Substituted fused bicyclic compounds as kinase inhibitors and their applications

Abstract

This invention provides substituted fused bicyclic compounds as kinase inhibitors and their applications, said substituted fused bicyclic compounds having the structure shown in Formula I, wherein rings A, R0, B1-B3, D1-D3, R7, and R8 are as defined herein. Compounds of Formula I are NUAK1 / 2 inhibitors. Therefore, the compounds of this invention can be used for the treatment and prevention of NUAK1 / 2-mediated diseases, disorders, and conditions, such as cancer, and for the preparation of medicaments for the treatment and prevention of NUAK1 / 2-mediated diseases, disorders, and conditions.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry. Specifically, it relates to substituted fused bicyclic compounds and their applications as therapeutically effective kinase inhibitors and anticancer drugs. Background Technology

[0002] AMPK (Adenosine 5'-monophosphate (AMP)-activated protein kinase) is an AMP-dependent protein kinase, a serine / threonine protein kinase, which plays an important role in many aspects of cellular energy metabolism, glucose and cholesterol metabolism, and cell proliferation (Tiziana et al., 2015; Vincent et al., 2015). AMPK activity is mainly regulated by the intracellular AMP / ATP ratio (Sanz P et al., 2008). When the intracellular ATP concentration decreases, the increased 5'-AMP activates AMPK. AMPK has a heterotrimeric structure, consisting of a catalytic subunit α and two regulatory subunits β and γ. One piece of evidence linking AMPK to tumorigenesis is that AMPK is a substrate of the tumor suppressor kinase LKB1. Currently, 12 AMPK-related kinases with structures similar to the AMPK α subunit have been identified, including BRSK1, BRSK2, NUAK1, NUAK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4, and MELK. All of these kinases, except MELK, can be specifically phosphorylated and activated by LKB1 at threonine position 172, which corresponds to the catalytic subunit of AMPK (Sun et al., 2013).

[0003] NUAK1 (also known as AMPK-related protein kinase 5 or ARK5) and NUAK2 (also known as NUAK family SNF1-like kinase 2 or SNARK) are members of the AMPK-related protein kinase family and share a high degree of structural similarity. Structurally, they are similar to the α-catalytic subunit of AMPK and both contain a ubiquitin-binding domain at the C-terminus of their catalytic region (Bright NJ et al., 2009), which is essential for the phosphorylation and activation of LKB1. Amino acid sequence analysis showed that human NUAK1 and NUAK2 share an overall homology of 55% (Suzuki et al., 2003).

[0004] NUAK1, a member of the AMPK-related kinase family discovered by Suzuki et al. in 2003, consists of 661 amino acids and has a molecular weight of 74 kDa. NUAK1 is expressed in the heart, kidney, liver, brain, and skeletal muscle, and is highly expressed in various cancer cells, including multiple myeloma. Studies have shown that NUAK1 is associated with the AKT signaling pathway, particularly with IGF-induced cell migration and invasion (Kusakai et al., 2004). NUAK1 is highly relevant to cancer cell generation and survival, inhibiting tumor cell apoptosis induced by glucose starvation and factors such as cytokines and TNFα (Atsushi et al., 2003), and is a major factor in AKT-dependent tumor survival and metastasis. In summary, NUAK1 is highly expressed in tumor cells such as breast cancer (Liu F et al., 2013), liver cancer (Cui J et al., 2013), and pancreatic cancer (HUANG X et al., 2014), playing an important role in tumor metastasis and invasion, making it a potential therapeutic target for cancer.

[0005] NUAK2 is the fourth member of the AMPK-associated protein kinase family (Dmytro et al., 2012) and possesses autophosphorylation capabilities. The human NUAK2 gene is located on chromosome 1q32.1, consists of 628 amino acids, and has a molecular weight of 69 kDa. NUAK2 is primarily distributed in the cell nucleus and can be activated in response to cellular and environmental stresses, forming part of the cellular stress response. The activation and regulatory mechanisms of NUAK2 are broadly similar to those of AMPK (Bekri et al., 2014), with its activity mainly regulated by the intracellular AMP / ATP ratio, such as glucose deprivation or chemical ATP production (Waise et al., 2019; Rune et al., 2009). The death receptor CD95 induces apoptosis in many tissues, and studies have reported that NUAK2 is one of the CD95 regulatory genes, inducing apoptosis through a TNF-α and NF-κB-mediated mechanism (Zagorska et al., 2010). Studies have found that NUAK2 is highly expressed in various tumor cells, and the growth and survival of melanoma are closely related to NUAK2 kinase. Knocking out NUAK2 and inhibiting the PI3K pathway can effectively control CDK2 expression. CDK2 inactivation specifically inhibits the proliferation of melanoma cells with low NUAK2 expression and PTEN deficiency, suggesting that CDK2 blockade can treat PTEN-deficient melanoma by interfering with NUAK2 (Namiki et al., 2015).

[0006] The activity regulation of NUAK1 is similar to that of AMPK. Its catalytic domain contains a highly conserved T-loop, indicating activation by upstream kinases via phosphorylation of threonine. Experiments show that phosphorylation of threonine at position 211 of NUAK1 by LKB1 or phosphorylation of serine at position 600 by AKT activates NUAK1 activity. The activated NUAK1 activity is 10-20 times higher than the baseline level (Lizcano et al., 2004). The activity regulation mechanism of NUAK2 is highly similar to that of AMPK. Phosphorylation of threonine at position 208 of the T-loop of NUAK2 by LKB1 is equivalent to phosphorylation at position 172 of AMPK. This activation increases NUAK2 activity by 50-fold, demonstrating the important role of NUAK2 in LKB1 function. In conclusion, NUAK1 and NUAK2 play important roles in normal cellular energy homeostasis and in tumor formation, invasion, and metastasis. NUAK1 and NUAK2 may be potential therapeutic targets for cancer and metabolic diseases.

[0007] Banerjee et al. (Biochemical J. 2014, 457(1), 215) reported highly specific NUAK1 kinase inhibitors WZ4003 and HTH-01-015. Their study found that in drug-resistant cells that highly expressed the NUAK1 [A195T] mutant rather than wild-type NUAK1, WZ4003 or HTH-01-015 inhibited NUAK1 phosphorylation at the Ser445 site of MYPT1. The inhibitory effects of WZ4003 and HTH-01-015 on the migration of MEFs (mouse embryonic fibroblasts) in the wound healing assay were similar to those of NUAK1 knockout. The inhibitory effects of WZ4003 and HTH-01-015 on MEF proliferation were also comparable to those of shRNA knockout of NUAK1. In the 3D U2OS cell invasion assay, the inhibitory effects of WZ4003 and HTH-01-015 on U2OS cell invasion were also comparable to those of NUAK1 knockout. Therefore, WZ4003 and HTH-01-015 can serve as useful tools for studying the biological functions of NUAK kinase.

[0008] WO2011156786 discloses 6-(alkynyl)pyrido[2,3-d]pyrimidine-7(8H)-one derivatives as PAK inhibitors. US20150126508 discloses pteridinone derivatives as EGFR, BLK, and FLT3 inhibitors. KR2020036638 discloses pyrido[2,3-d]pyrimidine derivatives with inhibitory activity against various kinases, particularly EGFR wild-type or mutant. US20210070731 discloses tricyclic compounds as kinase inhibitors (NUAK1, NUAK2, SIK1, CLK1, and CLK2, etc.). WO2021048618 and WO2021048620 disclose 1,4-dihydrobenzo[d]pyrazolo[3,4-f][l,3]diazazepine derivatives as kinase modulators (especially LRRK2, NUAK1, and TYK2). Summary of the Invention

[0009] The present invention provides novel substituted fused bicyclic compounds, or pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemates, isotopically labeled compounds, solvates, hydrates or prodrugs thereof, as kinase inhibitors, particularly NUAK1 / 2 inhibitors, with structures as shown in Formula I (including Formulas II and III).

[0010] The present invention also provides pharmaceutical compositions comprising an effective amount of a compound of formula I (including formulas II and III) or a pharmaceutically acceptable salt thereof, geometric isomer, enantiomer, diastereomer, racemic compound, isotopically labeled compound, solvate, hydrate or prodrug for the treatment or prevention of NUAK1 / 2 mediated diseases, particularly cancer.

[0011] In one specific embodiment, the pharmaceutical composition may also contain one or more pharmaceutically acceptable carriers or diluents for the treatment of cancer.

[0012] In one specific embodiment, the pharmaceutical composition may also contain at least one known anticancer drug or a pharmaceutically acceptable salt of said anticancer drug for the treatment of cancer.

[0013] The present invention also relates to methods for preparing novel compounds of structural formula I (including formulas II and III) or pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemates, isotopically labeled compounds, solvates, hydrates or prodrugs thereof. Detailed Implementation

[0014] It should be understood that the features of the various embodiments described herein can be combined arbitrarily to form the technical solutions described herein; the definitions of each group herein apply to any embodiment described herein, for example, the definitions of alkyl substituents herein apply to any embodiment described herein, unless the alkyl substituents have been clearly defined in the embodiment.

[0015] The term "hydrogen (H)" as used in this article includes its isotopes deuterium (D) and tritium (T).

[0016] As used in this article, "alkyl" refers to an alkyl group itself or a straight-chain or branched group with up to ten carbon atoms. Useful alkyl groups include straight-chain or branched C1-C1 groups. 10 Alkyl group, preferably C1-C6 alkyl. In some embodiments, the alkyl group is C1-C4 alkyl. Typical C1-C6 alkyl groups... 10 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl, and octyl.

[0017] The term "alkoxy" as used in this article refers to an alkoxy group that has undergone oxidation by the aforementioned C1-C2O 10 Alkyl groups, preferably C1-C6 or C1-C4 alkyl-substituted alkyl groups, such as methoxy, ethoxy, etc. The alkyl group in the alkoxy group may be optionally substituted. Substituents in the alkoxy group include, but are not limited to, halogens, morpholino groups, amino groups, and carboxyl groups (including their ester groups), wherein the amino group includes alkylamino and dialkylamino groups.

[0018] The term "amino" as used herein can be represented by –NR′R″, where R′ and R″ are each independently hydrogen, optionally substituted C1-C. 10 Alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or R′ and R″ together with the N to which they are attached to form an optionally substituted 4- to 7-membered cycloamino group, said cycloamino group optionally containing one or more (e.g., 2, 3) additional heteroatoms selected from O, N, and S. Preferred amino groups include NH2, and at least one of R′ and R″ is a C1-C6 alkyl group (preferably C1-C4 alkyl).

[0019] The term "oxo" as used in this article refers to =O.

