaction mixture was concentrated. The residue was alkalized with saturated sodium bicarbonate solution (20 mL), precipitating a solid. The solid was filtered through a sintered funnel, washed with water (50 mL), then with n-heptane (30 mL), and dried under vacuum to give a crude product. The crude product was purified by rapid silica gel chromatography (dry loading) with an elution gradient of 0 to 60% EtOAc in heptane. The purified fraction was concentrated to give methyl 1-(p-hydroxyphenyl)cyclopropanecarboxylic acid (920 mg, 4.79 mmol, yield: 53.3%) as a yellow oil.

[0828] Step 3: Preparation of methyl 1-(4-hydroxy-3-nitrophenyl)cyclopropane-1-carboxylate

[0829] To a solution of methyl 1-(p-hydroxyphenyl)cyclopropanecarboxylate (920 mg, 4.79 mmol) cooled to 0 °C in acetic acid (7.5 mL, 140 mmol), 0.5 mL of nitric acid (0.2 mL, 4.79 mmol) in acetic acid was added dropwise to the reaction mixture. The mixture was stirred at the same temperature for 10 min and then continued stirring at room temperature for 1 h. The reaction was monitored by TLC. Water (10 mL) was added to the reaction mixture at 0 °C, and the mixture was extracted with EtOAc (15 mL) and washed with brine. The organic layer was dried over sodium sulfate and concentrated to give the crude product. The crude product was purified by rapid silica gel chromatography (dry loading) with an elution gradient of 0 to 30% EtOAc in heptane. The purified fraction was concentrated to give methyl 1-(4-hydroxy-3-nitrophenyl)cyclopropanecarboxylate (690 mg, 2.91 mmol, crude product) as a pale yellow oil. LC-MS (m / z) = 236.0 [MH] - .

[0830] Step 4: Preparation of methyl 1-(3-amino-4-hydroxyphenyl)cyclopropane-1-carboxylate.

[0831] To a stirred solution of methyl 1-(4-hydroxy-3-nitrophenyl)cyclopropanecarboxylate (640 mg, 2.7 mmol) in 1,4-dioxane (7 mL, 82.1 mmol) and water (3 mL, 167 mmol), zinc (1.41 g, 8 equivalents, 21.6 mmol) and ammonium chloride (1.15 g, 8 equivalents, 21.6 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC. Once the reaction was complete, the mixture was filtered, diluted with EtOAc (5 mL), washed with water (3 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure to give crude methyl 1-(3-amino-4-hydroxyphenyl)cyclopropanecarboxylate (620 mg, 2.99 mmol) as a pale green solid.

[0832] Step 5: Preparation of methyl 1-(2-aminobenzo[d]oxazol-5-yl)cyclopropane-1-carboxylate.

[0833] At room temperature, bromoformonitrile (350 mg, 1.2 equivalents, 3.3 mmol) was added to a stirred solution of methyl 1-(3-amino-4-hydroxyphenyl)cyclopropanecarboxylate (570 mg, 2.75 mmol) in methanol (6 mL, 148 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. The reaction mixture was quenched with saturated NaHCO3 (3 mL). The MeOH was evaporated under reduced pressure and quenched with ethyl acetate (10 mL). 2) Extraction of the residue. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give methyl 1-(2-amino-1,3-benzoxazol-5-yl)cyclopropanecarboxylate as a black solid (610 mg, 2.63 mmol, yield: 95.49%). LC-MS (m / z) = 233.1 [M+H] + .

[0834] Step 6: Preparation of methyl 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)cyclopropane-1-carboxylate

[0835] To a solution of methyl 1-(2-amino-1,3-benzoxazol-5-yl)cyclopropanecarboxylate (0.6 g, 2.58 mmol) in dimethylformamide (8 mL, 103 mmol), cesium carbonate (1.68 g, 2 equivalents, 5.17 mmol) and 5-fluoro-2-(methylthio)-1,3-benzoxazole (473 mg, 2.58 mmol) were added, and the mixture was heated at 85 °C for 16 h. The reaction mixture was monitored by TLC. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (10 mL), washed with water (5 mL), and the combined organic layers were dried over sodium sulfate and concentrated to give the crude product. The crude product was purified by rapid silica gel chromatography (dry loading) with an elution gradient of 0 to 60% EtOAc in heptane. The purified fraction was concentrated to give methyl 1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]cyclopropanecarboxylate (240 mg, 653 µmol, yield: 25.29%) as a pale yellow solid. LC-MS (m / z) = 368.1 [M+H] + .

[0836] Step 7: Preparation of 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)cyclopropane-1-carboxylic acid

[0837] Lithium hydroxide (62.6 mg, 4 equivalents, 2.61 mmol) was added to a stirred solution of methyl 1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]cyclopropanecarboxylic acid (240 mg, 653 μmol) in tetrahydrofuran (1 mL, 12.3 mmol), methanol (1 mL, 24.7 mmol), and water (0.5 mL, 27.8 mmol), and the reaction was stirred at room temperature for 16 hours. The progress of the reaction mixture was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was acidified with 1N HCl to pH (2-3), and the solid was filtered through a sintered funnel to give the desired product 1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]cyclopropanecarboxylic acid (218 mg, 617 µmol) as a grayish-white solid. 80 mg of the product was neutralized with saturated NaOH solution to pH (8-9), and the liquid was concentrated under reduced pressure to give 95.5 mg of sodium 1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]cyclopropaneformate as a grayish-white solid. This compound was registered as a sodium salt. LC-MS (m / z) = 354.3 [M+H] + .

[0838] 1 H NMR (400 MHz, DMSO-d6) δ ppm: δ 7.35 (s, 1H), 7.16-7.13 (m, 2H), 7.01 (d, J = 8.00 Hz, 1H), 6.84 (d, J = 8.00 Hz, 1H), 6.68-6.63 (m, 1H), 1.21-1.21 (m, 2H), 0.69-0.69 (m, 2H).

[0839] Example 100 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- N , N Synthesis of 1-dimethylcyclopropane-1-carboxamide

[0840] Add 2,4,6-tripropyl-1,3,5,2λ to a solution of 1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]cyclopropanecarboxylic acid (0.2 g, 566 µmol) in dichloromethane (24 mL, 375 mmol). 5 ,4λ 5 ,6λ 5 --Trioxane-2,4,6-trione 50% v / v (667 µL, 2 equivalents, 1.13 mmol) and 2-(2-aminoethoxy)ethanol (71.4 mg, 1.2 equivalents, 679 µmol). N-ethylbis(isopropyl)amine (296 µL, 3 equivalents, 1.7 mmol) was added to the mixture at 0 °C, and the reaction mixture was stirred at room temperature for 12 h. The reaction progress was monitored by TLC and LCMS data. After the reaction was complete, the reaction mixture was quenched with water (3.0 mL) and extracted with ethyl acetate (2 x 5.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product (315 mg). The crude substance was purified by the preparative HPLC method described below to give N-[2-(2-hydroxyethoxy)ethyl]1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]cyclopropaneformamide (138 mg, 314 µmol, yield: 55.51%) as a white solid. LC-MS (m / z) = 441.4 [M+H] + .

[0841] 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.57-7.51 (m, 2H), 7.45 (s, 1H),7.35-7.33 (m, 1H), 7.23 (d, J = 8.40 Hz, 1H), 7.08-7.03 (m, 1H), 6.74-6.71 (m,1H), 3.42-3.40 (m, 2H), 3.35-3.33 (m, 4H), 3.18-3.13 (m, 2H), 1.39-1.38 (m,2H), 1.01-1.01 (m,2H).

