1H-Imidazo[4,5-H]quinazoline compounds as novel selective FLT3 inhibitors

Abstract

The present invention provides 1H-imidazo[4,5-h]quinazoline compounds of formula (I), which are broad spectrum inhibitors of FLT3 kinase with potent activity, and are applicable to the treatment of cell proliferative disorders. TIFF2023538774000084.tif28162

Description

[Technical Field]

[0001] The present disclosure relates to 1H-imidazo[4,5-h]quinazoline compounds that have the biological activity of inhibiting cell proliferation and modulating serine-threonine protein kinase activity and tyrosine kinase activity. More specifically, the present disclosure provides 1H-imidazo[4,5-h]quinazoline compounds as novel selective FLT3 kinase inhibitors that are pan-FLT3 and pan-FLT3 mutant inhibitors, and are effective in treating cell proliferative disorders associated with FLT3 and its mutants. [Background technology]

[0002] Leukemia is a broad term used to describe cancers of blood cells. Types of leukemia vary depending on the type of blood cell that becomes cancerous and whether it multiplies rapidly or rapidly. Leukemia is most common in adults over the age of 55, but it is also the most common cancer in children under the age of 15. Acute myeloid leukemia (AML) is the most common acute leukemia in adults and the second most common in children. AML is characterized by the malignant transformation of hematopoietic stem / progenitor cells (HSCs) after a somatic driver gene mutation in conjunction with other passenger gene mutations or after lesions that occur simultaneously with the driver gene mutation. Malignant precursor cells replace healthy blood cells in the bone marrow and blood, causing acute symptoms such as anemia, bleeding and bruising, infection, and bone pain.

[0003] One kinase family of particular interest in AML is FLT3 (FMS-like tyrosine kinase 3). FLT3 is a transmembrane protein consisting of four domains: an extracellular ligand-binding domain containing five immunoglobulin-like structures, a transmembrane (TM) domain, a juxtamembrane (JM) domain, and a cytoplasmic C-terminal tyrosine kinase (TK) domain (Agnes F, et al. Gene 1994; 145:283-288; Scheijen B, et al. Oncogene 2002; 21:3314-3333). FLT3 is overexpressed in 70-100% of AML cases and in a high proportion of T-cell acute lymphoblastic leukemia (ALL) cases (Griffin JD, et al. Haematol J. 2004; 5:188-190). FLT3 is also overexpressed in a small group of patients with chronic myeloid leukemia (CML) undergoing blast crisis.

[0004] Early evidence was accumulating that many types of leukemia and myeloproliferative syndromes harbor tyrosine kinase mutations. Two types of activating mutations are present in FLT3 from leukemia patients: internal tandem duplication (ITD) mutations occurring within the autoinhibitory juxtamembrane domain (Nakao M, et al. Leukemia 1996; 10:1911-1918; Thiede C, et al. Blood 2002; 99:4326-4335), and mutations in the activation loop, including Asp835Tyr(D835Y), Asp835Val(D835V), Asp835His(D835H), Asp835Glu(D835E), Asp835Ala(D835A), Asp835Asn(D835N), Asp835 deletion, and Ile836 deletion (Yamamoto Y, et al., Blood 2001; 97:2434-2439; Abu-Duhier FM, et al. al. Br. J. Haematol. 2001; 113:983-988). Internal tandem duplication (ITD) mutations within the JM domain account for approximately 17-34% of FLT3 activating mutations in AML.

[0005] Due to the significant side effects and high incidence of FLT3, several FLT3 tyrosine kinase inhibitors have been developed. These inhibitors act through competitive inhibition of adenosine triphosphate (ATP) at the TK domain, reducing autophosphorylation and subsequent activation. First-generation FLT3 inhibitors (e.g., tandutinib, sorafenib, midostaurin, lestaurtinib, SU11248, SU5614, and SU5416) are relatively nonspecific to FLT3 and typically inhibit other RTK IIIs (e.g., KIT and PDGFR). Second-generation FLT3 inhibitors (e.g., quizartinib, crenolanib, ponatinib, pacritinib, and gilteritinib) are more effective and selective.

[0006] However, the therapeutic effects of FLT3 inhibition, especially in monotherapy, often lead to drug resistance and disease relapse. Furthermore, high toxicity and poor clinical efficacy can lead to off-target inhibition. Therefore, there is a need to develop novel, potent, and selective FLT3 inhibitors. Summary of the Invention

[0007] The present disclosure provides 1H-imidazo[4,5-h]quinazoline compounds as selective inhibitors of FLT3 tyrosine kinase and its mutants (e.g., ITD, D835Y, and F691L). The compounds of the present disclosure are effective in treating cell proliferative disorders associated with FLT3 and its mutants.

[0008] In some embodiments, the present disclosure provides a compound of formula (I): [ka] [In the formula, Y is N or CR6; where R6 is H, -OR a , -SR a , -NR b R c , -C(O)R a , -C(O)OR a , -C(O)NR b R c, -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -N(R b )-C(O)R a , -N(R b )-C(O)OR a , or -N(R b )-C(O)NR b R c , C 1-6 Alkyl, or C 1-6 is haloalkyl; X is -OR a , -SR a , -NR b R c , -C(O)R a , -C(O)OR a , -C(O)NR b R c , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -N(R b )-C(O)R a , -N(R b )-C(O)OR a , or -N(R b )-C(O)NR b R c and; where R a is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3 to 7-membered heterocyclyl, -LC 6-10 aryl, or -L-5 to 10 membered heteroaryl; R b is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3 to 7-membered heterocyclyl, -LC 6-10aryl, or -L-5 to 10 membered heteroaryl; R c is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3 to 7-membered heterocyclyl, -LC 6-10 aryl, or -L-5 to 10 membered heteroaryl; or R b , R c and the N atom to which they are attached form a 3- to 7-membered heterocyclyl, or a 5- to 10-membered heteroaryl; where L is a chemical bond, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, or -C 2-6 alkynylene- selected from; Ring A is -L'-3 to 11-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5; wherein L' is selected from a chemical bond, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 is H, halogen, oxo, -OR, -SR-, -NR'R'', C 1-6 Alkyl, or C 1-6 haloalkyl; or two R5 are joined together to form -C 1-4 Alkylene-, -C 2-4 Alkenylene- or -C 2-4 may form alkynylene-; R, R' and R'' are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 alkynyl; or R', R'' and the N atom to which they are attached form a 3- to 7-membered heterocyclyl or a 5- to 10-membered heteroaryl; R1 is H, halogen, -CN, -OR a , -SRa , -NR b R c , C 1-6 Alkyl, or C 1-6 is haloalkyl; R2 is H, halogen, -CN, -OR a , -SR a , -NR b R c , C 1-6 Alkyl, or C 1-6 is haloalkyl; R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; and R4 is H, halogen, -CN, -OR a , -SR a , -NR b R c , C 1-6 Alkyl, or C 1-6 haloalkyl] or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0009] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, and optionally a pharmaceutically acceptable excipient.

[0010] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, and further comprising another therapeutic agent.

[0011] In another aspect, the disclosure provides a kit comprising a compound of the disclosure, another therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0012] In another aspect, the present disclosure provides the use of a compound of the present disclosure in the manufacture of a medicament for treating and / or preventing a disease mediated by FLT3.

[0013] In another aspect, the present disclosure provides a method for treating and / or preventing a disease mediated by FLT3 in a subject, the method comprising administering to the subject a compound of the present disclosure or a composition of the present disclosure.

[0014] In another aspect, the present disclosure provides a compound of the present disclosure or a composition of the present disclosure for use in treating and / or preventing a disease mediated by FLT3.

[0015] In another embodiment, the FLT3-mediated disease is a proliferative disease selected from leukemia, myeloma, myeloproliferative disorders, myelodysplastic syndromes, idiopathic hypereosinophilic syndrome (HES), bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, salivary gland cancer, small cell lung cancer, skin cancer, gastric cancer, testicular cancer, thyroid cancer, uterine cancer, and hematological malignancies.

[0016] Other objects and advantages of the present disclosure will become apparent to those skilled in the art from the specific embodiments, examples, and claims of the present disclosure.

[0017] (definition) Chemical term definitions Specific functional groups and chemical term definitions are explained in more detail below.

[0018] When a range of values is listed, it is intended that each value and subrange thereof be included within that range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C5-6 It is intended to include alkyl.

[0019] It should be understood that, as described herein, any moiety defined below may be substituted with various substituents, and that each definition is intended to include substituted moieties within the respective scope set forth below. Unless otherwise indicated, the term "substituted" is as defined below.

[0020] "C 1-6 "Alkyl" refers to a straight or branched chain, monovalent saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl is preferred. Typical C 1-6 Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, n-hexyl, isohexyl, and the like. 1-6 "Alkyl" also includes heteroalkyl groups, the carbon atoms of which may be substituted with 1 to 3 atoms selected from O, S, N, or substituted nitrogen atoms. Alkyl groups can be substituted with any substitutable moiety, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0021] "C 2-6 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond, including, but not limited to, ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like. In some embodiments, C 2-4 Alkenyl is preferred. 2-6 "Alkenyl" also includes heteroalkenyl groups, the carbon atoms of which may be substituted with 1 to 3 atoms selected from O, S, N, or substituted nitrogen atoms. The alkenyl group may be substituted with any substitutable moiety, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0022] "C 2-6"Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms containing at least one carbon-carbon triple bond and optionally one or more unsaturated double bonds. In some embodiments, C 2-4 Alkynyl is preferred. Exemplary alkynyls include ethynyl, propynyl, iso-propynyl, butynyl, iso-butynyl, pentynyl, and hexynyl. 2-6 "Alkynyl" also includes heteroalkynyl groups, the carbon atoms of which may be replaced with 1 to 3 atoms selected from O, S, N, or substituted nitrogen atoms. Alkynyl groups can be substituted with any substitutable moiety, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0023] "-C 1-6 Alkylene-, -C 2-6 Alkenylene- or -C 2-6 "Alkynylene-" refers to the group "C" defined above. 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 "alkynyl" refers to a divalent group.

[0024] "C 1-6 "Alkylene" is a C alkylene group obtained by removing one hydrogen to obtain a divalent alkylene group. 1-6 In some embodiments, C refers to an alkyl group, which may be substituted or unsubstituted alkylene. 1-4Alkylene is particularly preferred. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. Examples of substituted alkylene groups (e.g., substituted with one or more alkyl (methyl) groups) include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0025] "C 2-6 "Alkenylene" is a C alkyl group obtained by removing one hydrogen to obtain a divalent alkenylene group. 2-6 It refers to an alkenyl group, which may be substituted or unsubstituted alkenylene. In some embodiments, C 2-4 Alkenylene is particularly preferred. Examples of unsubstituted alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH-, -CH-CH=CH-). Examples of substituted alkenylene groups (e.g., substituted with one or more alkyl (methyl) groups) include, but are not limited to, substituted ethenylene (-C(CH)=CH-, -CH=C(CH)-), substituted propenylene (e.g., -C(CH)=CHCH-, -CH=C(CH)CH-, -CH=CHCH(CH)-, -CH=CHC(CH)-, -CH(CH)-CH=CH-, -C(CH)-CH=CH-, -CH-C(CH)=CH-, -CH-CH=C(CH)-).