[0020] As used herein, "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic group containing 6 to 14 carbon atoms, either as a single group or as part of another group. An aryl group may be substituted by one or more of the substituents described herein.

[0021] Useful aryl groups include C6-C 14 Aryl groups, preferably C6-C 10 Aryl group. Typical C6-C 14 Aryl groups include phenyl, naphthyl, phenanthryl, anthraceneyl, indyl, azulel, biphenyl, biphenylene, and fumonisinyl.

[0022] In this document, carbocyclic groups refer to saturated or partially saturated cyclic hydrocarbon groups composed of carbon and hydrogen, including cycloalkyl and cycloalkenyl groups. Useful cycloalkyl groups are C3-C8 cycloalkyl groups. Useful cycloalkenyl groups include C3-C8 cycloalkenyl groups. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Typical cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Carbocyclic groups such as C3-C8 cycloalkyl and C3-C8 cycloalkenyl groups may be substituted with one or more of the substituents described herein.

[0023] Useful halogens or halogen groups include fluorine, chlorine, bromine, and iodine.

[0024] Useful acyl groups include C1-C6 acyl groups, such as acetyl groups. The acyl group may optionally be substituted with a group selected from halogens, amino groups, and aryl groups, wherein the amino and aryl groups are optionally substituted. When halogenated, the number of halogen substituents can range from 1 to 5. Examples of halogenated acyl groups include chloroacetyl and pentafluorobenzoyl. When substituted with an amino group, the amino group may be substituted with one or two substituents as described herein. In some embodiments, the amino acyl group is -C(O)-NR′R″, where R′ and R″ are each independently hydrogen, optionally substituted C1-C6 groups. 10 The alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl groups are used. Preferably, R′ and R″ are each independently H, optionally substituted C1-C4 alkyl, or optionally substituted C3-C6 cycloalkyl. When the alkyl, cycloalkyl, aryl, and heteroaryl groups in R′ and R″ are substituted herein, the substituents are as described in any embodiment herein, with preferred substituents including halogens, hydroxyl groups, amino groups, and alkyl groups.

[0025] Useful acylamino groups (acylamino groups) are any C1-C6 acyl (alkanoyl) group attached to an amino nitrogen atom, such as acetamido, acetamido, propionyl, butyryl, pentanoyl, and hexanoyl, as well as aryl-substituted C1-C6 acylamino groups, such as benzoylamino. Useful acyl groups include C1-C6 acyl groups, such as acetyl. The acyl group may optionally be substituted with a group selected from aryl and halogen groups, wherein the aryl group is optionally substituted. When halogenated, the number of halogen substituents can range from 1 to 5. Examples of substituted acyl groups include chloroacetyl and pentafluorobenzoyl, etc.

[0026] As used herein, "heterocyclic group" refers to a saturated or partially saturated 3-7 membered monocyclic group, 7-10 membered bicyclic group, helical ring group, or bridged ring group, consisting of a carbon atom and 1-4 heteroatoms selected from O, N, and S, wherein the heteroatoms nitrogen and sulfur can be arbitrarily oxidized, and nitrogen can be arbitrarily quaternized. Heterocyclic groups also include fused heterocycles formed by the fusion of any heterocycle defined above with a benzene ring in the aforementioned bicyclic system. If the resulting compound is stable, the carbon or nitrogen atom of the heterocycle can be substituted. The heterocyclic group can be substituted by one or more substituents as described herein.

[0027] Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, pyrrolidinyl, imidazoalkyl, imidazolinyl, dihydroindolyl, isodihydroindolyl, quininecycloyl, morpholinyl, oxazinyl, isochromyl, chromanyl, pyrazolyl, pyrazolyl, tetrahydroisoquinolinyl, tetronoyl, tetramoyl, dihydropyridinyl, dihydropyrimidinyl, aziridine, oxacyclobutyl, and oxacyclopropyl, which may be substituted by one or more of the substituents described herein.

[0028] As used herein, "heteroaryl" refers to a group containing 5–14 ring atoms, with 6, 10, or 14 π electrons shared in the ring system. The ring atoms in a heteroaryl group are carbon atoms and 1–3 heteroatoms selected from oxygen, nitrogen, and sulfur. A heteroaryl group may be substituted by one or more of the substituents described herein.

[0029] Useful heteroaryl groups include thienyl (phenylthio), benzo[d]isothiazo-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, oxanthiinyl, phenoxanthiinyl, pyrroleyl, imidazolyl, pyrazolyl, pyridyl (including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indazinyl, isoindolyl, 3H-indolyl, indolyl, indazoleyl, purine, 4H-quinazinyl, isoquinolinyl, quinolinyl, quinoxalinyl, phthalazinyl, naphridyl, dihydronaphridyl, quinazolinyl, cinnazolyl, pteridinyl, carbazolyl, β-carbazolyl, phenanthridine, acridineyl. Naphthalene-intercalated diazoxide-phenyl, phenanthroline, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazonyl, phenotoxazinyl, 1,4-dihydroquinoxalin-2,3-dione, 7-aminoisocoumarin, pyridopyrimidin-4-one, tetrahydropyridopyrimidinyl, tetrahydropentamembered [c]pyrazol-3-yl, benzisoxazolyl such as 1,2-benzisoxazol-3-yl, Benzimidazolyl, 2-hydroxyindoleyl, thiadiazolyl, 2-oxobenzimidazolyl, imidazopyridinyl, imidazopyridinyl, triazolpyridinyl, triazolpyridinyl, dihydropyridinylpyrimidinyl, tetrahydropyridinylpyrimidinyl, pyrazolpyridinyl, pyrrolidinepyrimidinyl, pyrrolidinepyridinyl, pyrrolidinepyrazinyl, pyridinyltriazinyl, or triazolidinepyrazinyl. When the heteroaryl group contains a nitrogen atom in the ring, such nitrogen atom can be in the form of an N-oxide, such as pyridinyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.

[0030] Unless otherwise stated herein, when substituted, the alkyl, cycloalkyl, alkoxy, amide, carbonyl, heterocyclic, aryl, or heteroaryl groups described in any embodiment herein may be substituted by one or more (e.g., 1, 2, 3, or 4) substituents selected from the following groups: halogen, cyano, nitro, hydroxy, carboxyl, C1-C6 amide, C1-C6 alkoxy, aryloxy, C1-C6 alkyl, C1-C6 acyl, C6-C6... 10 Aryl, C3-C8 cycloalkyl, heterocyclic or heteroaryl and carbonyl groups, etc. The substituent itself may also be optionally substituted. More preferably, the substituents include, but are not limited to, halogens, carbonyls, C1-C6 amides, C1-C6 alkoxys, C1-C6 alkyls and C1-C6 acyls.

[0031] It should be understood that in the embodiments described herein, when the substituent is cycloalkyl, heterocyclic, aryl, or heteroaryl, the number of such heterocyclic, aryl, or heteroaryl substituents is generally one. Furthermore, it should be understood that the connection or substitution between the groups in this invention should satisfy the bond valence theory; unless otherwise stated, when the bond valence theory is not satisfied, it is generally supplemented with H. The circles in each structural formula represent the number and position of double bonds, satisfying the covalent bond theory.

[0032] Specifically, the present invention provides compounds of Formula I or pharmaceutically acceptable salts thereof, geometric isomers, enantiomers, diastereomers, racemates, isotopically labeled compounds, solvates, hydrates, or prodrugs: Wherein, ring A is a substituted heterocyclic group or heteroaryl group; R0 is selected from optionally substituted carbocyclic groups and optionally substituted heterocyclic groups; B1 is selected from N and CR1; B2 is selected from N and CR2; B3 is selected from N and CR3; D1 is selected from N and CR4; D2 is selected from N and CR5; D3 is selected from N and CR6; R1, R2, R3, R4, R5 and R6 are each independently selected from H, halogens, optionally substituted alkyl groups and optionally substituted alkoxy groups; R7 is selected from halogens, optionally substituted C1-C6 alkyl groups, and optionally substituted C1-C6 alkoxy groups; R8 is selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted heterocyclic and optionally substituted heteroaryl; or R8 is connected to D1 or D2 to form an optionally substituted heterocyclic or heteroaryl.

[0033] In some embodiments of Formula I, R0 is attached to the adjacent position of the carbon atom in the ring bridged by ring A and rings containing B1-B3. In some embodiments, R0 is attached to the nitrogen atom in ring A; in other embodiments, R0 is attached to the carbon atom in ring A.

[0034] In some embodiments of Formula I, the compound of Formula I has the structure shown in Formula Ia or Ib: In the formula, rings A, R0, B1, B2, B3, D1, D2, D3, R7, and R8 are as described in Formula I.

[0035] In some embodiments of formulas I, Ia, and Ib, ring A is a substituted six-membered heterocyclic group or a six-membered heteroaryl group.

[0036] In some embodiments of formulas I, Ia, and Ib, preferably, when substituted, the substituents on ring A can be one, two, or three, and the substituents can be selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, halogen, cyano, oxo, optionally substituted C3-C7 cycloalkyl, optionally substituted heterocyclic, optionally substituted C1-C6 acyl, and -NR. a R b , where R a and R b Each is independently an H or C1-C4 alkyl group. When the C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 acyl groups are substituted, the number of substituents can be 1-5, and the substituents can be selected from halogens, hydroxyl groups, and -NR. a R b , where R a and R b Each is independently an H or C1-C4 alkyl group. When the C3-C7 cycloalkyl group is substituted, the number of substituents can be 1, 2, or 3, and the substituents can be selected from halogens, C1-C4 alkyl groups, halogenated C1-C4 alkyl groups, C1-C4 alkoxy groups, halogenated C1-C4 alkoxy groups, hydroxyl groups, and -NR groups. a R b , where R a and R b Each heterocyclic group is independently H or C1-C4 alkyl. The heterocyclic group is preferably a 3-7 membered heterocyclic group, more preferably a 3-7 membered heterocyclic group containing nitrogen and / or oxygen, including but not limited to azirobutyl, oxobutyl, oxopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazine, and piperidinyl. When the heterocyclic group is substituted, the number of substituents can be 1, 2, or 3, and the substituents can be selected from halogens, C1-C4 alkyl groups, halogenated C1-C4 alkyl groups, C1-C4 alkoxy groups, halogenated C1-C4 alkoxy groups, hydroxyl groups, and -NR groups. a R b , where R a and R b Each is independently H or C1-C4 alkyl. In some embodiments, the ring atom adjacent to the N substituted with R0 is substituted with =O.