[0842] Purification conditions Column: Xterra C18 (250x19)mm; 10u Flow rate: 19.0 mL / min Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile The desired product Rt is obtained at 10.82 min.

[0843] Example 101 Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)propionic acid

[0844] Step 1: Synthesis of methyl 2-(4-((tert-butyldimethylsilyl)oxy)phenyl)acetate

[0845] Imidazole (6.15 g, 90.3 mmol, 3 equivalents) was added to a stirred solution of methyl (p-hydroxyphenyl)acetate (5 g, 30.1 mmol, 1 equivalent) in DMF (50 mL). After cooling the reaction mixture to 0 °C, (tert-butyl)(chloro)bis(methyl)silane (9.07 g, 60.2 mmol, 2 equivalents) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with ice-cold water (20 mL), extracted with EtOAc (2 x 50 mL), and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography, eluting with 5% EtOAc-heptane to give methyl {p-[(tert-butyl)bis(methyl)siloxy]phenyl}acetate (7 g, 83% yield) as a colorless liquid. LC-MS (m / z) = 281.2 [M + H] + .

[0846] Step 2: Synthesis of methyl 2-(4-((tert-butyldimethylsilyl)oxy)phenyl)propionate

[0847] Then, lithium bis(isopropyl)imine (18.7 mL, 37.4 mmol, 1.5 equivalent) was added to a THF (70 mL) solution of methyl p-[(tert-butyl)bis(methyl)siloxy]phenyl}acetate (7 g, 25 mmol, 1 equivalent) cooled to -78 °C, and the mixture was stirred at the same temperature for 1 hour. Iodomethane (3.11 mL, 49.9 mmol, 2 equivalent) was added, and the temperature was gradually cooled to -20 °C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (2 x 50 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product. It was purified by rapid column chromatography, eluting with 2.5% EtOAc-heptane, to give methyl 2-{p-[(tert-butyl)bis(methyl)siloxy]phenyl}propionate (7.1 g, 96% yield) as a colorless liquid. LC-MS (m / z) = 295.2 [M+H] + .

[0848] Step 3: Synthesis of methyl 2-(4-hydroxyphenyl)propionate

[0849] Then, TBAF (10.2 mL, 1 equivalent) was added to a THF (30 mL) solution of methyl 2-{p-[(tert-butyl)bis(methyl)siloxy]phenyl}propionate (3 g, 10.2 mmol, 1 equivalent) cooled to 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with H₂O (30 mL), extracted with ethyl acetate (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated to give crude methyl 2-(p-hydroxyphenyl)propionate (1.8 g). LC-MS (m / z) = 181.1 [M+H] + .

[0850] Step 4: Synthesis of methyl 2-(4-hydroxy-3-nitrophenyl)propionate

[0851] To a solution of methyl 2-(p-hydroxyphenyl)propionate (2.6 g, 14.4 mmol, 1 equivalent) cooled to 0 °C in acetic acid (10 mL), 0.5 mL of nitric acid in acetic acid (602 µL, 14.4 mmol) was added dropwise to the reaction mixture. The mixture was stirred at the same temperature for 10 min and then continued stirring at room temperature for 1 h. The reaction was monitored by TLC and LCMS. Water (30 mL) was added to the reaction mixture at 0 °C, and the mixture was extracted with EtOAc (50 mL) and washed with brine. The organic layer was dried over sodium sulfate and concentrated to give a crude product, which was purified by rapid column chromatography, eluting with 8% EtOAc-heptane, to give methyl 2-(4-hydroxy-3-nitrophenyl)propionate (2 g, 62%) as a yellow liquid. LC-MS (m / z) = 224.0 [M - H].

[0852] Step 5: Synthesis of methyl 2-(3-amino-4-hydroxyphenyl)propionate

[0853] Iron (496 mg, 2 equivalents, 8.88 mmol) and ammonium chloride (713 mg, 3 equivalents, 13.3 mmol) were added to a solution of methyl 2-(4-hydroxy-3-nitrophenyl)propionate (1 g, 4.44 mmol, 1 equivalent) in ethanol (10 mL) and water (8 mL), and the mixture was stirred at 70 °C for 16 h. The reaction progress was monitored by TLC. The reaction mixture was filtered through celite. The filtrate was absorbed into water and extracted with ethyl acetate to the organic layer. The organic layer was dried over NaSO4 and concentrated to give methyl 2-(3-amino-4-hydroxyphenyl)propionate (0.6 g, yield: 70%) as a brown solid. LC-MS (m / z) = 196.1 [M+ H] + .

[0854] Step 6: Synthesis of methyl 2-(2-aminobenzo[d]oxazol-5-yl)propionate

[0855] To a stirred solution of methyl 2-(3-amino-4-hydroxyphenyl)propionate (2 g, 10.2 mmol, 1 equivalent) in methanol (20 mL), bromoformonitrile (1.3 g, 12.3 mmol, 1.2 equivalent) was added. The reaction mixture was stirred at room temperature for 16 hours, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude residue. The residue was alkalized with saturated aqueous Na₂CO₃ solution (30 mL) to form a solid, which was filtered and dried to give methyl 2-(2-amino-1,3-benzoxazol-5-yl)propionate (2.1 g, 93% yield) as a brown solid. LC-MS (m / z) = 221.2 [M + H] + .

[0856] Step 7: Synthesis of methyl 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)propionate

[0857] To a DMF (5 mL) solution of methyl 2-(2-amino-1,3-benzoxazol-5-yl)propionate (0.5 g, 2.27 mmol, 1 equivalent), 5-fluoro-2-(methylthio)-1,3-benzoxazole (0.41 g, 2.27 mmol, 1 equivalent) and dicesium carbonate (1.11 g, 3.41 mmol, 1.5 equivalent) were added, and the reaction mixture was heated at 85 °C for 16 h. The reaction progress was monitored by TLC and LCMS. Once the reaction was complete, the reaction mixture was diluted with ice-cold water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude sample was loaded onto a Flash column, and MPLC was performed using 15%-20% EtOAc in heptane as the eluent to give methyl 2-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionate as a white solid (0.3 g, yield: 37%). LC-MS (m / z) = 356.0 [M + H] + .

[0858] Step 8: Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)propionic acid

[0859] Lithium hydroxide (0.084 g, 3.52 mmol, 5 equivalents) was added to a stirred solution of methyl 2-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionate (0.25 g, 0.70 mmol, 1 equivalent) in methanol (2 mL), THF (2 mL), and water (2 mL). The reaction mixture was stirred at room temperature for 16 hours, and the reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude residue. The residue was acidified with dilute HCl (5 mL) to form a solid, which was filtered and dried to obtain a crude product. This crude product was purified by preparative chromatography, and the collected fractions were concentrated to obtain 2-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionic acid (0.17 g, 83%) (registered as sodium salt) as a white, gelatinous solid. LC-MS (m / z) = 342.3 [M + H] + .

[0860] Purification conditions Column: Sunfire C18 (19 mm x 250 mm x 5 mic) Mobile phase (A): 5 mM ammonium bicarbonate aqueous solution Mobile phase (B): Acetonitrile Flow rate: 19 mL / min

[0861] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.32 (s, 1 H), 7.15 - 7.08 (m, 2 H), 7.02 (d, J = 8.0 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 1 H), 6.64 (t, J = 8.4 Hz, 1 H),3.31 - 3.27 (m, 1 H), 1.27 (d, J = 6.8 Hz, 3 H).