[0026] "C 2-6 "Alkynylene" is a C alkyl group obtained by removing one hydrogen to obtain a divalent alkynylene group.2-6 In some embodiments, C refers to an alkynyl group, which may be substituted or unsubstituted alkynylene. 2-4 Alkynylene is particularly preferred. Examples of alkynylene groups include, but are not limited to, ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH2-), and the like.

[0027] "Halo" or "halogen" means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0028] "C 1-6 "Haloalkyl" refers to the above "C" substituted with one or more halogens. 1-6 "Alkyl" refers to an "alkyl" group. Examples include monohalogenated, dihalogenated, and polyhalogenated (including perhalogenated) alkyls. The monohalogen substituent of the group can be an iodine, bromine, chlorine, or fluorine atom, and the dihalogen and polyhalogen substituents can be two or more of the same halogen atoms or a combination of different halogens. Examples of preferred haloalkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. Haloalkyl groups can be substituted with any substitutable moiety, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0029] "C 3-7 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and 0 heteroatoms. In some embodiments, C 3-6 Cycloalkyl is particularly preferred, C 5-6Cycloalkyl is more preferred. Cycloalkyl also includes rings in which a cycloalkyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the attachment point is on the cycloalkyl ring, and in such cases the number of carbon atoms refers to the number of carbon atoms in the cycloalkyl ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), cycloheptyl (C), cycloheptenyl (C), cycloheptadienyl (C), cycloheptatrienyl (C), and the like.

[0030] "3- to 11-membered heterocyclyl" refers to a 3- to 11-membered non-aromatic ring group having ring carbon atoms and 1 to 5 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the bonding moiety can be a carbon atom or a nitrogen atom, as long as valence permits. In some embodiments, a 3- to 9-membered non-aromatic ring group having ring carbon atoms and 1 to 5 ring heteroatoms is preferred. In some embodiments, a 3- to 7-membered non-aromatic ring group having ring carbon atoms and 1 to 4 ring heteroatoms is preferred. In some embodiments, a 3- to 6-membered heterocyclyl is a 3- to 6-membered non-aromatic ring group having ring carbon atoms and 1 to 3 ring heteroatoms is preferred. In some embodiments, a 4- to 6-membered heterocyclyl is a 4- to 6-membered non-aromatic ring group having ring carbon atoms and 1 to 3 ring heteroatoms is preferred. In some embodiments, 5- to 6-membered heterocyclyl is more preferred, being a 5- to 6-membered non-aromatic ring group having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring in which the heterocyclyl ring defined above is fused with one or more cycloalkyl groups, with the bonding site on the cycloalkyl ring, or a ring in which the heterocyclyl ring defined above is fused with one or more aryl or heteroaryl groups, with the bonding site on the heterocyclyl ring; in such cases, the number of ring members refers to the number of ring members in the heterocyclyl ring. Examples of 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Examples of 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and maleimidyl. Examples of 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one.Examples of 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Examples of 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl. Examples of 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, benzothiophene, benzoxazolinonyl, etc. Examples of 6-membered heterocyclyl groups (also referred to as 6,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0031] The 3- to 11-membered heterocyclyl also includes a spiroheterocyclyl group, which is a group in which two rings (e.g., heterocyclyl and carbocyclyl) share one carbon atom. Here, at least one ring is a heterocyclyl as defined above. More specifically, the spiroheterocyclyl is a spiro ring formed by two 4-membered rings, two 5-membered rings, two 6-membered rings, one 4-membered ring and one 5-membered ring, one 4-membered ring and one 6-membered ring, or one 5-membered ring and one 6-membered ring, where at least one ring is a 4- to 6-membered heterocyclyl as defined above, and a 4- to 6-membered heterocyclyl containing one, two, or three heteroatoms O, N, or S is preferred. A 4- to 6-membered heterocyclyl containing one heteroatom N is more preferred. Specific spiroheterocyclyl groups include, but are not limited to, the following: [ka] Examples include:

[0032] Specific examples of preferred heterocyclyl groups include pyrrolinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, dihydropyranyl, dihydrofuryl, thiazolidinyl, dihydrothiazolyl, 2,3-dihydro-benzo[1,4]dioxole, indolinyl, isoindolinyl, dihydrobenzothiophene, dihydrobenzofuranyl, isodihydrobenzopyranyl, dihydrobenzopyranyl, 1,2-dihydroisoquinoline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorene, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxole, 2,3-dihydro- Hydro-lH-lk'-benzo[d]isothiazol-6-yl, 2,3-di-benzo[l,4]dioxinyl, dihydrobenzofuran, 2-oxaziridin-1-yl, 2-oxoazetidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 2-oxoazepan-1-yl, 2-oxoazocane-1-yl, 2-oxoazonan-1-yl, 2-oxoazepan-1-yl These include hexan-1-yl, aziridine, azetidine, pyrrolidinyl, piperidine, azepane, azocane, azonane, azecane, piperidinyl, piperazinyl, morpholinyl, diazaspiro[3.3]heptane, diazaspiro[3.4]octane, diazaspiro[3.5]nonane, diazaspiro[4.4]nonane, diazaspiro[4.5]decane, and diazaspiro[5.5]undecane.

[0033] "C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring group (arranged in a ring and sharing 6 or 10 π electrons) having 6 to 10 ring carbon atoms and 0 heteroatoms. In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl. Aryl also includes rings in which an aryl ring, as defined above, is fused to one or more cycloalkyl or heterocyclyl groups, where the attachment point is on the aryl ring, and in such cases the number of carbon atoms refers to the number of carbon atoms in the aryl ring.

[0034] "5- to 10-membered heteroaryl" refers to a 5- to 10-membered monocyclic or bicyclic (annularly arranged and sharing 6 or 10 π-electrons) 4n+2 aromatic ring group having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the linking moiety can be a carbon atom or a nitrogen atom, as far as valence permits. Heteroaryl bicyclic groups can contain one or more heteroatoms in one or both rings. Heteroaryl also includes rings in which the heteroaryl ring, as defined above, is fused with one or more cycloalkyl or heterocyclyl groups, where the linking moiety is on the heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the heteroaryl ring. In some embodiments, 5- to 6-membered heteroaryls that are 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring groups having ring carbon atoms and 1 to 4 ring heteroatoms are particularly preferred. Examples of 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Examples of 7-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl.Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0035] Specific examples of preferred heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl), pyranyl, 2-furyl, 3-furan, etc., 2-thienyl, 3-thienyl, oxazolyl, isoxazolyl, oxazolyl (1,2,4-oxazolyl, 1,3,4-oxazolyl, 1,2,5-oxazolyl), thiazolyl, and thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl).

[0036] "Oxo" refers to =O.

[0037] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted groups. In general, the term "substituted," whether preceded by the term "optionally," refers to the replacement of at least one hydrogen on the group (e.g., a carbon or nitrogen atom) with a permissible substituent. Substitution, for example, refers to a group that, upon substitution, results in a stable compound (e.g., a compound that does not spontaneously undergo rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when substituted at more than one position in a given structure, the substituents are either the same or different. The term "substituted" is expected to include substitution with all permissible substituents for organic compounds, any substituent that results in the formation of a stable compound as described herein. To accomplish the present invention, heteroatoms (e.g., nitrogen) may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom to form a stable moiety.

[0038] Examples of substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NRbb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc)2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R dd or substituted with a group;

[0039] Two geminal hydrogens on a carbon atom are bonded to the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc is replaced by;

[0040] Each R aa are independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R aa The groups taken together form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0041] Each R bb are independently hydrogen, -OH, or -OR aa , -N(R cc )2, -CN, -C(=O)Raa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R bb The groups taken together form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0042] Each R cc are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R cc The groups taken together form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0043] Each R dd are independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(Rff )2、-N(R ff )2、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2、-SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2、-C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(ORee )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg or two geminal R dd the substituents may together form =O or =S;

[0044] Each R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group;

[0045] Each R ff are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ff The groups taken together form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R gg substituted with a group; and

[0046] Each R gg are independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclyl, C6-C 10 Aryl, C3-C7 heterocyclyl, C5-C 10 Heteroaryl or two geminal R gg The substituents may together form =O or =S; where X - is the counter ion.

[0047] Examples of nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R attached to a nitrogen atom cc and heterocyclyl or heteroaryl rings formed by the groups taken together, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc and R dd is as defined above.

[0048] (Other definitions) The term "cancer" includes, but is not limited to, cancer of the breast, ovary, cervix, prostate, testicle, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, bile duct, oral cavity and pharynx (mouth), lip, tongue, mouth, pharynx, small intestine, colorectal, large intestine, rectum, brain tumors and cancers of the central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular adenoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorders, lymphatic vessel diseases, Hodgkin's disease, hairy cell carcinoma, and leukemia.

[0049] As used herein, the term "pharmaceutically acceptable salts" refers to carboxylate salts and amino acid addition salts of the compounds of the present disclosure that are suitable, within the scope of ordinary medical judgment, for contact with the tissues of a patient without undue toxicity, irritation, allergic response, and the like, and are effective for their intended use, including, where possible, zwitterionic forms of the compounds of the present disclosure.

[0050] The term "salts" refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds of the present disclosure. These salts can be prepared in situ during the final isolation and purification of the compounds, or by reacting the purified free base form of the compound with a suitable organic or inorganic acid, respectively, and isolating the resulting salt. To the extent that the compounds of the present disclosure are basic compounds, they can form several different salts with various inorganic and organic acids. The salts should be pharmaceutically acceptable for administration to animals; however, in practice, salts of pharmaceutically unacceptable basic compounds are often first isolated from the reaction mixture and then administered with an alkaline reagent to convert them to the free base compound, which is then subsequently converted to a pharmaceutically acceptable acid addition salt. Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid in a conventional manner for forming salts. The free base can be regenerated by contacting the salt with a base in a conventional manner and then isolating the free base. The free base forms may differ somewhat depending on the physical properties of each salt form (such as solubility in polar solvents), but for purposes of the present invention, the salts are equivalent to the respective free bases.

[0051] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (such as infants, children, and young adults) or adult subjects (such as young adults, middle-aged adults, or geriatrics)) and / or non-human animals (mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In a specific embodiment, the subject is a human. In a specific embodiment, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0052] Disease, disorder, and condition are used interchangeably herein.

[0053] As used herein, unless otherwise specified, the term "treatment" includes actions that reduce the severity of a particular disease, disorder or condition, or actions that prevent or slow the progression of a disease, disorder or condition while the subject is suffering from the disease, disorder or condition ("ameliorative treatment"), and also actions that occur before the subject is affected with a particular disease, disorder or condition ("prophylactic treatment").