[0037] In any of the foregoing embodiments of Formulas I, Ia, and Ib, R0 is an optionally substituted cycloalkyl or optionally substituted cycloalkenyl group, preferably a C3-C7 cycloalkyl or C3-C7 cycloalkenyl group. In some embodiments, R0 is an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl group. In some embodiments, the cyclopentenyl group is cyclopent-1-en-1-yl. In some embodiments, R0 is an optionally substituted 3-7 membered heterocyclic group. Preferred heterocyclic groups are 3-6 membered nitrogen- and / or oxygen-containing heterocyclic groups, including azirobutyl, oxacyclobutyl, oxacyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazine, and piperidinyl, etc. When substituted, R0 has one, two, or three substituents, which can be selected from halogens, C1-C6 alkyl groups, halo-C1-C6 alkyl groups, hydroxyl groups, C1-C6 alkoxy groups, halo-C1-C6 alkoxy groups, and -NR groups. a R b , where R a and R b Each is independently H or C1-C4 alkyl.

[0038] In any of the foregoing embodiments of formulas I, Ia, and Ib, B1 is N or CR1, B2 is N, and B3 is N or CR3; R1 is preferably H, a halogen, or a C1-C4 alkyl group, and R3 is preferably H, a halogen, or a C1-C4 alkyl group. In some embodiments, B1, B2, and B3 are each independently N or CH. Preferably, B1 is N; B2 is N; and B3 is CR3, wherein R3 is H or a C1-C4 alkyl group. More preferably, B1 is N; B2 is N; and B3 is CH.

[0039] In any of the foregoing embodiments of formulas I, Ia, and Ib, D1, D2, and D3 are each independently N or CH; or D1 is CR4, D2 is CR5, and D3 is CR6. Preferably, R4, R5, and R6 are each independently H, a halogen, and a C1-C4 alkyl group. Preferably, D1, D2, and D3 are all CH.

[0040] In any of the foregoing embodiments of formulas I, Ia, and Ib, the alkyl and alkoxy groups in R1, R2, R3, R4, R5, and R6 are C1-C4 alkyl and C1-C4 alkoxy groups, respectively. When substituted, the number of substituents on the alkyl and alkoxy groups can be 1, 2, 3, 4, or 5, and these substituents can be independently selected from halogens, hydroxyl groups, and -NR. a R b , where R a and R b Each is independently H or C1-C4 alkyl.

[0041] In any of the foregoing embodiments of formulas I, Ia, and Ib, R7 is a halogen, an optionally substituted C1-C3 alkyl group, and an optionally substituted C1-C3 alkoxy group. Preferably, R7 is a halogen and an optionally substituted methoxy group; more preferably, R7 is a methoxy group. Preferably, when the C1-C3 alkyl group and C1-C3 alkoxy group are substituted, the number of substituents can be 1, 2, 3, 4, or 5, and the substituents can be independently selected from halogens, hydroxyl groups, and -NR. a R b , where R a and R b Each is independently H or C1-C4 alkyl. In some embodiments, R7 is a halogen, a C1-C3 alkoxy (such as methoxy, ethoxy, and propoxy), or a halogenated C1-C3 alkoxy (such as trifluoromethoxy).

[0042] In any of the foregoing embodiments of Formulas I, Ia, and Ib, R8 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, and optionally substituted heterocyclic group. The heterocyclic group is preferably a 4-7 member containing nitrogen and / or oxygen, including azirrobutyl, oxobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazine, 1,4-diazacycloheptyl (e.g., 1,4-diazacycloheptane-1-yl), and piperidinyl, etc. Preferably, the substituent on R8 can be 1 to 4 groups selected from the following: C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyl, heterocyclic group optionally substituted with 1 to 4 C1-C6 alkyl groups (such as 4-7 nitrogen- and / or oxygen-containing heterocyclic groups as described above), halogen, -NR a R b and hydroxyl groups, wherein R a and R b Each is independently H and C1-C6 alkyl. Preferably, the substituent on R8 is one, two, or three substituents selected from hydroxyl, halogen, C1-C4 alkyl, and halo-C1-C4 alkyl. In a preferred embodiment, R8 is optionally substituented with one or two substituents selected from -NR. a R b Substituents of C1-C4 alkyl and halogenated C1-C4 alkyl groups are 4-7 member nitrogen-containing heterocyclic groups, including aziridine, pyrrolidinyl, piperazine, 1,4-diazacycloheptyl and piperidinyl.

[0043] In any of the foregoing embodiments of Formulas I, Ia, and Ib, R8 is connected to D1 or D2 to form a substituted 4-7-membered heterocyclic group or a 5-14-membered heteroaryl group. Preferred 4-7-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazineyl, 1,4-diazacycloheptyl (e.g., 1,4-diazacycloheptane-1-yl), and piperidinyl; preferred 5-14-membered heteroaryl groups include, but are not limited to, furanyl, pyranyl, pyrrolidinyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and indazinyl. When the heterocyclic group and heteroaryl group are substituted, the number of substituents can be 1, 2, or 3, and the substituents can be selected from C1-C6 alkyl, C1-C6 acyl, heterocyclic groups optionally substituted with 1-4 C1-C6 alkyl groups (such as the 4-7-membered heterocyclic groups described above), halogens, -NR, etc. a R b and hydroxyl groups, wherein R a and R b Each is independently H and C1-C6 alkyl.

[0044] In some embodiments of formulas I, Ia, and Ib, ring A is preferably a substituted 6-membered nitrogen-containing heterocyclic group or a 6-membered nitrogen-containing heteroaryl group; more preferably, the bicyclic ring formed by ring A together with the fused aromatic ring containing B1, B2, and B3 is selected from: Wherein, *1 and *2 indicate the connection positions of the group with the remaining R0 and -NH of the compound; R3 is H or C1-C3 alkyl (preferably methyl); R9 is H or C1-C3 alkyl (preferably methyl); R 10 It is H, C1-C3 alkyl (preferably methyl), C2-C4 acyl (preferably acetyl) or cyano; R 12 It is H or C1-C3 alkyl (preferably methyl).

[0045] Preferably, the compounds of formula I, Ia, and Ib have the structure shown in formula II (including formula IIa, IIb, and IIc): Among them, R0, B1, B2, B3, D1, D2, D3, R7 and R8 are as described in Formula I; A1 is selected from N and CR9; A2 is selected from N and CR. 10 ; A3 is selected from O, S, NR 11 and CR 13 R' 13 ; A4 is selected from O, S, NR 12 and CR 14 R' 14 ; R9 and R 10 Each can be independently H, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy or optionally substituted C1-C6 acyl; R 11 and R 12 Each is independently an H or optionally substituted C1-C6 alkyl group; R 13 、R' 13 R 14 and R' 14 Each is independently H, an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C6 alkoxy group.

[0046] In compounds of formulas IIa, IIb, and IIc, R0 is an optionally substituted cycloalkyl or optionally substituted cycloalkenyl group, preferably a C3-C7 cycloalkyl or C3-C7 cycloalkenyl group. In some embodiments, R0 is an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl group. In some embodiments, the cyclopentenyl group is cyclopent-1-en-1-yl. In some embodiments, R0 is an optionally substituted 3-7 membered heterocyclic group. Preferred heterocyclic groups are 3-6 membered nitrogen- and / or oxygen-containing heterocyclic groups, including azirrobutyl, oxacyclobutyl, oxacyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazine, and piperidinyl, etc. When substituted, R0 has one, two, or three substituents, which can be selected from halogens, C1-C6 alkyl groups, halo-C1-C6 alkyl groups, hydroxyl groups, C1-C6 alkoxy groups, halo-C1-C6 alkoxy groups, and -NR groups. a R b , where R a and R b Each is independently H or C1-C4 alkyl.

[0047] In compounds of formulas IIa, IIb, and IIc, preferably, B1 is N or CR1, B2 is N, and B3 is N or CR3; R1 is preferably H, a halogen, or a C1-C4 alkyl group, and R3 is preferably H, a halogen, or a C1-C4 alkyl group. More preferably, B1, B2, and B3 are each independently N or CH. Preferably, B1 is N; B2 is N; and B3 is CR3, wherein R3 is H or a C1-C4 alkyl group. More preferably, B1 is N; B2 is N; and B3 is CH.

[0048] In compounds of formulas IIa, IIb, and IIc, preferably, D1, D2, and D3 are each independently N or CH; or D1 is CR4, D2 is CR5, and D3 is CR6. Preferably, R4, R5, and R6 are each independently H, a halogen, and a C1-C4 alkyl group. Preferably, D1, D2, and D3 are all CH.

[0049] In any of the foregoing embodiments of compounds of formulas IIa, IIb, and IIc, R7 is a halogen, an optionally substituted C1-C3 alkyl group, and an optionally substituted C4 group. 1- C3 alkoxy, preferably, R7 is a halogen and optionally a substituted methoxy group. Preferably, when the C1-C3 alkyl and C1-C3 alkoxy groups are substituted, the number of substituents can be 1, 2, 3, 4 or 5, and the substituents can be independently selected from halogens, hydroxyl groups and -NR. a R b , where R a and R b Each is independently H or C1-C4 alkyl. In some embodiments, R7 is a halogen, a C1-C3 alkoxy (such as methoxy, ethoxy, and propoxy), or a halogenated C1-C3 alkoxy (such as trifluoromethoxy).

[0050] In any of the foregoing embodiments of compounds of formulas IIa, IIb, and IIc, R8 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, or optionally substituted heterocyclic group. The heterocyclic group is a 4-7 member, preferably a 4-6 member, containing nitrogen and / or oxygen, including azirrobutyl, oxobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazine, 1,4-diazacycloheptyl (e.g., 1,4-diazacycloheptane-1-yl), and piperidinyl, etc. Preferably, the substituent on R8 can be 1-4 groups selected from the following: C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyl, heterocyclic group optionally substituted with 1-4 C1-C6 alkyl groups (such as 4-6 nitrogen- and / or oxygen-containing heterocyclic groups as described above), halogen, -NR a R b and hydroxyl groups, wherein R a and R b Each is independently H and C1-C6 alkyl. Preferably, the substituent on R8 is one, two, or three substituents selected from hydroxyl, halogen, C1-C4 alkyl, and halo-C1-C4 alkyl. In a preferred embodiment, R8 is optionally substituented with one or two substituents selected from -NR. a R b Substituents of C1-C4 alkyl and halogenated C1-C4 alkyl groups are 4-7 member nitrogen-containing heterocyclic groups, including aziridine, pyrrolidinyl, piperazine, 1,4-diazacycloheptyl and piperidinyl.