[0862] Example 102 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)- N Synthesis of 2-(2-hydroxyethoxy)ethyl)propionamide

[0863] Step 1: Synthesis of 2-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-N-(2-(hydroxymethoxy)ethyl)propionamide

[0864] Add 2-(2-aminoethoxy)ethanol (0.18 g, 1.76 mmol, 2 equivalents) and 2,4,6-tripropyl-1,3,5,2λ to a DCM (3 mL) solution of 2-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionic acid (0.3 g, 0.87 mmol, 1 equivalent) to the solution. 5 ,4λ 5 ,6λ 5- Trioxane-2,4,6-trione (1.05 mL, 1.76 mmol, 2 equivalents). N-ethylbis(isopropyl)amine (0.45 mL, 2.64 mmol, 3 equivalents) was added to the above mixture at 0 °C, and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS data. After the reaction was complete, the reaction mixture was quenched with water (8.0 mL) and extracted with ethyl acetate (2 x 5.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude product. The crude product was purified according to the preparation conditions mentioned below, and the collected fraction was concentrated to give N-[2-(2-hydroxyethoxy)ethyl]2-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]propionamide (14 mg, 3% yield) as a white solid. LC-MS (m / z) = 429.4 [M+H] + .

[0865] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.08 (t, J = 5.6 Hz, 1 H), 7.56 - 7.45(m, 3 H), 7.34 - 7.31 (dd, J = 2.8 Hz, J = 2.8 Hz, 1 H), 7.20 - 7.18 (dd, J = 1.6Hz, J = 1.6 Hz, 1 H), 7.07 - 7.02 (m, 1 H), 3.74 - 3.69 (m, 1 H), 3.47 - 3.34 (m, 5 H), 3.26 - 3.13 (m, 3 H), 1.35 (d, J = 6.8 Hz, 3 H).

[0866] Example 103 2-(benzo[d]oxazol-2-ylamino)- N Synthesis of 1-(1-(2-hydroxyethyl)pyrrolidine-3-yl)benzo[d]oxazol-5-carboxamide

[0867] Example 103 was synthesized in a manner similar to that of Example 22.

[0868] Example 104 1-(2-((5-fluorobenzo[d]oxazol-2-yl)amino)benzo[d]oxazol-5-yl)-N Synthesis of 1-(2-(2-hydroxyethoxy)ethyl)cyclopropane-1-carboxamide

[0869] Add 2,4,6-tripropyl-1,3,5,2λ to a solution of 1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]cyclopropanecarboxylic acid (0.2 g, 566 μmol) in dichloromethane (24 mL, 375 mmol). 5 ,4λ 5 ,6λ 5 -trioxane-2,4,6-trione 50% v / v (667 µL, 2 equivalents, 1.13 mmol) and 2-(2-aminoethoxy)ethanol (71.4 mg, 1.2 equivalents, 679 µmol). N-ethylbis(isopropyl)amine (296 µL, 3 equivalents, 1.7 mmol) was added to the above mixture at 0 °C, and the reaction mixture was stirred at room temperature for 12 h. The reaction progress was monitored by TLC and LCMS data. After the reaction was complete, the reaction mixture was quenched with water (3.0 mL) and extracted with ethyl acetate (2 x 5.0 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude product (315 mg). The crude substance was purified by the preparative HPLC method described below to give N-[2-(2-hydroxyethoxy)ethyl]1-[2-(5-fluoro-1,3-benzoxazol-2-ylamino)-1,3-benzoxazol-5-yl]cyclopropaneformamide (138 mg, 314 µmol, yield: 55.51%) as a white solid. LC-MS (m / z) = 441.4 [M+H] + .

[0870] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.57-7.51 (m, 2H), 7.45 (s, 1H),7.35-7.33 (m, 1H), 7.23 (d, J = 8.40 Hz, 1H), 7.08-7.03 (m, 1H), 6.74-6.71 (m,1H), 3.42-3.40 (m, 2H), 3.35-3.33 (m, 4H), 3.18-3.13 (m, 2H), 1.39-1.38 (m,2H), 1.01-1.01 (m,2H).

[0871] Purification conditions Column: Xterra C18 (250x19)mm; 10u Flow rate: 19.0 mL / min Mobile phase A: 0.1% ammonia Mobile phase B: Acetonitrile The desired product Rt is obtained at 10.82 min. Example A

[0872] Cell target binding

[0873] HEK293 ARE luciferase reporter cells (Signosis) were maintained according to the manufacturer's instructions. To assess target binding, cells were seeded into 96-well plates and treated with different concentrations of the compound or DMSO carrier. Cells were incubated at 37°C and 5% CO2 for 6 hours. After this time, cells were washed and lysed using RIPA buffer containing a mixture of protease inhibitors. Luciferase activity was assessed using the substrate (Signosis) according to the manufacturer's instructions. Table A shows the results of cell target binding with the compounds described herein. Table A. Results of cell target binding "+" indicates that the average EC50 value is at least 10 µM; "++" indicates that the average EC50 value is between 5 and 10 µM; "+++" indicates that the average EC50 value is between 2.5 and 5 µM; "++++" indicates that the average EC50 value is less than 2.5 µM. Example B

[0874] Cellular HO-1 protein induction

[0875] HepG2 cells (ATCC) were maintained according to the manufacturer's instructions. To assess HO-1 protein induction, cells were seeded in 96-well plates and treated for 18 hours at 37°C and 5% CO2 with different concentrations of the compound or DMSO carrier. After this time, cells were washed and lysed using RIPA lysis buffer containing a mixture of protease inhibitors. HO-1 induction was measured by ELISA (R&D Systems) according to the manufacturer's instructions. Table B shows the results of HO-1 protein induction in cells using the compounds described herein. Table B. Results of HO-1 protein induction in cells. “+” indicates that the average EC50 value is at least 10 µM; “++” indicates that the average EC50 value is between 5 and 10 µM; “+++” indicates that the average EC50 value is between 2.5 and 5 µM; “++++” indicates that the average EC50 value is less than 2.5 µM. Example C

[0876] F-cell (fetal hemoglobin (HbF)) induction (Method 1)

[0877] Mobilized peripheral blood CD34+ cells from normal human donors were thawed, washed, counted, and diluted in culture medium. Cells were then seeded at 10,000 cells per well in 96-well plates. Cells were cultured for 7 days (37°C and 5% CO2) in X-Vivo 15 medium containing 10 ng / mL recombinant human IL-3 (rhL-3), 100 ng / mL recombinant human stem cell factor (rhSCF), and 100 ng / mL recombinant human Flt-3 (rhFlt-3) ligand. On day 7, the plates were centrifuged, the medium was removed, and the cells were washed. Cells were then cultured for 7 days in X-Vivo-15 medium containing 10 ng / mL rhL-3, 100 ng / mL rhSCF, and 3 U / mL erythropoietin. From day 7 to day 14, cells were treated with different concentrations of the compounds described herein or DMSO loaders. On day 14, flow cytometry was used to stain CD71, CD235, and HbF to confirm HbF induction. Alternatively, the percentage of intact HbF was determined by ELISA (Fortis Life Sciences, E88-134 and E88-136) or HPLC-UV (Ou and Rognerud, Clin. Chem., 1993), or Hb subunits were determined by HPLC-MS. Table C shows the cellular CD71 brightening of the compounds described herein. + HbF + The result of induction. Table C. Cellular CD71 bright + HbF + The result of induction "+" indicates that the multiple is no more than 1.0; "++" indicates that the multiple is between 1.0 and 1.5; "+++" indicates that the multiple is between 1.5 and 2; "++++" indicates that the multiple is at least 2.0.