[0054] Generally, the "effective amount" of a compound refers to an amount sufficient to produce a desired biological response. As can be understood by those skilled in the art, the effective amount of the compound of the present disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the method of administration, and the age, health condition, and symptoms of the subject. The effective amount includes a therapeutically effective amount and a prophylactically effective amount.

[0055] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms of the disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapeutic agents, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall therapeutic benefit, reduces or avoids the cause of a symptom or disease, or enhances the therapeutic effect of another therapeutic agent.

[0056] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with that disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of that disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylactic benefit or enhances the prophylactic benefit of other prophylactic agents.

[0057] "Combination" and like terms refer to simultaneous or sequential administration of a compound of the present disclosure and one or more other therapeutic agents. For example, a compound of the present disclosure may be administered simultaneously with the other therapeutic agent in separate dosage forms, or sequentially, or may be administered together with one or more other therapeutic agents in a single dosage form.

[0058] Detailed Description of the Embodiments As used herein, the term "compound of the present disclosure" refers to a compound of Formula (I) or (II) below, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0059] Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that all optical isomers and mixtures thereof are included unless otherwise specified. Furthermore, all isomeric compounds and carbon-carbon double bonds included in this disclosure can occur in Z and E forms unless otherwise specified. For compounds that exist in different tautomeric forms, and one of them is not limited to a specific tautomer, all tautomers are intended to be included.

[0060] In certain embodiments, the present disclosure provides a compound of formula (I): [ka] [In the formula, Y is N or CR6; where R6 is H, -OR a , -SR a , -NR b R c , -C(O)R a , -C(O)OR a , -C(O)NR b R c , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -N(R b )-C(O)R a , -N(R b)-C(O)OR a , or -N(R b )-C(O)NR b R c , C 1-6 Alkyl, or C 1-6 is haloalkyl; X is -OR a , -SR a , -NR b R c , -C(O)R a , -C(O)OR a , -C(O)NR b R c , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -N(R b )-C(O)R a , -N(R b )-C(O)OR a , or -N(R b )-C(O)NR b R c and; where R a is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3 to 7-membered heterocyclyl, -LC 6-10 aryl, or -L-5 to 10 membered heteroaryl; R b is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3 to 7-membered heterocyclyl, -LC 6-10 aryl, or -L-5 to 10 membered heteroaryl; R c is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, -LC 3-7 Cycloalkyl, -L-3 to 7-membered heterocyclyl, -LC 6-10 aryl, or -L-5 to 10 membered heteroaryl; or R b , R c and the N atom to which they are attached form a 3- to 7-membered heterocyclyl, or a 5- to 10-membered heteroaryl; where L is a chemical bond, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, or -C 2-6 alkynylene- selected from; Ring A is -L'-3 to 11-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5; wherein L' is selected from a chemical bond, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 is H, halogen, oxo, -OR, -SR-, -NR'R'', C 1-6 Alkyl, or C 1-6 haloalkyl; or two R5 are joined together to form -C 1-4 Alkylene-, -C 2-4 Alkenylene- or -C 2-4 may form alkynylene-; R, R' and R'' are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 alkynyl; or R', R'' and the N atom to which they are attached form a 3- to 7-membered heterocyclyl or a 5- to 10-membered heteroaryl; R1 is H, halogen, -CN, -OR a , -SR a , -NR b R c , C 1-6 Alkyl, or C 1-6 is haloalkyl; R2 is H, halogen, -CN, -OR a , -SRa , -NR b R c , C 1-6 Alkyl, or C 1-6 is haloalkyl; R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; and R4 is H, halogen, -CN, -OR a , -SR a , -NR b R c , C 1-6 Alkyl, or C 1-6 haloalkyl] or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0061] Y In a specific embodiment, Y is N; in another specific embodiment, Y is CR6; in another specific embodiment, Y is CH.

[0062] X In specific embodiments, X is -OR a In another specific embodiment, X is -SR a In another specific embodiment, X is —NR b R c In another specific embodiment, X is —C(O)R a In another specific embodiment, X is —C(O)OR a In another specific embodiment, X is —C(O)NR b R c In another specific embodiment, X is —OC(O)R a In another specific embodiment, X is -OC(O)OR a In another specific embodiment, X is —OC(O)NR b Rc In another specific embodiment, X is —N(R b )-C(O)R a In another specific embodiment, X is —N(R b )-C(O)OR a In another specific embodiment, X is —N(R b )-C(O)NR b R c is.

[0063] In further specific embodiments of X, R a is H; and in yet other specific embodiments of X, R a is C 1-6 alkyl; and in yet another specific embodiment of X, R a is C 1-6 haloalkyl; and in yet another specific embodiment of X, R a is C 2-6 alkenyl; and in yet another specific embodiment of X, R a is C 2-6 alkynyl; and in yet other specific embodiments of X, R a Ha-LC 3-7 cycloalkyl; and in yet other specific embodiments of X, R a is -L-3 to 7 membered heterocyclyl; and in other specific embodiments of X, R a Ha-LC 6-10 aryl; and in yet other specific embodiments of X, R a is -L-5 to 10 membered heteroaryl.

[0064] In further specific embodiments of X, R b is H; and in yet other specific embodiments of X, R b is C 1-6 alkyl; and in yet another specific embodiment of X, R b is C 1-6 haloalkyl; and in yet another specific embodiment of X, R b is C 2-6alkenyl; and in yet another specific embodiment of X, R b is C 2-6 alkynyl; and in yet other specific embodiments of X, R b Ha-LC 3-7 cycloalkyl; and in yet other specific embodiments of X, R b is -L-3 to 7 membered heterocyclyl; and in other specific embodiments of X, R b Ha-LC 6-10 aryl; and in yet other specific embodiments of X, R b is -L-5 to 10 membered heteroaryl.

[0065] In further specific embodiments of X, R c is H; and in yet other specific embodiments of X, R c is C 1-6 alkyl; and in yet another specific embodiment of X, R c is C 1-6 haloalkyl; and in yet another specific embodiment of X, R c is C 2-6 alkenyl; and in yet another specific embodiment of X, R c is C 2-6 alkynyl; and in yet other specific embodiments of X, R c Ha-LC 3-7 cycloalkyl; and in yet other specific embodiments of X, R c is -L-3 to 7 membered heterocyclyl; and in other specific embodiments of X, R c Ha-LC 6-10 aryl; and in yet other specific embodiments of X, R c is -L-5 to 10 membered heteroaryl.

[0066] In further specific embodiments of X, R b , R c and the N atom to which they are attached form a 3- to 7-membered heterocyclyl; and in yet another specific embodiment of X, R b, R c and the N atom to which they are attached form a 5-10 membered heteroaryl.

[0067] Other R a , R b or R c In a specific embodiment, L is a chemical bond; a , R b or R c In specific embodiments, L is -C 1-6 alkylene-; and other R a , R b or R c In specific embodiments, L is -C 2-6 alkenylene-; and other R a , R b or R c In specific embodiments, L is -C 2-6 It is alkynylene.

[0068] Ring A In a specific embodiment, ring A is -L'-3- to 11-membered heterocyclyl; in another specific embodiment, ring A is 3- to 11-membered heterocyclyl; in another specific embodiment, ring A is -L'-3- to 7-membered heterocyclyl; in another specific embodiment, ring A is 3- to 7-membered heterocyclyl; in another specific embodiment, ring A is -L'-4- to 6-membered heterocyclyl; in another specific embodiment, ring A is 4- to 6-membered heterocyclyl; in another specific embodiment, ring A is 6-membered heterocyclyl.

[0069] In a more specific embodiment, ring A is [ka] wherein Z is O, S, or NR5; R5 is H, C 1-6 Alkyl, or C 1-6 haloalkyl; or two R5 are joined together to form -C 1-4 Alkylene-, -C2-4 Alkenylene- or -C 2-4 m may be 1, 2, 3, 4, 5, 6, 7, or 8.

[0070] In an even more specific embodiment, ring A is [ka] wherein Z is O, or NR 51 and; R 51 ~R 59 is H or C 1-6 alkyl; or R 51 ~R 59 The two are combined into -C 1-4 It may also form alkylene-.

[0071] In still other specific embodiments, ring A is [ka] and preferably, ring A is [ka] is.

[0072] In a specific embodiment, ring A is unsubstituted; in another specific embodiment, ring A is substituted with one R5; in another specific embodiment, ring A is substituted with two R5; in another specific embodiment, ring A is substituted with three R5; in another specific embodiment, ring A is substituted with four R5; in another specific embodiment, ring A is substituted with five R5; in another specific embodiment, ring A is substituted with six R5; in another specific embodiment, ring A is substituted with seven R5; in another specific embodiment, ring A is substituted with eight R5.

[0073] In a specific embodiment of Ring A, R5 is H; in another specific embodiment of Ring A, R5 is halogen; in another specific embodiment of Ring A, R5 is oxo; in another specific embodiment of Ring A, R5 is -OR; in another specific embodiment of Ring A, R5 is -SR-; in another specific embodiment of Ring A, R5 is -NR'R''; in another specific embodiment of Ring A, R5 is C 1-6 In another specific embodiment of Ring A, R5 is C 1-6 haloalkyl; In another specific embodiment of Ring A, two R5 are bonded together to form -C 1-4 In another specific embodiment of ring A, two R5 may be bonded together to form -C 2-4 In another specific embodiment of ring A, two R5 may be bonded together to form -C 2-4 It may also form alkynylene-.

[0074] R1 In a specific embodiment, R1 is H; in another specific embodiment, R1 is halogen; in another specific embodiment, R1 is -CN; in another specific embodiment, R1 is -OR a In another specific embodiment, R1 is -SR a In another specific embodiment, R is -NR b R c In another specific embodiment, R is C 1-6 alkyl; in another specific embodiment, R is C 1-6 It is haloalkyl.

[0075] R2 In a specific embodiment, R2 is H; in another specific embodiment, R2 is halogen; in another specific embodiment, R2 is -CN; in another specific embodiment, R2 is -OR a In another specific embodiment, R2 is -SRa In another specific embodiment, R2 is -NR b R c In another specific embodiment, R2 is C 1-6 alkyl; in another specific embodiment, R2 is C 1-6 It is haloalkyl.

[0076] R3 In specific embodiments, R3 is C 1-6 alkyl; in another specific embodiment, R3 is C 1-6 haloalkyl; in another specific embodiment, R3 is C 3-7 In another specific embodiment, R3 is cycloalkyl; in another specific embodiment, R3 is 3-7 membered heterocyclyl; in another specific embodiment, R3 is C 6-10 aryl; in another specific embodiment, R3 is 5-10 membered heteroaryl.

[0077] R4 In a specific embodiment, R4 is H; in another specific embodiment, R4 is halogen; in another specific embodiment, R4 is -CN; in another specific embodiment, R4 is -OR a In another specific embodiment, R4 is -SR a In another specific embodiment, R4 is -NR b R c In another specific embodiment, R4 is C 1-6 alkyl; in another specific embodiment, R4 is C 1-6 It is haloalkyl.

