1h-imidazo [4, 5-h] quinazoline compounds as novel selective FLT3 inhibitors

Abstract

The present application provides 1H-imidazo [4, 5-h] quinazoline compounds of formula (I). The compound is a broad-spectrum inhibitor with strong activity on FLT3 kinase, and is suitable for treating cell proliferative disorders. (I)

Description

[0001] This application is a divisional application of a Chinese patent application (Filing date: August 27, 2021; Application No. 202180051993.3 (International Application No. PCT / CN2021 / 114930); Invention name: 1H-Imidazo[4,5-h]quinazoline Compounds as Novel Selective FLT3 Inhibitors). TECHNICAL FIELD

[0002] The present disclosure relates to 1H-imidazo[4,5-h]quinazoline compounds having biological activities of inhibiting cell proliferation, modulating serine-threonine protein kinase activity, and modulating tyrosine kinase activity. More specifically, the present disclosure provides 1H-imidazo[4,5-h]quinazoline compounds as novel selective Flt3 kinase inhibitors, which are pan-inhibitors of Flt3 and its mutants, and are effective in treating cell proliferative disorders associated with Flt3 and its mutants. BACKGROUND

[0003] Leukemia is a broad term for cancers of the blood cells. The type of leukemia depends on the type of blood cell that becomes cancerous and whether it is fast or slow growing. Leukemia most often occurs 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 form of acute leukemia in adults and the second most common leukemia in children. AML is characterized by the malignant transformation of hematopoietic stem / progenitor cells (HSCs). This occurs after acquisition of a somatic driver mutation that cooperates with accumulated passenger mutations, or coincidentally after acquisition of the driver mutation. The malignant precursor cells accumulate in the bone marrow and blood at the expense of healthy blood cells, leading to acute symptoms including anemia, bleeding and bruising, infection, and bone pain.

[0004] One kinase family of particular interest in AML is FLT3 (FMS-related tyrosine kinase 3). FLT3 is a transmembrane protein consisting of four domains; an extracellular ligand-binding domain consisting of 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 at the level described in 70-100% of AML cases and a high percentage of T acute lymphoblastic leukemia (ALL) cases (Griffin J D, et al. Haematol J. 2004; 5:188-190). It is also overexpressed in a smaller subset of blast phase chronic myeloid leukemia (CML).

[0005] There is increasing evidence that tyrosine kinase mutations are present in many types of leukemia and myeloproliferative syndromes. Two types of FLT3 activating mutations have been described in leukemia patients. These include a series of internal tandem duplications (ITD) that occur within the autoinhibitory juxtamembrane domain (Nakao M, et al. Leukemia 1996; 10:1911-1918; Thiede C, et al. Blood 2002; 99:4326-4335) and activating loop mutations 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 F M, et al. Br. J. Haematol. 2001; 113:983-988). Internal tandem duplication (ITD) mutations within the JM domain account for about 17-34% of FLT3 activating mutations in AML.

[0006] Due to the adverse significance and high frequency of FLT3, several FLT3 tyrosine kinase inhibitors have been developed. These inhibitors act by competitively inhibiting the interaction with adenosine triphosphate on the TK domain, resulting in a decrease in autophosphorylation and its consecutive activation. First generation FLT3 inhibitors, including tandutinib, sorafenib, midostaurin, lestaurtinib, SU11248, SU5614, and SU5416, are relatively non-specific for FLT3, often inhibiting other class III RTKs, such as KIT and PDGFR. Second generation FLT3 inhibitors, including quizartinib, crenolanib, ponatinib, pacritinib, and gilteritinib, are more potent and more selective.

[0007] However, the therapeutic benefits of FLT3 inhibition, particularly as monotherapy, often lead to the development of treatment resistance and disease recurrence. In addition, off-target inhibition can be associated with increased toxicity and modest clinical benefit. Thus, the need for developing novel potent and selective FLT3 inhibitors remains unmet. SUMMARY

[0008] The present disclosure provides 1H-imidazo[4,5-h]quinazoline compounds as selective inhibitors of Flt3 tyrosine kinase and mutants thereof, such as ITD, D835Y, and F691L. The compounds disclosed herein are effective in treating cell proliferative disorders associated with Flt3 and mutants thereof.

[0009] In one aspect, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof:

[0010] (I)

[0011] wherein:

[0012] Y is N, or CR6;

[0013] wherein R6is H, -OR a , -SR a , -NR b R c , -C(O)R a , -C(O)OR a , -C(O)NR b R c , -O-C(O)R a , -O-C(O)OR a , -O-C(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 Halogenated alkyl groups;

[0014] 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 ;

[0015] Where R a For 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 heterocyclic groups, -LC 6-10 Aryl, or -L-5 to 10-membered heteroaryl;

[0016] R b For 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 heterocyclic groups, -LC 6-10 Aryl, or -L-5 to 10-membered heteroaryl;

[0017] R c For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-7cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6-10 aryl, or -L-5- to 10-membered heteroaryl;

[0018] 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;

[0019] wherein L is selected from a bond, -C 1-6 alkylene-, -C 2-6 alkenylene-, or -C 2-6 alkynylene-;

[0020] Ring A is -L’-3- to 11-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0021] wherein L’ is selected from a bond, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0022] R5is H, halo, oxo, -OR, -SR-, -NR’R”, C 1-6 alkyl, or C 1-6 haloalkyl; alternatively, two R5may be joined together to form -C 1-4 alkylene-, -C 2-4 alkenylene-, or -C 2-4 alkynylene-;

[0023] 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; alternatively, 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;

[0024] R1is H, halo, -CN, -OR a , -SR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;

[0025] R2is H, halo, -CN, -OR a , -SR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;

[0026] R3is 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

[0027] R4is H, halogen, -CN, -OR a , -SR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl.

[0028] In another aspect, the present disclosure provides a pharmaceutical composition containing a compound of the present disclosure, and optionally a pharmaceutically acceptable excipient.

[0029] In another aspect, the present disclosure provides a pharmaceutical composition containing a compound of the present disclosure and a pharmaceutically acceptable excipient, further containing another therapeutic agent.

[0030] In another aspect, the present disclosure provides a kit comprising a compound of the present disclosure, and another therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0031] In another aspect, the present disclosure provides use of a compound of the present disclosure in the manufacture of a medicament for treating and / or preventing a Flt3-mediated disease.

[0032] In another aspect, the present disclosure provides a method of treating and / or preventing a Flt3-mediated disease in a subject, comprising administering to the subject a compound of the present disclosure or a composition of the present disclosure.

[0033] 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 Flt3-mediated disease.

[0034] In another aspect, the Flt3-mediated disease is a proliferative disease selected from the group consisting of leukemia, myeloma, myeloproliferative disease, myelodysplastic syndrome, 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, renal cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and hematological malignancy.

[0035] Other objects and advantages of the present disclosure will be clear to a person skilled in the art from the detailed embodiments, examples, and claims disclosed herein.

[0036] Definitions

[0037] Chemical Definitions

[0038] The definitions of specific functional groups and chemical terms are described in more detail below.

[0039] When a range of values is listed, it is intended to include each value and sub-range within the range. For example, "C 1-6 "Alkyl" includes 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 C 5-6 alkyl groups.

[0040] It should be understood that when described herein, any of the moieties defined below can be substituted on any of the available carbons and non-substituted moieties are intended to include the substituted moieties as described below. Unless otherwise specified, the term "substituted" means that any of the groups described below can be substituted for a hydrogen on the indicated atom or group.

[0041] "C 1-6 Alkyl" means a straight or branched chain saturated monovalent alkyl (hydrocarbon) group containing from 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl groups are preferred. Typical C 1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, and the like. The term "C 1-6 alkyl" also includes heteroalkyl groups in which 1 to 3 atoms selected from O, S, N, or substituted nitrogen atoms can replace carbon atoms. The alkyl group can be substituted at any available attachment point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0042] "C 2-6 Alkenyl" means a straight or branched chain hydrocarbon group having from 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 groups are preferred. The term "C 2-6"Alkenyl" also includes heteroalkenyl groups wherein one to three atoms selected from O, S, N, or substituted nitrogen atoms can replace a carbon atom. Alkenyl groups can be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0043] "C 2-6 "Aryl" refers to an aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (i.e., phenyl) or multiple condensed rings (i.e., naphthyl) wherein the condensed rings are each aromatic ring systems. The aryl group can be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. 2-4 "Aryl" refers to an aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (i.e., phenyl) or multiple condensed rings (i.e., naphthyl) wherein the condensed rings are each aromatic ring systems. The aryl group can be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. 2-6 "Aryl" refers to an aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (i.e., phenyl) or multiple condensed rings (i.e., naphthyl) wherein the condensed rings are each aromatic ring systems. The aryl group can be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0044] "C 1-6 "Aryl" refers to an aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (i.e., phenyl) or multiple condensed rings (i.e., naphthyl) wherein the condensed rings are each aromatic ring systems. The aryl group can be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. 2-6 "Aryl" refers to an aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (i.e., phenyl) or multiple condensed rings (i.e., naphthyl) wherein the condensed rings are each aromatic ring systems. The aryl group can be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. 2-6 "Aryl" refers to an aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (i.e., phenyl) or multiple condensed rings (i.e., naphthyl) wherein the condensed rings are each aromatic ring systems. The aryl group can be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. 1-6 "Aryl" refers to an aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (i.e., phenyl) or multiple condensed rings (i.e., naphthyl) wherein the condensed rings are each aromatic ring systems. The aryl group can be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. 2-6 "Aryl" refers to an aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (i.e., phenyl) or multiple condensed rings (i.e., naphthyl) wherein the condensed rings are each aromatic ring systems. The aryl group can be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. 2-6 "Aryl" refers to an aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (i.e., phenyl) or multiple condensed rings (i.e., naphthyl) wherein the condensed rings are each aromatic ring systems. The aryl group can be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0045] "C 1-6 "Aryl" refers to an aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (i.e., phenyl) or multiple condensed rings (i.e., naphthyl) wherein the condensed rings are each aromatic ring systems. The aryl group can be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. 1-6 "Aryl" refers to an aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (i.e., phenyl) or multiple condensed rings (i.e., naphthyl) wherein the condensed rings are each aromatic ring systems. The aryl group can be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. 1-4 "Aryl" refers to an aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (i.e., phenyl) or multiple condensed rings (i.e., naphthyl) wherein the condensed rings are each aromatic ring systems. The aryl group can be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. 2-), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0046] “C 2-6 "Alkenyl" refers to the group that has been de-carbonied. 2-6 The alkenyl group is formed by adding one hydrogen atom to form a divalent alkenyl group, and can be either substituted or unsubstituted alkenyl groups. In some embodiments, C 2-4 Alkenyl groups are particularly preferred. Exemplary unsubstituted alkenyl groups include, but are not limited to, vinylidene (-CH=CH-) and propenylidene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenyl groups, such as alkenyl groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylidene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylidene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and so on.

[0047] “C 2-6 "Iso-ynyl" refers to the group that has the C group removed. 2-6 One hydrogen atom of the alkynyl group forms a divalent alkynyl group, and can be a substituted or unsubstituted alkynyl group. In some embodiments, C 2-4 The ethynyl group is particularly preferred. Exemplary ethynyl groups include, but are not limited to: ethynyl group (-C≡C-), substituted or unsubstituted propynyl group (-C≡CCH2-), etc.

[0048] "Halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0049] “C 1-6 "Halogenated alkyl" indicates the above "C" 1-6"Alkyl," which is substituted with one or more halo groups. Examples include mono-halo substitution, di-halo substitution, and poly-haloalkyl including per-halo generation. A single halo substituent can have one iodine, bromine, chlorine, or fluorine atom; two halo substituents can have two of a same halogen atom or a combination of halogen atoms; and multiple halo substituents can have two or more of the same halogen atoms or a combination of halogen atoms. Preferred haloalkyl examples include fluoro methyl, difluoro methyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. The haloalkyl group can be substituted at any available attachment point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0050] "C 3-7 "Cycloalkyl" refers to a non-aromatic hydrocarbon group having from 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-6 "Cycloalkyl" refers to a non-aromatic hydrocarbon group having from 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C 5-6 "Cycloalkyl" refers to a non-aromatic hydrocarbon group having from 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like.