[0051] In any of the preceding embodiments of Formula II, R8 is connected to D1 or D2 to form a substituted 4-7-membered heterocyclic group or a 5-14-membered heteroaryl group. Preferred 4-7-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazineyl, 1,4-diazacycloheptyl (e.g., 1,4-diazacycloheptane-1-yl), and piperidinyl; preferred 5-14-membered heteroaryl groups include, but are not limited to, furanyl, pyranyl, pyrrolidinyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and indazinyl. When the heterocyclic group and heteroaryl group are substituted, the number of substituents can be 1, 2, or 3, and the substituents can be selected from C1-C6 alkyl, C1-C6 acyl, heterocyclic groups optionally substituted with 1-4 C1-C6 alkyl groups (such as the 4-7-membered heterocyclic groups described above), halogens, and -NR. a R b and hydroxyl groups, wherein R a and R b Each is independently H and C1-C6 alkyl.

[0052] In any of the foregoing embodiments of the compound of formula IIa, R9 and R 10 When the respective C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 acyl groups are substituted, the number of substituents can be 1, 2, 3, 4, or 5, and the substituents can be independently selected from halogens, hydroxyl groups, and -NR. a R b , where R a and R b Each is independently an H or C1-C4 alkyl group. Preferred are R9 and R... 10 Each is independently H, C1-C4 alkyl, CN, or C2-C4 acyl. In some embodiments, R9 is H or C1-C3 alkyl (preferably methyl); R 10 It is H, C1-C3 alkyl (preferably methyl), cyano, or C2-C4 acyl (preferably acetyl).

[0053] In any of the foregoing embodiments of the compound of formula IIa, preferably, A1 and A2 are each independently N, CH, C-CN, C-(C1-C3 alkyl), or C-(C2-C4 acyl). In some embodiments, A1 is N and A2 is C-CN. 10 , where R 10 The alkyl group is selected from H and C1-C3 alkyl groups. In some embodiments, A1 is CR9 and A2 is N, wherein R9 is selected from H and C1-C3 alkyl groups. In some embodiments, A1 is CR9 and A2 is CR 10 R9 is selected from H and C1-C3 alkyl groups, R 10 Selected from H, C1-C3 alkyl, cyano and C2-C4 acyl.

[0054] In any of the foregoing embodiments of the compound of formula IIb, R 11 and R 12 When the respective C1-C6 alkyl groups are substituted, the number of substituents can be 1, 2, 3, 4, or 5, and the substituents can be independently selected from halogens, hydroxyl groups, and -NR. a R b , where R a and R b Each is independently H or C1-C4 alkyl.

[0055] In any of the foregoing embodiments of the compound of formula IIb, R 13 、R' 13 R 14 and R' 14 When the respective C1-C6 alkyl and C1-C6 alkoxy groups are substituted, the number of substituents can be 1, 2, 3, 4, or 5, and the substituents can be independently selected from halogens, hydroxyl groups, and -NR. a R b , where R a and R b Each is independently H or C1-C4 alkyl.

[0056] In any of the foregoing embodiments of the compound of formula IIb, A3 is selected from O, NR 11 and CR 13 R' 13 A4 is selected from O and NR. 12 and CR 14 R' 14 Preferably, A3 is selected from O and CR. 13 R' 13 A4 is selected from O and NR. 12 and CR 14 R' 14 Preferably, R 11 R 12 R 13 、R' 13 R 14 and R' 14 Each is independently H or C1-C3 alkyl; preferably R 11 and R 12 Both are H, R 13 and R' 13 At least one of them is H, R 14 and R' 14 At least one of them is H. In some embodiments, A3 and A4 are each independently O, CH2 or NH.

[0057] In any of the foregoing embodiments of the compound of formula IIc, A1 and A2 are each independently N, CH, C-CN, C-(C1-C3 alkyl), or C-(C2-C4 acyl). Preferably, A1 and A2 are each independently N or CH. More preferably, A1 is CH and A2 is CN.

[0058] In some embodiments of formula IIa, preferably, the fused bicyclic ring containing A1, A2, B1, B2 and B3 is selected from: Wherein, *1 and *2 indicate the connection positions of the group with the remaining R0 and -NH of the compound; R3 is H or C1-C3 alkyl (preferably methyl); R9 is H or C1-C3 alkyl (preferably methyl); R 10 It is H, C1-C3 alkyl (preferably methyl), cyano, or C2-C4 acyl (preferably acetyl).

[0059] In some embodiments of formula IIb, preferably, the fused bicyclic ring containing A3, A4, B1, B2, and B3 is selected from: Wherein, *1 and *2 indicate the connection positions of the group with the remaining parts of the compound, R0 and -NH; R 12 It is H or C1-C3 alkyl (preferably methyl).

[0060] In some embodiments of formula IIc, preferably, the fused bicyclic ring containing A1, A2, B1, B2 and B3 is selected from:

[0061] In one or more of the foregoing embodiments, the compounds of formula II have the structures shown in formula III (including formulas IIIa, IIIb, IIIc, IIId, and IIIe): Among them, R0, B1, B2, B3, R7, R9, R 10 and R 12 As described in formulas I, Ia, Ib, IIa, IIb, or IIc; Cy is selected from optionally substituted heterocyclic groups.

[0062] In compounds of formulas IIIa, IIIb, IIIc, IIId, and IIIe, R0 is an optionally substituted cycloalkyl or optionally substituted cycloalkenyl group, preferably a C3-C7 substituted cycloalkyl or C3-C7 cycloalkenyl group. In some embodiments, R0 is an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl group. In some embodiments, the cyclopentenyl group is cyclopent-1-en-1-yl. In some embodiments, R0 is an optionally substituted 3-7 membered heterocyclic group. Preferred heterocyclic groups are 3-6 membered nitrogen- and / or oxygen-containing heterocyclic groups, including azirrobutyl, oxacyclobutyl, oxacyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazine, and piperidinyl, etc. When substituted, R0 has one, two, or three substituents, which can be selected from halogens, C1-C6 alkyl groups, halo-C1-C6 alkyl groups, hydroxyl groups, C1-C6 alkoxy groups, halo-C1-C6 alkoxy groups, and -NR groups. a R b , where R a and R b Each is independently H or C1-C4 alkyl.

[0063] In compounds of formulas IIIa, IIIb, IIIc, IIId, and IIIe, R7 is a halogen, an optionally substituted C1-C3 alkyl group, and an optionally substituted C1-C3 alkoxy group. Preferably, R7 is a halogen and an optionally substituted methoxy group. Preferably, when the C1-C3 alkyl group and C1-C3 alkoxy group are substituted, the number of substituents can be 1, 2, 3, 4, or 5, and the substituents can be independently selected from halogens, hydroxyl groups, and -NR. a R b , where R a and R b Each is independently H or C1-C4 alkyl. In some embodiments, R7 is a halogen, a C1-C3 alkoxy (such as methoxy, ethoxy, and propoxy), or a halogenated C1-C3 alkoxy (such as trifluoromethoxy).

[0064] In any of the foregoing embodiments of the compound of formula IIIa, R9 and R 10 When the respective C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 acyl groups are substituted, the number of substituents can be 1, 2, 3, 4, or 5, and the substituents can be independently selected from halogens, hydroxyl groups, and -NR. a R b , where R a and R b Each is independently an H or C1-C4 alkyl group. Preferred are R9 and R... 10 Each is independently H, C1-C4 alkyl, CN, or C2-C4 acyl. In some embodiments, R9 is H or C1-C3 alkyl (preferably methyl); R 10It is H, C1-C3 alkyl (preferably methyl), cyano, or C2-C4 acyl (preferably acetyl).

[0065] In any of the foregoing embodiments of the IIId compound, R 12 When the C1-C6 alkyl group is substituted, the number of substituents can be 1, 2, 3, 4, or 5, and the substituents can be independently selected from halogens, hydroxyl groups, and -NR. a R b , where R a and R b Each is independently H or C1-C4 alkyl.

[0066] In compounds of formulas IIIa, IIIb, IIIc, and IIId, preferably, B1 is N or CR1, B2 is N, and B3 is N or CR3; R1 is preferably H, a halogen, or a C1-C4 alkyl group, and R3 is preferably H, a halogen, or a C1-C4 alkyl group. More preferably, B1, B2, and B3 are each independently N or CH. Preferably, B1 is N; B2 is N; and B3 is CR3, wherein R3 is H or a C1-C4 alkyl group. More preferably, B1 is N; B2 is N; and B3 is CH.

[0067] In any of the foregoing embodiments of compounds of formulas IIIa, IIIb, IIIc, and IIId, Cy is an optionally substituted 4-7 membered heterocyclic group, such as optionally substituted 4-7 membered nitrogen- and / or oxygen-containing heterocyclic groups, including azirrobutyl, oxobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazine, 1,4-diazacycloheptane-1-yl, and piperidinyl. Preferably, Cy is an optionally substituted piperazine, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted 1,4-diazacycloheptane-1-yl. Preferably, when substituted, Cy has 1, 2, or 3 substituents, which may be selected from C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyl, heterocyclic groups optionally substituted with 1-4 C1-C6 alkyl groups (such as the 4-6 member nitrogen- and / or oxygen-containing heterocyclic groups described above), halogens, -NR, etc. a R b and hydroxyl groups, wherein R a and R b Each is independently H and C1-C6 alkyl. More preferably, Cy is a piperazine group optionally substituted with 1-3 substituents selected from C1-C6 alkyl and hydroxyl groups, optionally substituted with 1 substituent selected from C1-C6 alkyl and -NR. a R b The substituent is a piperidinyl group, optionally substituted with 1-3 C1-C6 alkyl groups, a 1,4-diazacycloheptane-1-yl group, and optionally a morpholinyl group substituted with 1-3 C1-C6 alkyl groups; wherein, Ra and R b It is selected alone from H and C1-C4 alkyl groups.