[0878] F-cell (fetal hemoglobin (HbF)) induction (Method 2)

[0879] Mobilized peripheral blood CD34+ cells from normal human donors were thawed, washed, counted, and diluted in culture medium. Cells were then seeded at 10,000 cells per well in 96-well plates. Cells were cultured for 7 days (37°C and 5% CO2) in X-Vivo-15 medium containing 1 ng / mL recombinant human IL-3 (rhL-3), 10 ng / mL recombinant human stem cell factor (rhSCF), 3 U / mL heparin, and 3 U / mL erythropoietin. On day 4, cells were diluted 1:4 in the same medium mixture. On day 7, the plates were centrifuged, the medium was removed, and cells were washed. Cells were then cultured in X-Vivo-15 medium containing 10 ng / mL rhSCF, 3 U / mL heparin, and 3 U / mL erythropoietin until day 12. Finally, cells were cultured in medium containing 200 μg / mL transferrin, 3 U / mL heparin, and 3 U / mL erythropoietin. Cells were treated with varying concentrations of the compounds described herein or DMSO carrier throughout the culture period (from day 0 to day 14). On day 14, HbF induction was confirmed by flow cytometry staining for CD71, CD235, and HbF. Alternatively, the percentage of intact HbF was determined by ELISA (Fortis Life Sciences, E88-134 and E88-136) or HPLC-UV (Ou and Rognerud, Clin. Chem., 1993), or the subunits of Hb were determined by HPLC-MS. Example D

[0880] Thermodynamic solubility

[0881] The assay sample was prepared as follows: 1 mg of the compound was added to a centrifuge tube, along with 1 mL of buffer (phosphate-buffered saline, fasting simulated intestinal fluid, fasting simulated gastric fluid, or eating simulated intestinal fluid) to achieve a concentration of 1 mg / mL. The tube containing the assay sample was then shaken at the desired temperature for the required time, followed by centrifugation to separate the undissolved drug from the dissolved drug. The supernatant was collected and filtered. The filtrate sample was transferred to a 96-well plate and analyzed by HPLC or UPLC in comparison with a compound calibration standard. Example E

[0882] Metabolic stability in hepatocytes

[0883] Frozen hepatocytes were thawed, washed, and counted. They were diluted to the desired concentration in culture medium and seeded into 96-well plates. Each test compound and positive control was added to the plate to initiate the reaction. The plate was incubated on a rocker for the required time, then one portion of the contents was transferred from each well and mixed with acetonitrile containing an internal standard to terminate the reaction. The samples were centrifuged, and the supernatant was transferred to a 96-well plate and diluted with distilled water for analysis by LC-MS / MS. Example F

[0884] In vivo pharmacokinetics (PK)

[0885] The compound was administered orally (po) or intravenously (iv). For oral delivery, animals were fasted. The compound was suspended in 0.5% w / v methylcellulose or 0.5% w / v methylcellulose:Tween 80 (99.5:0.5, v / v) and then administered to different species. For intravenous delivery, animals were fed. The compound was dissolved in DMSO:Solutol + ethanol (1:1, v / v):0.9% saline (10:10:80, v / v / v), DMSO:Kolliphor RH40 + ethanol (1:1, v / v):0.9% saline (10:10:80, v / v / v), or PEG400:water (1:1, v / v) and then administered to one of the different species according to Table D. At predetermined time points, whole blood was collected in EDTA-K2 tubes, and plasma was collected after centrifugation at 2,000 xg for 10 minutes at 4°C. Plasma concentrations (ng / mL) were determined using a calibration curve and an applicable LC-MS method. An example of such a method is provided below in Example I. Table D. Representative experimental designs for in vivo PK studies. Example G

[0886] In vivo pharmacokinetic (PK) / pharmacodynamic (PD) models

[0887] The compound was suspended in 0.5% w / v methylcellulose or 0.5% w / v methylcellulose: Tween 80 (99.5:0.5, v / v) and then administered orally (po) to mice (female or male, C57BL / 6) at different dose intensities and levels. Mice were administered once or twice daily for ≥1 day. At predetermined time points, a portion of whole blood was collected in EDTA-K2 tubes and processed into plasma. Plasma concentrations (ng / mL) were determined by a suitable LC-MS method. An example of such a method is provided below in Example I. Plasma levels of HO-1 were determined by ELISA according to the manufacturer's instructions (Abcam, ab204524). A second portion of whole blood was collected into RNAlater ® In a solution (or equivalent solution). Follow standard procedures (e.g., using RNeasy). ® RNA was extracted using the kit (following the manufacturer's instructions), and the mRNA levels of each gene were determined by qPCR. Finally, white blood cells (WBCs) were collected from a third portion of whole blood by lysing red blood cells and centrifuging to collect the WBCs. RNA was extracted from the WBCs and the mRNA levels of each gene were determined as described above. Example H

[0888] Townes mouse model of sickle cell disease (SCD)

[0889] The compound was suspended in 0.5% w / v methylcellulose or 0.5% w / v methylcellulose:Tween 80 (99.5:0.5, v / v) and then administered orally (po) to mice (female or male, towns, homozygous / homozygous) at different dose intensities and levels. Mice were administered once daily or twice daily for ≥1 day. At predetermined time points, a portion of whole blood was collected in EDTA-K2 tubes and processed into plasma. Plasma exposure (ng / mL) was determined according to PK or PK / PD methods. F-cell levels were determined using anti-HbF antibody by standard flow cytometry. %HbF levels were determined by HPLC-UV (Ou and Rognerud, Clin. Chem., 1993) or ELISA (Fortis Life Sciences, E88-134 and E88-136), and Hb subunit (α, β, γ) levels were determined by LC-MS. Other analytes and / or biomarkers were determined according to the PK / PD model description. Example I

[0890] Plasma Sample Preparation and Tandem Mass Spectrometry Analysis Methods

[0891] Methods for preparing plasma samples for mass spectrometry analysis and their analysis are well known to those skilled in the art. Furthermore, those skilled in the art will understand that developing LC-MS / MS analytical methods for a given compound requires a certain degree of parameter optimization to obtain optimal results. These parameters may include, but are not limited to: mobile phase, LC gradient, injection volume, column, flow rate, ionization mode, residence time, declustering voltage, inlet potential, collision energy, collision cell outlet potential, and... m / z Conversion, etc. Nevertheless, this article still provides two plasma sample preparation and LC-MS / MS analysis methods that can be used in the practice of this invention.