[0051] "3- to 11-membered heterocyclyl" refers to a 3- to 11-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. In some embodiments, 3- to 9-membered heterocyclyl groups are preferred, which are 3- to 9-membered non-aromatic ring systems having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3- to 7-membered heterocyclyl groups are preferred, which are 3- to 7-membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, 3- to 6-membered heterocyclyl groups are preferred, which are 3- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 4- to 6-membered heterocyclyl groups are preferred, which are 4- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 5- to 6-membered heterocyclyl groups are more preferred, which are 5- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the above heterocyclyl ring is fused with one or more cycloalkyl rings, wherein the point of attachment is on the cycloalkyl ring, or with one or more aryl or heteroaryl rings, wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azepanyl, oxepanyl, and thiepanyl.Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl groups) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0052] 3- to 11-membered heterocyclyl also includes spiroheterocyclyl groups, i.e., groups in which two rings (e.g., a heterocyclyl and a carbocycloalkane) share one carbon atom, wherein at least one of the rings is a heterocyclyl group as defined above. More specifically, the spiroheterocyclyl group is a spirocycle 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, wherein at least one of the rings is a 4- to 6-membered heterocyclyl group as defined above, preferably a 4- to 6-membered heterocyclyl group containing 1, 2, or 3 O, N, or S heteroatoms, more preferably a 4- to 6-membered heterocyclyl group containing 1 N heteroatom. Specific spiroheterocyclyl groups include, but are not limited to:

[0053] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0054] Preferred examples of heterocyclic groups include: pyrrolinyl, imidazoalkyl, pyrazolyl, tetrahydropyranyl, dihydropyranyl, dihydrofuranyl, thiazoalkyl, dihydrothiazolyl, 2,3-dihydro-benzo[1,4]dioxyl, dihydroindolyl, isodihydroindene, dihydrobenzothiophene, dihydrobenzofuranyl, isobenzodihydropyranyl, benzodihydropyranyl, 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-triazol[3,4-a]isoquinoline, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxalkyl, 2,3-dihydro-1H-lk'-benzo[d]isoquinoline Thiazol-6-yl, 2,3-di-benzo[l,4]dioxinyl, dihydrobenzofuran, 2-oxazheptacyclopropyl-1-yl, 2-oxazheptacyclobutyl-1-yl, 2-oxazpyrrolidone-1-yl, 2-oxazheptacyclohexyl-1-yl, 2-oxazheptacyclo ... The compounds include alkyl, aziridine propane, aziridine butane, pyrrolidinyl, aziridine hexane, aziridine heptane, aziridine octane, aziridine nonane, aziridine decane, 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.

[0055] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system.

[0056] "5- to 10-membered heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which an above-described heteroaryl ring is fused with one or more cycloalkyl or heterocyclyl rings, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to designate the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0057] Preferred examples of heteroaryl groups include: pyrrole, 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-furanyl, 3-furan, etc., 2-thienyl, 3-thienyl, oxazolyl, isoxazolyl, oxazolyl (1,2,4-oxazolyl, 1,3,4-oxazolyl, 1,2,5-oxazolyl, thiazolyl, thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl).

[0058] "Oxyto" means =O.

[0059] Alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups, as defined herein, are optionally substituted groups. Generally, the term "substituted," whether or not preceded by the term "optional," means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is substituted by a permissible substituent, such as a substituent that, upon substitution, produces a stable compound, for example, a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reactions). Unless otherwise stated, a "substituted" group has substituents at one or more substituted positions of the group, and when more than one position is substituted in any given structure, the substituents at each position are the same or different. The term "substituted" includes substitution with all permissible substituents of an organic compound (any substituent described herein that results in the formation of a stable compound). For the purposes of this invention, a heteroatom, such as nitrogen, may have a hydrogen substituent and / or any suitable substituent described herein that satisfies the heteroatom's valence and results in the formation of a stable moiety.

[0060] Exemplary 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 , -NR bb 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, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0061] Or the two hydrogen-bearing groups on the carbon atom: =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 replace;

[0062] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0063] R bb Each is independently selected from: 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) cc)OR aa )2, -SO2R cc )2, -SO2R cc )2, -SO2R cc )2, -SO2R cc )2, -SO2R cc )2, -SO2R aa )2, -SO2R cc )2, -SO2R cc )2, -SO2R cc )2, -SO2R aa )2, -SO2R aa )2, -SO2R cc )2, -SO2R cc )2, -SO2R bb )2, -SO2R dd )2, -SO2R

[0064] R cc )2, -SO2R cc )2, -SO2R dd )2, -SO2R

[0065] R dd )2, -SO2R ee )2, -SO2R ff )2, -SO2R ff )2, -SO2R ff )2, -SO2R + X - )2, -SO2R ee )2, -SO2R ff )2, -SO2R ee )2, -SO2R ee )2, -SO2R ee )2, -SO2R ee )2, -SO2R ee )2, -SO2R ee )2, -SO2R ff )2, -SO2R ff )2, -SO2R)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)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents can be combined to form =O or =S;

[0066] R ee is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

[0067] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0068] R gg Each of these is 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(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -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 groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -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 groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 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 group, -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 ynyl, C3-C7 carbocyclic, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0069] Exemplary substituents on the nitrogen atom 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 -SO2Raa -C(=NR bb )R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2 cc -SO2N(R cc )2 cc -SO2OR aa -SOR cc -C(=S)N(R cc )2 cc -C(=S)SR aa -P(=O)2R aa -P(=O)(R cc )2 cc -P(=O)2N(R cc )2 dd -P(=O)(NR aa )2 bb cc dd

[0070] Other Definitions

[0071] The term "cancer" includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lip, tongue, mouth, pharynx, small intestine, colorectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, myeloid disorders, lymphoid disorders, Hodgkin's disease, hairy cells cancer, and leukemia.

[0072] The term "pharmaceutically acceptable salt" as used herein, represents those carboxylic acid salts, amino acid addition salts of the compounds of the disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without an undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, effective for their intended applications, including (where possible) the zwitterionic forms of the compounds of the disclosure. ​​​

[0073] The term "salt" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present disclosure. These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. The compounds of the present disclosure are basic in nature, and they are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for use in medicine, they are also useful in the preparation of the parent compound in accordance with the procedures of this disclosure, and many of them are used as intermediates in the purification of the parent compound. The acid addition salts of the base compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt. The free base form is regenerated by contacting the salt with base or treating it with an ion exchange resin. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base forms for present purposes.

[0074] A "subject" for administration includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) and / or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a bovine, a porcine, a equine, an ovine, a caprine, a rodent, a feline, and / or a canine. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0075] "Disease," "disorder," and "condition" are used interchangeably herein.

[0076] The term "treatment" as used herein includes an action that occurs while a subject has a particular disease, disorder, or condition, that reduces the severity of the disease, disorder, or condition, or retards or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), and also includes an action that occurs before a subject has a particular disease, disorder, or condition ("prophylactic treatment"), unless otherwise indicated.

[0077] Generally, an "effective amount" of a compound refers to an amount that is sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the present disclosure can vary depending on, e.g., the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0078] As used herein, unless otherwise indicated, 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 associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall prophylaxis or enhances the therapeutic efficacy of another therapeutic agent.

[0079] As used herein, unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0080] "Combination" and related terms mean simultaneous or sequential administration of a compound of the present disclosure and another therapeutic agent. For example, a compound of the present disclosure can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or administered simultaneously with another therapeutic agent in a single unit dosage form. DETAILED DESCRIPTION

[0081] As used herein, a "compound of the present disclosure" refers to a compound of Formula (I) or (II), a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof.

[0082] Compounds are generally described herein using standard nomenclature. For compounds with asymmetric centers, it is understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. In addition, unless otherwise indicated, all isomeric forms of the compounds of the present disclosure are encompassed that can exist due to the presence of carbon-carbon double bonds. One compound is not limited to any particular tautomer, but rather is intended to encompass all tautomers.

[0083] In one embodiment, the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof:

[0084] (I)

[0085] wherein:

[0086] Y is N, or CR6;

[0087] wherein R6is H, -OR a a b R c a a b R c a a b R c b a b a b b R c C 1-6 alkyl, or C 1-6 haloalkyl;

[0088] X is -OR a a b R c a a b R c a a b R c b a b a b b R c ;

[0089] wherein R a is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, -L-3 to 7-membered heterocyclyl, -L-C 6-10 aryl, or -L-5 to 10-membered heteroaryl; ​​​​​​​​​​​​​​​​​​​​​​​​​​​​

[0090] R b is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6-10 aryl, or -L-5- to 10-membered heteroaryl;

[0091] R c is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6-10 aryl, or -L-5- to 10-membered heteroaryl;

[0092] 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;

[0093] wherein L is selected from a bond, -C 1-6 alkylene-, -C 2-6 alkenylene-, or -C 2-6 alkynylene-;

[0094] Ring A is -L’-3- to 11-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0095] wherein L’ is selected from a bond, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0096] R5is H, halo, oxo, -OR, -SR-, -NR’R”, C 1-6 alkyl, or C 1-6 haloalkyl; alternatively, two R5may be joined together to form -C 1-4 alkylene-, -C 2-4 alkenylene-, or -C 2-4 alkynylene-;

[0097] 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; alternatively, 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;

[0098] R1is H, halogen, -CN, -OR a , -SR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;

[0099] R2is H, halogen, -CN, -OR a , -SR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;

[0100] R3is 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

[0101] R4is H, halogen, -CN, -OR a , -SR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl.

[0102] Y

[0103] In one specific embodiment, Y is N; in another specific embodiment, Y is CR6; in another specific embodiment, Y is CH.

[0104] X

[0105] In one specific embodiment, 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 -O-C(O)R a ; in another specific embodiment, X is -O-C(O)OR a; in another embodiment, X is -O-C(O)NR b R c ; in another embodiment, X is -N(R b )-C(O)R a ; in another embodiment, X is -N(R b )-C(O)OR a ; in another embodiment, X is -N(R b )-C(O)NR b R c .

[0106] In a more specific embodiment of X, R a is H; in another more specific embodiment of X, R a is C 1-6 alkyl; in another more specific embodiment of X, R a is C 1-6 haloalkyl; in another more specific embodiment of X, R a is C 2-6 alkenyl; in another more specific embodiment of X, R a is C 2-6 alkynyl; in another more specific embodiment of X, R a is -L-C 3-7 cycloalkyl; in another more specific embodiment of X, R a is -L-3 to 7 membered heterocyclyl; in another more specific embodiment of X, R a is -L-C 6-10 aryl; in another more specific embodiment of X, R a is -L-5 to 10 membered heteroaryl.

[0107] In a more specific embodiment of X, R b is H; in another more specific embodiment of X, R b is C 1-6 alkyl; in another more specific embodiment of X, R b is C 1-6 haloalkyl; in another more specific embodiment of X, R b is C 2-6 alkenyl; in another more specific embodiment of X, R b is C 2-6 alkynyl; in another more specific embodiment of X, R b is -L-C 3-7 cycloalkyl; in another more specific embodiment of X, R b-L-3- to 7-membered heterocyclyl; in another more specific embodiment of X, R b -L-C 6-10 aryl; in another more specific embodiment of X, R b -L-5- to 10-membered heteroaryl.

[0108] in a more specific embodiment of X, R c H; in another more specific embodiment of X, R c C 1-6 alkyl; in another more specific embodiment of X, R c C 1-6 haloalkyl; in another more specific embodiment of X, R c C 2-6 alkenyl; in another more specific embodiment of X, R c C 2-6 alkynyl; in another more specific embodiment of X, R c -L-C 3-7 cycloalkyl; in another more specific embodiment of X, R c -L-3- to 7-membered heterocyclyl; in another more specific embodiment of X, R c -L-C 6-10 aryl; in another more specific embodiment of X, R c -L-5- to 10-membered heteroaryl.

[0109] in a more specific embodiment of X, R b , R c and the N atom to which they are attached form a 3- to 7-membered heterocyclyl; in another more specific embodiment of X, R b , R c and the N atom to which they are attached form a 5- to 10-membered heteroaryl.

[0110] in a more specific embodiment of R a , R b or R c , L is a chemical bond; in a still more specific embodiment of R a , R b or R c , L is -C 1-6 alkylene-; in a still more specific embodiment of R a , R b or R c , L is -C 2-6 alkenylene-; in a still more specific embodiment of R a , R b or R cIn yet another more specific embodiment, L is -C 2-6 alkynylene-.

[0111] Ring A

[0112] In one 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.

