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 compounds are broad-spectrum inhibitors with strong activity against FLT3 kinase and are useful in the treatment of cell proliferative disorders.

Description

TECHNICAL FIELD

[0001] 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

[0002] Leukemia is a broad term covering a family of 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 55 years of age, but it is also the most common cancer in children under 15 years of age. 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.

[0003] 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 this level 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).

[0004] An increasing body of evidence suggests that tyrosine kinase mutations are present in many types of leukemia and myeloproliferative syndromes. Two types of FLT3-activating mutations have been described in patients with leukemia. 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.

[0005] Due to the adverse implications 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 reduced 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.

[0006] 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

[0007] 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.

[0008] In one aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or mixture thereof:

[0009]

[0010] wherein:

[0011] Y is N, or CR6;

[0012] 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 ,

[0013] -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 )

[0014] C(O)OR a , or -N(R b )-C(O)NR b R c , C 1-6 1-6 alkyl, or C 1-6 1-6 haloalkyl;

[0015] 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 ,

[0016] -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)

[0017] C(O)NR b R c ;

[0018] 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;

[0019] 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;

[0020] 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;

[0021] 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;

[0022] wherein L is selected from a bond, -C 1-6 alkylene-, -C 2-6 alkenylene-, or -C 2-6 alkynylene-;

[0023] Ring A is -L’-3- to 11-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0024] wherein L’ is selected from a bond, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0025] R5is H, halo, oxo, -OR, -SR-, -NR’R”, C 1-6alkyl, 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-;

[0026] R, R' and R" are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl; or R', R" and the N atom to which they are attached form a 3- to 7- membered heterocyclyl, or a 5- to 10-membered heteroaryl;

[0027] R1is H, halogen, -CN, -OR a , -SR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;

[0028] R2is H, halogen, -CN, -OR a , -SR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;

[0029] 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

[0030] R4is H, halogen, -CN, -OR a , -SR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl.

[0031] In another aspect, the present disclosure provides a pharmaceutical composition containing a compound of the present disclosure, and optionally a pharmaceutically acceptable excipient.

[0032] In another aspect, the present disclosure provides a pharmaceutical composition containing a compound of the present disclosure and a pharmaceutically acceptable excipient, which further contains another therapeutic agent.

[0033] In another aspect, the present disclosure provides a kit comprising a compound of the present disclosure, and a further therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0034] In another aspect, the present disclosure provides the use of a compound of the present disclosure in the manufacture of a medicament for the treatment and / or prevention of a Flt3-mediated disease.

[0035] 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.

[0036] In another aspect, the present disclosure provides a compound of the present disclosure or a composition of the present disclosure for use in the treatment and / or prevention of a Flt3-mediated disease.

[0037] 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.

[0038] Other objects and advantages of the present disclosure will be readily apparent to one skilled in the art from the specific embodiments, examples, and claims that follow.

[0039] Definitions

[0040] Chemical Definitions

[0041] The definitions of specific functional groups and chemical terms are more fully described below.

[0042] When a range of values is listed, each value and sub-range within the range is intended. 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.

[0043] It should be understood that, as described herein, any part defined below may be substituted by a number of substituents, and the corresponding definitions are listed below within their scope, including such substituted parts. Unless otherwise stated, the term "substitution" is defined below.

[0044] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated monovalent alkane (hydrocarbon) group containing 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, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, etc. The term "C" is also used. 1-6 "Alkyl" also includes heteroalkyl, wherein one to three atoms selected from O, S, N or substituted nitrogen atoms may replace carbon atoms. Alkyl groups may be substituted at any available connection point, for example, one to five substituents, one to three substituents or one substituent.

[0045] “C 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond, including but not limited to vinyl, 3-buten-1-yl, 2-vinylbutyl, 3-hexen-1-yl, etc. In some embodiments, C 2-4 Alkenyl groups are preferred. The term "C" is used. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one to three atoms selected from O, S, N, or substituted nitrogen atoms may replace carbon atoms. Alkenyl groups may be substituted at any available connection point, for example, one to five substituents, one to three substituents, or one substituent.

[0046] “C 2-6 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, wherein there is at least one carbon-carbon triple bond and optionally one or more unsaturated carbon-carbon double bonds. In some embodiments, C 2-4 Alkynyl groups are preferred. Typical alkynyl groups include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, and hexynyl. The term "C" is used in conjunction with these groups. 2-6 "Alkyne" also includes heteroyne, wherein one to three atoms selected from O, S, N, or substituted nitrogen atoms may replace carbon atoms. The alkynyl group may be substituted at any available connection point, for example, one to five substituents, one to three substituents, or one substituent.

[0047] -C 1-6 alkylene-, -C 2-6 imide- or -C 2-6 "Immyne-" refers to the "C" defined above. 1-6 Alkyl, C 2-6 alkenyl or C2-6 The divalent group of "alkynyl".

[0048] “C 1-6 "Alkylene" refers to the removal of C 1-6 An alkyl group is formed by the presence of one hydrogen atom to form a divalent alkylene group, and can be either substituted or unsubstituted. In some embodiments, C 1-4 Alkylenes are particularly preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0049] “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)-), etc.

[0050] “C 2-6 "Iso-ynyl" refers to the group that has the C group removed. 2-6alkynyl is divalent and can be substituted or unsubstituted alkynylene. In some embodiments, C 2-4 Alkynyl is divalent and can be substituted or unsubstituted alkynylene. In some embodiments, C

[0051] "Halogen" or "halo" means fluorine, chlorine, bromine, or iodine.

[0052] "C 1-6 "Haloalkyl" means the above "C 1-6 alkyl" groups substituted with one or more halogen groups. Examples include mono-halo substitution, di-halo substitution, and poly-halo substitution including per-halo. A mono-halo substituent can have one iodine, bromine, chlorine, or fluorine atom in the group; di-halo and poly-halo substituents can have two or more of the same halogen atoms or a combination of different halogens. Preferred haloalkyl examples include fluoro-methyl, di-fluoro-methyl, tri-fluoro-methyl, chloro-methyl, di-chloro-methyl, tri-chloro-methyl, penta-fluoro-ethyl, hepta-fluoro-propyl, di-fluoro-chloro-methyl, di-chloro-fluoro-methyl, di-fluoro-ethyl, di-fluoro-propyl, di-chloro-ethyl, and di-chloro-propyl. The haloalkyl group can be substituted at any available attachment point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0053] "C 3-7 "Cycloalkyl" means a non-aromatic cyclic hydrocarbon group having from 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-6 Cycloalkyl is particularly preferred, more preferred C 5-6 Cycloalkyl. Cycloalkyl also includes ring systems in which the above cycloalkyl ring is fused with one or more aryl or heteroaryl rings, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons designates the number of carbons in the cycloalkyl ring system. 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.