[0068] Preferred compound examples of Formula I include, but are not limited to: 8-Cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pteridine-7(8H)-one (Example 1); 1-Cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 2); 1-Cyclopropyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 3); 1-Cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-3-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 4); 1-Cyclopentyl-7-(((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 5); 1-Cyclohexyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 6); 1-Cyclopentyl-7-((2-ethoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 7); 1-Cyclopentyl-7-((2-isopropoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 8); 1-Cyclopentyl-7-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 9); 1-Cyclopentyl-7-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 10); 7-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-cyclopentylpyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 11); 7-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-cyclopentylpyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 12); 1-Cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methylpyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 13); 1-Cyclobutyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 14); 1-Cyclopropyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 15); 7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(tetrahydro-2H-pyran-4-yl)pyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 16); 7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(piperidin-4-yl)pyrimido[4,5-d]pyrimidin-2(1H)-one (Example 17); 7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(1-methylpiperidin-4-yl)pyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 18); 8-Cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Example 19); 8-Cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Example 20); 8-Cyclopropyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Example 21); 8-Cyclohexyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Example 22); 8-Cyclopropyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Example 23); 5-Cyclopentyl-3-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-e][1,2,4]triazine-6(5H)-one (Example 24); 1-Cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-2-oxo-1,2-dihydro-1,6-naphthidium-3-carboxynitrile (Example 25); 8-Cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxynitrile (Example 26); 8-Cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Example 27); 8-Cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (Example 28); 8-Cyclohexyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (Example 29); 8-Cyclopropyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (Example 30); 8-Cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-6H-pyrimidino[5,4-b][1,4]oxazine-7(8H)-one (Example 31); 7-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-cyclopentyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 32); 7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrimidin[4,5-d]pyrimidin-2(1H)-one (Example 33); 8-Cyclopentyl-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrido[4,3-d]pyrimidine-2-amine (Example 34); 8-(cyclopent-1-en-1-yl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrido[4,3-d]pyrimidine-2-amine (Example 35); 6-Acetyl-8-cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Example 36); 6-Acetyl-8-cyclopentyl-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-methylpyrido[2,3-d]pyrimidine- 7(8H)-keto (Example 37); 8-Cyclohexyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Example 38); 8-Cyclobutyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Example 39); 8-Cycloheptyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-methylpyrido[2,3-d]pyrimidin-7(8H)-one (Example 40); 8-Cycloheptyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Example 41); Or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemic compound, isotope-labeled compound, solvate, hydrate or prodrug.

[0069] Some compounds of this invention can exist as stereoisomers, including optical isomers. This invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as individual enantiomers that can be isolated according to methods well known to those skilled in the art.

[0070] Examples of pharmaceutically usable salts in this invention include inorganic and organic acid salts, such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, and oxalate; as well as inorganic and organic base salts formed with bases such as sodium hydroxyl, tris(hydroxymethyl)aminomethane (TRIS, tromethamine), and N-methylglucosamine.

[0071] Examples of prodrugs of the compounds of the present invention include simple esters of compounds containing carboxylic acids (e.g., esters obtained by condensation with C1-C4 alcohols according to methods known in the art); esters of compounds containing hydroxyl groups (e.g., esters obtained by condensation with C1-C4 carboxylic acids, C3-C6 diacids, or their anhydrides such as succinic anhydride and fumaric anhydride according to methods known in the art); imines of compounds containing amino groups (e.g., imines obtained by condensation with C1-C4 aldehydes or ketones according to methods known in the art); carbamates of compounds containing amino groups, such as those esters described by Leu et al. (J.Med.Chem.42:3623-3628 (1999)) and Greenwald et al. (J.Med.Chem.42:3657-3667 (1999)); and aldol acetals or ketal acetals of compounds containing alcohols (e.g., those acetals obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0072] This invention also includes all suitable isotopic variations of the compounds of the invention or pharmaceutically acceptable salts thereof. An isotopic variation of the compounds of the invention or pharmaceutically acceptable salts thereof refers to the substitution of at least one atom by an atom having the same atomic number but a different atomic mass than that found in nature. Isotopes that can be introduced into the compounds of the invention or pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of H, C, N, and O, for example... 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 35 S, 18 F, 36 Cl and 125 I. Suitable isotopic derivatives of the compounds of the present invention or of pharmaceutically acceptable salts thereof can be prepared by conventional techniques using suitable isotopic derivatives with appropriate reagents.

[0073] The compounds of the present invention can be prepared using methods known to those skilled in the art or the novel methods of the present invention. Specifically, the compounds of the present invention having Formula I can be prepared as shown in the reaction examples in reaction scheme 1. Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate reacts with cyclopentylamine in dichloromethane at room temperature under triethylamine catalysis to give the product ethyl 4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylate. Ethyl 4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylate is reduced by lithium aluminum hydride to give the product (4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-yl)methanol. (4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-yl)methanol is refluxed in thionyl chloride to give the product 5-(chloromethyl)-N-cyclopentyl-2-(methylthio)pyrimidine-4-amine. 5-(chloromethyl)-N-cyclopentyl-2-(methylthio)pyrimidin-4-amine reacts with ammonia in tetrahydrofuran at room temperature to give the product 5-(aminomethyl)-N-cyclopentyl-2-(methylthio)pyrimidin-4-amine. 5-(aminomethyl)-N-cyclopentyl-2-(methylthio)pyrimidin-4-amine reacts with 1,1'-carbonyldiimidazole to give the cyclized product 1-cyclopentyl-7-(methylthio)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one. 1-Cyclopentyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one was oxidized with 3-chloroperoxybenzoic acid to give the product 1-cyclopentyl-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one. 1-Cyclopentyl-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one was then reacted with 2-methoxy-4-(4-methylpiperazin-1-yl)aniline under trifluoroacetic acid catalysis to give the product 1-cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one. 1-Cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one was oxidized under potassium tert-butoxide conditions to give the product 1-cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidino[4,5-d]pyrimidin-2(1H)-one. Reaction Scheme 1

[0074] Other related compounds can be prepared using similar methods. For example, replacing cyclopentylamine with cyclohexylamine yields the target compound 1-cyclohexyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyrimidin-2(1H)-one. Replacing 2-ethoxy-4-(4-methylpiperazin-1-yl)aniline with 2-ethoxy-4-(4-methylpiperazin-1-yl)aniline yields the target compound 1-cyclopentyl-7-((2-ethoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyrimidin-2(1H)-one. Replacing 2-methoxy-4-(4-methylpiperazin-1-yl)aniline with 2-isopropoxy-4-(4-methylpiperazin-1-yl)aniline yields the target compound 1-cyclopentyl-7-((2-isopropoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyrimidin-2(1H)-one. Replacing ethyl 4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-carboxylate with ethyl 4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-carboxylate yields the target compound 1-cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methylpyrimidinyl[4,5-d]pyrimidin-2(1H)-one. Replacing cyclopentylamine with cyclobutylamine yields the target compound 1-cyclobutyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyrimidin-2(1H)-one.

[0075] The compounds of this invention can be prepared as shown in the reaction examples of reaction scheme 2. (4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)methanol is oxidized with manganese dioxide to give the product 4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-carboxaldehyde. 4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-carboxaldehyde is reacted with ethyl (triphenylphosphine) acetate via a Wittig reaction to give the product ethyl 3-(4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)acrylate. ethyl 3-(4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)acrylate is cyclized under the catalysis of 1,8-diazabicycloundec-7-ene to give the product 8-cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one. 8-Cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one was oxidized with 3-chloroperoxybenzoic acid to give the product 8-cyclopentyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one. 8-Cyclopentyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one was then reacted with 2-methoxy-4-(4-methylpiperazin-1-yl)aniline under trifluoroacetic acid catalysis to give the product 8-cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one. Reaction Scheme 2

[0076] Other related compounds can be prepared using similar methods. For example, replacing ethyl 2-(triphenyl-15-phosphono)propionate with ethyl 2-(diethoxyphosphoryl)propionate yields the target compound 8-cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-6-methylpyrido[2,3-d]pyrimidin-7(8H)-one. Replacing cyclopentylamine with cyclohexylamine yields the target compound 8-cyclohexyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridyl[2,3-d]pyrimidin-7(8H)-one.

[0077] The compounds of this invention can be prepared as shown in the reaction examples of reaction scheme 3. 5-Bromo-2,4-dichloropyrimidine reacts with cyclopentylamine under triethylamine catalysis to give the product 5-bromo-2-chloro-N-cyclopentylpyrimidine-4-amine. 5-Bromo-2-chloro-N-cyclopentylpyrimidine-4-amine reacts with ethyl acrylate under a palladium catalyst such as ((PhCN)₂PdCl₂) via a Heck reaction to give the product 3-(2-chloro-4-(cyclopentylamino)pyrimidine-5-yl)ethyl acrylate. Ethyl 3-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)acrylate and 2-methoxy-4-(4-methylpiperazin-1-yl)aniline under palladium catalyst (Pd(OAc)2) undergo a Buchwald–Hartwig coupling reaction to give ethyl 3-(4-(cyclopentylamino)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)acrylate. Ethyl 3-(4-(cyclopentylamino)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)acrylate is then reduced by palladium on carbon / hydrogen to give ethyl 3-(4-(cyclopentylamino)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)propionate. Ethyl 3-(4-(cyclopentylamino)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)propionate was hydrolyzed under sodium hydroxide catalysis to give the product 3-(4-(cyclopentylamino)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)propionic acid. 3-(4-(cyclopentylamino)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)propionic acid was cyclized under the catalysis of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) to give the product 8-cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. Reaction scheme 3

[0078] Other related compounds can be prepared using similar methods. For example, replacing cyclopentylamine with cyclohexylamine yields the target compound 8-cyclohexyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one. Replacing cyclopentylamine with cyclopropylamine yields the target compound 8-cyclopropyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one.

[0079] The compounds of this invention can be prepared as shown in the reaction examples of reaction scheme 4. Oxidation of 8-iodo-2-(methylthio)pyrido[4,3-d]pyrimidine with m-chloroperoxybenzoic acid yields the product 8-iodo-2-(methylsulfinyl)pyrido[4,3-d]pyrimidine. 8-iodo-2-(methylsulfinyl)pyrido[4,3-d]pyrimidine undergoes a substitution reaction with 2-methoxy-4-(4-methylpiperazin-1-yl)aniline under trifluoroacetic acid catalysis to yield the product 8-iodo-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrido[4,3-d]pyrimidine-2-amine. 8-Iodo-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrido[4,3-d]pyrimidin-2-amine reacts with 2-(cyclopentyl-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane under Pd(PPh3)2Cl2 catalysis to give the product 8-(cyclopentyl-1-en-1-yl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrido[4,3-d]pyrimidin-2-amine. 8-(cyclopent-1-en-1-yl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrido[4,3-d]pyrimidine-2-amine was reduced with p-toluenesulfonyl hydrazine to give the target compound 8-cyclopentyl-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrido[4,3-d]pyrimidine-2-amine. Reaction scheme 4

[0080] The compounds of this invention can be prepared as shown in the reaction examples of reaction scheme 5. 2-Chloro-8-cyclopentyl-5-methylpyridano[2,3-d]pyrimidin-7(8H)-one reacts with NBS in the presence of oxalic acid to give the product 6-bromo-2-chloro-8-cyclopentyl-5-methylpyridano[2,3-d]pyrimidin-7(8H)-one. 6-Bromo-2-chloro-8-cyclopentyl-5-methylpyridano[2,3-d]pyrimidin-7(8H)-one reacts with tributyl(1-ethoxyethylene)tin in the presence of di(tri-tert-butylphosphine)palladium to undergo a Stille coupling reaction, followed by reaction with dilute hydrochloric acid to give the product 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyridano[2,3-d]pyrimidin-7(8H)-one. 6-Acetyl-2-chloro-8-cyclopentyl-5-methylpyridano[2,3-d]pyrimidin-7(8H)-one was coupled with 2-methoxy-4-(4-methylpiperazin-1-yl)aniline in a Buchwald–Hartwig coupling reaction catalyzed by the methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphine)xanthan][2'-amino-1,1'-biphenyl]palladium(II)dichloromethane complex (Pd-G3) to give the target compound 6-acetyl-8-cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methylpyridano[2,3-d]pyrimidin-7(8H)-one. Reaction scheme 5

[0081] Other related compounds can be prepared using a similar method. For example, by replacing 2-methoxy-4-(4-methylpiperazin-1-yl)aniline with 4-(4-amino-3-methoxyphenyl)piperazin-1-carboxylic acid tert-butyl ester, the target compound 6-acetyl-8-cyclopentyl-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one can be prepared.