[0113] In one more specific embodiment, Ring A is ; wherein Z is O, S, or NR5; R5is H, C 1-6 alkyl, or C 1-6 haloalkyl; alternatively, two R5may be joined together to form -C 1-4 alkylene-, -C 2-4 alkenylene-, or -C 2-4 alkynylene-; and m = 1, 2, 3, 4, 5, 6, 7, or 8.

[0114] In yet another more specific embodiment, Ring A is ; wherein Z: O, or NR 51 ; and R 51 to R 59 are H, or C 1-6 alkyl; alternatively, two of R 51 to R 59 may be joined together to form -C 1-4 alkylene-.

[0115] In yet another more specific embodiment, Ring A is , , , , , , , , , , , or ; preferably, Ring A is , , , , , , , , ,or .

[0116] In one embodiment, ring A is not substituted; in another embodiment, ring A is substituted with one R5 group; in another embodiment, ring A is substituted with two R5 groups; in another embodiment, ring A is substituted with three R5 groups; in another embodiment, ring A is substituted with four R5 groups; in another embodiment, ring A is substituted with five R5 groups; in another embodiment, ring A is substituted with six R5 groups; in another embodiment, ring A is substituted with seven R5 groups; in another embodiment, ring A is substituted with eight R5 groups.

[0117] In one specific embodiment of ring A, R5 is H; in another specific embodiment of ring A, R5 is halogenated; in another specific embodiment of ring A, R5 is oxidized; 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 Alkyl; in another specific embodiment of cycloa, R5 is C 1-6 Halogenated alkyl group; in another specific embodiment of ring A, the two R5s can be linked together to form -C. 1-4 Alkylene; in another specific embodiment of cyclic A, the two R5s can be linked together to form -C 2-4 alkenyl-; in another specific embodiment of cycloa, two R5s can be linked together to form -C 2-4 Ethyne-.

[0118] R1

[0119] In one specific embodiment, R1 is H; in another specific embodiment, R1 is a halogen; in yet another specific embodiment, R1 is -CN; in yet another specific embodiment, R1 is -OR a In another specific implementation, R1 is -SR a In another specific implementation, R1 is -NR b R c In another specific implementation, R1 is C 1-6 Alkyl; in another specific embodiment, R1 is C 1-6 Halogenated alkyl groups.

[0120] R2

[0121] In one specific embodiment, R2 is H; in another specific embodiment, R2 is a halogen; in yet another specific embodiment, R2 is -CN; in yet another specific embodiment, R2 is -OR a In another specific implementation, R2 is -SR a In another specific implementation, R2 is -NR b R c In another specific implementation, R2 is C 1-6 Alkyl; in another specific embodiment, R2 is C 1-6 Halogenated alkyl groups.

[0122] R3

[0123] In one specific implementation, R3 is C 1-6 Alkyl; in another specific embodiment, R3 is C 1-6 Halogenated alkyl; in another specific embodiment, R3 is C 3-7 Cycloalkyl; in another specific embodiment, R3 is a 3- to 7-membered heterocyclic group; in another specific embodiment, R3 is a C 6-10 Aryl; in another specific embodiment, R3 is a 5- to 10-membered heteroaryl group.

[0124] R4

[0125] In one specific embodiment, R4 is H; in another specific embodiment, R4 is a halogen; in yet another specific embodiment, R4 is -CN; in yet another specific embodiment, R4 is -OR a In another specific implementation, R4 is -SR a In another specific implementation, R4 is -NR b R c In another specific implementation, R4 is C. 1-6 Alkyl; in another specific embodiment, R4 is C 1-6 Halogenated alkyl groups.

[0126] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution of Y or any combination thereof can be combined with X, ring A, and R. 1、 R 2、 This disclosure is intended to include any combination of the technical solutions of R3 and R4, or any combination thereof. Due to space limitations, all such technical solutions are not listed individually.

[0127] In specific embodiments, this disclosure relates to compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, or mixtures thereof, wherein Y is N.

[0128] In specific embodiments, this disclosure relates to compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, or mixtures thereof, wherein,

[0129] 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 ;

[0130] Preferably, X is -OR a -SR a , or -NR b R c ;

[0131] Preferably, X is -OR a ;

[0132] Preferably, X is -NR b R c .

[0133] In specific embodiments, this disclosure relates to compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, or mixtures thereof, wherein,

[0134] R a For 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 Aryl; and

[0135] Where L is selected from chemical bonds, or -C 1-6 alkylene-;

[0136] Preferably,

[0137] R a C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, or -LC 3-7 cycloalkyl; and

[0138] Where L is selected from chemical bonds, or -C 1-6 Alkylene-.

[0139] In specific embodiments, this disclosure relates to compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, or mixtures thereof, wherein,

[0140] R b For 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 Aryl;

[0141] R c For 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 Aryl;

[0142] or R b R c And the N atoms connected to them form 3- to 7-membered heterocyclic groups, or 5- to 10-membered heteroaryl groups; and

[0143] Where L is selected from chemical bonds, or -C 1-6 alkylene-;

[0144] Preferably,

[0145] R b For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, or -LC 3-7 cycloalkyl;

[0146] R c For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, or -LC 3-7 cycloalkyl;

[0147] or R bR c and the N atom to which they are attached forms a 3- to 7-membered heterocyclyl; and

[0148] wherein L is selected from a bond, or -C 1-6 alkylene-;

[0149] Preferably,

[0150] R b is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0151] R c is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0152] or R b , R c and the N atom to which they are attached forms a 4- to 6-membered heterocyclyl.

[0153] In particular embodiments, the present disclosure relates to a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate thereof, or a mixture thereof, wherein,

[0154] Ring A is -L'-3- to 7-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0155] wherein L' is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0156] R5is H, halo, oxo, -OR, -SR-, -NR'R", C 1-6 alkyl, or C 1-6 haloalkyl; alternatively, two R5may be joined together to form -C 1-4 alkylene-, -C 2-4 alkenylene-, or -C 2-4 alkynylene-; and

[0157] 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;

[0158] Preferably,

[0159] Ring A is -L'-4- to 6-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0160] wherein L' is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0161] R5is H, oxo, -OR, -NR'R", C 1-6 alkyl, or C 1-6 haloalkyl; or, two R5may be joined together to form a -C 1-4 alkylene-; and

[0162] 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;

[0163] Preferably,

[0164] Ring A is -L'-4- to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0165] wherein L' is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0166] R5is H, oxo, -OR, -NR'R", or C 1-6 alkyl; or, two R5may be joined together to form a -C 1-4 alkylene-; and

[0167] 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;

[0168] Preferably,

[0169] Ring A is ;

[0170] wherein Z is O, S, or NR5;

[0171] R5is H, C 1-6 alkyl, or C 1-6 haloalkyl; or, two R5may be joined together to form a -C 1-4 alkylene-, -C 2-4 alkenylene-, or -C 2-4 alkynylene-;

[0172] m = 1, 2, 3, 4, 5, 6, 7, or 8;

[0173] Preferably,

[0174] Ring A is ;

[0175] wherein Z is O, or NR 51 ;

[0176] R 51 to R 59 is H, or C 1-6 alkyl; alternatively, R 51 to R 59 two of which can be linked together to form -C 1-4 alkylene-;

[0177] Preferably,

[0178] Ring A is , , , , , , , , , , , or ;

[0179] Preferably,

[0180] Ring A is , , , , , , , , , or .

[0181] In particular embodiments, the present disclosure relates to a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0182] R1is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0183] Preferably, R1is H.

[0184] In particular embodiments, the present disclosure relates to a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0185] R2is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0186] Preferably, R2is H.

[0187] In particular embodiments, the present disclosure relates to a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0188] R3is C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3- to 7-membered heterocyclyl;

[0189] Preferably, R3is C 1-6 alkyl, or C 1-6 haloalkyl;

[0190] Preferably, R3is C 1-6 alkyl;

[0191] Preferably, R3is Et or iPr.

[0192] In particular embodiments, the present disclosure relates to a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0193] R4is H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0194] Preferably, R4is H.

[0195] In particular embodiments, the present disclosure relates to a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0196] Y is N, or CR6;

[0197] wherein R6is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0198] X is -OR a , -SR a , or -NR b R c ;

[0199] wherein R a is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6-10 aryl, or -L-5- to 10-membered heteroaryl;

[0200] R b is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0201] R c is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0202] 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;

[0203] wherein L is selected from a bond, -C 1-6 alkylene-, -C 2-6 alkenylene-, or -C 2-6 alkynylene-;

[0204] Ring A is -L’-3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0205] wherein L’ is selected from a bond, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0206] R5is H, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, -OR, -SR-, or -NR’R’’; alternatively, two R5may be joined together to form -C 1-4 alkylene-, -C 2-4 alkenylene-, or -C 2-4 alkynylene-;

[0207] R, R’, and R’’ are each independently H, C 1-6 alkyl, or C 1-6 haloalkyl; alternatively, 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;

[0208] R1is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0209] R2is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0210] R3is C 1-6 alkyl, or C 1-6 haloalkyl; and

[0211] R4is H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0212] In particular embodiments, the present disclosure relates to a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0213] Y is N, or CR6;

[0214] wherein R6is H, or C 1-6 alkyl;

[0215] X is -OR a , or -NR b R c ;

[0216] wherein R a is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, or -L-C 6-10 aryl;

[0217] R b is H, or C 1-6 alkyl;

[0218] R c is H, or C 1-6 alkyl;

[0219] or R b , R c and the N atom to which they are attached form a 4- to 6-membered heterocyclyl;

[0220] wherein L is selected from a bond, or -C 1-6 alkylene-;

[0221] Ring A is -L’-4- to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0222] wherein L’ is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0223] R5is H, oxo, C 1-6 alkyl, -OR, or -NR’R’’; alternatively, two R5may be joined together to form -C 1-4 alkylene-;

[0224] R, R’ and R’’ are each independently H, or C1-6 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;

[0225] R1is H, or C 1-6 alkyl;

[0226] R2is H, or C 1-6 alkyl;

[0227] R3is C 1-6 alkyl; and

[0228] R4is H, or C 1-6 alkyl.

[0229] In particular embodiments, the present disclosure relates to compounds of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0230] Y is N, or CH;

[0231] X is -OR a , or -NR b R c ;

[0232] wherein R a is Me, Et, iPr, , , , or ;

[0233] R b is H, Me;

[0234] R c is H, Me;

[0235] or R b , R c and the N atom to which they are attached form ;

[0236] Ring A is , , , , , , , , , , , or ;

[0237] R1is H, or Me;

[0238] R2is H, or Me;

[0239] R3is Me, Et, or iPr; and

[0240] R4is H, or Me.

[0241] In particular embodiments, the present disclosure relates to a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, which is a compound of formula (II):

[0242] (II)

[0243] Y is N, or CH;

[0244] Ring A is -L’-3 to 7 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0245] wherein L’ is selected from a bond, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0246] R5is H, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, -OR, -SR-, or -NR’R’’; or, two R5may be joined together to form -C 1-4 alkylene-, -C 2-4 alkenylene-, or -C 2-4 alkynylene-;

[0247] 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;

[0248] R a is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, -L-3 to 7 membered heterocyclyl, -L-C 6-10 aryl, or -L-5 to 10 membered heteroaryl;

[0249] wherein L is selected from a bond, -C 1-6 alkylene-, -C 2-6 alkenylene-, or -C 2-6 alkynylene-;

[0250] R2is H, C1-6 alkyl, or C 1-6 haloalkyl;

[0251] R3 is Et, or iPr; and

[0252] R4 is H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0253] In one embodiment, the disclosure relates to a compound of Formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0254] Y is N, or CH;

[0255] Ring A is -L'-4- to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0256] L' is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0257] R5 is H, oxo, C 1-6 alkyl, -OR, or -NR'R"; or, two R5 can be joined together to form -C 1-4 alkylene-;

[0258] 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;

[0259] R a is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, or -L-C 6-10 aryl;

[0260] wherein L is selected from a bond, or -C 1-6 alkylene-;

[0261] R2 is H, or C 1-6 alkyl;

[0262] R3 is Et, or iPr; and

[0263] R4 is H, or C 1-6 alkyl.

[0264] In one embodiment, the present disclosure relates to a compound of Formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein:

[0265] Y is N, or CH;

[0266] Ring A is , , , , , , , , , , or ;

[0267] R a is Me, Et, iPr, , , , or ;

[0268] R2is H, or Me;

[0269] R3is Et, or iPr; and

[0270] R4is H, or Me.