[0892] Plasma sample preparation (Method 1)

[0893] Working solutions of the desired series of concentrations were obtained by diluting the stock solution of the compound with a 50% aqueous acetonitrile solution. 5 μL of the working solution (5, 10, 20, 50, 100, 500, 1000, 5000, 10000 ng / mL) was added to 50 μL of blank beagle plasma to obtain 55 μL of calibration standards ranging from 0.5 to 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL). Six quality control (QC) samples of plasma at concentrations of 1 ng / mL, 2 ng / mL, 5 ng / mL, 50 ng / mL, 400 ng / mL, and 800 ng / mL were prepared on the day of analysis, independent of the samples used for the calibration curves. These QC samples were prepared in the same manner as the calibration standards on the day of analysis. 55 μL of standard, 55 μL of QC sample, and 55 μL of unknown sample (50 μL plasma plus 5 μL blank solution) were added to 200 μL of acetonitrile containing the internal standard (IS) mixture to precipitate the protein. The sample was vortexed for 30 seconds and centrifuged at 3,900 rpm for 15 minutes at 4 °C. The supernatant was diluted 3-fold with water, and 5 µL of the diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0894] LC-MS / MS analysis (Method 1)

[0895] LC-MS / MS analysis was performed using a Shimadzu HPLC system coupled to a SCIEX Triple Quad 5500+ LC-MS / MS instrument. Samples were separated on a Raptor Biphenyl 2.7 µL (50 x 2.1 mm) column using 5 µL injection volumes and mobile phases A (95:5 water:acetonitrile + 0.1% formic acid) and B (5:95 water:acetonitrile + 0.1% formic acid). The gradients used were: 0–0.3 min, 95% A; 1.9–2.2 min, 5% A; 2.2–2.5 min, 95% A, at a flow rate of 0.6 mL / min. The gradients are shown in Table E below. Table E. LC gradients used in LC-MS / MS (Method 1).

[0896] Electrospray ionization in positive ion mode was used, and tandem mass spectrometry was acquired in multiple reaction monitoring (MRM) mode. The gas temperature was 550 °C. MS / MS parameters were set as shown in Table F. Dexamethasone was added to the sample as an internal standard. Table F. MS / MS parameters of dexamethasone detected using LC-MS / MS (Method 1).

[0897] For optimal detection, these parameters can be adjusted based on the characteristics of the target compound.

[0898] Plasma sample preparation (Method 2)

[0899] To prepare the quality control (QC) sample, a 2.5 µL working stock solution of the compound was added to a 22.5 µL blank beagle plasma to obtain the desired concentration. To prepare the study sample, the vial containing the study sample was removed from a -20°C cryogenic freezer and thawed to room temperature. 25 µL volumes of sample were aliquoted into pre-labeled vials. Both the QC and study samples were processed as described below. 400 µL of 100% acetonitrile containing 100 ng / mL of 15 µL was added to a 25 µL sample to precipitate the protein. The sample was vortexed for 5 min and centrifuged at 14,000 rpm for 5 min at 4°C. A supernatant was then separated, and 2 µL was injected into the LC-MS / MS system as described below.

[0900] LC-MS / MS analysis (Method 2)

[0901] LC-MS / MS analysis was performed using an HPLC system coupled to a SCIEX Triple Quad 5500+ LC-MS / MS instrument. Samples were separated on a Zorbax SB phenyl 3.5 µm (50 x 4.6 mm) column using an injection volume of 2 µL and an isocratic gradient (45% A, 55% B) at a flow rate of 0.9 mL / min for 2 min. Mobile phase A consisted of 0.1% formic acid + 5 mM ammonium formate aqueous solution; mobile phase B consisted of acetonitrile. Electrospray ionization was performed in positive ion mode, and tandem mass spectra were acquired in MRM mode. MS / MS parameters were set as shown in Table G. Warfarin was incorporated into the sample as an internal standard. Table G. MS / MS parameters of warfarin detected using LC-MS / MS (Method 2).

[0902] For optimal detection, these parameters can be adjusted based on the characteristics of the target compound.

[0903] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and various modifications or variations thereof are suggestive to those skilled in the art and are included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference for all purposes.

Claims

1. Compound of formula (I): （I） Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein: R 1 , R 3 , R 4 , and R 8 are each independently hydrogen, Ci-C6alkyl, C3-C6cycloalkyl, halogen, halogenated Ci-C6alkyl, or OR 10 wherein R 10 is hydrogen, Ci-C6alkyl, C3-C6cycloalkyl, or halogenated Ci-C6alkyl; R 2 Hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halogenated C1-C6 alkyl, OR 10 hydroxyl C1-C6 alkyl or -C(O)NR 11 R 12 , where R 11 and R 12 Each of them is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, or hydroxy-C1-C6 alkoxy-C1-C6 alkyl; R 5 It is hydrogen, hydroxyl C1-C6 alkyl or carboxyl C1-C6 alkyl; R 6 and R 7 Independently hydrogen, hydroxyl C1-C6 alkyl, -XC(O)R 13 -YC(O)NR 14 R 15 -Z-NR 16 R 17 , heteroaryl or -S(O)2R 18 ,in X is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 13 -OH or -OR 10 ; Y is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 14 and R 15 Each of the following can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl-C3-C6 cycloalkylamino, C1-C6 amine, carboxyl-C1-C6 alkyl, -S(O)2R 19 phenyl, heteroaryl, or together with the nitrogen atoms they are attached to form 3-8 membered monocyclic heterocyclic groups, wherein R 19 It is a C1-C6 alkyl group; The phenyl group is optionally substituted with a C1-C6 alkyl group; The heteroaryl group is optionally substituted with a C1-C6 alkyl group; and The 3-8 membered monocyclic heterocyclic group is optionally substituted with C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, hydroxy-C1-C6 alkyl, or amino-C1-C6 alkyl. Z is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 16 and R 17 Each of the following can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or -(C1-C6 alkyl)-C(O)R 20 -C(O)R 21 Or, together with the nitrogen atoms they are attached to, they form 3-8 membered monocyclic heterocyclic groups, in which R 20 -OH, OR 10 or NR 22 R 23 , where R 22 and R 23 Each of them is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or hydroxy-C1-C6 alkyl-C3-C6 cycloalkylamino; R 21 It is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halogenated C1-C6 alkyl, amino, or mono- or di-C1-C6 alkylamino; and The 3-8 membered monocyclic heterocyclic group is optionally substituted with C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, hydroxy-C1-C6 alkyl, or amino-C1-C6 alkyl; and R 18 It is a C1-C6 alkyl or -NH-(C1-C6 alkyl); and R 9 It is hydrogen, C1-C6 alkyl, or N-protecting group.

2. The compound according to claim 1, wherein R 1 It is hydrogen.

3. The compound according to claim 1, wherein R 1 It is a methyl group.

4. The compound according to claim 1, wherein R 1 It is fluorinated.

5. The compound according to claim 1, wherein R 1 OR 10 And R 10 It is a methyl group.

6. The compound according to any one of claims 1-5, wherein R 2 It is hydrogen.

7. The compound according to any one of claims 1-5, wherein R 2 It is a methyl group.

8. The compound according to any one of claims 1-5, wherein R 2 It is fluorinated.

9. The compound according to any one of claims 1-5, wherein R 2 OR 10 And R 10 It is a methyl group.

10. The compound according to any one of claims 1-5, wherein R 2 -C(O)NR 11 R 12 And R 11 It is hydrogen, and R 12 It is a C1-C6 alkoxy-C1-C6 alkyl group.