[0054] "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. 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.

[0055] 3- to 11-membered heterocyclyl also includes spiroheterocyclyl, i.e., a group in which two rings (e.g., a heterocyclyl and a carbocyclic alkyl) share one carbon atom, wherein at least one ring is a heterocyclyl as defined above. More specifically, the spiroheterocyclyl is a spirocycle formed of 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 ring is a 4-6 membered heterocyclyl as defined above, preferably a 4-6 membered heterocyclyl containing 1, 2, or 3 O, N, or S heteroatoms, more preferably a 4-6 membered heterocyclyl containing 1 N heteroatom. Specific spiroheterocyclyls include, but are not limited to:

[0056]

[0057]

[0058] Specific examples of preferred heterocyclyls include pyrrolinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, dihydropyranyl, dihydrofuranyl, thiazolidinyl, dihydrothiazolyl, 2-oxoaziridin-1-yl, 2-oxoazetidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxoazacyclohexan-1-yl, 2-oxoazacycloheptan-1-yl, 2-oxoazacyclooctan-1-yl, 2-oxoazacyclononan-1-yl, 2-oxoazacyclodecan-1-yl, aziridine, azetidine, pyrrolidinyl, azacyclohexane, azacycloheptane, azacyclooctane, azacyclononane, azacyclodecane, 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.

[0059] “C 6-10 “Aryl” means a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 p electrons shared in a cyclic array) 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 (“C10 aryl”; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl rings, with the point of attachment being on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. 10 “Aryl” means a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 p electrons shared in a cyclic array) 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 (“C10 aryl”; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl rings, with the point of attachment being on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system.

[0060] "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.

[0061] 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).

[0062] "Oxyto" means =O.

[0063] 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.

[0064] 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;

[0065] 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;

[0066] 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;

[0067] 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) ccOR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R bb 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;

[0068] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R groups. cc 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;

[0069] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff)2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee , -OC(=NR ff )R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(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;

[0070] 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;

[0071] 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;

[0072] 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.

[0073] 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

[0074] Other Definitions

[0075] 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, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, myeloid disorders, lymphoid disorders, Hodgkin's disease, hairy cell carcinoma, and leukemia.

[0076] 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. ​​​

[0077] 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 application. 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 can be regenerated by contacting the salt with base or with an acid and isolation of the free base form. The free base form differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the free base compounds for the purposes of the present application.

[0078] 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.

[0079] "Disease," "disorder," and "condition" are used interchangeably herein.

[0080] Unless otherwise indicated, the term "treatment" as used herein includes actions that occur when a subject is suffering from a particular disease, disorder, or condition, and that decrease the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition ("therapeutic treatment"), and also includes actions that occur before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0081] Generally, an "effective amount" of a compound refers to a quantity sufficient to effect at least partial biological response. 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 such factors as 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 therapeutic and prophylactic effective amounts.

[0082] 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.

[0083] 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.

[0084] "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 other therapeutic agents in separate unit dosage forms, or administered simultaneously with other therapeutic agents in a single unit dosage form. DETAILED DESCRIPTION

[0085] 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.

[0086] Compounds are generally described herein using standard nomenclature. For compounds with asymmetric centers, it should be 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 embraced by the present disclosure are possible in Z and E form with carbon-carbon double bonds. Where compounds exist in different tautomeric forms, one compound is not intended to exclude the other tautomers.

[0087] In one embodiment, the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof:

[0088]

[0089] wherein:

[0090] Y is N, or CR6;

[0091] 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 ,

[0092] -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 )-

[0093] C(O)OR a , or -N(R b )-C(O)NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;

[0094] wherein X is -OR a , -SR a , -NR b R c , -C(O)R a , -C(O)OR a , -C(O)NR b R c , -O-C(O)R a ,

[0095] -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 )-

[0096] C(O)NR b R c ;

[0097] wherein R a is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, -LC 3-7 Cycloalkyl, -L-3 to 7-membered heterocyclic groups, -LC 6-10 Aryl, or -L-5 to 10-membered heteroaryl;

[0098] 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;

[0099] 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;

[0100] 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;

[0101] Where L is selected from chemical bonds, -C 1-6 alkylene-, -C 2-6 imidene- or -C 2-6 Iso-ynyl-;

[0102] 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;

[0103] Where L' is selected from chemical bonds, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0104] 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

[0105] -or-C 2-4 Iso-ynyl-;

[0106] R, R' and R" are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl; or R', R" and the N atom to which they are attached form a 3- to 7- membered heterocyclyl, or a 5- to 10-membered heteroaryl;

[0107] R1is H, halogen, -CN, -OR a , -SR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;

[0108] R2is H, halogen, -CN, -OR a , -SR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;

[0109] 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

[0110] R4is H, halogen, -CN, -OR a , -SR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl.

[0111] Y

[0112] In one specific embodiment, Y is N; in another specific embodiment, Y is CR6; in another specific embodiment, Y is CH.

[0113] X

[0114] 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 embodiment, X is -O-C(O)R b R c ; in another embodiment, X is -O-C(O)OR a ; in another 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 .

[0115] 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.

[0116] 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, Rb C; 2-6 alkynyl; in another more specific embodiment of X, R b -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.

[0117] 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.

[0118] 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.

[0119] 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 bor R c In yet another more specific embodiment, L is -C 2-6 alkenylene-; in R a , R b or R c In yet another more specific embodiment, L is -C 2-6 alkynylene-.

[0120] Ring A

[0121] 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.

[0122] 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.

[0123] 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-.

[0124] In yet another more specific embodiment, Ring A is Preferably, Ring A is

[0125] 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.

[0126] 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-.

[0127] R1

[0128] 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.