[0271] In one embodiment, the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, which is a compound of Formula (II):

[0272] (II)

[0273] wherein:

[0274] Y is N, or CH;

[0275] Ring A is ;

[0276] wherein Z is O, S, or NR5;

[0277] R5is H, C 1-6 alkyl, or C 1-6 haloalkyl; or, two R5may be joined together to form -C 1-4 alkylene-, -C 2-4 alkenylene-, or -C 2-4 alkynylene-;

[0278] m = 1, 2, 3, 4, 5, 6, 7, or 8;

[0279] R a is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, or -L-3- to 7-membered heterocyclyl;

[0280] wherein L is selected from a bond, -C 1-6 alkylene-, -C 2-6 alkenylene-, or -C 2-6 alkynylene-;

[0281] R2is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0282] R3is Et, or iPr; and

[0283] R4is H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0284] In one embodiment, the disclosure relates to a compound of Formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0285] Y is N, or CH;

[0286] Ring A is ;

[0287] wherein Z is O, or NR 51 ;

[0288] R 51 through R 59 are each independently H, or C 1-6 alkyl; alternatively, two of R 51 through R 59 may be linked together to form -C 1-4 alkylene-;

[0289] R a is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or -L-C 3-7 cycloalkyl;

[0290] wherein L is selected from a bond, or -C 1-6 alkylene-;

[0291] R2is H, or C 1-6 alkyl;

[0292] R3is Et, or iPr; and

[0293] R4is H, or C 1-6 alkyl.

[0294] In one embodiment, the disclosure relates to a compound of Formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0295] Y is N, or CH;

[0296] Ring A is , , , , , , , , , or ;

[0297] R a is Me, Et, iPr, , , or ;

[0298] R2is H, or Me;

[0299] R3is Et, or iPr;

[0300] R4is H, or Me.

[0301] In one embodiment, the disclosure relates to a compound disclosed herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein the compound is selected from:

[0302] , , , , , , , , , , , , , , , , , , , , , and .

[0303] The compounds of the present disclosure can include one or more asymmetric centers and can thus occur as various stereoisomeric forms, such as enantiomeric and / or diastereomeric forms. For example, the compounds of the present disclosure can be individual enantiomers, diastereomers or geometric isomers (e.g., cis- and trans-isomers), or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or the preferred isomer can be prepared by asymmetric synthesis.

[0304] Pharmaceutical compositions, formulations, and kits

[0305] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure (also referred to as the “active ingredient”) and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present disclosure.

[0306] Pharmaceutically acceptable excipients for use in the present disclosure refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound with which they are co-administered. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silicic acid, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0307] The present disclosure also includes kits (e.g., pharmaceutical packs). The kits provided can include a compound of the present disclosure, other therapeutic agents, and first and second containers (e.g., vials, ampules, bottles, syringes, and / or dispersable packets or other suitable containers) containing the compound of the present disclosure, other therapeutic agents. In some embodiments, the kits provided can also optionally include a third container with a pharmaceutically-acceptable excipient for diluting or suspending the compound of the present disclosure and / or other therapeutic agents. In some embodiments, the combination of the compound of the present disclosure and other therapeutic agents provided in the first and second containers form a single unit dosage form.

[0308] Dosing

[0309] The pharmaceutical compositions provided by the present disclosure can be administered by a variety of routes including, but not limited to: oral administration, parenteral administration, inhalation, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration, administration via an implant, or other modes of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0310] Generally, an effective amount of a compound provided herein is administered. The amount of a compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0311] When used to prevent a condition described by the present disclosure, a compound provided herein is administered to a subject at risk of developing the condition, typically on the advice and under the supervision of a doctor, at a dosage level as described above. Subjects at risk of developing a particular condition include, generally, those who have a family history of the condition, or those who, through genetic testing or screening, are determined to be particularly susceptible to developing the condition.

[0312] A pharmaceutical composition provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to the administration of a compound or a pharmaceutical composition thereof over an extended period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, and so on, or can continue indefinitely, for example, for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood, for example, within a therapeutic window, over an extended period of time.

[0313] Various methods of administration can be used to further deliver the pharmaceutical compositions of the present disclosure. For example, in some embodiments, the pharmaceutical compositions can be administered as a bolus, e.g., to raise the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active component through the body, e.g., an intramuscular or subcutaneous bolus dose releases the active component slowly, while a bolus delivered directly to a vein, e.g., by IV infusion, can deliver more rapidly, such that the concentration of the active component in the blood rises quickly to an effective level. In other embodiments, the pharmaceutical compositions can be administered as a continuous infusion, e.g., by IV infusion, to provide a steady state concentration of the active component in the body of the subject. Further, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0314] Oral compositions can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage form, e.g., in ampules of pre-measured amounts. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-measured ampules or syringes of liquid compositions, or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is typically the minor component, present in amounts of, e.g., from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight, with the remainder being various carriers or excipients and processing aids useful in forming the desired dosing form.

[0315] For oral dosage, a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. With these dosing modes, each dose provides about 0.01 to about 20 mg / kg of the compound of the present disclosure, with preferred doses providing from about 0.1 to about 10 mg / kg, especially from about 1 to about 5 mg / kg, per dose.

[0316] To provide blood levels similar to, or lower than, those achieved using injectable doses, transdermal doses are typically selected in amounts of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

[0317] Dosage levels from about 1 to about 120 hours, especially 24 to 96 hours, of from about 0.1 mg / kg / hr to at least 10 mg / kg / hr can be injected. To obtain sufficient steady state levels, a preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more can also be administered. The maximum total dose for a 40 to 80 kg human patient should not exceed about 2 g / day.

[0318] Liquid forms suitable for oral administration can include a suitable aqueous or nonaqueous vehicle with buffers, suspending agents and dispensing agents, colorants, flavorants and the like. Solid forms can include, for example, any of the following ingredients, or compounds of similar nature: a binder such as, for example, microcrystalline cellulose, gum tragacanth or gelatin; an excipient, such as, for example, starch or lactose, a disintegrating agent, such as, for example, alginic acid, Primogel, or corn starch; a lubricant, such as, for example, magnesium stearate; a glidant, such as, for example, colloidal silicon dioxide; a sweetening agent, such as, for example, sucrose or saccharin; or a flavoring agent, such as, for example, peppermint, methyl salicylate, or orange flavoring.

[0319] Injectable compositions will typically be based upon sterile saline or phosphate buffered saline for injection, or other injectable vehicles known in the art. As before, the active compound will typically be the minor component in such compositions, generally ranging from about 0.05 to 10% by weight, with the remainder being the injectable carrier or the like.

[0320] Transdermal compositions will typically be formulated to contain active ingredients in a mixture with a penetrant, such as, for example, a local ointment or cream. When formulated as an ointment, the active ingredient will typically be combined with a petrolatum or water miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include additional components to enhance penetration of the active ingredient or formulation through the skin. All such known transdermal formulations and components are contemplated to be within the scope of the present disclosure.

[0321] The compounds of the present disclosure can also be administered transdermally via a transdermal patch. Thus, transdermal delivery can be achieved using a reservoir or porous matrix-type patch, or a variety of solid matrixes.

[0322] The above-mentioned components for the compositions to be orally administered, injected or topically administered are merely representative. Other materials and processing techniques can be found in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0323] The disclosed compounds can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[0324] This disclosure also relates to pharmaceutically acceptable formulations of the compounds of this disclosure. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfonyl ether-substituted groups. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0325] treat

[0326] This disclosure provides methods for treating the following disorders or conditions in mammals (including humans): cell proliferation disorders, such as cancer, vascular smooth muscle hyperplasia associated with atherosclerosis, postoperative vascular stenosis, restenosis, and endometriosis; infections, including viral infections, such as DNA viruses like herpes and RNA viruses like HIV, and fungal infections; autoimmune diseases, such as psoriasis, inflammations such as rheumatoid arthritis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, and glomerulonephritis; and organ transplant rejection, including host disease of the transplant, wherein the method comprises administering a therapeutically effective amount of the disclosed compound or a combination thereof to the mammal.

[0327] This disclosure further provides compounds of this disclosure that can be used to treat abnormal cell proliferation, such as cancer. This disclosure further provides a method for treating abnormal cell proliferation, such as cancers selected from the following: cancers of the breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lips, tongue, oral cavity, pharynx, small intestine, colorectal, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorders, lymphatic disorders, Hodgkin's disease, pilonidal carcinoma, and leukemia, the method comprising administering a therapeutically effective amount of the disclosed compound or a combination thereof to a subject in need of such treatment.

[0328] Further, the present disclosure relates to methods of treating a subject suffering from a disease caused by vascular smooth muscle cell proliferation. The compounds of the present disclosure are effective in inhibiting the proliferation and migration of vascular smooth muscle cells. The methods include administering to a subject in need of treatment a compound of the present disclosure or a composition thereof in an amount sufficient to inhibit vascular smooth muscle proliferation and / or migration.

[0329] The present disclosure further provides methods of treating a subject suffering from gout comprising administering to said subject in need of treatment a compound of the present disclosure or a composition thereof in an amount sufficient to treat the condition.

[0330] The present disclosure further provides methods of treating a subject suffering from a kidney disease, such as polycystic kidney disease, comprising administering to said subject in need of treatment a compound of the present disclosure or a composition thereof in an amount sufficient to treat the condition.

[0331] Due to their inhibitory activity against Flt3 and other kinases, the compounds of the present disclosure are also useful research tools for studying the mechanism of action of these kinases in vitro and in vivo.

[0332] 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 utilize the compounds of the present disclosure in the treatment of cancer, a therapeutically effective amount of a pharmaceutically acceptable composition comprising at least one compound of the present disclosure is administered to a patient in need of such treatment, e.g., one suffering from cancer or another proliferative disease.

[0333] An effective amount of a compound of the present disclosure is typically in the range of 0.01 mg to 50 mg of compound per kilogram of patient body weight, preferably 0.1 mg to 25 mg of compound per kilogram of patient body weight, in single or divided doses. Typically, a compound of the present disclosure can be administered to such a patient in need thereof at a daily dose in the range of about 1 mg to about 3500 mg per patient, preferably 10 mg to 1000 mg per patient. For example, the daily dose per patient can 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 administration can be one or more times per day, per week (or at intervals of days), or on an intermittent schedule. For example, the compound can be administered one or more times per day, on an indefinite or continuous basis for a period of weeks, e.g., 4-10 weeks, e.g., on a weekly basis (e.g., on Mondays). Alternatively, the compound can be administered daily for a period of days (e.g., 2-10 days), followed by a period of days (e.g., 1-30 days) without administration of the compound, the cycle being repeated indefinitely or for a given number of times, e.g., 4-10 cycles. For example, a compound of the present disclosure can be administered daily for 5 days, followed by 9 days of discontinuance, followed by 5 days of daily administration, followed by 9 days of discontinuance, and so on, the cycle being repeated indefinitely or for 4-10 times in total.

[0334] The present application has the following specific embodiments:

[0335] 1. A compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof:

[0336] (I)

[0337] wherein:

[0338] Y is N, or CR6;

[0339] wherein R6is H, -OR a , -SR a , -NR b R c , -C(O)R a , -C(O)OR a , -C(O)NR b R c , -O-C(O)R a , -O-C(O)OR a , -O-C(O)NR b R c , -N(R b )-C(O)R a , -N(R b )-C(O)ORa , -N(R b )-C(O)NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;

[0340] X is -OR a , -SR a , -NR b R c , -C(O)R a , -C(O)OR a , -C(O)NR b R c , -O-C(O)R a , -O-C(O)OR a , -O-C(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 ;

[0341] wherein R a is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6-10 aryl, or -L-5- to 10-membered heteroaryl;

[0342] R b is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6-10 aryl, or -L-5- to 10-membered heteroaryl;

[0343] R c is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C6-10 aryl, or -L-5- to 10-membered heteroaryl;

[0344] or R b , R c and the N atom to which they are attached form a 3- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl;

[0345] wherein L is selected from a bond, -C 1-6 alkylene-, -C 2-6 alkenylene-, or -C 2-6 alkynylene-;

[0346] Ring A is -L’-3- to 11-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0347] wherein L’ is selected from a bond, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0348] R5is H, halo, oxo, -OR, -SR-, -NR’R”, C 1-6 alkyl, or C 1-6 haloalkyl; alternatively, two R5may be joined together to form -C 1-4 alkylene-, -C 2-4 alkenylene-, or -C 2-4 alkynylene-;

[0349] 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; alternatively, R’, R”, and the N atom to which they are attached form a 3- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl;

[0350] R1is H, halo, -CN, -OR a , -SR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;

[0351] R2is H, halo, -CN, -OR a , -SR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;

[0352] R3is C1-6 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

[0353] R4is H, halogen, -CN, -OR a , -SR a , -NR b R c , -C(O)R 1-6 , -C(O)OR 1-6 , -C(O)NR a R a , -O-C(O)R b , or -N(R c )-C(O)R a ;

[0354] 2. The compound of Formula (I) according to embodiment 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof, wherein Y is N.