[0078] Any technical solution or any combination thereof in any one of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments or any combination thereof.For example, any technical solution or any combination thereof of Y can be combined with any technical solution or any combination thereof of X, ring A, R1, R2, R3 and R4.The present disclosure is intended to include all combinations of the above technical solutions, but due to space limitations, it is not possible to list them all in this specification.

[0079] In specific embodiments, the present disclosure refers to compounds of formula (I) wherein Y is N, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0080] In specific embodiments, the present disclosure provides a compound of formula (I), wherein: X is -OR a , -SR a , -NR b R c , -C(O)R a , -C(O)OR a , -C(O)NR b R c , -OC(O)R a , or -N(R b )-C(O)R a and; Preferably, X is -OR a , -SR a , or -NR b R c and; Preferably, X is -OR a and; Preferably, X is —NR b R c is) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0081] In specific embodiments, the present disclosure provides a compound of formula (I), wherein: R aH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, or -LC 6-10 is aryl; and where L is a chemical bond, or -C 1-6 alkylene- selected from; Preferably, R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or -LC 3-7 is cycloalkyl; and where L is a chemical bond, or -C 1-6 alkylene-), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0082] In specific embodiments, the present disclosure provides a compound of formula (I), wherein: R b is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, or -LC 6-10 is aryl; R c is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, or -LC 6-10 is aryl; or R b , R c and the N atom to which they are attached form a 3- to 7-membered heterocyclyl, or a 5- to 10-membered heteroaryl; and where L is a chemical bond, or -C1-6 alkylene- selected from; Preferably, R b is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or -LC 3-7 is cycloalkyl; R c is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or -LC 3-7 is cycloalkyl; or R b , R c and the N atom to which they are attached form a 3- to 7-membered heterocyclyl; and where L is a chemical bond, or -C 1-6 alkylene- selected from; Preferably, R b is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; R c is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; or R b , R c and the N atom to which they are attached form a 4- to 6-membered heterocyclyl), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0083] In specific embodiments, the present disclosure provides a compound of formula (I), wherein: Ring A is -L'-3 to 7-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5; wherein L' is selected from a chemical bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 is H, halogen, oxo, -OR, -SR-, -NR'R'', C 1-6 Alkyl, or C 1-6 haloalkyl; or two R5 are joined together to form -C 1-4 Alkylene-, -C 2-4 Alkenylene- or -C 2-4 alkynylene-; and R, R' and R'' are each independently H, C 1-6 Alkyl, or C 1-6 haloalkyl; or R', R'' and the N atom to which they are attached form a 3- to 7-membered heterocyclyl or a 5- to 10-membered heteroaryl; Preferably, Ring A is -L'-4 to 6-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5; wherein L' is selected from a chemical bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 is H, oxo, -OR, -NR'R'', C 1-6 Alkyl, or C 1-6 haloalkyl; or two R5 are joined together to form -C 1-4 may form alkylene-; and R, R' and R'' are each independently H, C 1-6 Alkyl, or C 1-6 haloalkyl; or R', R'' and the N atom to which they are attached form a 4- to 6-membered heterocyclyl; Preferably, Ring A is -L'-4 to 6-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5; wherein L' is selected from a chemical bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 is H, oxo, -OR, -NR'R'', or C 1-6 alkyl; or two R5 are bonded together to form -C 1-4may form alkylene-; and R, R' and R'' are each independently H or C 1-6 alkyl; or R', R'' and the N atom to which they are attached form a 4- to 6-membered heterocyclyl; Preferably, Ring A is [ka] and; where Z is O, S, or NR5; R5 is H, C 1-6 Alkyl, or C 1-6 haloalkyl; or two R5 are joined together to form -C 1-4 Alkylene-, -C 2-4 Alkenylene- or -C 2-4 may form alkynylene-; m is 1, 2, 3, 4, 5, 6, 7, or 8; Preferably, Ring A is [ka] and; where Z is O or NR 51 and; R 51 ~R 59 is H or C 1-6 alkyl; or R 51 ~R 59 The two are combined into -C 1-4 alkylene-forming; Preferably, Ring A is [ka] and; Preferably, Ring A is [ka] or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0084] In specific embodiments, the present disclosure provides a compound comprising: R1 is H, C 1-6 Alkyl, or C 1-6 haloalkyl; preferably, R1 is H; Reference is made to a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0085] In specific embodiments, the present disclosure provides a compound comprising: R2 is H, C 1-6 Alkyl, or C 1-6 haloalkyl; preferably, R2 is H; Reference is made to a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0086] In specific embodiments, the present disclosure provides a compound comprising: R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, or 3- to 7-membered heterocyclyl; preferably, R3 is C 1-6 Alkyl or C 1-6 haloalkyl; preferably, R3 is C 1-6 alkyl; preferably, R3 is Et or iPr; Reference is made to a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0087] In specific embodiments, the present disclosure provides a compound comprising: R4 is H, C 1-6 Alkyl, or C 1-6 haloalkyl; preferably, R4 is H; Reference is made to a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0088] In specific embodiments, the present disclosure provides a compound of formula (I), wherein: Y is N or CR6; where R6 is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; X is -OR a , -SR a , or -NR b R c and; where R a is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3 to 7-membered heterocyclyl, -LC 6-10 aryl, or -L-5 to 10 membered heteroaryl; R b is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; R c is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; or R b , R c and the N atom to which they are attached form a 4- to 6-membered heterocyclyl, or a 5- to 10-membered heteroaryl; where L is a chemical bond, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, or -C 2-6 alkynylene- selected from; Ring A is -L'-3 to 7-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5; wherein L' is selected from a chemical bond, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 is H, halogen, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -OR, -SR-, or -NR'R''; or two R5 are joined together to form -C 1-4 Alkylene-, -C 2-4 Alkenylene- or -C 2-4 may form alkynylene-; R, R' and R'' are each independently H, C 1-6 Alkyl, or C 1-6 haloalkyl; or R', R'' and the N atom to which they are attached form a 3- to 7-membered heterocyclyl or a 5- to 10-membered heteroaryl; R1 is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; R2 is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; R3 is C 1-6 Alkyl, or C 1-6 haloalkyl; and R4 is H, C 1-6 Alkyl, or C 1-6 haloalkyl), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0089] In specific embodiments, the present disclosure provides a compound of formula (I), wherein: Y is N or CR6; where R6 is H or C 1-6 is alkyl; X is -OR a , or -NR b R c and; where R a is C 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, or -LC 6-10 is aryl; R b is H or C 1-6 is alkyl; R c is H or C 1-6 alkyl; or R b , R c and the N atom to which they are attached form a 4- to 6-membered heterocyclyl; where L is a chemical bond, or -C 1-6 alkylene- selected from; Ring A is -L'-4 to 6-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5; wherein L' is selected from a chemical bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 is H, oxo, C 1-6 alkyl, -OR, or -NR'R''; or two R5 are joined together to form -C 1-4 may form alkylene-; R, R' and R'' are each independently H or C 1-6 alkyl; or R', R'' and the N atom to which they are attached form a 4- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl; R1 is H or C 1-6 is alkyl; R2 is H or C 1-6 is alkyl; R3 is C 1-6 is alkyl; and R4 is H or C 1-6 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0090] In specific embodiments, the present disclosure provides a compound of formula (I), wherein: Y is N or CH; X is -OR a , or -NR b R c and; where R a Me, Et, iPr, [ka] and; R b is H, or Me; R c is H or Me; or R b , R c and the N atoms to which they are attached are [ka] Forming; Ring A is [ka] and; R1 is H or Me; R2 is H, or Me; R3 is Me, Et, or iPr; and R4 is H, or Me), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0091] In specific embodiments, the present disclosure provides compounds having formula (II): [ka] [In the formula, Y is N or CH; Ring A is -L'-3 to 7-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5; wherein L' is selected from a chemical bond, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 is H, halogen, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, -OR, -SR-, or -NR'R''; or two R5 are joined together to form -C 1-4 Alkylene-, -C 2-4 Alkenylene- or -C 2-4 may form alkynylene-; R, R' and R'' are each independently H, C 1-6 Alkyl, or C 1-6 haloalkyl; or R', R'' and the N atom to which they are attached form a 4- to 6-membered heterocyclyl or a 5- to 10-membered heteroaryl; R a is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3 to 7-membered heterocyclyl, -LC 6-10 aryl, or -L-5 to 10 membered heteroaryl; where L is a chemical bond, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, or -C 2-6 alkynylene- selected from; R2 is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; R3 is Et, or iPr; and R4 is H, C 1-6 Alkyl, or C 1-6 haloalkyl] or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0092] In specific embodiments, the present disclosure provides a compound of formula (II): Y is N or CH; Ring A is -L'-4 to 6-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5; L' is selected from a chemical bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 is H, oxo, C 1-6 alkyl, -OR, or -NR'R''; or two R5 are joined together to form -C 1-4 may form alkylene-; R, R' and R'' are each independently H or C 1-6 alkyl; or R', R'' and the N atom to which they are attached form a 4- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl; R a is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, or -LC 6-10 is aryl; where L is a chemical bond, or -C 1-6 alkylene- selected from; R2 is H or C 1-6 is alkyl; R3 is Et, or iPr; and R4 is H or C 1-6 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0093] In specific embodiments, the present disclosure provides a compound of formula (II): Y is N or CH; Ring A is [ka] and; R a Me, Et, iPr, [ka] and; R2 is H, or Me; R3 is Et, or iPr; and R4 is H or Me or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0094] In specific embodiments, the present disclosure provides compounds having formula (II): [ka] [In the formula, Y is N or CH; Ring A is [ka] and; where Z is O, S, or NR5; R5 is H, C 1-6 Alkyl, or C 1-6 haloalkyl; or two R5 are joined together to form -C 1-4 Alkylene-, -C 2-4 Alkenylene- or -C 2-4 may form alkynylene-; m is 1, 2, 3, 4, 5, 6, 7, or 8; R a is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 cycloalkyl, or -L-3 to 7-membered heterocyclyl; where L is a chemical bond, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, or -C 2-6alkynylene- selected from; R2 is H, C 1-6 Alkyl, or C 1-6 is haloalkyl; R3 is Et, or iPr; and R4 is H, C 1-6 Alkyl, or C 1-6 haloalkyl) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0095] In specific embodiments, the present disclosure provides a compound of formula (II): Y is N or CH; Ring A is [ka] and; where Z is O or NR 51 and; R 51 ~R 59 are each independently H or C 1-6 alkyl; or R 51 ~R 59 The two are combined into -C 1-4 alkylene-forming; R a is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or -LC 3-7 is cycloalkyl; where L is a chemical bond, or -C 1-6 alkylene- selected from; R2 is H or C 1-6 is alkyl; R3 is Et, or iPr; and R4 is H or C 1-6 alkyl) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0096] In specific embodiments, the present disclosure provides a compound of formula (II): Y is N or CH; Ring A is [ka] and; R a Me, Et, iPr, [ka] and; R2 is H, or Me; R3 is Et, or iPr; R4 is H or Me or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0097] In specific embodiments, the present disclosure provides compounds wherein the compound is: [ka] [ka] or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0098] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds described herein may exist as single enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or as mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, such as chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts. Alternatively, preferred isomers can be prepared by asymmetric synthesis.