[0129] R2

[0130] 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 -ORa ; in another specific embodiment, R2is -SR a ; in another specific embodiment, R2is -NR b R c ; in another specific embodiment, R2is C 1-6 alkyl; in another specific embodiment, R2is C 1-6 haloalkyl.

[0131] R3

[0132] In one specific embodiment, R3is C 1-6 alkyl; in another specific embodiment, R3is C 1-6 haloalkyl; in another specific embodiment, R3is C 3-7 cycloalkyl; in another specific embodiment, R3is 3- to 7-membered heterocyclyl; in another specific embodiment, R3is C 6-10 aryl; in another specific embodiment, R3is 5- to 10-membered heteroaryl.

[0133] R4

[0134] In one specific embodiment, R4is H; in another specific embodiment, R4is halogen; in another specific embodiment, R4is -CN; in another specific embodiment, R4is -OR a ; in another specific embodiment, R4is -SR a ; in another specific embodiment, R4is -NR b R c ; in another specific embodiment, R4is C 1-6 alkyl; in another specific embodiment, R4is C 1-6 haloalkyl.

[0135] Any of the above specific embodiments or any combination thereof can be combined with any of the other specific embodiments or any combination thereof. For example, any of the specific embodiments of Y or any combination thereof can be combined with any of the specific embodiments of X, ring A, R1, R2, R3, and R4or any combination thereof. The disclosure is intended to include all such combinations of the specific embodiments, which are not listed one by one due to the volume.

[0136] In specific embodiments, the disclosure relates to compounds of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein Y is N.

[0137] 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,

[0138] 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 ;

[0139] Preferably, X is -OR a , -SR a , or -NR b R c ;

[0140] Preferably, X is -OR a ;

[0141] Preferably, X is -NR b R c .

[0142] 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,

[0143] 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-C 6-10 aryl; and

[0144] wherein L is selected from a bond, or -C 1-6 alkylene-;

[0145] Preferably,

[0146] 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; and

[0147] wherein L is selected from a bond, or -C 1-6 alkylene-.

[0148] 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,

[0149] 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, or -L-C 6-10 aryl;

[0150] 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, or -L-C 6-10 aryl;

[0151] or R b , R c and the N atom to which they are attached form a 3- to 7-membered heterocyclyl group; and

[0152] wherein L is selected from a bond, or -C 1-6 alkylene-;

[0153] Preferably,

[0154] R b is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or -L-C 3-7 cycloalkyl;

[0155] 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;

[0156] or R b , R c and the N atom to which they are attached form a 3- to 7-membered heterocyclyl group; and

[0157] wherein L is selected from a bond, or -C 1-6alkylene-;

[0158] Preferably,

[0159] R b is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0160] R c is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0161] or R b , R c and the N atom to which they are attached form a 4- to 6-membered heterocyclyl.

[0162] 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,

[0163] Ring A is -L'-3- to 7-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0164] wherein L' is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0165] R5is H, halo, oxo, -OR, -SR-, -NR'R", 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-; and

[0166] 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;

[0167] Preferably,

[0168] Ring A is -L'-4- to 6-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0169] wherein L' is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0170] R5is H, oxo, -OR, -NR'R", C1-6 alkyl, or C 1-6 haloalkyl; or, two R5may be joined together to form a -C 1-4 alkylene-; and

[0171] 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;

[0172] Preferably,

[0173] Ring A is -L’-4- to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0174] wherein L’ is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0175] 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

[0176] 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;

[0177] Preferably,

[0178] Ring A is

[0179] wherein Z is O, S, or NR5;

[0180] 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 alkylene-, -C 2-4 alkylene-;

[0181] m = 1, 2, 3, 4, 5, 6, 7, or 8;

[0182] Preferably,

[0183] Ring A is

[0184] wherein Z is O, or NR 51 ;

[0185] R 51 to R59 H, or C 1-6 alkyl; or, R 51 to R 59 two of which can be linked together to form -C 1-4 alkylene-;

[0186] Preferably,

[0187] Ring A is

[0188] Preferably,

[0189] Ring A is

[0190] 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,

[0191] R1is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0192] Preferably, R1is H.

[0193] 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,

[0194] R2is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0195] Preferably, R2is H.

[0196] 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,

[0197] R3is C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, or 3- to 7-membered heterocyclyl;

[0198] Preferably, R3is C 1-6 alkyl, or C 1-6 haloalkyl;

[0199] Preferably, R3is C 1-6 alkyl;

[0200] Preferably, R3is Et or iPr.

[0201] 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,

[0202] R4is H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0203] Preferably, R4is H.

[0204] 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,

[0205] Y is N, or CR6;

[0206] wherein R6is H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0207] X is -OR a , -SR a , or -NR b R c ;

[0208] 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;

[0209] R b is H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0210] R c is H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0211] 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;

[0212] wherein L is selected from a bond, -C 1-6 alkylene-, -C 2-6 alkenylene-, or -C 2-6 alkynylene-;

[0213] Ring A is -L'-3 to 7 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0214] wherein L' is selected from a bond, -0-, -S-, -NH-, -0-CH2-, -CH2-0-, -NH-CH2-, or -CH2-NH-;

[0215] 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 a -C 1-4 alkylene-, -C 2-4 alkenylene-, or -C 2-4 alkynylene-;

[0216] 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;

[0217] R1is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0218] R2is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0219] R3is C 1-6 alkyl, or C 1-6 haloalkyl; and

[0220] R4is H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0221] 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,

[0222] Y is N, or CR6;

[0223] wherein R6is H, or C 1-6 alkyl;

[0224] X is -OR a , or -NR b R c ;

[0225] wherein R a is C 1-6alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L-C 3-7 cycloalkyl, or -L-C 6-10 aryl;

[0226] R b is H, or C 1-6 alkyl;

[0227] R c is H, or C 1-6 alkyl;

[0228] or R b , R c and the N atom to which they are attached form a 4- to 6-membered heterocyclyl;

[0229] wherein L is selected from a bond, or -C 1-6 alkylene-;

[0230] Ring A is -L’-4- to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0231] wherein L’ is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0232] R5is H, oxo, C 1-6 alkyl, -OR, or -NR’R”; 1-4 alkylene-;

[0233] 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;

[0234] R1is H, or C 1-6 alkyl;

[0235] R2is H, or C 1-6 alkyl;

[0236] R3is C 1-6 alkyl; and

[0237] R4is H, or C 1-6 alkyl.