[0355] 3. The compound of Formula (I) according to embodiment 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof, wherein,

[0356] X is -OR a , -SR a , -NR b R c , -C(O)R a , -C(O)OR a , -C(O)NR b R c , -O-C(O)R a , or -N(R b )-C(O)R a ;

[0357] Preferably, X is -OR a , -SR a , or -NR b R c ;

[0358] Preferably, X is -OR a ;

[0359] Preferably, X is -NR b R c .

[0360] 4. The compound of Formula (I) according to embodiment 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof, wherein,

[0361] R a is H, C 1-6 alkyl, C 1-6 haloalkyl, C2-6 alkenyl, C 2-6 alkynyl, -LC 3-7 cycloalkyl, or -LC 6-10 Aryl; and

[0362] Where L is selected from chemical bonds, or -C 1-6 alkylene-;

[0363] Preferably,

[0364] R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, or -LC 3-7 cycloalkyl; and

[0365] Where L is selected from chemical bonds, or -C 1-6 Alkylene-.

[0366] 5. A compound of formula (I) according to embodiment 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0367] R b For 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 Aryl;

[0368] R c For 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 Aryl;

[0369] or R b R c And the N atoms connected to them form 3- to 7-membered heterocyclic groups, or 5- to 10-membered heteroaryl groups; and

[0370] Where L is selected from chemical bonds, or -C 1-6 alkylene-;

[0371] Preferably,

[0372] R b For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 alkenyl, C 2-6 alkynyl, or -L-C 3-7 cycloalkyl;

[0373] R c is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or -L-C 3-7 cycloalkyl;

[0374] or R b , R c and the N atom to which they are attached form a 3- to 7-membered heterocyclyl; and

[0375] wherein L is selected from a bond, or -C 1-6 alkylene-;

[0376] Preferably,

[0377] R b is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0378] R c is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0379] or R b , R c and the N atom to which they are attached form a 4- to 6-membered heterocyclyl.

[0380] 6. The compound of Formula (I) of any one of embodiments 1-5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0381] Ring A is -L’-3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0382] wherein L’ is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0383] R5is H, halo, oxo, -OR, -SR-, -NR’R”, C 1-6 alkyl, or C 1-6 haloalkyl; alternatively, two R5may be joined together to form a -C 1-4 alkylene-, -C 2-4 alkenylene-, or -C 2-4 alkynylene-; and

[0384] 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;

[0385] Preferably,

[0386] Ring A is -L'-4- to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0387] wherein L' is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0388] R5is H, oxo, -OR, -NR'R", C 1-6 alkyl, or C 1-6 haloalkyl; or, two R5may be joined together to form a -C 1-4 alkylene-; and

[0389] 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;

[0390] Preferably,

[0391] Ring A is -L'-4- to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0392] wherein L' is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0393] R5is H, oxo, -OR, -NR'R", or C 1-6 alkyl; or, two R5may be joined together to form a -C 1-4 alkylene-; and

[0394] 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;

[0395] Preferably,

[0396] Ring A is ,

[0397] wherein Z is O, S, or NR5;

[0398] R5is H, C 1-6 alkyl, or C 1-6 haloalkyl; or, two R5may be joined together to form a -C 1-4 alkylene-, -C 2-4 alkenylene-, or -C 2-4 alkynylene-;

[0399] m = 1, 2, 3, 4, 5, 6, 7, or 8;

[0400] Preferably,

[0401] Ring A is ,

[0402] wherein Z: O, or NR 51 ;

[0403] R 51 to R 59 are H, or C 1-6 alkyl; or, R 51 to R 59 may be joined together to form a -C 1-4 alkylene-;

[0404] Preferably,

[0405] Ring A is , , , , , , , , , , , or ;

[0406] Preferably,

[0407] Ring A is , , , , , , , , , or .

[0408] 7. The compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, according to any one of embodiments 1-6, wherein,

[0409] R1is H, C 1-6 alkyl, or C1-6 haloalkyl;

[0410] Preferably, R1is H.

[0411] 8. The compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof, according to any one of embodiments 1-7, wherein,

[0412] R2is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0413] Preferably, R2is H.

[0414] 9. The compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof, according to any one of embodiments 1-8, wherein,

[0415] R3is C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3- to 7-membered heterocyclyl;

[0416] Preferably, R3is C 1-6 alkyl, or C 1-6 haloalkyl;

[0417] Preferably, R3is C 1-6 alkyl;

[0418] Preferably, R3is Et or iPr.

[0419] 10. The compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof, according to any one of embodiments 1-9, wherein,

[0420] R4is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0421] Preferably, R4is H.

[0422] 11. The compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof, according to any one of embodiments 1-9, wherein:

[0423] Y is N, or CR6;

[0424] wherein R6is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0425] X is -ORa , -SR a , or -NR b R c ;

[0426] wherein R a is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6-10 aryl, or -L-5- to 10-membered heteroaryl;

[0427] R b is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0428] R c is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0429] 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;

[0430] wherein L is selected from a bond, -C 1-6 alkylene-, -C 2-6 alkenylene-, or -C 2-6 alkynylene-;

[0431] Ring A is -L’-3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0432] wherein L’ is selected from a bond, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0433] R5is H, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, -OR, -SR-, or -NR’R’’; alternatively, two R5may be joined together to form -C 1-4 alkylene-, -C 2-4 alkenylene-, or -C 2-4 alkynylene-;

[0434] R, R’ and R’’ are each independently H, C 1-6 alkyl, or C 1-6haloalkyl; 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;

[0435] R1is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0436] R2is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0437] R3is C 1-6 alkyl, or C 1-6 haloalkyl; and

[0438] R4is H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0439] 12. The compound of Formula (I) according to embodiment 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof, wherein:

[0440] Y is N, or CR6;

[0441] wherein R6is H, or C 1-6 alkyl;

[0442] X is -OR a , or -NR b R c ;

[0443] wherein R a is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, or -L-C 6-10 aryl;

[0444] R b is H, or C 1-6 alkyl;

[0445] R c is H, or C 1-6 alkyl;

[0446] or R b , R c and the N atom to which they are attached form a 4- to 6-membered heterocyclyl;

[0447] wherein L is selected from a bond, or -C 1-6 alkylene-;

[0448] Ring A is -L'-4 to 6 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0449] wherein L' is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0450] R5is H, oxo, C 1-6 alkyl, -OR, or -NR'R"; or, two R5may be joined together to form a -C 1-4 alkylene-;

[0451] 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;

[0452] R1is H, or C 1-6 alkyl;

[0453] R2is H, or C 1-6 alkyl;

[0454] R3is C 1-6 alkyl; and

[0455] R4is H, or C 1-6 alkyl.

[0456] 13. The compound of Formula (I) according to embodiment 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein:

[0457] Y is N, or CH;

[0458] X is -OR a , or -NR b R c ;

[0459] wherein R a is Me, Et, iPr, , , , or ;

[0460] R b is H, Me;

[0461] R c is H, Me;

[0462] or R b , R c , and the N atom to which they are attached form ;

[0463] Ring A is , , , , , , , , , , , or ;

[0464] R1is H, or Me;

[0465] R2is H, or Me;

[0466] R3is Me, Et, or iPr; and

[0467] R4is H, or Me.

[0468] 14. The compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof, according to any one of embodiments 1-9, which is a compound of Formula (II):

[0469] (II)

[0470] Y is N, or CH;

[0471] Ring A is -L’-3 to 7 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0472] wherein L’ is selected from a bond, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0473] R5is H, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, -OR, -SR-, or -NR’R’’; or, two R5may be joined together to form -C 1-4 alkylene-, -C 2-4 alkenylene-, or -C 2-4 alkynylene-;

[0474] 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;

[0475] R a is H, C 1-6alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, -L-3 to 7 membered heterocyclyl, -L-C 6-10 aryl, or -L-5 to 10 membered heteroaryl;

[0476] wherein L is selected from a bond, -C 1-6 alkylene-, -C 2-6 alkenylene-, or -C 2-6 alkynylene-;

[0477] R2is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0478] R3is Et, or iPr; and

[0479] R4is H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0480] 15. The compound of Formula (II) according to Embodiment 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein:

[0481] Y is N, or CH;

[0482] Ring A is -L’-4 to 6 membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0483] L’ is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0484] R5is H, oxo, C 1-6 alkyl, -OR, or -NR’R’’; or, two R5may be joined together to form -C 1-4 alkylene-;

[0485] 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;

[0486] R a is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, or -L-C 6-10 aryl;

[0487] wherein L is selected from a chemical bond, or -C 1-6 alkylene-;

[0488] R2is H, or C 1-6 alkyl;

[0489] R3is Et, or iPr; and

[0490] R4is H, or C 1-6 alkyl.

[0491] 16. The compound of Formula (II) according to Embodiment 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein:

[0492] Y is N, or CH;

[0493] Ring A is , , , , , , , , , , , or ;

[0494] R a is Me, Et, iPr, , , , or ;

[0495] R2is H, or Me;

[0496] R3is Et, or iPr; and

[0497] R4is H, or Me.

[0498] 17. The compound of Formula (I) according to any one of Embodiments 1-9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, which is a compound of Formula (II):

[0499] (II)

[0500] wherein:

[0501] Y is N, or CH;

[0502] Ring A is ;

[0503] Where Z represents O, S, or NR5;

[0504] R5 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl group; or, two R5 groups can be linked together to form a -C group. 1-4 alkylene-, -C 2-4 imide- or -C 2-4 Iso-ynyl-;

[0505] m = 1, 2, 3, 4, 5, 6, 7 or 8;

[0506] R a For 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 heterocyclic groups;

[0507] Where L is selected from chemical bonds, -C 1-6 alkylene-, -C 2-6 imidene- or -C 2-6 Iso-ynyl-;

[0508] R2 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl groups;

[0509] R3 is Et, or iPr; and

[0510] R4 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl groups.

[0511] 18. A compound of formula (II) according to embodiment 17, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein:

[0512] Y is either N or CH;

[0513] Ring A is ;

[0514] Where Z is O, or NR 51 ;

[0515] R 51 To R 59 Each independently is H or C. 1-6 Alkyl; or, R 51 To R 59 The two in can be connected together to form -C 1-4 alkylene-;

[0516] Ra is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or -L-C 3-7 cycloalkyl;

[0517] wherein L is selected from a chemical bond, or -C 1-6 alkylene-;

[0518] R2is H, or C 1-6 alkyl;

[0519] R3is Et, or iPr; and

[0520] R4is H, or C 1-6 alkyl.

[0521] 19. The compound of Formula (II) according to Embodiment 17, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein:

[0522] Y is N, or CH;

[0523] Ring A is , , , , , , , , , or ;

[0524] R a is Me, Et, iPr, , , or ;

[0525] R2is H, or Me;

[0526] R3is Et, or iPr;

[0527] R4is H, or Me.

[0528] 20. The compound according to Embodiment 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein the compound is selected from:

[0529] , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and .

[0530] 21. A pharmaceutical composition comprising:

[0531] a compound according to any one of embodiments 1-20, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof;

[0532] a pharmaceutically acceptable excipient; and

[0533] optionally, one or more additional therapeutic agents.

[0534] 22. A kit comprising:

[0535] a first container containing a compound according to any one of embodiments 1-20, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof; and

[0536] optionally, a second container containing one or more additional therapeutic agents; and

[0537] optionally, a third container containing a pharmaceutically acceptable excipient for diluting or suspending the compound and / or additional therapeutic agent(s).

[0538] 23. Use of a compound according to any one of embodiments 1-20, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof, or a pharmaceutical composition according to embodiment 21, or a kit according to embodiment 22, for the manufacture of a medicament for the treatment and / or prevention of a FLT3-mediated disease.