11. The compound according to any one of claims 1-5, wherein R 2 -C(O)NR 11 R 12 And R 11 It is hydrogen, and R 12 for .

12. The compound according to any one of claims 1-11, wherein R 3 It is hydrogen.

13. The compound according to any one of claims 1-11, wherein R 3 It is a methyl group.

14. The compound according to any one of claims 1-11, wherein R 3 It is either fluorinated or chlorinated.

15. The compound according to any one of claims 1-11, wherein R 3 It is a halogenated C1-C6 alkyl group.

16. The compound according to any one of claims 1-11, wherein R 3 It is difluoromethyl or trifluoromethyl.

17. The compound according to any one of claims 1-11, wherein R 3 OR 10 And R 10 It is methyl or difluoromethyl.

18. The compound according to any one of claims 1-17, wherein R 4 It is hydrogen.

19. The compound according to any one of claims 1-17, wherein R 4 It is a methyl group.

20. The compound according to any one of claims 1-17, wherein R 4 It is fluorinated.

21. The compound according to any one of claims 1-20, wherein R 5 It is hydrogen.

22. The compound according to any one of claims 1-20, wherein R 5 It is a hydroxyl C1-C6 alkyl group, and wherein R 5 for .

23. The compound according to any one of claims 1-20, wherein R 5 It is a carboxyl C1-C6 alkyl group, and wherein R 5 for .

24. The compound according to any one of claims 1-23, wherein R 6 and R 7 Only one of them is hydrogen.

25. The compound according to any one of claims 1-23, wherein R 6 and R 7 Each is hydrogen.

26. The compound according to any one of claims 1-23, wherein R 6 and R 7 One is hydrogen, and the other is a hydroxyl C1-C6 alkyl group.

27. The compound according to claim 26, wherein the hydroxyl C1-C6 alkyl group is... , or .

28. The compound according to any one of claims 1-23, wherein R 6 -XC(O)R 13 And X is the key.

29. The compound according to claim 28, wherein R 7 It is hydrogen.

30. The compound according to claim 28 or claim 29, wherein R 13 It is -OH.

31. The compound according to claim 28 or claim 29, wherein R 13 For -OR 10 And R 10 It is a methyl group.

32. The compound according to any one of claims 1-23, wherein R 6 -XC(O)R 13 , where X is methyl or ethyl.

33. The compound according to any one of claims 1-23, wherein R 6 -XC(O)R 13 And X is hydroxyethyl.

34. The compound according to any one of claims 1-23, wherein R 6 -XC(O)R 13 And X is cyclopropyl.

35. The compound according to any one of claims 32-34, wherein R 13 It is -OH.

36. The compound according to any one of claims 1-23, wherein R 6 -YC(O)NR 14 R 15 And Y is a bond.

37. The compound according to claim 36, wherein R 7 It is hydrogen.

38. The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 It is hydrogen.

39. The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 It is a C1-C6 alkyl group.

40. The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 It is a methyl group.

41. The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 It is a C1-C6 alkoxy-C1-C6 alkyl group.

42. The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 for .

43. The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 It is a hydroxyl C1-C6 alkoxy C1-C6 alkyl group.

44. The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 for or .

45. The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 It is a halogenated C1-C6 alkyl group.

46. ​​The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 for .

47. The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 It is a hydroxyl C1-C6 alkyl C3-C6 cycloalkylamino group.

48. The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 for or .

49. The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 It is a C1-C6 amine.

50. The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 for or .

51. The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 It is a heteroaryl group.

52. The compound according to claim 36 or claim 37, wherein R 14 It is hydrogen, and R 15 for .

53. The compound according to claim 36 or claim 37, wherein R 14 It is a C1-C6 alkyl group, and R 15 It is a C1-C6 alkyl group.

54. The compound according to claim 36 or claim 37, wherein R 14 It is methyl, and R 15 It is a methyl group.

55. The compound according to any one of claims 1-23, wherein R 6 -YC(O)NR 14 R 15 And Y is a C1-C6 alkyl group.

56. The compound according to claim 55, wherein R 7 It is hydrogen.

57. The compound according to any one of claims 1-23, wherein R 6 -YC(O)NR 14 R 15 And Y is a methyl group.

58. The compound according to claim 57, wherein R 7 It is hydrogen.

59. The compound according to any one of claims 55-58, wherein R 14 It is hydrogen, and R 15 It is a C1-C6 alkyl group.

60. The compound according to any one of claims 55-58, wherein R 14 It is hydrogen, and R 15 It is a methyl group.

61. The compound according to any one of claims 55-58, wherein R 14 It is hydrogen, and R 15 It is a hydroxyl C1-C6 alkyl group.

62. The compound according to any one of claims 55-58, wherein R 14 It is hydrogen, and R 15 for .

63. The compound according to any one of claims 55-58, wherein R 14 It is hydrogen, and R 15 It is a hydroxyl C1-C6 alkoxy C1-C6 alkyl group.

64. The compound according to any one of claims 55-58, wherein R 14 It is hydrogen, and R 15 for .

65. The compound according to any one of claims 55-58, wherein R 14 It is hydrogen, and R 15 It is a carboxyl C1-C6 alkyl group.

66. The compound according to any one of claims 55-58, wherein R 14 It is hydrogen, and R 15 for .

67. The compound according to any one of claims 55-58, wherein R 14 It is hydrogen, and R 15 is -S(O)2R 19 And R 19 It is a methyl group.

68. The compound according to any one of claims 55-58, wherein R 14 It is hydrogen, and R 15 It is a heteroaryl group.

69. The compound according to any one of claims 55-58, wherein R 14 It is hydrogen, and R 15 for , or .

70. The compound according to any one of claims 55-58, wherein R 14 and R 15 Together with the nitrogen atoms they are attached to, they form a 6-membered monocyclic heterocyclic group.

71. The compound according to claim 70, wherein the 6-membered monocyclic heterocyclic group is .

72. The compound according to any one of claims 55-58, wherein R 14 It is methyl, and R 15 It is a methyl group.

73. The compound according to any one of claims 1-23, wherein R 6 -YC(O)NR 14 R 15 , where Y is ethyl.

74. The compound according to claim 73, wherein R 7 It is hydrogen.

75. The compound according to any one of claims 1-23, wherein R 6 -YC(O)NR 14 R 15 And where Y is hydroxyethyl.

76. The compound according to claim 75, wherein R 7 It is hydrogen.

77. The compound according to any one of claims 1-23, wherein R 6 -YC(O)NR 14 R 15 And Y is cyclopropyl.

78. The compound according to claim 77, wherein R 7 It is hydrogen.

79. The compound according to any one of claims 73-78, wherein R 14 It is hydrogen, and R 15 It is a hydroxyl C1-C6 alkoxy C1-C6 alkyl group.

80. The compound according to any one of claims 73-78, wherein R 14 It is hydrogen, and R 15 for .

81. The compound according to any one of claims 73-78, wherein R 14 It is hydrogen, and R 15 It is a C1-C6 alkyl group.

82. The compound according to any one of claims 73-78, wherein R 14 It is hydrogen, and R 15 It is a methyl group.

83. The compound according to any one of claims 73-78, wherein R 14 It is methyl, and R 15 It is a methyl group.

84. The compound according to any one of claims 1-23, wherein R 6 -Z-NR 16 R 17 , where Z is the key.

85. The compound according to claim 84, wherein R 7 It is hydrogen.

86. The compound according to claim 84 or claim 85, wherein R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21 It can be hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or C1-C6 amine.

87. The compound according to claim 84 or claim 85, wherein R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21 It is a methyl group.

88. The compound according to claim 84 or claim 85, wherein R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21 It is a methoxy group.

89. The compound according to claim 84 or claim 85, wherein R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21 -NH2 or .