[0238] 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,

[0239] Y is N, or CH;

[0240] X is -OR a , or -NR b R c ;

[0241] wherein R a is Me, Et, iPr,

[0242] R b is H, Me;

[0243] R c is H, Me;

[0244] or R b , R c and the N atom to which they are attached form

[0245] Ring A is

[0246] R1is H, or Me;

[0247] R2is H, or Me;

[0248] R3is Me, Et, or iPr; and

[0249] R4is H, or Me.

[0250] 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):

[0251]

[0252] Y is N, or CH;

[0253] Ring A is -L’-3 to 7 membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups;

[0254] wherein L’ is selected from a bond, -O-, -S-, -NH-, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0255] 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 -C2-4 Iso-ynyl-;

[0256] 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;

[0257] 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;

[0258] Where L is selected from chemical bonds, -C 1-6 alkylene-, -C 2-6 imidene- or -C 2-6 Iso-ynyl-;

[0259] R2 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl groups;

[0260] R3 is Et, or iPr; and

[0261] R4 represents H and C. 1-6 Alkyl, or C 1-6 Halogenated alkyl groups.

[0262] In one specific embodiment, this disclosure relates to compounds of formula (II), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, or mixtures thereof, wherein,

[0263] Y is either N or CH;

[0264] 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;

[0265] L' is selected from chemical bonds, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-;

[0266] 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-;

[0267] R, R', and R” are each independently H or C 1-6alkyl; 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;

[0268] 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;

[0269] wherein L is selected from a bond, or -C 1-6 alkylene-;

[0270] R2is H, or C 1-6 alkyl;

[0271] R3is Et, or iPr; and

[0272] R4is H, or C 1-6 alkyl.

[0273] In a particular embodiment, the present disclosure relates to a compound of Formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0274] Y is N, or CH;

[0275] Ring A is

[0276] R a is Me, Et, iPr,

[0277] R2is H, or Me;

[0278] R3is Et, or iPr; and

[0279] R4is H, or Me.

[0280] 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):

[0281]

[0282] wherein:

[0283] Y is N, or CH;

[0284] Ring A is

[0285] wherein Z is O, S, or NR5;

[0286] 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-;

[0287] m = 1, 2, 3, 4, 5, 6, 7, or 8;

[0288] 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;

[0289] wherein L is selected from a bond, -C 1-6 alkylene-, -C 2-6 alkenylene-, or -C 2-6 alkynylene-;

[0290] R2is H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0291] R3is Et, or iPr; and

[0292] R4is H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0293] In one specific embodiment, the present disclosure relates to a compound of Formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0294] Y is N, or CH;

[0295] Ring A is

[0296] wherein Z is O, or NR 51 ;

[0297] R 51 through R 59 are each independently H, or C 1-6 alkyl; or, R 51 through R 59 two of which can be joined together to form a -C 1-4 alkylene-;

[0298] 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;

[0299] wherein L is selected from a chemical bond, or -C 1-6 alkylene-;

[0300] R2is H, or C 1-6 alkyl;

[0301] R3is Et, or iPr; and

[0302] R4is H, or C 1-6 alkyl.

[0303] In one embodiment, the disclosure relates to a compound of Formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or mixture thereof, wherein,

[0304] Y is N, or CH;

[0305] Ring A is

[0306] R a is Me, Et, iPr,

[0307] R2is H, or Me;

[0308] R3is Et, or iPr;

[0309] R4is H, or Me.

[0310] 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:

[0311]

[0312]

[0313] The compounds of the present disclosure can include one or more asymmetric centers and can thus occur as various stereoisomers, for example, enantiomeric and / or diastereomeric forms. For example, the compounds of the present disclosure can be in the form of individual enantiomers, diastereomers or geometric isomers (such as cis- and trans-isomers), or can be in the form of mixtures 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 isomers can be prepared by asymmetric synthesis.

[0314] Pharmaceutical compositions, formulations, and kits

[0315] 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.

[0316] 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 wool fat.

[0317] 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 packs 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 comprising a pharmaceutically-acceptable excipient for diluting or suspending the compound of the present disclosure and / or other therapeutic agents. In some embodiments, the compound of the present disclosure and other therapeutic agents provided in the first and second containers form a unit dosage form in combination.

[0318] Dosing

[0319] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to: oral administration, parenteral administration, administration by inhalation, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration, administration via an implant, or other means 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.

[0320] 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.

[0321] When used to prevent a condition described herein, 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.

[0322] 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 forth, 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.

[0323] Various methods of administration can be used to further deliver a pharmaceutical composition of the present disclosure. For example, in some embodiments, a pharmaceutical composition can be administered as a bolus, for example, to raise the concentration of a compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient through the body, for example, a bolus dose intramuscularly or subcutaneously releases the active ingredient slowly, while a bolus delivered directly to a vein, for example, by IV infusion, can deliver more rapidly, such that the concentration of the active ingredient in the blood rises quickly to an effective level. In other embodiments, a pharmaceutical composition can be administered as a continuous infusion, for example, by IV infusion, to provide a steady state concentration of the active ingredient in the body of the subject. Further, in other embodiments, a bolus dose of a pharmaceutical composition can be administered first, followed by a continuous infusion.

[0324] 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, each unit containing a predetermined amount of the active ingredient(s) considered as a dosage to produce the desired therapeutic effect, in association with appropriate pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured, disposable syringes or injectable liquids in sealed containers, foils or ampules, or tablets or capsules in blister or strain packs, or the like, for retail or wholesale distribution. In such compositions, the compound(s) is usually a minor component (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.

[0325] For oral dosage form, a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these dosing patterns, each dose provides from 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.

[0326] To provide blood levels similar to or lower than those achieved using injectable doses, transdermal doses are typically selected in amounts 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.

[0327] Injectable dose levels range from about 0.1 mg / kg / hr to at least 10 mg / kg / hr for from about 1 to about 120 hours, especially 24 to 96 hours. To achieve adequate steady state levels, a preloading bolus of from about 0.1 mg / kg to about 10 mg / kg or more can also be administered. The maximum total dose should not exceed about 2 g / day for a 40 to 80 kg human patient.