[0539] 24. The use of embodiment 23, wherein the FLT3-mediated disease comprises a cell proliferative disorder, including but not limited to leukemia, myeloma, myeloproliferative disease, myelodysplastic syndrome, 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, renal cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and hematological malignancies.

[0540] EMBODIMENTS

[0541] The following examples are provided in order to give those skilled in the art a complete disclosure and description of how to make, prepare and evaluate the methods and compounds claimed herein, and are intended to be purely exemplary of the application and are not intended to be limiting in any way.

[0542] Preparation schemes for the compounds disclosed herein are shown in the following schemes.

[0543] Scheme 1

[0544]

[0545] In step 1, S1 is reacted with concentrated HC1 and iso-nitrous acid ester 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 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).

[0546] Scheme 2

[0547]

[0548] Compounds of formula (I) can also be prepared using Scheme 2, starting with S7 (wherein R2 is H), bromination of S7, followed by coupling with boronic acid.

[0549] Example 1: Preparation of N-(5-(4-ethylpiperazin-l-yl)-4-methoxypyridin-2-yl)-l- isopropyl-lH-imidazo[4,5-h]quinazolin-8-amine (I-2)

[0550]

[0551] Step 1

[0552]

[0553] To 1 (450 g, 4.6 mol, 1.00 eq) was added concentrated HC1 (38 mL, 0.46 mol, 0.1 eq) and the mixture was cooled with ice water to 0 °C. o C. At this temperature, isopropyl nitrite (1076 g, 9.2 mol, 2.00 eq) was added dropwise. 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 under vacuum to give the title compound (300 g, 95% purity) as a light yellow solid.

[0554] Steps 2 and 3

[0555]

[0556] To a solution of 2 (300 g, 1.9 mol, 1.00 eq) and paraformaldehyde (43 g, 2.09 mmol, 1.10 eq) in EtOH (2.3 L) was added isopropylamine (123 g, 2.09 mol, 1.10 eq) dropwise. The mixture was stirred at room temperature for 2 hours, then refluxed for another 3 hours. The mixture was concentrated to give crude compound 3.

[0557] To a solution of crude compound 3 in AcOH (2.1 L) was added Fe (powder) (620 g, 9.5 mol, 5 eq). The mixture was refluxed for 48 hours. After cooling to room temperature, the mixture was diluted with EtOAc (1000 mL) and filtered. The filtrate was concentrated. The residue was diluted with water (2000 mL) and basified with 2M NaOH (aq.) until pH ~ 9. The mixture was then extracted with EtOAc (1000 mL x 3). The organic layers were combined, dried over Na2S04and concentrated. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (1 / 1) to give compound 4 (248 g, 96% purity) as a brown oil.

[0558] Step 4

[0559]

[0560] A solution of 4 (248 g, 1.4 mol, 1.00 eq) in DMF (700 mL) and DMF-DMA (700 mL) was heated at 110 °C for 8 hours. The solvent was removed under vacuum to give 306 g of crude product 5, which was used directly in the next step without further purification. o C. At this temperature, isopropyl nitrite (1076 g, 9.2 mol, 2.00 eq) was added dropwise. 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 under vacuum to give the title compound (300 g, 95% purity) as a light yellow solid.

[0561] Step 5

[0562]

[0563] Add guanidine hydrochloride (237 g) and t-BuONa (480 g) to a solution of 5 (306 g crude product) in EtOH (2.5 L). Heat the mixture at 80 °C. o Stirred at C for 16 hours. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1 / 1) to provide compound 6 (125 g, 95% purity) as a yellow solid.

[0564] Step 6

[0565]

[0566] To a solution of compound 6 (22.9 g, 100 mmol, 1.00 eq) in DCM (800 mL), DDQ (27.2 g, 120 mmol, 1.20 eq) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1 / 1) to give compound 7 (11.3 g, 94% purity) as a yellow solid.

[0567] Step 7

[0568]

[0569] Add 7 (131 mg, 579 μmol, 1.00 eq), t-BuONa (111 mg, 1.16 mmol, 2.00 eq), and BrettPhos Pd G3 (53 mg, 57.9 μmol, 0.10 eq) to a solution of 8 (148 mg, 579 μmol, 1.00 eq) in dioxane (3 mL). Stir the resulting mixture at 100 °C for 2 hours under a nitrogen atmosphere. Dilute the suspension with DCM (10 mL) and filter. Wash the filter cake with DCM (10 mL). Concentrate the filtrate under vacuum. Purify the residue by silica gel column chromatography, eluting with DCM / MeOH (10 / 1), to give a crude product (150 mg) as a pale yellow solid. Purify the crude product by preparative TLC to give target I-2 (50 mg, 20.0%) as a grayish-white solid. 1H-NMR (DMSO-d6, 400 MHz) 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=7.2 Hz, 3H).

[0570] Example 2-18

[0571] Example 2-18 was prepared using similar procedure as Example 1 with different S8.

[0572]

[0573]

[0574]

[0575]

[0576] Example 19: Preparation of l-isopropyl-N-(3-methoxy-4-morpholinophenyl)-4- methyl-lH-imidazo[4,5-h]quinazolin-8-amine (II-1)

[0577] Step 1

[0578]

[0579] To a solution of 7 (200 mg, 880 μmol, 1.00 eq) in DMF (10 mL) was added N- bromosuccinimide (235 mg, 1.32 mmol, 1.50 eq). The resulting reaction mixture was stirred at room temperature for 4 hours. The suspension was diluted with EtOAc (40 mL) and washed with brine (10 mL x 3). The combined organic layers were dried over anhydrous Na2S04and filtered, the filter cake was washed with EtOAc (10 mL). The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with EtOAc to give compound 9 (240 mg, 89.1%) as off-white solid. LCMS [M+l]+= 306.1 and 308.0.

[0580] Step 2

[0581]

[0582] To a solution of 9 (240 mg, 784 μmol, 1.00 eq) in dioxane (16 mL) and H2O (4 mL) was added methylboronic acid (469 mg, 7.84 mmol, 10.0 eq), Cs2CO3 (769 mg, 2.35 mmol, 3.00 eq) and Pd(dppf)Cl2 (57 mg, 78.4 μmol, 0.10 eq). The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 16 hours. The suspension was diluted with water (20 mL) and extracted with EtOAc (10 mL x3). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc to afford compound 10 (82 mg, 43.4%) as off-white solid. LCMS [M+1] + = 242.2.

[0583] Step 3

[0584]

[0585] To a solution of 11 (77 mg, 337 μmol, 1.00 eq) in dioxane (5 mL) was added 10 (81 mg, 337 μmol, 1.0 eq), t-BuONa (81 mg, 842 μmol, 2.50 eq) and Brettphos Pd G3 (31 mg, 33.7 μmol, 0.10 eq). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 16 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to afford the title compound (40 mg, 27.4%) as yellow solid. LCMS [M+1] + = 434.3. 1 H NMR (300 MHz, 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 = 1.2 Hz, 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 = 6.6 Hz, 6H).

[0586] Example 20: Preparation of N-(4-ethoxy-5-(piperazin-l-yl)pyridin-2-yl)-l- isopropyl-5-methyl-lH-imidazo[4,5-h]quinolin-8-amine (III-1)

[0587]

[0588] Step 1

[0589]

[0590] To 12 (20.0 g, 178 mmol, 1.00 eq) was added concentrated HC1 (1.5 mL, 12 M, 17.8 mmol, 0.10 eq) followed by heating to 5 o C was added isoamyl nitrite (41.7 g, 357 mmol, 2.00 eq). The mixture was then allowed to warm to room temperature and stirred for 14 hours. The solid was filtered off. 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 light yellow solid.

[0591] Steps 2 and 3

[0592]

[0593] To a solution of 13 (28.8 g, 169 mmol, 1.00 eq) in EtOH (500 mL) was added paraformaldehyde (5.58 g, 186 mmol, 1.10 eq), isopropylamine (11.0 g, 186 mmol, 1.10 eq). The mixture was stirred at room temperature for 1 hour and then refluxed for an additional 2 hours. The mixture was concentrated to give crude compound 14.

[0594] To a solution of crude compound 14 in AcOH (500 mL) was added Fe (powder) (66.2 g, 1.18 mol, 7.00 eq). The resulting mixture was refluxed for 48 hours. After cooling to room temperature, the mixture was diluted with EtOAc (500 mL) and filtered. The filtrate was concentrated under vacuum. The residue was suspended in EtOAc (1000 mL) and saturated sodium bicarbonate (500 mL). The solid was filtered off. The organic layer was separated and the aqueous layer was extracted with DCM / MeOH (10 / 1, 500 mL x 2). The combined organic layers were dried over Na2S04and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with 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.

[0595] Steps 4 and 5

[0596]

[0597] To a solution of 15 (23.1 g, 120 mmol, 1.00 eq) in DMF (250 mL) was added DMF-DMA (250 mL). The resulting solution was stirred at 110 °C for 8 hours. The solvent was removed under vacuum to give crude compound 16 (30.0 g), which was used directly in the next step without further purification. o C for 8 hours. The solvent was removed under vacuum to give crude compound 16 (30.0 g), which was used directly in the next step without further purification.

[0598] To a solution of crude compound 16 (30.0 g) in EtOH (300 mL) was added guanidine hydrochloride (11.5 g, 120 mmol, 1.00 eq) and t-BuONa (34.6 g, 360 mmol, 3.00 eq). The resulting mixture was stirred at 80 °C for 12 hours. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography eluted with 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.

[0599] Step 6

[0600]

[0601] To a solution of 17 (9.70 g, 39.9 mmol, 1.00 eq) in DCM (400 mL) was added DDQ (10.9 g, 48 mmol, 1.20 eq). The resulting mixture was stirred at room temperature for 1 hour. The mixture solution was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (1 / 1) to give compound 18 (800 mg, 8.32%) and 5.1 g (crude) as a light yellow solid. LCMS [M+H] + = 242.2.

[0602] Step 7

[0603]

[0604] To a solution of 19 (63 mg, 184 μmol, 1.00 eq) in dioxane (3 mL) was added 18 (44 mg, 184 μmol, 1.00 eq), t-BuONa (35 mg, 369 μmol, 2.00 eq) and Brettphos Pd G3 (33 mg, 36.9 μmol, 0.20 eq). The resulting mixture was stirred at 110 °C for 2 h under nitrogen atmosphere. The mixture was concentrated in vacuo. The residue was purified by preparative TLC eluted with EtOAc to give compound 20 (63 mg, 62.5%) as a light yellow solid. LCMS [M+H] + = 547.4.

[0605] Step 8

[0606]

[0607] To a solution of 20 (63 mg, 115 μmol, 1.00 eq) in DCM (5 mL) was added TFA (1.0 mL). The resulting 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 solution (2 mL) and stirred for 10 min. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC eluted with DCM / MeOH (10 / 1) to give the target III-1 (20 mg, 38.9%) as an off-white solid. LCMS [M+H] + = 447.3. 1 H NMR (300 MHz, 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 = 1.2 Hz, 1H), 6.01-5.97 (m, 1H), 4.17 (q, J = 6.9 Hz, 2H), 3.16-3.11 (m, 8H), 2.71 (s, 3H), 1.54 (d, J = 6.6 Hz, 6H), 1.43 (t, J = 6.9 Hz, 3H).

[0608] Example 21: Preparation of N-(4-isopropoxy-5-(piperazin-1-yl)pyridin-2-yl)-1- methyl-1H-imidazo[4,5-h]quinolin-8-amine (IV-1)

[0609]

[0610] Steps 1 and 2

[0611]

[0612] To a solution of compound 2 (21.0 g, 135 mmol, 1.00 eq) in EtOH (300 mL), polyoxymethylene (4.44 g, 148 mmol, 1.10 eq) and methylamine (74 mL, 2 M in THF, 148 mmol, 1.10 eq) were added. The resulting mixture was stirred at room temperature for 1 hour, and then refluxed for 2 hours. The mixture was concentrated to give crude compound 21.

[0613] Fe (powder) (37.5 g, 672 mol, 5.00 eq) was added to a solution of crude compound 21 in AcOH (300 mL). The resulting mixture was stirred at 120 °C for 48 hours. After cooling to room temperature, the mixture was diluted with EtOAc (500 mL) and filtered. The filtrate was concentrated. The residue was suspended in EtOAc (500 mL) and saturated sodium bicarbonate (300 mL) and filtered. The organic layer was separated and the aqueous layer was extracted with DCM / MeOH (10 / 1, 500 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EtOAc, to give compound 22 (15.8 g, 78.2%) as a brown oil. LCMS [M+H] + =151.1.