[0082] An important aspect of this invention is the discovery that compounds of formula I (including formulas II and III) are kinase inhibitors, particularly NUAK1 / 2 inhibitors. Therefore, Formula I (including Formulas II and III) or its pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers, racemates, isotopically labeled compounds, solvates, hydrates, or prodrugs may be used as standalone active ingredients for the treatment and prevention of NUAK1 / 2-mediated diseases, disorders, and conditions; or for the preparation of medicaments for the treatment and prevention of NUAK1 / 2-mediated diseases, disorders, and conditions; or as NUAK1 / 2 inhibitors in combination with other anticancer drugs, including but not limited to DSB inducers (such as radiation), topoisomerase II inhibitors (such as etoposide, doxorubicin), and / or PARP inhibitors (such as olaparib, niraparib, rucaparib, talazoparib, pamiparib, fluzoparib, and senaparib), for the treatment and prevention of NUAK1 / 2-mediated diseases, disorders, and conditions, or for the preparation of medicaments for the treatment and prevention of NUAK1 / 2-mediated diseases, disorders, and conditions.

[0083] In this invention, the NUAK1 / 2-mediated diseases, disorders, and conditions include cancer. Cancer can be a solid tumor or a hematologic malignancy, including but not limited to liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, and colon cancer. Colorectal cancer, malignant pancreatic islet tumors, malignant carcinoid cancers, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer. Preferably, the cancer is mediated by NUAK1 / 2 and associated with NUAK1 / 2; "mediated" and "associated" mean playing a role in the occurrence and development of cancer, such as causing cancer occurrence and / or promoting cancer development or metastasis.

[0084] Therefore, the present invention provides a method for treating or preventing NUAK1 / 2-mediated diseases, disorders, and symptoms, the method comprising administering to a desired subject an effective amount of a compound of formula I (including formulas II and III) or a pharmaceutically acceptable salt thereof, geometric isomer, enantiomer, diastereomer, racemate, isotopically labeled compound, solvate, hydrate, or prodrug, or a pharmaceutical composition containing an effective amount of a compound of formula I (including formulas II and III) or a pharmaceutically acceptable salt thereof, geometric isomer, enantiomer, diastereomer, racemate, isotopically labeled compound, solvate, hydrate, or prodrug. In this invention, the subject includes mammals, more specifically humans. In some embodiments, the method of treating or preventing NUAK1 / 2-mediated diseases, disorders, and symptoms further comprises simultaneously or sequentially administering to the desired subject a therapeutically effective amount of at least one known anticancer drug or a pharmaceutically acceptable salt thereof; said at least one known anticancer drug or a pharmaceutically acceptable salt thereof as described in any embodiment herein.

[0085] In implementing the treatment method of the present invention, an effective amount of a pharmaceutical preparation is administered to a patient with one or more of these symptoms. The pharmaceutical preparation contains an effective therapeutic concentration of a compound of formula I (including formulas II and III), formulated for oral, intravenous, topical, or external administration, for the treatment of cancer and other diseases. The dosage is the amount of medicine that effectively improves or eliminates one or more symptoms. For the treatment of a specific disease, an effective amount is an amount sufficient to improve or alleviate, in some way, the symptoms associated with the disease. Such a dosage may be administered as a single dose or may be administered according to an effective treatment regimen. The dosage may cure the disease, but administration is generally intended to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired symptom improvement.

[0086] In another embodiment, a pharmaceutical composition is provided comprising a compound of formula I (including formulas II and III) of the present invention as a NUAK1 / 2 inhibitor, or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, isotopically labeled compound, solvate, hydrate, or prodrug and a pharmaceutically acceptable carrier.

[0087] Another embodiment of the present invention relates to a pharmaceutical composition that can effectively treat cancer, comprising a compound of formula I (including formulas II and III) of the present invention as a NUAK1 / 2 inhibitor or a pharmaceutically acceptable salt thereof, a geometric isomer, an enantiomer, a diastereomer, a racemic compound, an isotopically labeled compound, a solvate, a hydrate or a prodrug, and at least one known anticancer drug or a pharmaceutically acceptable salt thereof.

[0088] In this article, the at least one known anticancer drug or its pharmaceutically acceptable salt includes other anticancer drugs related to DNA damage and repair mechanisms, including PARP inhibitors olaparib, niraparib, rucaparib, talazoparib, pamiparib, fluzoparib, and senaparib; HDAC inhibitors vorinostat, romidesin, pabistat, and belistat, etc. The at least one known anticancer drug or its pharmaceutically acceptable salt also includes other anticancer drugs related to cell division checkpoints, including CDK4 / 6 inhibitors such as palbociclib, ATM inhibitors, ATR inhibitors, Wee1 inhibitors, MYT1 inhibitors, DNA-PK inhibitors, etc., and combinations with other targeted anticancer drugs, including USP1 inhibitors, PRMT5 inhibitors, Polθ inhibitors, RAD51 inhibitors, etc. Other known anticancer drugs that can be used in combination therapy include, but are not limited to, alkylating agents such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, and carboplatin; topoisomerase I inhibitors such as camptothecin, irinotecan, and topotecan; topoisomerase II inhibitors such as doxorubicin, epirubicin, aclarubicin, mitoxantrone, methyl hydroxyrosine, and mentholtoporp; RNA / DNA Antimetabolites such as 5-azacytidine, gemcitabine, 5-fluorouracil, and methotrexate; DNA antimetabolites such as 5-fluoro-2′-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, and thioguanine; antimitotic agents such as colchicine, vincristine, vinorelbine, paclitaxel, ixaprilone, cabazitaxel, and docetaxel; antibodies such as monoclonal antibodies, panitumumab, nazotocin, nivolumab, pembrolizumab, etc. Ramucirumab, Bevacizumab, Pertuzumab, Trastuzumab, Cetuximab, Obinutuzumab, Ofamumab, Rituximab, Alemtuzumab, Tiimumab, Tosimomab, Bentuximab, Daremumab, Erotozumab, T-DM1, Ofatumumab, Dinutuximab, Blinatumomab, Ipilimumab, Avastin, Herceptin, and Rituximab; kinase inhibitors such as Imatinib, Genomicon. Fertrinib, Erlotinib, Ostinib, Afatinib, Ceritinib, Alectinib, Crizotinib, Erlotinib, Lapatinib, Sorafenib, Regorafenib, Vemurafenib, Dabrafenib, Aflibercept, Sunitinib, Nilotinib, Dasatinib, Bosutinib, Pramipinib, Ibrutinib, Cabozantinib, Lenvatinib, Vandetanib, Trametinib, Carbitinib, Axitinib, Tessiromoxetine, Idelalisib, Pazopanib, Tetracycline, and Everolimus.Other known anticancer drugs that can be used in combination therapy include tamoxifen, letrozole, fulvestrant, mitoxantridine, octreotide, retinoid, arsenic, zoledronic acid, bortezomib, carfilzomib, Ixazomib, vemodega, sondega, denosumab, thalidomide, lenalidomide, venetoclax, Aldesleukin (recombinant human interleukin-2), and Sipueucel-T (prostate cancer treatment vaccine).

[0089] In carrying out the method of the present invention, the compound of the present invention may be administered together with at least one known anticancer drug as a single pharmaceutical composition. Alternatively, the compound of the present invention may also be administered separately from at least one known anticancer drug. In one embodiment, the compound of the present invention and at least one known anticancer drug are administered approximately simultaneously, i.e., all drugs are administered simultaneously or sequentially, as long as the compound simultaneously reaches therapeutic concentrations in the blood. In another embodiment, the compound of the present invention and at least one known anticancer drug are administered according to their respective dosage regimens, as long as the compound reaches therapeutic concentrations in the blood.

[0090] Another embodiment of the present invention is a biocoupler containing the compound described herein, which can effectively inhibit tumors as a kinase inhibitor. The biocoupler of the present invention contains the compound described herein and at least one known therapeutically active antibody, such as Herceptin or Rituxan, or a growth factor, such as EGF or FGF, or a cytokine, such as interleukin-2 or 4, or any molecule capable of binding to the cell surface, or a combination thereof. This antibody, along with other molecules, can deliver the compound to its target site, making it an effective anticancer drug. This biocoupler can also enhance the anticancer effects of therapeutically active antibodies, such as Herceptin or Rituxan.

[0091] Another embodiment of the invention relates to a pharmaceutical composition capable of effectively inhibiting tumors, comprising a NUAK1 / 2 inhibitor of formula I (including formulas II and III), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemic mixture, solvate, hydrate, or prodrug thereof, for combination therapy with radiotherapy. In this embodiment, the compound of the invention and radiotherapy may be administered at the same time or at different times.

[0092] Another embodiment of the invention relates to a pharmaceutical composition effective for postoperative treatment of cancer, comprising a NUAK1 / 2 inhibitor of formula I (including formulas II and III), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemic mixture, solvate, hydrate, or prodrug thereof. The invention also relates to a treatment method involving surgical removal of a tumor followed by treatment of cancer in the mammal with the pharmaceutical composition of the invention.

[0093] The pharmaceutical compositions of the present invention comprise pharmaceutical formulations in which the contents of all the compounds of the present invention effectively achieve their intended objectives. Although individual needs vary, those skilled in the art can determine the optimal dosage of each component of the pharmaceutical formulation. Generally, the compounds, or their available salicies, are administered orally to mammals daily at a dosage of about 0.0025 to 50 mg / kg body weight. However, it is preferable to administer orally at a dosage of about 0.01 to 10 mg / kg. If a known anticancer drug is also administered, its dosage should effectively achieve its intended purpose. The optimal dosages of these known anticancer drugs are well known to those skilled in the art.