[0099] Pharmaceutical Compositions, Formulations, and Kits In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In a specific embodiment, the pharmaceutical composition comprises an effective amount of a compound of the present disclosure. In a specific embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In a specific embodiment, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present disclosure.

[0100] The pharmaceutically acceptable excipient used in the present disclosure refers to a non-toxic carrier, adjuvant or vehicle that does not impair the pharmacological activity of the compound that is formulated together.The pharmaceutically acceptable carrier, adjuvant or vehicle that can be used in the compositions of the present disclosure includes but is not limited to ion exchanger, alumina, aluminum stearate, lecithin, serum protein (for example, human serum albumin), buffer substance (for example, phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acid, water, salt or electrolyte (for example, protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substance, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol and lanolin.

[0101] The present disclosure also includes kits (e.g., pharmaceutical packages). The provided kits may include a compound of the present disclosure, another therapeutic agent, and a first and second container (such as a vial, an ampoule, a bottle, a syringe, and / or a dispersible package or other suitable container) containing the compound of the present disclosure and / or another therapeutic agent. In some embodiments, the provided kits may include a third container containing a pharmaceutically acceptable excipient for diluting or suspending the compound of the present disclosure and / or another therapeutic agent, if desired. In some embodiments, the compound of the present disclosure provided in the first container and the other therapeutic agent provided in the second container are combined into a unit dosage form.

[0102] (Administration) The pharmaceutical compositions provided by the present disclosure may be administered by a variety of routes, including, but not limited to, oral, parenteral, inhalation, topical, rectal, nasal, oral, vaginal, implant, or other means. For example, as used herein, parenteral administration includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraventricular, intralesional, and intracranial injection or infusion.

[0103] Generally, the compounds provided herein are administered in an effective amount. The amount of compound actually administered will typically be determined by a physician, taking into account the relevant circumstances, including the condition being treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0104] When used to prevent the disorders of the present disclosure, the compounds provided herein are generally administered under the direction and supervision of a physician at the dosage levels described above to subjects at risk of developing the condition. Subjects at risk of developing a particular condition generally include those with a family history of the condition or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0105] The pharmaceutical compositions provided herein can be administered for a long period of time ("long-term administration"). Long-term administration refers to the administration of a compound or its pharmaceutical composition for a long period of time, such as for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years or more, or can be administered indefinitely (for example, for the life expectancy of the subject). In a specific embodiment, long-term administration is intended to provide a constant level (for example, therapeutic range) of the compound in the blood for a long period of time.

[0106] The pharmaceutical compositions of the present disclosure may be delivered using various dosing methods. For example, in specific embodiments, the pharmaceutical composition may be administered as a bolus to increase the blood compound concentration to an effective level. The bolus administration is performed depending on the desired systemic concentration of the active ingredient. For example, intramuscular or subcutaneous bolus administration slowly releases the active ingredient, while direct intravenous bolus administration (e.g., intravenous drip injection) provides faster delivery and quickly increases the blood active ingredient concentration to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion (e.g., intravenous drip injection) to maintain a steady-state active ingredient concentration in the subject's body. Furthermore, in another embodiment, the pharmaceutical composition may be administered as an initial bolus, followed by a continuous infusion.

[0107] Compositions for oral administration can take the form of bulk solutions or suspensions, or powders. However, more commonly, compositions are presented in unit dosage forms for precise administration. The term "unit dosage form" refers to physically discrete forms suitable for single administration to human patients and other mammals, each containing a predetermined amount of active agent and appropriate pharmaceutical excipients to achieve the desired therapeutic effect. Typical unit dosage forms include prefilled, pre-processed ampoules or syringes for liquid compositions, or pills, tablets, capsules, and the like for solid compositions. In such compositions, the compound typically accounts for less than half the total weight (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder consisting of various vehicles or excipients and processing aids useful for forming the desired dosage form.

[0108] A typical oral administration regimen is 1 to 5 times, particularly 2 to 4 times, and generally 3 times per day. Using these administration patterns, each dose of the compound of the present application is about 0.01 to about 20 mg / kg, preferably about 0.1 to about 10 mg / kg, and particularly about 1 to about 5 mg / kg.

[0109] In general, the concentration for transdermal administration is selected to be the same as or lower than the blood concentration when an injection is used, and is generally in the range of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0110] The dosage for injection ranges from about 0.1 mg / kg / hour to at least 10 mg / kg / hour for a total of about 1 hour to about 120 hours, particularly 24 to 96 hours. A preliminary bolus of about 0.1 mg / kg to about 10 mg / kg or more may be administered to achieve an adequate steady-state level. The maximum total dose for a 40-80 kg human patient is not to exceed about 2 g / day.

[0111] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle, buffers, dispersing and dispensing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following ingredients: binders (e.g., microcrystalline cellulose, gum tragacanth, or gelatin); excipients (e.g., starch or lactose); disintegrants (e.g., alginic acid, Primojel, or corn starch); lubricants (e.g., magnesium stearate); flow agents (e.g., colloidal silicon dioxide); sweeteners (e.g., sucrose or saccharin); or flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring), or compounds of the same nature.

[0112] Injectable compositions are generally based on injectable sterile saline or phosphate buffer or other injectable excipients known to those skilled in the art. As mentioned above, the active compound in such compositions is generally a minor component, often about 0.05 to 10% by weight, with the remainder being the injectable excipients and the like.

[0113] Transdermal compositions are generally formulated as topical ointments or creams containing active ingredients.When formulated as an ointment, the active ingredient is usually combined with an ointment base that is miscible with either paraffin or water.Alternatively, when formulated as a cream, the active ingredient can be formulated with, for example, an oil-in-water cream base.Such transdermal formulations are well known to those skilled in the art, and generally contain other ingredients that enhance the stability of transdermal absorption of the active ingredient or formulation.All such known transdermal formulations and ingredients are included in the scope provided herein.

[0114] The compounds provided herein can also be administered by a transdermal device, thus using a patch either of the reservoir or permeable membrane type, or of the solid matrix type.

[0115] The above components of compositions for oral, injectable, or topical administration are merely representative. Other materials, processing techniques, and the like are described in Chapter 8 of Remington's Pharmaceutical Sciences (17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania), the contents of which are incorporated herein by reference.

[0116] The compounds of the present disclosure can also be administered in sustained release forms or in sustained release drug delivery systems. Representative sustained release materials are described in Remington's Pharmaceutical Sciences.

[0117] The present disclosure also relates to pharmaceutically acceptable formulations of the compounds of the present disclosure. In certain embodiments, the formulation includes water. In other embodiments, the formulation includes a cyclodextrin derivative. The most common cyclodextrins are α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, which consist of 6, 7, and 8 α-l,4-linked glucose units, each of which optionally includes one or more substituents (including, but not limited to, methyl groups, hydroxyalkyl groups, acyl groups, and sulfoalkyl ether substituents) attached to the sugar moiety. In specific embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as Captisol (see, e.g., U.S. Pat. No. 5,376,645). In specific embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., a 10-50% aqueous solution).

[0118] (treatment) The present disclosure provides methods for treating the following disorders or conditions in mammals, such as humans: cell proliferative diseases (e.g., cancer, atherosclerosis-associated vascular smooth muscle cell hyperplasia, postoperative vascular stenosis, restenosis, and endometriosis); infectious diseases (viral infections (e.g., DNA viruses such as herpes, and RNA viruses such as HIV), and fungal infections); autoimmune diseases (e.g., inflammation such as psoriasis, rheumatoid arthritis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, and glomerulonephritis); and organ transplant rejection (e.g., graft-versus-host disease) by administering a therapeutically effective amount of a compound of the present disclosure or a composition thereof to a mammal.

[0119] The present disclosure further provides compounds of the present disclosure that are useful for treating abnormal cell growth (e.g., cancer). The present disclosure further provides a method of treating abnormal cell growth (e.g., cancer selected from the following: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, bile duct, oral cavity and pharynx (mouth), lip, tongue, mouth, pharynx, small intestine, colorectal, large intestine, rectum, brain tumor and central nervous system cancer, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular adenoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorders, lymphatic vessel diseases, Hodgkin's disease, hairy cell carcinoma, and leukemia), comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of the present disclosure, or a composition thereof.

[0120] Furthermore, the present disclosure relates to a method for treating a subject suffering from a disease caused by the proliferation of vascular smooth muscle cells. The compound of the present disclosure effectively inhibits the proliferation and migration of vascular smooth muscle cells. The method comprises administering to a subject in need of treatment a sufficient amount of the compound of the present disclosure or a composition thereof to inhibit the proliferation and / or migration of vascular smooth muscle cells.

[0121] The present disclosure further provides a method of treating a subject suffering from gout, comprising administering to a subject in need thereof a compound of the present disclosure or a composition thereof in an amount sufficient to treat the condition.

[0122] The present disclosure further provides a method for treating a subject suffering from a kidney disease (e.g., polycystic kidney disease), comprising administering to a subject in need thereof a compound of the present disclosure or a composition thereof in an amount sufficient to treat the condition.

[0123] The compounds of the present disclosure, due to their inhibitory activity against FLT3 and other kinases, are also useful as research tools for studying the mechanisms of action of those kinases in vitro and in vivo.

[0124] The compounds of the present disclosure are useful in the treatment of cancer (e.g., leukemia and cancers of the lung, breast, prostate, and skin (e.g., melanoma)) and other proliferative diseases (including, but not limited to, psoriasis, HSV, HIV, restenosis, and atherosclerosis). To treat cancer with the compounds of the present disclosure, a therapeutically effective amount of a composition comprising at least one pharmaceutically acceptable compound of the present disclosure is administered to a patient in need of such treatment (e.g., a patient with cancer or another proliferative disorder).

[0125] An effective amount of a compound of the present disclosure is generally administered in a single or multiple doses at an average daily dose of 0.01 mg to 50 mg of compound per kg of patient body weight, preferably 0.1 mg to 25 mg of compound per kg of patient body weight. Generally, a compound of the present disclosure may be administered to a patient in need of treatment at a daily dose ranging from about 1 mg to about 3500 mg per patient, preferably 10 mg to 1000 mg per patient. For example, a daily dose for a patient may be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900, or 1000 mg. The compound may be administered one or more times per day, one or more times per week (or every few days), or intermittently. For example, the compound may be administered continuously or weekly (e.g., every Monday) for several weeks (e.g., 4-10 weeks), once or more times daily. Alternatively, a cycle of several days (e.g., 2-10 days) of administration followed by several days (e.g., 1-30 days) without administration of the compound may be repeated indefinitely or a set number of times (e.g., 4-10 cycles). For example, a compound of the present disclosure may be administered daily for 5 days, followed by no administration for 9 days, followed by administration for 5 days, followed by no administration for 9 days, and so on, and this cycle may be repeated indefinitely or 4-10 times.