[0614] Steps 3 and 4

[0615]

[0616] Add DMF-DMA (45 mL) to a solution of 22 (15.8 g, 105 mmol, 1.00 eq) in DMF (45 mL). Incubate the resulting solution at 110 °C. o Stirring at C for 8 hours. Solvent removal under vacuum yields crude product 23, which is used directly in the next step without further purification. LCMS [M+H] + =205.2.

[0617] Guanidine hydrochloride (25.1 g, 263 mmol, 2.50 eq) and t-BuONa (50.6 g, 526 mmol, 5.00 eq) were added to a solution of crude product 23 in EtOH (300 mL). The resulting mixture was heated at 70 °C. oCstirred for 16 h. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography eluting with EtOAc to afford compound 24 (6.30 g, 29.8%) as a yellow solid. LCMS [M+H] + = 202.2.

[0618] Step 5

[0619]

[0620] To a solution of 24 (3.0 g, 14.9 mmol, 1.00 eq) in DCM (100 mL) was added DDQ (4.1 g, 18 mmol, 1.20 eq). The resulting mixture was stirred at room temperature for 1 h. The mixture solution was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to afford compound 25 (1.20 g, 40.4%) as a yellow solid. LCMS [M+H] + = 200.1.

[0621] Step 6

[0622]

[0623] To a solution of 26 (109 mg, 306 μmol, 1.00 eq) in dioxane (5 mL) was added 25 (61 mg, 306 μmol, 1.00 eq), t-BuONa (60 mg, 613 μmol, 2.00 eq) and Brettphos Pd G3 (14 mg, 15.3 μmol, 0.05 eq). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2 h. The mixture was concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc to afford compound 27 (92 mg, 57.9%) as a yellow solid. LCMS [M+H] + = 519.3.

[0624] Step 7

[0625]

[0626] To a solution of 27 (92 mg, 177 μmol, 1.00 eq) in DCM (5 mL) was added TFA (0.1 mL). The resulting mixture was stirred at room temperature for 1 hour. 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 eq) under stirring for 10 minutes, followed by the addition of DCM (10 mL). The solid was filtered off. The filtrate was concentrated, and the residue was purified by preparative TLC to give the title compound IV-1 (19.4 mg, 26.1%). LCMS [M+H] + = 419.3. 1 H NMR (300 MHz, 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 = 6.0 Hz, 6H).

[0627] 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 -1)

[0628]

[0629] Steps 1 and 2

[0630]

[0631] To a solution of 2 (21.0 g, 135 mmol, 1.00 eq) in EtOH (300 mL) was added paraformaldehyde (4.44 g, 148 mmol, 1.10 eq), ethylamine (6.67 g, 148 mmol, 1.10 eq). The resulting solution was stirred at room temperature for 1 hour, and then refluxed for another 2 hours. The mixture was concentrated in vacuo to give the crude compound 28, which was used directly in the next step without further purification. LCMS [M+H] + = 181.1.

[0632] To a solution of crude compound 28 in AcOH (300 mL) was added Fe (powder) (37.6 g, 672 mmol, 5.0 eq). The resulting mixture was refluxed for 48 h. After cooling to room temperature, the mixture was diluted with EtOAc (500 mL) and filtered. The filtrate was concentrated. The residue was suspended in EtOAc (500 mL) and saturated sodium bicarbonate (300 mL). The mixture was filtered. The organic layer was separated and the aqueous layer was extracted with DCM / MeOH (10 / 1, 500 mL x 2). The combined organic layers were dried over Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with EtOAc to give compound 29 (14.3 g, 64.7% over two steps) as a brown oil. LCMS [M+H] + = 165.1.

[0633] Steps 3 and 4

[0634]

[0635] To a solution of 29 (14.3 g, 87.1 mmol, 1.00 eq) in DMF (42 mL) was added DMF-DMA (42 mL). The resulting solution was stirred at 130 °C for 8 h. The solvent was removed in vacuo to give crude 30 which was used directly in the next step without further purification. LCMS [M+H]+ = 220.2.

[0636] To a solution of crude 30 in EtOH (300 mL) was added guanidine hydrochloride (8.32 g, 89.1 mmol, 1.00 eq) and t-BuONa (25.1 g, 261 mmol, 3.00 eq). The resulting mixture was refluxed for 16 h. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (1 / 1) to give compound 31 (6.4 g, 34.1%) as a yellow solid. LCMS [M+H] + = 216.2.

[0637] Step 5

[0638]

[0639] To a solution of 31 (6.40 g, 29.7 mmol, 1.00 eq) in DCM (200 mL) was added DDQ (8.09 g, 35.6 mmol, 1.20 eq). The resulting mixture was stirred at room temperature for 1 hour. The mixture solution was concentrated in vacuum. The residue was purified by column chromatography on silica gel eluted with PE / EtOAc (1 / 1) to give compound 32 (2.10 g, 33.1%) as a yellow solid. LCMS [M+H] + = 214.2.

[0640] Step 6

[0641]

[0642] To a solution of 33 (87 mg, 323 μmol, 1.00 eq) in dioxane (5 mL) was added 32 (69 mg, 323 μmol, 1.00 eq), t-BuONa (62 mg, 645 μmol, 2.00 eq) and Brettphos Pd G3 (15 mg, 16.1 μmol, 0.05 eq). The resulting mixture was stirred at 90 °C for 2 hours under nitrogen atmosphere. The solid was filtered off. The filtrate was concentrated. The residue was purified by column chromatography on silica gel eluted with DCM / MeOH (15 / 1) to give the target V-1 (21.2 mg, 14.6%). LCMS [M+H] + = 447.4. 1 H NMR (300 MHz, 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 = 7.2 Hz, 2H), 4.17 (q, J = 6.9 Hz, 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 = 7.2 Hz, 3H).

[0643] Example 23: Preparation of l-isopropyl-N-(4-methoxy-5-morpholino-pyridin-2-yl)-2- methyl-lH-imidazo[4,5-h]quinazolin-8-amine l-1)

[0644]

[0645] Steps 1 and 2

[0646]

[0647] To a suspension of 2 (12.5 g, 80.1 mmol, 1.00 eq) in AcOH (150 mL) was added isopropylamine (5.21 g, 88.1 mol, 1.10 eq), followed by CH3CHO (3.88 g, 88.1 mmol, 1.10 eq). The resulting mixture was stirred at 80 °C for 3 hours. The mixture was used directly for the next step without further purification. LCMS [M+H] + = 209.2.

[0648] After cooling to room temperature, iron powder (22.4 g, 400 mmol, 5.00 eq) was added. The resulting mixture was refluxed for 48 hours. The solvent was removed under vacuum. The residue was diluted with EtOAc (200 mL) and filtered. The filtrate was concentrated to give the crude product. The crude product was poured into water (250 mL). The pH was adjusted to 8-9 with 1 N aqueous NaOH solution. The mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with 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.

[0649] Steps 3 and 4

[0650]

[0651] To a suspension of 35 (5.00 g, 26.0 mmol, 1.00 eq) in DMF (30 mL) was added DMF-DMA (30 mL). The resulting mixture was stirred at 110 °C for 8 hours. The mixture was concentrated under vacuum to give the crude product 36.

[0652] To a solution of the crude product 36 in EtOH (150 mL) was added guanidine hydrochloride (6.15 g, 65.0 mmol, 2.50 eq), t-BuONa (12.4 g, 130 mmol, 5.00 eq). The resulting mixture was refluxed for 16 hours. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (20 / 1) to give compound 37 (1.50 g, 23.7% over two steps) as a gray solid. LCMS [M+H] + = 244.2.

[0653] Step 5

[0654]

[0655] To a solution of 37 (200 mg, 822 μmol, 1.00 eq) in DCM (8 mL) was added DDQ (224 mg, 986 μmol, 1.20 eq). The resulting mixture was stirred at room temperature for 1 h. The mixture solution was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to afford compound 38 (110 mg, 55.5%) as a brown solid. LCMS [M+H] + = 242.2.

[0656] Step 6

[0657]

[0658] To a suspension of 38 (100 mg, 414 μmol, 1.00 eq) in dioxane (10 mL) was added 11 (117 mg, 497 μmol, 1.20 eq), t-BuONa (80 mg, 829 μmol, 2.00 eq) and Brettphos Pd G3 (19 mg, 20.7 μmol, 0.05 eq). The resulting mixture was stirred at 100 °C for 2 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 / 1) to afford the target VI-1 (22.4 mg, 12.5%) as a white solid. LCMS [M+H] + = 434.3. 1 H NMR (300 MHz, 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 = 8.7 Hz, 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 = 6.9 Hz, 6H).

[0659] Bioassay

[0660] The compounds of the present disclosure were tested in IC 50 Mode test, and the control compound staurosporine was tested in IC 50 Mode test. The reaction was performed in the presence of 10 μM ATP.

[0661] Conditions and protocol:

[0662] Procedure:

[0663] 1. Prepare compounds 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.

[0664] 2. In the case of CDK subtypes, add the required co-factors such as 1 μg (1.5 μM) of recombinant retinoblastoma protein to the substrate solution as described above.

[0665] 3. Dilute the kinase such as 10 ng of recombinant CDK4 / cyclin D1 (Life Technologies PV4204) in kinase buffer (20 mM Tris pH 7.5, 10 mM MgCl2, 0.01% NP-40, 2 mM DTT) and incubate with the specified concentration of inhibitor for 30 minutes at room temperature.

[0666] 4. Add the compounds in DMSO to the kinase reaction mixture using acoustic technology (Echo 550).

[0667] 5. Add33P-ATP (final specific activity 0.01 μCi / μl) to the reaction mixture to initiate the reaction.

[0668] 6. Incubate the reaction mixture for 120 minutes at room temperature.

[0669] 7. Spot the reaction on P81 ion exchange paper (Whatman # 3698-915).

[0670] 8. Wash the filters thoroughly with 0.75% phosphoric acid.

[0671] 9. Measure the radioactivity of the phosphorylated substrate remaining on the filter paper.

[0672] Data analysis:

[0673] Kinase activity data is expressed as the percentage of kinase activity remaining in the test sample compared to the vehicle (dimethyl sulfoxide) reaction. IC50values and curve fitting were obtained using Prism 4 software (GraphPad).

[0674] Using similar assay methods as described above, all kinase inhibition results for representative compounds are shown in the following table.