[0094] A single oral dose may comprise about 0.01 to 50 mg, preferably about 0.1 to 10 mg, of the compound of the present invention. A single dose may be administered once or multiple times daily as one or more tablets, each tablet containing about 0.1 to 50 mg, preferably about 0.25 to 10 mg, of the compound of the present invention or a solvate thereof.

[0095] In topical formulations, the concentration of the compounds of the present invention can be from about 0.01 to 100 mg per gram of carrier.

[0096] The compounds of the present invention can be administered as unprocessed pharmaceutical products. They can also be administered as part of a suitable pharmaceutical formulation containing a pharmaceutically acceptable carrier (including excipients and adjuvants). These pharmaceutically acceptable carriers facilitate the processing of the compounds into pharmaceutically acceptable formulations. Preferred pharmaceutical formulations, particularly those for oral administration and preferred routes of administration such as tablets, lozenges, and capsules, as well as solutions suitable for injection or oral administration, contain about 0.01% to 99%, preferably from about 0.25% to 75%, of the active compound and excipients.

[0097] The scope of this invention also includes non-toxic, pharmaceutically acceptable salts of the compounds of this invention. Acid addition salts are formed by mixing a solution of a non-toxic, pharmaceutically acceptable acid with a solution of the compound of this invention. Examples of the acids include hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, etc. Base addition salts are formed by mixing a solution of a non-toxic, pharmaceutically acceptable base with a solution of the compound of this invention. Examples of the bases include sodium hydroxide, potassium hydroxide, hydrocholine, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methylglucosamine, etc.

[0098] The pharmaceutical formulations of this invention can be administered to any mammal, provided they achieve the therapeutic effects of the compounds of this invention. Humans and veterinary animals are most important among these mammals, although this invention is not intended to be so limited.

[0099] The pharmaceutical formulation of this invention can be administered via any route to achieve its intended purpose. For example, it can be administered via parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, nasal, or topical routes. Alternatively or concurrently, it can be administered orally. The dosage of the drug will be determined based on the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

[0100] The pharmaceutical formulations of the present invention can be manufactured using known methods. For example, they can be manufactured by conventional mixing, granulation, tableting, dissolving, or freeze-drying processes. When manufacturing oral formulations, solid excipients and active compounds can be combined, and the mixture can be selectively ground. If desired or necessary, appropriate excipients can be added, and the granular mixture can be processed to obtain tablets or tablet cores.

[0101] Suitable excipients, especially fillers, include sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations and / or calcium phosphates, such as tricalcium phosphate or dicalcium phosphate; and binders, such as starch pastes including corn starch, wheat starch, rice starch, potato starch, gelatin, astragalus gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If desired, disintegrants, such as the starches mentioned above, as well as carboxymethyl starch, croscarmellose, agar, or alginate or its salts, such as sodium alginate, may be added. Adjuvants, especially flow conditioners and lubricants, include silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. If desired, a suitable coating that resists gastric juices can be provided to the tablet core. For this purpose, a concentrated sugar solution can be applied. This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures. To prepare a gastric juice-resistant coating, a suitable cellulose solution, such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate, can be used. Dyes or pigments may be added to the coating of the tablet or tablet core, for example, for identification or to characterize the dosage of the active ingredient.

[0102] Other orally edible pharmaceutical formulations include compressible capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers such as glycerin or sorbitol. The compressible capsule may contain an active compound in particulate form, mixed with fillers such as lactose; binders such as starch; and / or lubricants such as talc or magnesium stearate, and stabilizers. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid such as oils or liquid paraffin, in which stabilizers may be added.

[0103] Suitable formulations for parenteral administration include aqueous solutions of the active compound, such as solutions of water-soluble salts and alkaline solutions. Additionally, oily injectable suspensions of the appropriate active compound can be administered. Suitable lipophilic solvents or carriers include oils such as sesame oils, synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol 400, or hydrogenated castor oil, or cyclodextrin. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and / or dextran. Suspension stabilizers may also be included.

[0104] According to one aspect of the invention, the compounds of the invention are formulated for external and parenteral use and are used to treat skin cancer.

[0105] The topical formulations of this invention can be formulated into oils, creams, emulsions, ointments, etc., using a preferred suitable carrier. Suitable carriers include plant or mineral oils, white mineral oil (white paraffin), branched-chain fatty acids or oils, animal fats, and high molecular weight alcohols (greater than C10). 12 Preferred carriers are those in which the active ingredient can dissolve. Emulsifiers, stabilizers, moisturizers, and antioxidants may also be included, as well as agents that impart color or fragrance if desired. Furthermore, these topical formulations may contain transdermal penetration enhancers. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0106] Creams are preferably formulated with a mixture of mineral oil, self-emulsifying beeswax, and water, mixed with an active ingredient dissolved in a small amount of oil, such as almond oil. A typical example of a cream includes approximately 40 parts water, 20 parts beeswax, 40 parts mineral oil, and 1 part almond oil.

[0107] Ointments can be formulated by mixing a plant oil containing active ingredients, such as almond oil, with warm paraffin wax, and then allowing the mixture to cool. A typical example of an ointment consists of approximately 30% by weight almond oil and 70% by weight white paraffin wax.

[0108] This invention also relates to the preparation of medicaments for the treatment and prevention of NUAK1 / 2-mediated diseases, disorders, and clinical conditions using the compounds of this invention. These medicaments may include the aforementioned pharmaceutical compositions.