[0126] Example The following examples are set forth so as to fully disclose and describe to those of ordinary skill in the art how to perform, prepare, and evaluate the methods and compounds claimed herein, and are intended to be illustrative of the present invention and are not intended to limit the scope of the invention.

[0127] Methods for preparing the compounds of the present disclosure are shown in the following schemes. [ka]

[0128] In step 1, S1 is reacted with concentrated HCl and amyl nitrite to give S2. In step 2, a mixture of S2 and R4CHO is treated with R3NH2 to give S3. In step 3, S3 is reduced to give S4. In step 4, S4 is reacted with DMF-DMA to give S5. In step 5, S5 is treated with guanidine hydrochloride to give S6. In step 6, S6 is oxidized to give S7. In the final step 7, S7 is coupled with S8 to give the title compound of formula (I).

[0129] [ka] Compounds of formula (I) can also be prepared according to Scheme 2, starting with S7, where R2 is H. S7 is brominated and subsequently coupled with a boronic acid.

[0130] Example 1: Preparation of N-(5-(4-ethylpiperazin-1-yl)-4-methoxypyridin-2-yl)-1-isopropyl-1H-imidazo[4,5-h]quinazolin-8-amine (I-2) [ka]

[0131] Step 1 [ka]

[0132] To 1 (450 g, 4.6 mol, 1.00 equiv.) was added concentrated HCl (38 mL, 0.46 mol, 0.1 equiv.), and the mixture was cooled to 0 °C with ice water. Amyl nitrite (1076 g, 9.2 mol, 2.00 equiv.) was added dropwise at the same temperature. The reaction mixture was then warmed to room temperature and stirred overnight. The solid was filtered, and the filter cake was washed with petroleum ether (150 mL x 2) and dried in vacuo to give the title compound (300 g, 95% purity) as a pale yellow solid.

[0133] Steps 2 and 3 [ka]

[0134] To a solution of 2 (300 g, 1.9 mol, 1.00 equiv.) and polyoxymethylene (43 g, 2.09 mmol, 1.10 equiv.) in EtOH (2.3 L) was added isopropylamine (123 g, 2.09 mol, 1.10 equiv.) dropwise. The mixture was stirred at room temperature for 2 h and then refluxed for an additional 3 h. The mixture was concentrated to give crude compound 3.

[0135] To a solution of crude compound 3 in AcOH (2.1 L), Fe (powder) (620 g, 9.5 mol, 5 equiv.) was added and refluxed for 48 h. After cooling to room temperature, the mixture was diluted with EtOAc (1000 mL), filtered, and the filtrate was concentrated. The resulting residue was diluted with water (2000 mL) and basified with 2 M aqueous NaOH until pH 9. The mixture was then extracted with EtOAc (1000 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel column chromatography (elution solvent: PE / EtOAc (1 / 1)) to give compound 4 (248 g, 96% purity) as a brown oil.

[0136] Step 4 [ka]

[0137] A solution of 4 (248 g, 1.4 mol, 1.00 equiv) in DMF (700 mL) and DMF-DMA (700 mL) was heated at 110° C. for 8 h. The solvent was removed in vacuo to give crude product 5 (306 g), which was used directly in the next step without further purification.

[0138] Step 5 [ka]

[0139] To a solution of crude 5 (306 g) in EtOH (2.5 L), guanidine hydrochloride (237 g) and t-BuONa (480 g) were added and stirred for 16 h at 80° C. The solvent was removed under reduced pressure, and the resulting residue was purified by silica column chromatography (elution solvent: PE / EtOAc (1 / 1)) to give compound 6 (125 g, 95% purity) as a yellow solid.

[0140] Step 6 [ka]

[0141] To a solution of 6 (22.9 g, 100 mmol, 1.00 equiv.) in DCM (800 mL) was added DDQ (27.2 g, 120 mmol, 1.20 equiv.), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluent: PE / EtOAc (1 / 1)) to give compound 7 (11.3 g, 94% purity) as a yellow solid.

[0142] Step 7 [ka] To a solution of 8 (148 mg, 579 μmol, 1.00 equiv.) in dioxane (3 mL), 7 (131 mg, 579 μmol, 1.00 equiv.), t-BuONa (111 mg, 1.16 mmol, 2.00 equiv.), and BrettPhos Pd 3rd generation (53 mg, 57.9 μmol, 0.10 equiv.) were added and stirred at 100 °C under a nitrogen atmosphere for 2 h. The suspension was diluted with DCM (10 mL), filtered, and the filter cake was washed with DCM (10 mL). The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH (10 / 1)) to give the crude product (150 mg) as a pale yellow solid. The crude product was purified by preparative TLC to give the target product I-2 (50 mg, 20.0%) as an off-white solid. 1 H-NMR (DMSO-d6, 400MHz) δ 9.82(s,1H), 9.34(s,1H), 8.60(s,1H), 7.83(s,1H), 7.69-7.63(m,3H), 6.02-5.96(m,1H), 3.91(s,3H), 3.13-3.07(m,4H), 2.82-2.77(m,4H), 2.67-2.64(m,2H), 1.56(d,J=6.0Hz, 6H), 1.11(t,J=7.2Hz, 3H)

[0143] Examples 2 to 18 Following the same procedure as in Example 1, Examples 2 to 18 were prepared using different S8. [Table 1] [Table 2] [Table 3]

[0144] Example 19: Preparation of 1-isopropyl-N-(3-methoxy-4-morpholinophenyl)-4-methyl-1H-imidazo[4,5-h]quinazolin-8-amine (II-1) [ka]

[0145] Step 1 [ka] To a solution of 7 (200 mg, 880 μmol, 1.00 equiv.) in DMF (10 mL) was added N-bromosuccinimide (235 mg, 1.32 mmol, 1.50 equiv.), and the reaction mixture was stirred at room temperature for 4 h. The suspension was diluted with EtOAc (40 mL) and washed with brine (10 mL x 3). The combined organic layer was dried over anhydrous NaSO, filtered, and the filter cake was washed with EtOAc (10 mL). The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluting solvent: EtOAc) to give compound 9 (240 mg, 89.1%) as an off-white solid. LCMS [M+1] = 306.1 and 308.0.

[0146] Step 2 [ka] To a solution of 9 (240 mg, 784 μmol, 1.00 equiv.) in dioxane (16 mL) and HO (4 mL), methylboronic acid (469 mg, 7.84 mmol, 10.0 equiv.), CsCO (769 mg, 2.35 mmol, 3.00 equiv.), and Pd(dppf)Cl (57 mg, 78.4 μmol, 0.10 equiv.) were added and stirred at 80 °C for 16 h under a nitrogen atmosphere. The suspension was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (elution solvent: EtOAc) to give compound 10 (82 mg, 43.4%) as an off-white solid. LCMS [M+1] + =242.2

[0147] Step 3 [ka] To a solution of 11 (77 mg, 337 μmol, 1.00 equiv.) in dioxane (5 mL), 10 (81 mg, 337 μmol, 1.0 equiv.), t-BuONa (81 mg, 842 μmol, 2.50 equiv.), and Brettphos Pd G3 (31 mg, 33.7 μmol, 0.10 equiv.) were added and stirred at 100° C. for 16 hours under a nitrogen atmosphere. The mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluent: DCM / MeOH (10 / 1)) to give the title compound (40 mg, 27.4%) as a yellow solid. LCMS [M+1] + =434.3; 1 H NMR (300MHz, DMSO-d6) δ 9.66(s,1H), 9.25(s,1H), 8.57(s,1H), 7.81(s,1H), 7.68(s,1H), 7.46(d,J=1.2Hz, 1H), 6.05-5.96(m,1H), 3.92(s,3H), 3.76-3.73(m,4H), 3.02-2.98(m,4H), 2.61(s,3H), 1.57(d,J=6.6Hz, 6H)

[0148] Example 20: Preparation of N-(4-ethoxy-5-(piperazin-1-yl)pyridin-2-yl)-1-isopropyl-5-methyl-1H-imidazo[4,5-h]quinazolin-8-amine (III-1) [ka]

[0149] Step 1 [ka] To 12 (20.0 g, 178 mmol, 1.00 equiv.) was added concentrated HCl (1.5 mL, 12 M, 17.8 mmol, 0.10 equiv.) followed by amyl nitrite (41.7 g, 357 mmol, 2.00 equiv.) at 5 °C. The mixture was then warmed to room temperature and stirred for 14 h, and the solid was filtered. The filter cake was washed with PE (300 mL x 3) and dried under vacuum to give compound 13 (28.8 g, 94.9%) as a pale yellow solid.

[0150] Steps 2 and 3 [ka] To a solution of 13 (28.8 g, 169 mmol, 1.00 equiv.) in EtOH (500 mL) was added polyoxymethylene (5.58 g, 186 mmol, 1.10 equiv.) and isopropylamine (11.0 g, 186 mmol, 1.10 equiv.). The mixture was stirred at room temperature for 1 h and then refluxed for an additional 2 h. The mixture was concentrated to give crude compound 14. To a solution of crude compound 14 in AcOH (500 mL) was added Fe(powder) (66.2 g, 1.18 mol, 7.00 equiv.) and refluxed for 48 h. After cooling to room temperature, the mixture was diluted with EtOAc (500 mL) and filtered. The filtrate was concentrated in vacuo, and the resulting residue was suspended in EtOAc (1000 mL) and saturated sodium bicarbonate (500 mL), and the solid was filtered. The organic layer was separated, and the aqueous solution was extracted with DCM / MeOH (10 / 1, 500 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluting solvent: PE / EtOAc (1 / 2)) to give compound 15 (23.1 g, 76.6% over two steps) as a brown oil. LCMS [M+H] + =193.2

[0151] Steps 4 and 5 [ka] To a solution of 15 (23.1 g, 120 mmol, 1.00 equiv) in DMF (250 mL) was added DMF-DMA (250 mL) and stirred for 8 h at 110° C. The solvent was removed in vacuo to give crude compound 16 (30.0 g), which was used directly in the next step without further purification. To a solution of the crude compound 16 (30.0 g) in EtOH (300 mL), guanidine hydrochloride (11.5 g, 120 mmol, 1.00 equiv.) and t-BuONa (34.6 g, 360 mmol, 3.00 equiv.) were added, and the mixture was stirred at 80 °C for 12 h. The solvent was removed in vacuo, and the resulting residue was purified by silica gel column chromatography (elution solvent: PE / EtOAc (1 / 4)) to give compound 17 (9.70 g, 33.2% over two steps) as a yellow solid. LCMS [M+H] + =244.3

[0152] Step 6 [ka] To a solution of 17 (9.70 g, 39.9 mmol, 1.00 equiv.) in DCM (400 mL) was added DDQ (10.9 g, 48 mmol, 1.20 equiv.), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluent: PE / EtOAc (1 / 1)) to give compound 18 (800 mg, 8.32%) and the crude product (5.1 g) as a pale yellow solid. LCMS [M+H] + =242.2