[0675]

[0676] The foregoing is considered as illustrative only of the principles of the present disclosure. Further, various modifications and changes can be made as would be obvious to a person of ordinary skill in the art to which the present disclosure pertains without departing from the spirit and scope of the present disclosure. It is the intent, therefore, to be limited only as described by the scope of the claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof: (I) in: Y is N, or CR6; Where R6 represents 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 Halogenated alkyl groups; X is -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-O-C(O)R a 、-O-C(O)OR a 、-O-C(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 ; Where R a For 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 heterocyclic groups, -LC 6-10 Aryl, or -L-5 to 10-membered heteroaryl; R b For 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 heterocyclic groups, -LC 6-10 Aryl, or -L-5 to 10-membered heteroaryl; R c For 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 heterocyclic groups, -LC 6-10 Aryl, or -L-5 to 10-membered heteroaryl; Or R b R c They form 3- to 7-membered heterocyclic groups or 5- to 10-membered heteroaryl groups with the N atoms attached to them; Where L is selected from chemical bonds, -C 1-6 alkylene-, -C 2-6 imidene- or -C 2-6 Iso-ynyl-; Ring A is a -L'-3 to 11-membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R5 groups; Where L' is selected from chemical bonds, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 can be H, halogenated, oxidized, -OR, -SR-, -NR'R'', or C. 1-6 Alkyl, or C 1-6 Halogenated alkyl group; or, two R5 groups can be linked together to form a -C group. 1-4 alkylene-, -C 2-4 imide- or -C 2-4 Iso-ynyl-; R, R', and R'' are each independently H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, or C 2-6 Alkyne group; or R', R'' and the N atom attached to them form a 3- to 7-membered heterocyclic group, or a 5- to 10-membered heteroaryl group; R1 represents H, halogen, -CN, or -OR. a -SR a -NR b R c C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; R2 represents H, halogen, -CN, or -OR. a -SR a -NR b R c C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclic groups, C 6-10 aryl, or 5 to 10 heteroaryl; and R4 represents H, halogen, -CN, or -OR. a -SR a -NR b R c C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein, The compound of formula (I) described therein has any one of the following definitions i) to ix): i) Y is N; ii) X is -OR a , -SR a , -NR b R c , -C(O)R a , -C(O)OR a , -C(O)NR b R c , -O-C(O)R a , or -N(R b )-C(O)R a ; Preferably, X is -OR a -SR a , or -NR b R c ; Preferably, X is -OR a ; Preferably, X is -NR b R c ; iii) R a For 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 Aryl; and Where L is selected from chemical bonds, or -C 1-6 alkylene-; Preferably, R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, or -LC 3-7 cycloalkyl; and Where L is selected from chemical bonds, or -C 1-6 alkylene-; iv) R b For 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 Aryl; R c For 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 Aryl; Or R b R c And the N atoms connected to them form 3- to 7-membered heterocyclic groups, or 5- to 10-membered heteroaryl groups; and Where L is selected from chemical bonds, or -C 1-6 alkylene-; Preferably, R b For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, or -LC 3-7 cycloalkyl; R c For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, or -LC 3-7 cycloalkyl; Or R b R c And the N atoms connected to them form 3 to 7-membered heterocyclic groups; and Where L is selected from chemical bonds, or -C 1-6 alkylene-; Preferably, R b For H, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; R c For H, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; Or R b R c They form 4- to 6-membered heterocyclic groups with the N atoms they are connected to; v) Ring A is a -L'-3 to 7-membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R5 groups; Where L' is selected from chemical bonds, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 can be H, halogenated, oxidized, -OR, -SR-, -NR'R'', or C. 1-6 Alkyl, or C 1-6 Halogenated alkyl group; or, two R5 groups can be linked together to form a -C group. 1-4 alkylene-, -C 2-4 imide- or -C 2-4 etyne-; and R, R', and R'' are each independently H and C. 1-6 Alkyl, or C 1-6 Haloalkyl; or R', R'' and the N atom attached to them form a 3- to 7-membered heterocyclic group, or a 5- to 10-membered heteroaryl group; Preferably, Ring A is a -L'-4 to 6-membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R5 groups; Where L' is selected from chemical bonds, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 represents H, oxo, -OR, -NR'R'', C 1-6 Alkyl, or C 1-6 Halogenated alkyl group; or, two R5 groups can be linked together to form a -C group. 1-4 alkylene-; and R, R', and R'' are each independently H and C. 1-6 Alkyl, or C 1-6 Haloalkyl groups; or R', R'' and the N atom attached to them form 4 to 6-membered heterocyclic groups; Preferably, Ring A is a -L'-4 to 6-membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R5 groups; Where L' is selected from chemical bonds, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 can be H, oxo, -OR, -NR'R'', or C. 1-6 Alkyl; or, two R5s can be linked together to form a -C 1-4 alkylene-; and R, R', and R'' are each independently H or C 1-6 Alkyl groups; or R', R'' and the N atom attached to them form 4 to 6-membered heterocyclic groups; Preferably, Ring A is , Where Z represents O, S, or NR5; R5 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl group; or, two R5 groups can be linked together to form a -C group. 1-4 alkylene-, -C 2-4 imide- or -C 2-4 Iso-ynyl-; m = 1, 2, 3, 4, 5, 6, 7 or 8; Preferably, Ring A is , Where Z: O, or NR 51 ; R 51 To R 59 For H, or C 1-6 Alkyl; or, R 51 To R 59 The two in can be connected together to form -C 1-4 alkylene-; Preferably, Ring A is , , , , , , , , , , ,or ; Preferably, Ring A is , , , , , , , , ,or ; vi) R1 is H, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; Preferably, R1 is H; vii) R2 is H, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; Preferably, R2 is H; viii) R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl groups, or 3- to 7-membered heterocyclic groups; Preferably, R3 is C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; Preferably, R3 is C 1-6 alkyl; Preferably, R3 is Et or iPr; ix) R4 is H, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; Preferably, R4 is H.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein: Y is N, or CR6; Where R6 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; X is -OR a -SR a , or -NR b R c ; Where R a For 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 heterocyclic groups, -LC 6-10 Aryl, or -L-5 to 10-membered heteroaryl; R b For H, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; R c For H, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; Or R b R c They form 4- to 6-membered heterocyclic groups or 5- to 10-membered heteroaryl groups with the N atoms attached to them; Where L is selected from chemical bonds, -C 1-6 alkylene-, -C 2-6 imidene- or -C 2-6 Iso-ynyl-; Ring A is a -L'-3 to 7-membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R5 groups; Where L' is selected from chemical bonds, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 represents H, halogenated, oxidized, or C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR, -SR-, or -NR'R''; or, two R5 groups can be linked together to form -C. 1-4 alkylene-, -C 2-4 imide- or -C 2-4 Iso-ynyl-; R, R', and R'' are each independently H and C. 1-6 Alkyl, or C 1-6 Haloalkyl; or R', R'' and the N atom attached to them form a 3- to 7-membered heterocyclic group, or a 5- to 10-membered heteroaryl group; R1 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; R2 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; R3 is C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; and R4 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; Preferably, wherein: Y is N, or CR6; Where R6 is H, or C 1-6 alkyl; X is -OR a , or -NR b R c ; Where R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-7 cycloalkyl, or -LC 6-10 Aryl; R b For H, or C 1-6 alkyl; R c For H, or C 1-6 alkyl; Or R b R c They form 4- to 6-membered heterocyclic groups with the N atoms they are connected to; Where L is selected from chemical bonds, or -C 1-6 alkylene-; Ring A is a -L'-4 to 6-membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R5 groups; Where L' is selected from chemical bonds, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 represents H, oxidase, and C. 1-6 Alkyl, -OR, or -NR'R''; or, two R5s can be linked together to form -C. 1-4 alkylene-; R, R', and R'' are each independently H or C 1-6 Alkyl groups; or R', R'' and the N atom attached to them form 4- to 6-membered heterocyclic groups, or 5- to 6-membered heteroaryl groups; R1 is H, or C 1-6 alkyl; R2 is H, or C 1-6 alkyl; R3 is C 1-6 Alkyl groups; and R4 is H, or C 1-6 alkyl; Preferably, wherein: Y is either N or CH; X is -OR a , or -NR b R c ; Where R a For Me, Et, iPr, , , ,or ; R b For H and Me; R c For H and Me; Or R b R c and the N atoms connected to them form ; Ring A is , , , , , , , , , , ,or ; R1 is H, or Me; R2 is H, or Me; R3 is Me, Et, or iPr; and R4 is H, or Me.

4. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein the compound is of formula (II): (II) Y is either N or CH; Ring A is a -L'-3 to 7-membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R5 groups; Where L' is selected from chemical bonds, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 represents H, halogenated, oxidized, or C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR, -SR-, or -NR'R''; or, two R5 groups can be linked together to form -C. 1-4 alkylene-, -C 2-4 imide- or -C 2-4 Iso-ynyl-; R, R', and R'' are each independently H and C. 1-6 Alkyl, or C 1-6 Haloalkyl; or R', R'' and the N atom attached to them form a 4- to 6-membered heterocyclic group, or a 5- to 10-membered heteroaryl group; R a For 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 heterocyclic groups, -LC 6-10 Aryl, or -L-5 to 10-membered heteroaryl; Where L is selected from chemical bonds, -C 1-6 alkylene-, -C 2-6 imidene- or -C 2-6 Iso-ynyl-; R2 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; R3 is Et, or iPr; and R4 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; Preferably, wherein: Y is either N or CH; Ring A is a -L'-4 to 6-membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R5 groups; L' is selected from chemical bonds, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5 represents H, oxidase, and C. 1-6 Alkyl, -OR, or -NR'R''; or, two R5s can be linked together to form -C. 1-4 alkylene-; R, R', and R'' are each independently H or C 1-6 Alkyl groups; or R', R'' and the N atom attached to them form 4- to 6-membered heterocyclic groups, or 5- to 6-membered heteroaryl groups; R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -LC 3-7 cycloalkyl, or -LC 6-10 Aryl; Where L is selected from chemical bonds, or -C 1-6 alkylene-; R2 is H, or C 1-6 alkyl; R3 is Et, or iPr; and R4 is H, or C 1-6 alkyl; Preferably, wherein: Y is either N or CH; Ring A is , , , , , , , , , , ,or ; R a For Me, Et, iPr, , , ,or ; R2 is H, or Me; R3 is Et, or iPr; and R4 is H, or Me; Preferably, it is a compound of formula (II): (II) in: Y is either N or CH; Ring A is ; Where Z represents O, S, or NR5; R5 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl group; or, two R5 groups can be linked together to form a -C group. 1-4 alkylene-, -C 2-4 imide- or -C 2-4 Iso-ynyl-; m = 1, 2, 3, 4, 5, 6, 7 or 8; R a For 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 heterocyclic groups; Where L is selected from chemical bonds, -C 1-6 alkylene-, -C 2-6 imidene- or -C 2-6 Iso-ynyl-; R2 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; R3 is Et, or iPr; and R4 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; Preferably, wherein: Y is either N or CH; Ring A is ; Where Z is O, or NR 51 ; R 51 To R 59 Each independently is H or C. 1-6 Alkyl; or, R 51 To R 59 The two in can be connected together to form -C 1-4 alkylene-; R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, or -LC 3-7 cycloalkyl; Where L is selected from chemical bonds, or -C 1-6 alkylene-; R2 is H, or C 1-6 alkyl; R3 is Et, or iPr; and R4 is H, or C 1-6 alkyl; Preferably, , where: Y is either N or CH; Ring A is , , , , , , , , ,or ; R a For Me, Et, iPr, , ,or ; R2 is H, or Me; R3 is Et, or iPr; R4 is H, or Me.

5. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein the compound is selected from: , , , , , , , , , , , , , , , , , , , , , and .

6. A pharmaceutical composition comprising: The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof; Pharmaceutically acceptable excipients; and Optionally, one or more other therapeutic agents.

7. A kit containing: A first container containing a compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof; and Optionally, a second container contains one or more other therapeutic agents; and Optionally, a third container contains pharmaceutically acceptable excipients for diluting or suspending the compound and / or other therapeutic agents.

8. The use of the compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof, or the pharmaceutical composition according to claim 6, or the kit according to claim 7, in the preparation of a medicament for treating and / or preventing FLT3-mediated diseases; Preferably, the FLT3-mediated diseases are selected from cell proliferation disorders, including but not limited to leukemia, myeloma, myelodysplastic disorders, myelodysplastic syndrome, idiopathic eosinophilic syndrome (HES), bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, nasopharyngeal carcinoma, neuroendocrine carcinoma, 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 hematologic malignancies.

9. A method comprising the following steps: a. The compound was prepared in a 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; b. In the case of the CDK subtype, add the required cofactor, such as 1 μg (1.5 μM) of recombinant retinoblastoma protein, to the substrate solution as described above; c. Dilute kinases such as 10 ng recombinant CDK4 / cyclin D1 (Life Technologies PV4204) in kinase buffer (20 mM Tris pH7.5, 10 mM MgCl2, 0.01% NP-40, 2 mM DTT) and incubate at room temperature with the specified concentration of inhibitor for 30 minutes. d. The compounds in DMSO were added to the kinase reaction mixture using acoustic technology (Echo550); e. Add 33P-ATP (final specific activity 0.01 μCi / μl) to the reaction mixture to initiate the reaction; f. Incubate the reaction mixture at room temperature for 120 minutes; g. Spot the reaction onto P81 ion exchange paper (Whatman # 3698-915); h. Thoroughly clean the filter with 0.75% phosphoric acid; i. Measure the radiophosphorylated substrate remaining on the filter paper.

10. A method for preparing compound 13: Add concentrated HCl (1.5 mL, 12 M, 17.8 mmol, 0.10 eq) to 12 (20.0 g, 178 mmol, 1.00 eq), then at 5 o C. Add amyl nitrite (41.7 g, 357 mmol, 2.00 eq); then warm the mixture to room temperature and stir for 14 hours; filter out the solid; wash the filter cake with PE (300 mL x 3) and vacuum dry to give compound 13 (28.8 g, 94.9%) as a pale yellow solid.

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