[0328] Liquid forms suitable for oral administration can include a suitable aqueous or nonaqueous carrier 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 properties: binders such as, for example, microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as, for example, starch or lactose, disintegrating agents, such as, for example, alginic acid, Primogel, or cornstarch; lubricants, such as, for example, magnesium stearate; glidants, such as, for example, colloidal silicon dioxide; sweetening agents, such as, for example, sucrose or saccharin; or flavoring agents, such as, for example, peppermint, methyl salicylate, or orange flavoring.

[0329] Injectable compositions typically are based upon injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As before, in such compositions the active compound is typically the minor component, often from about 0.05 to 10% by weight, with the remainder being the injectable excipient or the like.

[0330] Transdermal compositions are typically formulated to contain active ingredients in a mixture with a carrier or diluent that is suitable for topical or transdermal application. Typically, the active compound is mixed with a transdermal penetration enhancer, such as Azone, dimethyl isosorbide, or other known transdermal penetration enhancers. Alternatively, the active compound can be admixed with a carrier such as liposomes, ethosomes, or other known carriers for topical or transdermal application. All such known transdermal carriers and enhancers are included within the scope of the present disclosure.

[0331] The compounds of the present disclosure can also be administered through a transdermal device. Transdermal administration can be achieved by means of a reservoir or porous matrix-type patch, or a variety of solid matrix systems.

[0332] The above ingredients for compositions for oral administration, injection, or topical administration are merely representative. Other materials and processing techniques, and the like are set out in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0333] The compounds of the present disclosure can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0334] The present disclosure also relates to pharmaceutically acceptable formulations of the compounds of the present 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, which consist of 6, 7, and 8 α-1,4-linked glucose units, respectively, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, e.g., U.S. 5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0335] Treatment

[0336] The present disclosure provides methods of treating the following disorders or conditions in mammals, including humans: cell proliferation disorders, such as cancer, vascular smooth muscle proliferation associated with atherosclerosis, post-surgical vascular stenosis, restenosis, and endometriosis; infections, including viral infections, such as DNA viruses, e.g., herpes, and RNA viruses, e.g., HIV, and fungal infections; autoimmune diseases, such as psoriasis, inflammatory diseases, such as rheumatoid arthritis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, and glomerulonephritis; organ transplant rejection, including host versus graft disease, which methods comprise administering to the mammal a therapeutically effective amount of a compound of the present disclosure or a composition thereof.

[0337] The present disclosure further provides compounds of the present disclosure useful for treating abnormal cell proliferation, e.g., cancer. The present disclosure further provides methods of treating abnormal cell proliferation, e.g., a cancer selected from the group consisting of breast, ovary, cervix, prostate, testes, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lip, tongue, oral cavity, pharynx, small intestine, colorectum, 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, myeloid disorders, lymphoid disorders, Hodgkin's disease, hairy cell carcinoma, and leukemia, which methods comprise administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure or a composition thereof.

[0338] Further, the present disclosure relates to methods of treating a subject suffering from a disease caused by vascular smooth muscle cell proliferation. Compounds of the present disclosure are effective in inhibiting the proliferation and migration of vascular smooth muscle cells. The methods comprise administering to a subject in need of treatment an amount of a compound of the present disclosure or a composition thereof sufficient to inhibit vascular smooth muscle proliferation and / or migration.

[0339] The present disclosure further provides methods of treating a subject suffering from gout, comprising administering to the subject in need of treatment an amount of a compound of the present disclosure or a composition thereof sufficient to treat the condition.

[0340] The present disclosure further provides methods of treating a subject suffering from a kidney disease, e.g., polycystic kidney disease, comprising administering to the subject in need of treatment an amount of a compound of the present disclosure or a composition thereof sufficient to treat the condition.

[0341] Due to their inhibitory activity against Flt3 and other kinases, the compounds of the present disclosure are also useful research tools for in vitro and in vivo studies of the mechanism of action of these kinases.

[0342] 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 of the compounds of the present disclosure is administered to a patient in need of such treatment, e.g., one who has cancer or another proliferative disease.

[0343] An effective amount of a compound of the present disclosure is typically in the range of 0.01 mg to 50 mg of the compound per kilogram of patient body weight per day, preferably 0.1 mg to 25 mg of the compound per kilogram of patient body weight per day, in single or divided doses. Typically, a compound of the present disclosure can be administered to such a patient in need thereof in a daily dose range of about 1 mg to about 3500 mg per patient, preferably 10 mg to 1000 mg. 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 once or multiple times per day, per week (or with several days in between), or on an intermittent schedule. For example, the compound can be administered one or more times per day on a weekly basis (e.g., on Mondays), for an indefinite or for a period of several weeks, e.g., 4-10 weeks. Alternatively, the compound can be administered daily for a period of several days (e.g., 2-10 days), followed by a period of several days (e.g., 1-30 days) without administration of the compound, with 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 a period of 5 days, followed by a period of 9 days without administration, followed by another period of 5 days of daily administration, followed by another period of 9 days without administration, and so on, with the cycle being repeated indefinitely or for a total of 4-10 times.

[0344] Examples

[0345] The following examples are provided in order to give those skilled in the art a complete disclosure and description of how to make, use, and evaluate the methods and compounds claimed herein, and are intended to be merely exemplary of the present application and not limiting thereof.

[0346] Preparation of the compounds disclosed herein is shown in the following schemes.

[0347] Scheme 1

[0348]

[0349] In step 1, S1 is reacted with concentrated HC1 and isoamyl nitrite to give S2. In step 2, a mixture of S2 and R4CHO is treated with R3NH2 to give S3. In step 3, S3 is reduced to 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).

[0350] Scheme 2

[0351]

[0352] 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.

[0353] Example 1: Preparation of N-(5-(4-ethylpiperazin-1-yl)-4-methoxy-pyridin-2-yl)-1- isopropyl-1H-imidazo[4,5-h]quinazolin-8-amine (I-2)

[0354]

[0355] Step 1

[0356]

[0357] 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 to 0 °C with ice water. At this temperature, isoamyl 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.

[0358] Steps 2 and 3

[0359]

[0360] 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 the crude compound 3.

[0361] 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 h. 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 2 M 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.