90. The compound according to any one of claims 1-23, wherein R 6 -Z-NR 16 R 17 , where Z is a methyl group.

91. The compound according to claim 90, wherein R 7 It is hydrogen.

92. The compound according to claim 90 or claim 91, wherein R 16 It is hydrogen, and R 17 It is a methyl group.

93. The compound according to claim 90 or claim 91, wherein R 16 It is hydrogen, and R 17 It is a C1-C6 alkoxy-C1-C6 alkyl group.

94. The compound according to claim 90 or claim 91, wherein R 16 It is hydrogen, and R 17 for .

95. The compound according to claim 90 or claim 91, wherein R 16 It is hydrogen, and R 17 -(C1-C6 alkyl)-C(O)R 20 And R 20 -OH, OR 10 or NR 22 R 23 And R 22 and R 23 Each of them is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or hydroxy-C1-C6 alkyl-C3-C6 cycloalkylamino.

96. The compound according to claim 90 or claim 91, wherein R 16 It is hydrogen, and R 17 -(C1-C6 alkyl)-C(O)R 20 And R 20 -OH or .

97. The compound according to claim 90 or claim 91, wherein R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21 It can be hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or C1-C6 amine.

98. The compound according to claim 90 or claim 91, wherein R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21 It is a methyl group.

99. The compound according to claim 90 or claim 91, wherein R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21 -NH2, or .

100. The compound according to claim 90 or claim 91, wherein R 16 It is hydrogen, and R 17 -C(O)R 21 And R 21 for .

101. The compound according to claim 90 or claim 91, wherein R 16 It is methyl, and R 17 It is a methyl group.

102. The compound according to claim 90 or claim 91, wherein R 16 It is methyl, and R 17 It is a hydroxyl C1-C6 alkyl group.

103. The compound according to claim 90 or claim 91, wherein R 16 It is methyl, and R 17 for .

104. The compound according to claim 90 or claim 91, wherein R 16 It is methyl, and R 17 It is a halogenated C1-C6 alkyl group.

105. The compound according to claim 90 or claim 91, wherein R 16 It is methyl, and R 17 for .

106. The compound according to claim 90 or claim 91, wherein R 16 It is ethyl, and R 17 It is an ethyl group.

107. The compound according to claim 90 or claim 91, wherein R 16 and R 17 Together with the nitrogen atoms to which they are attached, they form 3-8 membered monocyclic heterocyclic groups.

108. The compound according to claim 107, wherein the 3-8 membered monocyclic heterocyclic group is , , or .

109. The compound according to any one of claims 1-23, wherein R 6 for , , or .

110. The compound according to claim 109, wherein R 7 It is hydrogen.

111. The compound according to any one of claims 1-23, wherein R 6 is -S(O)2R 18 And R 18 It is a C1-C6 alkyl or -NH-(C1-C6 alkyl).

112. The compound according to claim 111, wherein R 7 It is hydrogen.

113. The compound according to any one of claims 1-23, wherein R 6 is -S(O)2R 18 And R 18 It can be -NH2 or -NHCH3.

114. The compound according to claim 113, wherein R 7 It is hydrogen.

115. The compound according to any one of claims 1-23, wherein R 6 It is a hydroxyl C1-C6 alkyl group, and R 7 For -OR 24 , where R 24 It is a C1-C3 alkyl group.

116. The compound according to any one of claims 1-23, wherein R 6 -XC(O)R 13 And R 7 For -OR 24 Where X is methyl, R 13 It is -OH, and R 24 It is a C1-C3 alkyl group.

117. The compound according to any one of claims 1-23, wherein R 6 -YC(O)NR 14 R 15 And R 7 For halogen, -OR 24 Or hydroxyl C1-C6 alkyl, wherein Y is a bond, R 14 and R 15 Each is independently hydrogen, C1-C6 alkyl, or hydroxyC1-C6 alkoxyC1-C6 alkyl, and R 24 It is a C1-C3 alkyl group.

118. The compound according to claim 117, wherein R 14 It is hydrogen, and R 15 It is a C1-C6 alkyl group.

119. The compound according to claim 117, wherein R 14 It is hydrogen, and R 15 It is a methyl group.

120. The compound according to claim 117, wherein R 14 It is hydrogen, and R 15 It is a hydroxyl C1-C6 alkoxy C1-C6 alkyl group.

121. The compound according to claim 117, wherein R 14 It is hydrogen, and R 15 for .

122. The compound according to claim 117, wherein R 7 It is fluorinated.

123. The compound according to claim 117, wherein R 7 It is a hydroxyl C1-C6 alkyl group.

124. The compound according to any one of claims 1-23, wherein R 6 -YC(O)NR 14 R 15 And R 7 For -OR 24 Or hydroxy C1-C6 alkyl, wherein Y is methyl, R 14 and R 15 Each is independently hydrogen or hydroxyl C1-C6 alkoxy C1-C6 alkyl, and R 24 It is a C1-C3 alkyl group.

125. The compound according to claim 124, wherein R 14 It is hydrogen, and R 15 It is a hydroxyl C1-C6 alkoxy C1-C6 alkyl group.

126. The compound according to claim 124, wherein R 14 It is hydrogen, and R 15 for .

127. The compound according to claim 124, wherein R 7 It is a hydroxyl C1-C6 alkyl group, preferably or .

128. The compound according to any one of claims 1-23, wherein R 6 -Z-NR 16 R 17 And R 7 For -OR 24 , where R 16 and R 17 Each is a C1-C6 alkyl group, Z is methyl, and R 24 It is a C1-C3 alkyl group.

129. The compound according to claim 128, wherein R 16 and R 17 Each is a methyl group.

130. The compound according to any one of claims 1-107, wherein R 8 It is hydrogen.

131. The compound according to any one of claims 1-107, wherein R 8 It is a methyl group.

132. The compound according to any one of claims 1-107, wherein R 8 It is cyclopropyl.

133. The compound according to any one of claims 1-107, wherein R 8 It is either fluorinated or chlorinated.

134. The compound according to any one of claims 1-107, wherein R 8 OR 10 And R 10 It is a methyl group.

135. The compound according to any one of claims 1-112, wherein R 9 It is hydrogen.

136. The compound according to any one of claims 1-112, wherein R 9 It is a methyl group.

137. The compound according to any one of claims 1-112, wherein R 9 It is an N-protecting group.

138. The compound according to any one of claims 1-23, wherein R 1 -R 4 Both are hydrogen.

139. The compound according to any one of claims 1-23, wherein R 5 and R 8 It is hydrogen.

140. The compound according to any one of claims 1-23, wherein R 2 It is a halogen.

141. The compound according to any one of claims 1-23, wherein R 4 It is a halogen.

142. The compound according to any one of claims 1-23, wherein R 2 and R 4 It is a halogen.

143. The compound according to any one of claims 1-23, wherein R 1 and R 2 It is a halogen.

144. The compound according to any one of claims 1-23, wherein R 2 It is halogen and R 4 It is a C1-C6 alkoxy group.

145. The compound according to any one of claims 1-23, wherein R 1 and R 2 It is a halogen.

146. The compound according to any one of claims 1-23, wherein R 1 It is a halogen, a C1-C6 alkoxy or a C1-C6 alkyl, and R 2 It is a halogen.

147. The compound according to any one of claims 1-23, wherein R 2 It is hydrogen or halogen, and R 3 It is trifluoromethyl.

148. The compound according to any one of claims 1-23, wherein R 2 It is a halogen, trifluoromethyl, C1-C3 alkyl, or C1-C3 alkoxy group, and R 1 R 3 R 4 R 5 R 7 and R 8 It is hydrogen.