[0153] Step 7 [ka] To a solution of 19 (63 mg, 184 μmol, 1.00 equiv.) in dioxane (3 mL), 18 (44 mg, 184 μmol, 1.00 equiv.), t-BuONa (35 mg, 369 μmol, 2.00 equiv.), and Brettphos Pd G3 (33 mg, 36.9 μmol, 0.20 equiv.) were added and stirred at 110° C. for 2 h under a nitrogen atmosphere. The mixture was concentrated in vacuo, and the resulting residue was purified by preparative TLC (elution solvent: EtOAc) to give compound 20 (63 mg, 62.5%) as a pale yellow solid. LCMS [M+H] + =547.4

[0154] Step 8 [ka] To a solution of 20 (63 mg, 115 μmol, 1.00 equiv.) in DCM (5 mL) was added TFA (1.0 mL), and the mixture was stirred at room temperature for 1 h. The solvent was concentrated in vacuo to give the crude product. The crude product was suspended in MeOH (5 mL) and saturated aqueous sodium carbonate (2 mL) and stirred for 10 min. The solid was filtered, the filtrate was concentrated in vacuo, and the residue was purified by preparative TLC (eluting solvent: DCM / MeOH (10 / 1)) to give the target compound III-1 (20 mg, 38.9%) as an off-white solid. LCMS [M+H] + =447.3; 1 H NMR (300MHz, DMSO-d6) δ 9.79(s,1H), 9.42(s,1H), 8.51(s,1H), 7.84(s,1H), 7.71(s,1H), 7.44(d,J=1.2Hz, 1H), 6.01-5.97(m,1H), 4.17 (q, J=6.9Hz, 2H), 3.16-3.11(m,8H), 2.71(s,3H), 1.54(d,J=6.6Hz, 6H), 1.43(t,J=6.9Hz, 3H)

[0155] Example 21: Preparation of N-(4-isopropoxy-5-(piperazin-1-yl)pyridin-2-yl)-1-methyl-1H-imidazo[4,5-h]quinazolin-8-amine (IV-1) [ka]

[0156] Steps 1 and 2 [ka] To a solution of 2 (21.0 g, 135 mmol, 1.00 equiv.) in EtOH (300 mL) was added polyoxymethylene (4.44 g, 148 mmol, 1.10 equiv.) and methylamine (74 mL, 2 M in THF, 148 mmol, 1.10 equiv.). The mixture was stirred at room temperature for 1 h and then refluxed for an additional 2 h. The mixture was concentrated to give crude compound 21. To a solution of crude compound 21 in AcOH (300 mL) was added Fe(powder) (37.5 g, 672 mol, 5.00 equiv.), and the mixture was stirred at 120° C. for 48 h. After cooling to room temperature, the mixture was diluted with EtOAc (500 mL), filtered, and the filtrate was concentrated. The resulting residue was suspended in EtOAc (500 mL) and saturated sodium bicarbonate (300 mL) and filtered. The organic layer was separated, and the aqueous solution was extracted with DCM / MeOH (10 / 1, 500 mL x 2). The combined organic layers were dried over NaSO and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluting solvent: EtOAc) to give compound 22 (15.8 g, 78.2%) as a brown oil. LCMS [M+H] + =151.1

[0157] Steps 3 and 4 [ka] To a solution of 22 (15.8 g, 105 mmol, 1.00 equiv) in DMF (45 mL) was added DMF-DMA (45 mL) and the solution was stirred at 110° C. for 8 h. The solvent was removed in vacuo to give crude product 23, which was used directly in the next step without further purification. LCMS [M+H] + =205.2 To a solution of the crude product 23 in EtOH (300 mL) were added guanidine hydrochloride (25.1 g, 263 mmol, 2.50 equiv.) and t-BuONa (50.6 g, 526 mmol, 5.00 equiv.), and the mixture was stirred at 70 °C for 16 h. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (elution solvent: EtOAc) to give compound 24 (6.30 g, 29.8%) as a yellow solid. LCMS [M+H] + =202.2

[0158] Step 5 [ka] To a solution of 24 (3.0 g, 14.9 mmol, 1.00 equiv.) in DCM (100 mL) was added DDQ (4.1 g, 18 mmol, 1.20 equiv.), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluent: PE / EtOAc (1 / 1)) to give compound 25 (1.20 g, 40.4%) as a yellow solid. LCMS [M+H] + =200.1

[0159] Step 6 [ka] To a solution of 26 (109 mg, 306 μmol, 1.00 equiv.) in dioxane (5 mL), 25 (61 mg, 306 μmol, 1.00 equiv.), t-BuONa (60 mg, 613 μmol, 2.00 equiv.), and Brettphos Pd G3 (14 mg, 15.3 μmol, 0.05 equiv.) were added and stirred at 100° C. for 2 hours under a nitrogen atmosphere. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (elution solvent: EtOAc) to give compound 27 (92 mg, 57.9%) as a yellow solid. LCMS [M+H] + =519.3

[0160] Step 7 [ka] To a solution of 27 (92 mg, 177 μmol, 1.00 equiv) in DCM (5 mL) was added TFA (0.1 mL) and stirred for 1 h at room temperature. The mixture was concentrated in vacuo to give the crude product. To a suspension of the crude product in MeOH (2 mL) was added Na2CO3 (57 mg, 0.48 mmol, 3.00 equiv) with stirring for 10 min, followed by DCM (10 mL). The solid was filtered, the filtrate was concentrated, and the resulting residue was purified by preparative TLC to give the title compound IV-1 (19.4 mg, 26.1%). LCMS [M+H] + =419.3; 1H NMR (300MHz, DMSO-d6) δ 9.64(s,1H), 9.33(s,1H), 8.35(s,1H), 7.80(s,2H), 7.69-7.62(m,2H), 4.86-4.77(m,1H), 4.42(s,3H), 2.95-2.91(m,4H), 2.85-2.82(m,4H), 1.35(d,J=6.0Hz, 6H)

[0161] Example 22: Preparation of N-(4-ethoxy-5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-1-ethyl-1H-imidazo[4,5-h]quinazolin-8-amine (V-1) [ka]

[0162] Steps 1 and 2 [ka] To a solution of 2 (21.0 g, 135 mmol, 1.00 equiv.) in EtOH (300 mL) was added polyoxymethylene (4.44 g, 148 mmol, 1.10 equiv.) and ethylamine (6.67 g, 148 mmol, 1.10 equiv.), and the solution was stirred at room temperature for 1 h and then refluxed for an additional 2 h. The mixture was concentrated in vacuo to give crude compound 28, which was used directly in the next step without further purification. LCMS [M+H] + =181.1 To a solution of crude compound 28 in AcOH (300 mL), Fe(powder) (37.6 g, 672 mmol, 5.0 equiv.) was added and refluxed for 48 h. After cooling to room temperature, the mixture was diluted with EtOAc (500 mL), filtered, and the filtrate was concentrated. The resulting residue was suspended in EtOAc (500 mL) and saturated sodium bicarbonate (300 mL), and the mixture was filtered. The organic layer was separated, and the aqueous solution was extracted with DCM / MeOH (10 / 1, 500 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluting solvent: EtOAc) to give compound 29 (14.3 g, 64.7% over two steps) as a brown oil. LCMS [M+H] + =165.1

[0163] Steps 3 and 4 [ka] To a solution of 29 (14.3 g, 87.1 mmol, 1.00 equiv) in DMF (42 mL) was added DMF-DMA (42 mL) and the solution was stirred at 130° C. for 8 h. The solvent was removed in vacuo to give crude product 30, which was used directly in the next step without further purification. LCMS [M+H] + =220.2 To a solution of the crude product 30 in 300 mL of EtOH, guanidine hydrochloride (8.32 g, 89.1 mmol, 1.00 equiv.) and t-BuONa (25.1 g, 261 mmol, 3.00 equiv.) were added, and the mixture was refluxed for 16 h. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (elution solvent: PE / EtOAc (1 / 1)) to give compound 31 (6.4 g, 34.1%) as a yellow solid. LCMS [M+H] + =216.2

[0164] Step 5 [ka] To a solution of 31 (6.40 g, 29.7 mmol, 1.00 equiv.) in DCM (200 mL), DDQ (8.09 g, 35.6 mmol, 1.20 equiv.) was added and stirred at room temperature for 1 h. The mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluent: PE / EtOAc (1 / 1)) to give compound 32 (2.10 g, 33.1%) as a yellow solid. LCMS [M+H] + =214.2

[0165] Step 6 [ka] To a solution of 33 (87 mg, 323 μmol, 1.00 equiv.) in dioxane (5 mL), 32 (69 mg, 323 μmol, 1.00 equiv.), t-BuONa (62 mg, 645 μmol, 2.00 equiv.), and Brettphos Pd G3 (15 mg, 16.1 μmol, 0.05 equiv.) were added. The mixture was stirred at 90°C for 2 hours under a nitrogen atmosphere, and the solid was filtered off. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: DCM / MeOH (15 / 1)) to give the target compound V-1 (21.2 mg, 14.6%). LCMS [M+H] + =447.4; 1 H NMR (300MHz, DMSO-d6) δ 9.69(s,1H), 9.33(s,1H), 8.43(s,1H), 7.81(s,1H), 7.70-7.63(m,3H), 4.88 (q, J=7.2Hz, 2H), 4.17 (q, J=6.9Hz, 2H), 3.09-2.59(m,4H), 2.59-2.56(m,2H), 2.43-2.36(m,4H), 1.46-1.39(m,6H), 1.05(t,J=7.2Hz, 3H)

[0166] Example 23: Preparation of 1-isopropyl-N-(4-methoxy-5-morpholinopyridin-2-yl)-2-methyl-1H-imidazo[4,5-h]quinazolin-8-amine (Vl-1) [ka]

[0167] Steps 1 and 2 [ka] To a suspension of 2 (12.5 g, 80.1 mmol, 1.00 equiv) in AcOH (150 mL) was added isopropylamine (5.21 g, 88.1 mol, 1.10 equiv), followed by CHCHO (3.88 g, 88.1 mmol, 1.10 equiv) and stirred for 3 h at 80 °C. This mixture was used directly in the next step without further purification. LCMS [M+H] + =209.2 After cooling to room temperature, Fe(powder) (22.4 g, 400 mmol, 5.00 equiv) was added, and the mixture was refluxed for 48 h. The solvent was removed in vacuo, and the resulting residue was diluted with EtOAc (200 mL) and filtered. The filtrate was concentrated to give the crude product. The resulting crude product was added to water (250 mL) and adjusted to pH 8-9 with aqueous NaOH (1N). The mixture was extracted with EtOAc (100 mL x 3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluting solvent: DCM / MeOH (20 / 1)) to give compound 35 (10.5 g, 68.2% over two steps) as a gray solid. LCMS [M+H] + =193.2