[0362] Step 4

[0363]

[0364] 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 h. The solvent was removed in vacuo to give 306 g of crude product 5 which was used directly in the next step without further purification.

[0365] Step 5

[0366]

[0367] To a solution of 5 (306 g of crude product) in EtOH (2.5 L) was added guanidine hydrochloride (237 g) and t-BuONa (480 g). The mixture was stirred at 80 °C for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluted with PE / EtOAc (1 / 1) to give compound 6 (125 g, 95% purity) as a yellow solid.

[0368] Step 6

[0369]

[0370] To a solution of 6 (22.9 g, 100 mmol, 1.00 eq) in DCM (800 mL) was added DDQ (27.2 g, 120 mmol, 1.20 eq). The 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 eluted with PE / EtOAc (1 / 1) to give compound 7 (11.3 g, 94% purity) as a yellow solid.

[0371] Step 7

[0372]

[0373] To a solution of 8 (148 mg, 579 pmol, 1.00 eq) in dioxane (3 mL) was added 7 (131 mg, 579 pmol, 1.00 eq), t-BuONa (111 mg, 1.16 mmol, 2.00 eq) and BrettPhos Pd G3 (53 mg, 57.9 pmol, 0.10 eq). The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The suspension was diluted with DCM (10 mL) and filtered. The filter cake was washed with DCM (10 mL). The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (10 / 1) to give the crude product (150 mg) as a light yellow solid. The crude product was purified by preparative TLC to give the target I-2 (50 mg, 20.0%) as an off-white solid. 1 H-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 = 6.0 Hz, 6H), 1.11 (t, J = 7.2 Hz, 3H).

[0374] Example 2-18

[0375] Example 2-18 was prepared using a similar procedure to Example 1 with a different S8.

[0376]

[0377]

[0378]

[0379]

[0380] Example 19: Preparation of l-isopropyl-N-(3-methoxy-4-morpholinophenyl)-4- methyl-lH-imidazo[4,5-h]quinazolin-8-amine (II-1)

[0381]

[0382] Step 1

[0383]

[0384] 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), washed with brine (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4and 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+1]+=306.1 and 308.0.

[0385] Step 2

[0386]

[0387] 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 x 3). The combined organic layers were dried over anhydrous Na2SO4and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with EtOAc to give compound 10 (82 mg, 43.4%) as off-white solid. LCMS [M+1]+=242.2. +

[0388] Step 3

[0389]

[0390] 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, eluted with DCM / MeOH (10 / 1) to give 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).

[0391] Example 20: Preparation of N-(4-ethoxy-5-(piperazin-l-yl)pyridin-2-yl)-l- isopropyl-5-methyl-lH-imidazo[4,5-h]quinazolin-8-amine (III-1)

[0392]

[0393] Step 1

[0394]

[0395] To 12 (20.0 g, 178 mmol, 1.00 eq) was added cone. HC1 (1.5 mL, 12 M, 17.8 mmol, 0.10 eq) followed by isoamyl nitrite (41.7 g, 357 mmol, 2.00 eq) at 5 °C. The mixture was then allowed to warm to room temperature and stirred for 14 h. 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.

[0396] Steps 2 and 3

[0397]

[0398] 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 h and then refluxed for another 2 h. The mixture was concentrated to give crude compound 14.

[0399] 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 h. After cooling to room temperature, the mixture was diluted with EtOAc (500 mL) and filtered. The filtrate was concentrated in vacuo. 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 in vacuo. 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. +

[0400] Steps 4 and 5

[0401]

[0402] 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 h. The solvent was removed in vacuo to give crude compound 16 (30.0 g), which was used directly in the next step without further purification.

[0403] 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 h. The solvent was removed in vacuo. 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. +

[0404] Step 6

[0405]

[0406] 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 h. The mixture solution was concentrated in vacuo. 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] = 244.3.​​+ = 242.2.

[0407] Step 7

[0408]

[0409] To a solution of 19 (63 mg, 184 pmol, 1.00 eq) in dioxane (3 mL) was added 18 (44 mg, 184 pmol, 1.00 eq), t-BuONa (35 mg, 369 pmol, 2.00 eq) and Brettphos Pd G3 (33 mg, 36.9 pmol, 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.

[0410] Step 8

[0411]

[0412] To a solution of 20 (63 mg, 115 pmol, 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) d 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).

[0413] Example 21: Preparation of N-(4-isopropoxy-5-(piperazin-l-yl)pyridin-2-yl)-l- methyl-lH-imidazo[4,5-h]quinazolin-8-amine (IV-1)

[0414]

[0415] Steps 1 and 2

[0416]

[0417] 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), methylamine (74 mL, 2 M in THF, 148 mmol, 1.10 eq). The resulting mixture was stirred at room temperature for 1 hour, then refluxed for another 2 hours. The mixture was concentrated to give crude compound 21.

[0418] To a solution of crude compound 21 in AcOH (300 mL) was added Fe (powder) (37.5 g, 672 mol, 5.00 eq). 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), 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 22 (15.8 g, 78.2%) as a brown oil. LCMS [M+H] + = 151.1.

[0419] Steps 3 and 4

[0420]

[0421] To a solution of 22 (15.8 g, 105 mmol, 1.00 eq) in DMF (45 mL) was added DMF-DMA (45 mL). The resulting solution was stirred at 110 °C for 8 hours. The solvent was removed in vacuo to give crude product 23, which was used directly in the next step without further purification. LCMS [M+H] + = 205.2.

[0422] To a solution of crude product 23 in EtOH (300 mL) was added guanidine hydrochloride (25.1 g, 263 mmol, 2.50 eq) and t-BuONa (50.6 g, 526 mmol, 5.00 eq). The resulting mixture was stirred at 70 °C for 16 hours. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with EtOAc to give compound 24 (6.30 g, 29.8%) as a yellow solid. LCMS [M+H] + = 202.2.

[0423] Step 5

[0424]

[0425] 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 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 25 (1.20 g, 40.4%) as a yellow solid. LCMS [M+H] + = 200.1.

[0426] Step 6

[0427]

[0428] 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 for 2 hours under nitrogen atmosphere. The mixture was concentrated. The residue was purified by column chromatography on silica gel eluted with EtOAc to give compound 27 (92 mg, 57.9%) as a yellow solid. LCMS [M+H] + = 519.3.