149. The compound according to any one of claims 1-23, wherein R 1 -R 5 R 7 and R 8 It is hydrogen.

150. The compound according to any one of claims 1-23, wherein R 2 It is a halogen, trifluoromethyl, C1-C3 alkyl, or C1-C3 alkoxy group, and R 1 R 3 R 4 R 5 R 6 and R 8 It is hydrogen.

151. The compound according to any one of claims 1-23, R 1 -R 6 and R 8 It is hydrogen.

152. Compound of formula (II): (II) Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, deuterated form, or tautomer thereof, wherein: R 1 R 3 R 4 and R 8 Each of these can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, halogenated C1-C6 alkyl, or OR. 10 , where R 10 It is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halo-C1-C6 alkyl; R 5 It is hydrogen, hydroxyl C1-C6 alkyl or carboxyl C1-C6 alkyl; R 6 Hydrogen, hydroxyl C1-C6 alkyl, -XC(O)R 13 -YC(O)NR 14 R 15 -Z-NR 16 R 17 , heteroaryl or -S(O)2R 18 ,in X is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 13 -OH or -OR 10 ; Y is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 14 and R 15 Each of the following can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl-C3-C6 cycloalkylamino, C1-C6 amine, carboxyl-C1-C6 alkyl, -S(O)2R 19 phenyl, heteroaryl ring structures, or 3-8 membered monocyclic heterocyclic groups formed together with the nitrogen atoms attached to them, wherein R 19 It is a C1-C6 alkyl group; The phenyl group is optionally substituted with a C1-C6 alkyl group; The heteroaryl group is optionally substituted with a C1-C6 alkyl group; and The 3-8 membered monocyclic heterocyclic group is optionally substituted with C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, hydroxy-C1-C6 alkyl, or amino-C1-C6 alkyl. Z is a bond, a C3-C6 cycloalkyl C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl, a halogen, a hydroxyl or an amino group; R 16 and R 17 Each of the following can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or -(C1-C6 alkyl)-C(O)R 20 -C(O)R 21 Or, together with the nitrogen atoms they are attached to, they form 3-8 membered monocyclic heterocyclic groups, in which R 20 -OH, OR 10 or NR 22 R 23 , where R 22 and R 23 Each of them is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or hydroxy-C1-C6 alkyl-C3-C6 cycloalkylamino; R 21 It is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkyl, or C1-C6 amine; and The 3-8 membered monocyclic heterocyclic group is optionally substituted with C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, hydroxy-C1-C6 alkyl, or amino-C1-C6 alkyl. The heteroaryl group is optionally substituted with a C1-C6 alkyl group, and is a pyrazole or triazole; and R 18 It is a C1-C6 alkyl or -NH-(C1-C6 alkyl); and R 7 For hydrogen, halogen, -OR 24 hydroxyl C1-C6 alkyl or -C(O)NR 25 R 26 ,in: R 24 It is a C1-C3 alkyl group, and R 25 and R 26 Each is independently hydrogen or hydroxyl C1-C3 alkoxy C1-C3 alkyl; R 9 It is hydrogen, C1-C6 alkyl, or N-protecting group.

153. The compound according to claim 1, wherein: Its pharmaceutically acceptable salt.

154. A pharmaceutical composition comprising a compound or salt according to any one of claims 1-153, and a pharmaceutically acceptable carrier, excipient, or diluent.

155. A method for treating an inflammatory condition or oxidative stress, the method comprising administering to a patient in need a therapeutically effective amount of the compound according to any one of claims 1-153 or the pharmaceutical composition according to claim 154.

156. The method of claim 155, wherein the inflammatory condition or oxidative stress is a blood disorder.

157. The method of claim 156, wherein the hematologic disorder is sickle cell-associated disease, β-thalassemia, hemoglobinopathies, or myelodysplastic syndrome.

158. The method of claim 155, wherein the inflammatory condition or oxidative stress is inflammatory bowel disease, arthritis, or neurodegenerative disease.

159. The method of claim 155, wherein the inflammatory condition or oxidative stress is an autoinflammatory syndrome.

160. The method of claim 155, wherein the inflammatory condition or oxidative stress is an inflammation-related condition.

161. The method of claim 160, wherein the inflammation-related condition is adult-onset Still's disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), macrophage activation syndrome (MAS), infantile enterocolitis autoinflammatory disease (AIFEC), bullous pemphigoid, pemphigus vulgaris, idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), systemic lupus erythematosus (SLE), multiple sclerosis, Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, amyotrophic lateral sclerosis (ALS). Chemotherapy, neurodegenerative diseases, Charcot-Marie-Tooth syndrome, traumatic brain injury (TBI), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), cryptothermal protein-associated periodic syndrome (CAPS), vitiligo, multiple self-healing palmoplantar carcinoma (MSPC), autoimmune Addison's disease, familial Mediterranean fever (FMF), autoimmune thyroiditis, stroke, type 2 diabetes (T2D), osteoarthritis, gout, atherosclerosis, hidradenitis suppurativa, psoriasis, thermoproteinosis, or sickle cell disease.

162. The method of claim 155, wherein the inflammatory condition or oxidative stress is an infectious disease, an autoimmune disease, cancer, a metabolic disorder, an eye disease, a liver disease, a kidney disease, a cardiovascular disease, a skin disease, a mitochondrial disease, a hematologic disorder, a muscle disease, or a nervous system disease.

163. The method of claim 155, wherein the inflammatory condition or oxidative stress is a fibrotic disease.

164. The method of claim 163, wherein the fibrotic disease is chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, bronchitis, asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, bronchitis, bronchiectasis, pulmonary edema, emphysema, or sarcoidosis.

165. The method of claim 163, wherein the fibrotic disease is a liver fibrotic disease caused by alcoholic cirrhosis, steatosis, cholestasis, drug side effects, viral infection, or a combination thereof.

166. The method of claim 163, wherein the fibrotic disease is a cutaneous fibrotic disease.

167. The method of claim 166, wherein the skin fibrosis is an autoimmune disease.

168. The method of claim 167, wherein the autoimmune disease is scleroderma or psoriasis.

169. The method of claim 155, wherein the inflammatory condition or oxidative stress is a diabetic condition.

170. The method of claim 169, wherein the diabetes condition is type 1 diabetes, type 2 diabetes, gestational diabetes, prediabetes, hyperglycemia, metabolic syndrome, or a secondary condition arising therefrom.

171. The method of claim 170, wherein the secondary condition is congestive heart failure or nephropathy.

172. The method of claim 155, wherein the inflammatory condition or oxidative stress is a cardiovascular disease.

173. The method according to claim 172, wherein the cardiovascular disease is hypertension, heart failure, hypercholesterolemia, atherosclerosis, arteriosclerosis, thrombosis, acute coronary thrombosis, deep vein thrombosis, peripheral vascular disease, congestive heart failure, acute coronary syndrome, dialysis fistula failure, ischemia-reperfusion injury, primary pulmonary hypertension, primary pulmonary hypertension, or secondary pulmonary hypertension.

174. The method of claim 155, wherein the inflammatory condition results in cell death or the release of pro-inflammatory cytokines or other inflammatory mediators caused by a coronavirus (e.g., SARS-CoV 2, SARS-CoV, or MERS), virus, bacteria, fungus, parasite, or other type of infection in the subject.

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