[0168] Steps 3 and 4 [ka] To a suspension of 35 (5.00 g, 26.0 mmol, 1.00 equiv) in DMF (30 mL) was added DMF-DMA (30 mL) and stirred for 8 h at 110° C. The mixture was concentrated in vacuo to give crude product 36. To a solution of the crude product 36 in EtOH (150 mL), guanidine hydrochloride (6.15 g, 65.0 mmol, 2.50 equiv.) and t-BuONa (12.4 g, 130 mmol, 5.00 equiv.) were added and the mixture was refluxed for 16 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH (20 / 1)) to give compound 37 (1.50 g, 23.7% yield over two steps) as a gray solid. LCMS [M+H] + =244.2

[0169] Step 5 [ka] To a solution of 37 (200 mg, 822 μmol, 1.00 equiv.) in DCM (8 mL), DDQ (224 mg, 986 μmol, 1.20 equiv.) was added and stirred at room temperature for 1 h. The mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluent: PE / EtOAc (1 / 1)) to give compound 38 (110 mg, 55.5%) as a brown solid. LCMS [M+H] + =242.2

[0170] Step 6 [ka] To a suspension of 38 (100 mg, 414 μmol, 1.00 equiv.) in dioxane (10 mL), 11 (117 mg, 497 μmol, 1.20 equiv.), t-BuONa (80 mg, 829 μmol, 2.00 equiv.), and Brettphos Pd G3 (19 mg, 20.7 μmol, 0.05 equiv.) were added and stirred at 100° C. for 2 h. The mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluent: PE / EtOAc (1 / 1)) to give the target compound VI-1 (22.4 mg, 12.5%) as a white solid. LCMS [M+H] + =434.3; 1H NMR (300MHz, DMSO-d6) δ 9.73 (br, 1H), 9.30(s,1H), 7.82(s,1H), 7.64-7.59(m,2H), 7.52(d,J=8.7Hz, 1H), 3.89(s,3H), 3.76-3.73(m,4H), 3.08-3.00(m,4H), 2.69(s,3H), 1.60(d,J=6.9Hz, 6H)

[0171] (Biological Assays) Compounds of the present disclosure were serially diluted 3-fold starting from 0.5 μM to calculate IC50 values for 10 doses, while the control compound staurosporine was serially diluted 4-fold starting from 20 μM to calculate IC50 values for 10 doses. The reaction was carried out in the presence of 10 μM ATP.

[0172] Conditions and Protocols procedure: 1. Compounds were prepared in freshly prepared reaction buffer containing 20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 0.02 mg / mL BSA, 0.1 mM Na3VO4, 2 mM DTT, and 1% DMSO. 2. For CDK subtypes, the necessary cofactors (such as 1 μg (1.5 μM) of recombinant retinoblastoma protein) were added to the substrate solution described above. 3. 10 ng of a kinase such as recombinant CDK4 / cyclin D1 (Life Technologies PV4204) was diluted in kinase buffer (20 mM Tris, pH 7.5, 10 mM MgCl2, 0.01% NP-40, 2 mM DTT) and incubated with various concentrations of inhibitor at room temperature for 30 minutes. 4. Compounds in DMSO were added to the kinase mixture using acoustic technology (Echo550). 5. 33P-ATP (final activity concentration: 0.01 μCi / μL) was added to this reaction mixture to promote the reaction. 6. The reaction mixture was incubated for 120 minutes at room temperature. 7. The reaction mixture was added dropwise to a P81 ion exchange filter paper (Whatman # 3698-915). 8. The filter paper was thoroughly washed with 0.75% phosphoric acid. 9. The amount of radioactive phosphorylated substrate remaining on the filter paper was measured.

[0173] Data Analysis: Kinase activity data were expressed as a percentage of kinase activity in the test samples compared to vehicle (dimethyl sulfoxide) reactions. IC50 calculations and curve fitting were performed using Prism4 software (GraphPad). The results of all kinase inhibition of representative compounds using the same assay method as above are shown in the table below. [Table 4]

[0174] Although the above describes the present disclosure in more detail in connection with certain preferred embodiments, the specific embodiments of the present disclosure are not limited to the description. It will be apparent to those skilled in the art that the present disclosure can be practiced with various mere omissions and substitutions without departing from the spirit and scope of the present invention.

Claims

1. Formula (I): 【Chemical 1】 [In the formula, Y is N or CH; X is -OR a , -SR a , or -NR b R c and; where R a is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3 to 7-membered heterocyclyl, -LC 6-10 aryl, or -L-5 to 10 membered heteroaryl; R b is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 is alkynyl; R c is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 is alkynyl; or R b , R c and the N atom to which they are attached form a 3- to 7-membered heterocyclyl; where L is a chemical bond, or -C 1-6 alkylene- selected from; Ring A is -L'-3 to 11-membered heterocyclyl and contains 1, 2, 3, 4, 5, 6, 7, or 8 R 5 may be optionally substituted with; wherein L' is selected from a chemical bond or -NH-CH2-; R 5 is H, halogen, oxo, -NR'R'', C 1-6 Alkyl, or C 1-6 haloalkyl; or two R 5 are combined and become one -C 1-4 may form alkylene-; R' and R'' are each independently H, C 1-6 Alkyl, or C 1-6 haloalkyl; or R', R'' and the N atom to which they are attached form a 3- to 7-membered heterocyclyl; R 1 is H or C 1-6 is alkyl; R 2 is H or C 1-6 is alkyl; R 3 is C 1-6 is alkyl; and R 4 is H or C 1-6 alkyl] or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

2. 2. A compound of formula (I) according to claim 1, wherein Y is N, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

3. wherein X is -OR a ; R a But C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or -LC 3-7 is cycloalkyl; and where L is a chemical bond, or -C 1-6 alkylene-, 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

4. During the ceremony, Ring A is -L'-3 to 7-membered heterocyclyl and 1, 2, 3, 4, 5, 6, 7, or 8 R 5 may be optionally substituted with; wherein L' is selected from a chemical bond or -NH-CH2-; R 5 H, halogen, oxo, -NR'R'', C 1-6 Alkyl, or C 1-6 haloalkyl; or two R 5 are combined and become one -C 1-4 may form alkylene-; and R' and R'' are each independently H, C 1-6 Alkyl, or C 1-6 haloalkyl; or R', R'' and the N atom to which they are attached form a 3- to 7-membered heterocyclyl; A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

5. In the formula, Ring A is 【Chemistry 2】 and where Z is O or NR 51 and; R 51 ~R 59 is H or C 1-6 alkyl; or R 51 ~R 59 Two of them are combined to form -C 1-4 may form alkylene- A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

6. In the formula, Ring A is 【Chemistry 3】 4. A compound of formula (I) according to any one of claims 1 to 3, wherein:

7. During the ceremony, R 1 But H, A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

8. During the ceremony, R 2 But H, A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

9. During the ceremony, R 3 is Et or iPr, A compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

10. During the ceremony, R 4 But H, A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

11. During the ceremony, Y is N or CH; X is -OR a , or -NR b R c and; where R a But C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, or -LC 6-10 is aryl; R b But H or C 1-6 is alkyl; R c But H or C 1-6 is alkyl; or R b , R c and the N atom to which they are attached form a 4- to 6-membered heterocyclyl; where L is a chemical bond, or -C 1-6 alkylene- selected from; Ring A is -L'-4 to 6-membered heterocyclyl and has 1, 2, 3, 4, 5, 6, 7, or 8 R 5 may be optionally substituted with; wherein L' is selected from a chemical bond or -NH-CH2-; R 5 But H, oxo, C 1-6 alkyl, or -NR'R''; or two R 5 are combined and become one -C 1-4 may form alkylene-; R' and R'' are each independently H or C 1-6 alkyl; or R', R'' and the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 1 But H or C 1-6 is alkyl; R 2 But H or C 1-6 is alkyl; R 3 But C 1-6 is alkyl; and R 4 But H or C 1-6 is alkyl, A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

12. In the formula, Y is N or CH; X is -OR a , or -NR b R c and; where R a But, Me, Et, iPr, 【Chemistry 4】 and; R b But H, Me; R c is H, Me; or R b , R c and the N atoms to which they are bonded are 【Chemistry 5】 Forming; Ring A is 【Chemistry 6】 and; R 1 is H, or Me; R 2 is H, or Me; R 3 is Me, Et, or iPr; and R 4 is H or Me, A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

13. The compound has the formula (II): 【Chemistry 7】 During the ceremony, Y is N or CH; Ring A is -L'-3 to 7-membered heterocyclyl and has 1, 2, 3, 4, 5, 6, 7, or 8 R 5 may be optionally substituted with; wherein L' is selected from a chemical bond or -NH-CH2-; R 5 H, halogen, oxo, C 1-6 Alkyl, C 1-6 haloalkyl, or -NR'R''; or two R 5 are combined and become one -C 1-4 may form alkylene-; R' and R'' are each independently H, C 1-6 Alkyl, or C 1-6 haloalkyl; or R', R'' and the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R a But H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -LC 3-7 Cycloalkyl, -L-3 to 7-membered heterocyclyl, -LC 6-10 aryl, or -L-5 to 10 membered heteroaryl; where L is a chemical bond, or -C 1-6 alkylene- selected from; R 2 But H or C 1-6 is alkyl; R 3 is Et, or iPr; and R 4 But H or C 1-6 is alkyl, A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

14. The compound has the formula (II): 【Chemistry 8】 During the ceremony, Y is N or CH; Ring A is 【Chemistry 9】 and; where Z is O or NR 51 and; R 51 ~R 59 are each independently H or C 1-6 alkyl; or R 51 ~R 59 Two of them are combined to form -C 1-4 may form alkylene-; R a But C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or -LC 3-7 is cycloalkyl; where L is a chemical bond, or -C 1-6 alkylene- selected from; R 2 But H or C 1-6 is alkyl; R 3 is Et, or iPr; and R 4 But H or C 1-6 is alkyl, A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

15. The compound of claim 1, wherein the compound has the formula (II): 【Chemistry 10】 During the ceremony, Y is N or CH; Ring A is 【Chemistry 11】 and; R a But, Me, Et, iPr, 【Chemistry 12】 and; R 2 is H, or Me; R 3 is Et, or iPr; R 4 is H or Me, A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

16. The compound is 【Chemistry 13】 【Chemistry 14】 10. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof, selected from the group consisting of:

17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof; and a pharmaceutically acceptable excipient; and A pharmaceutical composition optionally containing one or more other therapeutic agents.

18. a first container comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof; and Optionally, a second container containing one or more other therapeutic agents; and Optionally, a third container containing a pharmaceutically acceptable excipient for diluting or suspending the compound and / or other therapeutic agent. A kit consisting of:

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof, for use in the treatment and / or prevention of a disease mediated by FLT3.

20. 20. The pharmaceutical composition of claim 19, wherein the FLT3-mediated disease includes cell proliferative disorders including, but not limited to, leukemia, myeloma, myeloproliferative disorders, myelodysplastic syndromes, idiopathic hypereosinophilic syndrome (HES), bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, salivary gland cancer, small cell lung cancer, skin cancer, gastric cancer, testicular cancer, thyroid cancer, uterine cancer, and hematological malignancies.

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