[0429] Step 7

[0430]

[0431] 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 vacuum 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 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. 1H 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).

[0432] Example 22: Preparation of N-(4-ethoxy-5-(4-ethylpiperazin-l-yl)pyridin-2-yl)-l- ethyl-lH-imidazo[4,5-h]quinazolin-8-amine (V-l)

[0433]

[0434] Steps 1 and 2

[0435]

[0436] 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, then refluxed for another 2 hours. The mixture was concentrated in vacuo to give crude compound 28, which was used directly in the next step without further purification. LCMS [M+H] + = 181.1.

[0437] 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 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). 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 Na2S04and 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.

[0438] Steps 3 and 4

[0439]

[0440] 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 under vacuum to give crude 30, which was used directly for the next step without further purification. LCMS [M+H]+=220.2.

[0441] 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 under vacuum. The residue was purified by column chromatography on silica gel eluted with PE / EtOAc (1 / 1) to give compound 31 (6.4 g, 34.1%) as a yellow solid. LCMS [M+H]+=216.2. +

[0442] Step 5

[0443]

[0444] 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 h. The mixture solution was concentrated under 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. +

[0445] Step 6

[0446]

[0447] 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 h 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).

[0448] Example 23: Preparation of l-isopropyl-N-(4-methoxy-5-morpholino-pyridin-2-yl)-2- methyl-lH-imidazo[4,5-h]quinazolin-8-amine (VI-1)

[0449]

[0450] Steps 1 and 2

[0451]

[0452] 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 h. The mixture was used directly for the next step without further purification. LCMS [M+H] + = 209.2.

[0453] After cooling to room temperature, iron powder (22.4 g, 400 mmol, 5.00 eq) was added. The resulting mixture was refluxed for 48 h. 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 eluting 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.

[0454] Steps 3 and 4

[0455]

[0456] 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 h. The mixture was concentrated in vacuo to give crude 36.

[0457] To a solution of crude 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 h. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting 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.

[0458] Step 5

[0459]

[0460] To a solution of 37 (200 mg, 822 pmol, 1.00 eq) in DCM (8 mL) was added DDQ (224 mg, 986 pmol, 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 column chromatography on silica gel eluting with PE / EtOAc (1 / 1) to give compound 38 (110 mg, 55.5%) as a brown solid. LCMS [M+H] + = 242.2.

[0461] Step 6

[0462]

[0463] To a suspension of 38 (100 mg, 414 pmol, 1.00 eq) in dioxane (10 mL) was added 11 (117 mg, 497 pmol, 1.20 eq), t-BuONa (80 mg, 829 pmol, 2.00 eq) and Brettphos Pd G3 (19 mg, 20.7 pmol, 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 column chromatography on silica gel 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. 1H 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).

[0464] Bioassay

[0465] Compounds of the present disclosure were tested at 10 doses of IC 50 Mode test, and control compound staurosporine was tested at 10 doses of IC 50 Mode test. Reactions were performed in the presence of 10 mM ATP.

[0466] Conditions and protocol:

[0467] Procedure:

[0468] 1. Compounds were prepared in freshly prepared reaction buffer containing 20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij 35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT and 1% DMSO.

[0469] 2. In the case of CDK subtypes, the required co-factors such as 1 μg (1.5 μM) of recombinant retinoblastoma protein were added to the substrate solution as described above.

[0470] 3. Kinases such as 10 ng of recombinant CDK4 / cyclin D1 (Life Technologies PV4204) were diluted in kinase buffer (20 mM Tris pH 7.5, 10 mM MgCl2, 0.01% NP-40, 2 mM DTT) and incubated with the indicated concentration of inhibitor for 30 minutes at room temperature.

[0471] 4. Compounds in DMSO were added to the kinase reaction mixture using acoustic technology (Echo 550).

[0472] 5.33P-ATP (final specific activity 0.01 μCi / μl) was added to the reaction mixture to initiate the reaction.

[0473] 6. The reaction mixture was incubated for 120 minutes at room temperature.

[0474] 7. The reactions were spotted on P81 ion exchange paper (Whatman # 3698-915).

[0475] 8. The filters were washed thoroughly with 0.75% phosphoric acid.

[0476] 9. The residual radio-phosphorylated substrate on the filter paper was measured.

[0477] Data analysis:

[0478] Kinase activity data is expressed as the percentage of residual kinase activity in the test sample compared to the vehicle (dimethyl sulfoxide) reaction. IC50 values and curve fitting were obtained using Prism 4 software (GraphPad).

[0479] Using similar assay methods as described above, all kinase inhibition results for representative compounds are shown in the following table.

[0480]

[0481] The foregoing is considered as illustrative only of the principles of the disclosure. Further, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the disclosure to the exact construction and practice described. Accordingly, all suitable substitutions and modifications are intended to be encompassed by the disclosure and the text is intended to serve as a basis for patenting.

Claims

1. A compound of Formula (I), or a pharmaceutically acceptable salt, racemate or mixture thereof: wherein: Y is N or CH; ring A is -L'-3 to 7 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups; wherein L' is selected from a bond, -0-CH2-, -CH2-0-, -NH-CH2-, or -CH2-NH-; R1is H; R2is H; R3is H; and R4is H.

2. The compound of Formula (I) according to claim 1, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein, 3. The compound of Formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein, X is -OR a or -SR a ; 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; wherein L is selected from a chemical bond or -C 1-6 alkylene-; 4. The compound of Formula (I) according to claim 3, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein, 5. The compound of Formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein, R5is H, halo, oxo, -OR, -SR-, -NR'R", C 1-6 alkyl, or C 1-6 haloalkyl; or, two R5may be joined together to form a -C 1-4 alkylene-; R, R' and R" are each independently H or C 1-6 alkyl; ring A is -L'-4 to 6 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups; wherein L' is selected from a bond, -0-CH2-, -CH2-0-, -NH-CH2-, or -CH2-NH-; R2is H or C 1-6 alkyl; R3is C 1-6 alkyl; and R4is H or C 1-6 alkyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein, 6. The compound of Formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein, ring A is -L'-4 to 6 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups; wherein L' is selected from a bond, -0-CH2-, -CH2-0-, -NH-CH2-, or -CH2-NH-; X is -OR a .

7. The compound of Formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein, 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; and wherein L is selected from a chemical bond, or -C 1-6 alkylene-. wherein Z is O, S, or NR5; m = 1, 2, 3, 4, 5, 6, 7, or 8.

8. The compound of Formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein, 9. The compound of Formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein, 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 R, R' and R" are each independently H or C 1-6 alkyl.

10. The compound of Formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein, 11. The compound of Formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein, R2is H. 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 R, R' and R" are each independently H, or C 1-6 alkyl.

12. The compound of Formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein, Ring A is R3is Et or iPr. R5is H, C 1-6 alkyl, or C 1-6 haloalkyl; or, two R5may be joined together to form a -C 1-4 alkylene-; 13. The compound of Formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein, R4is H. Ring A is wherein Z: O, or NR 51 ; 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 a -C 1-4 alkylene- group.

14. The compound of Formula (I) according to claim 1, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein: Ring A is Y is N or CH; ring A is -L'-3 to 7 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups; wherein L' is selected from a bond, -NH-CH2-, or -CH2-NH-; R1is H; R2is H; R3is H; and R4is H. Ring A is ​ ​ ​ ​ ​ ​ ​ ​ X is -OR a or -SR a ; 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; wherein L is selected from a chemical bond or -C 1-6 alkylene-; ​ ​ 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-; R, R' and R" are each independently H or C 1-6 alkyl; ​ R2is H or C 1-6 alkyl; R3is C 1-6 alkyl; and R4is H or C 1-6 alkyl.

15. The compound of Formula (I) according to claim 14, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein: Y is N or CH; X is -OR a ; 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; wherein L is selected from a chemical bond or -C 1-6 alkylene-; Ring A is -L'-4 to 6 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups; wherein L' is selected from a bond, -NH-CH2-, or -CH2-NH-; R5is H, oxo, C 1-6 alkyl, -OR, or -NR'R"; or, two R5may be joined together to form a -C 1-4 alkylene-; R, R' and R" are each independently H or C 1-6 alkyl; R1is H; R2is H or C 1-6 alkyl; R3is C 1-6 alkyl; and R4is H or C 1-6 alkyl.

16. The compound of Formula (I) according to claim 14, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein: Y is N, or CH; X is -OR a ; wherein R a is Me, Et, iPr, Ring A is R1is H; R2is H or Me; R3is Me, Et, or iPr; and R4is H or Me.

17. The compound of Formula (I) according to claim 1, or a pharmaceutically acceptable salt, racemate or mixture thereof, which is a compound of Formula (II): Y is N or CH; Ring A is -L'-3 to 7 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups; wherein L' is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; 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-; R, R' and R" are each independently H or C 1-6 alkyl; 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; wherein L is selected from a chemical bond or -C 1-6 alkylene-; R2is H or C 1-6 alkyl; R3is Et or iPr; and R4is H or C 1-6 alkyl.

18. The compound of Formula (II) according to claim 17, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein: Y is N or CH; Ring A is -L'-4 to 6 membered heterocyclyl, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R5groups; L' is selected from a bond, -O-CH2-, -CH2-O-, -NH-CH2-, or -CH2-NH-; R5is H, oxo, C 1-6 alkyl, -OR, or -NR'R"; or, two R5may be joined together to form a -C 1-4 alkylene-; R, R' and R" are each independently H or C 1-6 alkyl; 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; wherein L is selected from a chemical bond or -C 1-6 alkylene-; R2is H or C 1-6 alkyl; R3is Et or iPr; and R4is H or C 1-6 alkyl.

19. The compound of Formula (II) according to claim 17, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein: Y is N, or CH; Ring A is R a Me, Et, iPr, R2is H or Me; R3is Et or iPr; and R4is H or Me.

20. The compound of Formula (I) according to claim 1, or a pharmaceutically acceptable salt, racemate or mixture thereof, which is a compound of Formula (II): wherein: Y is N or CH; Ring A is wherein Z is O, S, or NR5; R5is H, C 1-6 alkyl, or C 1-6 haloalkyl; or, two R5may be joined together to form a -C 1-4 alkylene-; m = 1, 2, 3, 4, 5, 6, 7, or 8; 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; wherein L is selected from a chemical bond or -C 1-6 alkylene-; R2is H or C 1-6 alkyl; R3is Et or iPr; and R4is H or C 1-6 alkyl.

21. The compound of Formula (II) according to claim 20, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein: Y is N or CH; Ring A is wherein Z is O, or NR 51 ; R 51 to R 59 each independently H or C 1-6 alkyl; or, R 51 to R 59 two of which can be linked together to form -C 1-4 alkylene-; 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; wherein L is selected from a chemical bond or -C 1-6 alkylene-; R2is H or C 1-6 alkyl; R3is Et or iPr; and R4is H or C 1-6 alkyl.

22. The compound of Formula (II) according to claim 17, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein: Y is N or CH; Ring A is R a Me, Et, iPr, R2is H or Me; R3is Et or iPr; R4is H or Me.

23. The compound according to claim 1, or a pharmaceutically acceptable salt, racemate or mixture thereof, wherein the compound is selected from:

24. A pharmaceutical composition comprising: a compound according to any one of claims 1-23, or a pharmaceutically acceptable salt, racemate or mixture thereof; a pharmaceutically acceptable excipient.

25. A kit comprising: a compound according to any one of claims 1-23, or a pharmaceutically acceptable salt, racemate or mixture thereof; and a pharmaceutically acceptable excipient. a first container comprising a compound according to any one of claims 1-23, or a pharmaceutically acceptable salt, racemate or mixture thereof; and a second container comprising a pharmaceutically acceptable excipient for diluting or suspending the compound and / or other therapeutic agents.

26. Use of a compound according to any one of claims 1-23, or a pharmaceutically acceptable salt, racemate or mixture thereof, or a pharmaceutical composition according to claim 24, or a kit according to claim 25, for the manufacture of a medicament for the treatment and / or prevention of a FLT3-mediated disease, wherein the FLT3-mediated disease is a cell proliferative disorder.

27. The use according to claim 26, wherein the cell proliferative disorder is 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 malignancies.

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