[0109] The following examples are illustrative and not intended to limit the methods and formulations of the present invention. Other appropriate modifications and improvements to various conditions and parameters that will be apparent to those skilled in the art and that are commonly encountered in clinical treatment are all within the spirit and scope of the present invention. Example General instructions All reagents used were commercially available, and solvents were dried and purified according to standard methods. Mass spectrometry samples were analyzed using a single quadrupole mass spectrometer (Platform II, Agilent 6110) with electrospray ionization. Recording was performed at 400 MHz using a Brücker Ascend 400 NMR spectrometer. 1 1H NMR spectra, chemical shifts were recorded in ppm starting from the low field with TMS as the internal standard (0.00 ppm), and coupling constant J values ​​were in Hz. Example 1 8-Cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pteridine-7(8H)-one a) Preparation of 2-chloro-N-cyclopentyl-5-nitropyrimidine-4-amine: Diisopropylethylamine (DIEA, 2.5 g, 19.1 mmol, 1.8 eq) was added to a solution of 2,4-dichloro-5-nitropyrimidine (2.0 g, 10.3 mmol, 1.0 eq) and cyclopentylamine (0.88 g, 10.3 mmol, 1.0 eq) in dichloromethane (DCM, 20 mL) at -78 °C. After stirring at -78 °C for 2 hours, the reaction solution was concentrated under reduced pressure. The crude product was washed with water (20 mL) to give the target product (2.3 g, 92% yield, white solid). LC-MS: 243.40 [M+1] + . b)N 4 -cyclopentyl-N 2 Preparation of 2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-5-nitropyrimidine-2,4-diamine: DIEA (0.8 g, 6.2 mmol, 1.5 eq) was added to a solution of 2-chloro-N-cyclopentyl-5-nitropyrimidine-4-amine (1.0 g, 4.13 mmol, 1.0 eq) and 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (1.1 g, 4.9 mmol, 1.2 eq) in tetrahydrofuran (THF, 10 mL). After stirring at room temperature for 3 hours, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (EA, 20 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 1:0–50:1) to give the target product (1.3 g, 74% yield, red solid). LC-MS: 428.35 [M+1] + . c)N 4 -cyclopentyl-N 2 Preparation of -(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4,5-triamine: [The text abruptly ends here, likely due to an incomplete translation or missing information.] 4 -cyclopentyl-N 2Pd / C (0.06 g, 20% W / W) was added to a methanol (3 mL) solution of 2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-5-nitropyrimidine-2,4-diamine (0.3 g, 0.7 mmol, 1.0 eq). After hydrogen purging, the mixture was stirred at room temperature for 3 hours, filtered, and the filter cake was washed with methanol (10 mL × 3). The organic phase was concentrated under reduced pressure to give the target product (0.27 g, 96% yield, black solid). LC-MS: 398.20 [M+1] + . d) Preparation of 8-cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pteridine-7(8H)-one: [The text abruptly ends here, likely due to an incomplete translation or missing information.] 4 -cyclopentyl-N 2 Acetic acid (0.2 mL) was added to a solution of 2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4,5-triamine (0.08 g, 0.2 mmol, 1.0 eq) and ethyl 2-oxoacetate (0.02 g, 0.4 mmol, 2.0 eq) in ethanol (6 mL). The reaction mixture was refluxed at 80 °C for 48 hours. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was slurried with PE:EA = 10:1 (5 mL × 2) to give the target product (0.01 g, 11% yield, yellow solid). LC-MS: 436.45 [M+1] + . 1 H NMR (400MHz, CD3OD): δ8.66(s,1H),7.79(s,1H),7.71-7.59(m,1H),6.69(s,1H),6.58(d,J=8.9Hz,1H),5.66(t,J=10.5Hz,1H), 3.84(s,3H),2.80(s,4H),2.48(s,3H),2.31-2.20(m,2H),2.14(s,2H),1.94(s,2H),1.79(t,J=12.2Hz,4H),1.65-1.48(m,2H). Example 2 1-Cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)- ketone a) Preparation of ethyl 4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylate: Cyclopentylamine (12.1 g, 141.8 mmol, 1.1 eq) was added to a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (30.0 g, 128.9 mmol, 1.0 eq) and triethylamine (26.0 g, 257.8 mmol, 2.0 eq) in dichloromethane (300 mL) at 0 °C. After stirring at 0 °C for 30 minutes, the reaction mixture was brought to room temperature and stirred overnight. The reaction was quenched with water (200 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the target product (35.0 g, 97% yield, colorless oil). LC-MS: 282.35 [M+1] + . b) Preparation of (4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)methanol: Ethyl 4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-carboxylic acid (5.0 g, 19.8 mmol, 1.0 eq) was added to a solution of lithium aluminum hydride (1.0 g, 26.6 mmol, 1.5 eq) in tetrahydrofuran (50 mL) at 0 °C. After stirring at 0 °C for 30 min, the reaction mixture was brought to room temperature and stirred for 5 h. Water (20 mL) and 15% NaOH solution (10 mL) were added to the reaction mixture at 0 °C, and then the mixture was stirred for 15 min. The mixture was filtered, and the filter cake was washed with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the target product (2.4 g, 50% yield, green solid). LC-MS: 240.35 [M+1] + . c) Preparation of 5-(chloromethyl)-N-cyclopentyl-2-(methylthio)pyrimidin-4-amine: 4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)methanol (10.0 g, 41.8 mmol, 1.0 eq) was added to thionyl chloride (100 mL), and the mixture was refluxed at 100 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the crude target product (10.0 g), which could be used directly in the next reaction without purification. d) Preparation of 5-(aminomethyl)-N-cyclopentyl-2-(methylthio)pyrimidine-4-amine: Ammonia gas was bubbled into a THF (100 mL) solution of 5-(chloromethyl)-N-cyclopentyl-2-(methylthio)pyrimidine-4-amine (crude product, 10.0 g) for 3 minutes at -78 °C. The mixture was stirred at -78 °C for 30 minutes, then the reaction mixture was brought to room temperature and stirred overnight. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1:2 to 0:1) to give the target product (6.8 g, 68% two-step yield, yellow oil). LC-MS: 239.40 [M+1] + . e) Preparation of 1-cyclopentyl-7-(methylthio)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one: 1,1'-carbonyldiimidazole (0.9 g, 5.7 mmol, 1.2 eq) was added to a solution of 5-(aminomethyl)-N-cyclopentyl-2-(methylthio)pyrimidin-4-amine (1.1 g, 4.8 mmol, 1.0 eq) in 11 mL of THF at 0 °C. The mixture was stirred at 0 °C for 30 minutes, and then the reaction mixture was heated to 75 °C in a sealed tube and stirred overnight. After the reaction was complete, EA (30 mL) was added to the reaction mixture, and then the mixture was washed with saturated sodium bicarbonate solution and saturated brine. The organic phase was separated, dried, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1 to 1:1) to obtain the target product (0.4 g, 35% yield, white solid). LC-MS: 265.30 [M+1] + . 1 H NMR (400MHz, CD3OD): δ8.09(s,1H),5.29–5.14(m,1H),4.27(s,2H),2.52(s,3H),2.28–2.13 (m,2H),2.01–1.91(m,2H),1.85(dd,J=19.1,10.1Hz,2H),1.61(dq,J=10.5,6.5,6.0Hz,2H). f) Preparation of 1-cyclopentyl-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one: At 0 °C, 3-chloroperoxybenzoic acid (0.13 g, 1.25 mmol, 1.1 eq) was added to a DCM solution (6 mL) of 1-cyclopentyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.3 g, 1.13 mmol, 1.0 eq). The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the reaction was quenched with sodium thiosulfate solution (5 mL), and the organic phase was washed with saturated sodium bicarbonate. The mixture was extracted with DCM (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the target crude product (0.2 g) was concentrated under reduced pressure and used directly in the next step without purification. LC-MS: 281.05 [M+1] + 279.05 [M-1] - . Preparation of 1-cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one: Trifluoroacetic acid (120.0 mg, 1.1 mmol, 5.0 eq) was added to a solution of 1-cyclopentyl-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (40.0 mg, 0.14 mmol, 1.0 eq) and 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (50.0 mg, 0.21 mmol, 1.5 eq) in acetonitrile (1 mL). The reaction mixture was stirred overnight at 85 °C. After the reaction was complete, DCM (10 mL) was added to the reaction mixture, and the mixture was washed (10 mL) with sodium bicarbonate solution. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (DCM:MeOH = 10:1) to give the target compound (13.0 mg, 20% two-step yield, green solid). Examples 3-4 were prepared using a synthesis method similar to that of Example 2. Example 5 1-Cyclopentyl-7-(((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidino[4,5-d]pyrimidin-2(1H)-one Potassium tert-butoxide (560.0 mg, 5.02 mmol, 10.0 eq) was added to a THF (3 mL) solution of 1-cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one (Example 2, 220.0 mg, 0.5 mmol, 1.0 eq). The reaction mixture was refluxed for 6 hours. After the reaction was complete, water (5 mL) was added to the reaction mixture, and the mixture was extracted with EA (5 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was first slurried with diethyl ether, and then purified by preparative high performance liquid chromatography (C18, CH3CN / H2O, 15–45%, 0.1% formic acid) to obtain the target compound (25.0 mg, 12% yield, yellow solid). Examples 6-18 were prepared using a synthesis method similar to that of Examples 2 and 5. Example 19 8-Cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one a) Preparation of 4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-carboxaldehyde: 4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)methanol (Example 2b, 580.0 mg, 2.3 mmol, 1.0 eq) and MnO2 (1.8 g, 23.1 mmol, 10.0 eq) were mixed in CHCl3 (10 mL) and stirred overnight at room temperature. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the target crude product (550.2 mg), which was used directly in the next reaction without purification. b) Preparation of ethyl 3-(4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)acrylate: Add 2-(triphenyl-λ) to a solution of 4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-carboxaldehyde (550.2 mg, 2.3 mmol, 1.0 eq) in THF (10 mL). 5 Ethyl phosphono)ethyl acetate (960.8 mg, 2.8 mmol, 1.2 eq). The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was complete, the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to give the target product (710.1 mg, 95% two-step yield, pale yellow solid). LC-MS: 308.15 [M+1] + . c) Preparation of 1-cyclopentyl-7-(methylthio)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one: 1,8-diazabicycloundec-7-ene (DBU, 1.0 g, 6.9 mmol, 3.0 eq) was added to a solution of ethyl 3-(4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)acrylate in pyrrolidone (NMP, 5 mL). The reaction mixture was stirred overnight at 120 °C. After the reaction was complete, water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1) to give the target product (0.2 g, 36% yield, off-white solid). LC-MS: 262.05 [M+1] + . d) Preparation of 8-cyclopentyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one: At 0 °C, 3-chloroperoxybenzoic acid (0.4 g, 2.1 mmol, 1.1 eq) was added to a DCM solution of 1-cyclopentyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.5 g, 1.9 mmol, 1.0 eq) in 10 mL of water. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was complete, it was quenched with saturated sodium thiosulfate solution (10 mL), washed with saturated sodium bicarbonate aqueous solution (10 mL), and extracted with DCM (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 3:1) to obtain the target product (0.3 g, 52% yield, pale yellow solid). LC-MS: 278.05 [M+1] + . 1 H NMR (400MHz, CDCl3): δ8.58(s,1H),7.57–7.47(m,1H),6.59(d,J=9.4Hz,1H),5.98–5.85( m,1H),2.67–2.57(m,3H),2.35(s,2H),2.07(s,2H),1.96–1.83(m,2H),1.73–1.65(m,2H). e) Preparation of 8-cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one: Trifluoroacetic acid (0.2 g, 1.7 mmol, 5.0 eq) was added to a solution of 8-cyclopentyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (93.0 mg, 0.3 mmol, 1.0 eq) and 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (89.0 mg, 0.4 mmol, 1.2 eq) in acetonitrile (10 mL). The reaction mixture was stirred overnight at 85 °C. After the reaction was complete, DCM (20 mL) was added to the reaction mixture, and the mixture was washed with saturated sodium bicarbonate aqueous solution (10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (DCM:MeOH = 10:1) to obtain the target compound (80.0 mg, 55% yield, off-white solid). Examples 20-24 were prepared using a synthesis method similar to that of Example 19. Example 25 1-Cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-2-oxo-1,2-dihydro-1,6-naphthidine-3-carboxynitrile) a) Preparation of 7-chloro-1-cyclopentyl-2-oxo-1,2-dihydro-1,6-naphthidine-3-carboxynitrile: Aniline (20.0 mg, 0.2 mmol, 0.1 eq) was added to a solution of 6-chloro-4-(cyclopentylamino)nicotinaldehyde (430.0 mg, 2.0 mmol, 1.0 eq) and 2-cyanoacetic acid (250.0 mg, 2.8 mmol, 1.4 eq) in acetic acid (10 mL) at room temperature, and the mixture was stirred at 110 °C for 6 hours. After the reaction was complete, the reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The organic phases were combined, washed with saturated sodium bicarbonate aqueous solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was slurried with isopropanol (3 mL) to give the target product (280.0 mg, 54% yield, white solid). LC-MS: 274.15 [M+1] + . b) Preparation of 1-cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-2-oxo-1,2-dihydro-1,6-naphthidine-3-carboxylonitrile): Trifluoroacetic acid (20.0 mg, 0.2 mmol, 0.5 eq) was added to a 2-butanol (5 mL) solution of 7-chloro-1-cyclopentyl-2-oxo-1,2-dihydro-1,6-naphthidine-3-carboxylonitrile (120.0 mg, 0.4 mmol, 1.0 eq) and 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (89.0 mg, 0.4 mmol, 1.0 eq) and stirred overnight at 120 °C. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (C18, CH3CN / H2O, 15-50%, 0.1% formic acid) to obtain the target compound (34.0 mg, 17% yield, pale yellow solid). Examples 26-27 were prepared using a synthesis method similar to that of Example 25. Example 28 8-Cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidine-7(6H)- ketone a) Preparation of 5-bromo-2-chloro-N-cyclopentylpyrimidine-4-amine: Cyclopentylamine (4.1 g, 48.3 mmol, 1.1 eq) was added to a DCM solution of 5-bromo-2,4-dichloropyrimidine (10.0 g, 43.9 mmol, 1.0 eq) and triethylamine (8.9 g, 87.7 mmol, 2.0 eq) in 100 mL of water at 0 °C. The mixture was stirred for 30 min, then brought to room temperature and stirred overnight. After the reaction was complete, the mixture was quenched with 100 mL of water and extracted with DCM (100 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the target product (8.0 g, 66% yield, colorless oil). LC-MS: 275.90 [M+1] + . b) Preparation of ethyl 3-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)acrylate: To a THF (10 mL) solution of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (1.0 g, 3.6 mmol, 1.0 eq), ethyl acrylate (0.9 g, 9.1 mmol, 2.5 eq), (PhCN)₂PdCl₂ (140.0 mg, 0.4 mmol, 0.1 eq), tris(o-methylphenyl)phosphine (111.0 mg, 0.4 mmol, 0.1 eq), and DIEA (2.3 g, 18.2 mmol, 5.0 eq) were added. The reaction mixture was stirred overnight at 70 °C under nitrogen protection. The reaction mixture was quenched with water (20 mL) and extracted with DCM (50 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1) to give the target product (0.8 g, 76% yield, yellow solid). LC-MS: 296.35 [M+1] + . c) Preparation of ethyl 3-(4-(cyclopentylamino)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)acrylate: To a solution of ethyl 3-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)acrylate (810.0 mg, 2.7 mmol, 1.0 eq) in dioxane (20 mL), 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (0.7 g, 3.3 mmol, 1.2 eq), Pd(OAc)2 (123.0 mg, 0.55 mmol, 0.2 eq), BINAP (171.0 mg, 0.28 mmol, 0.1 eq), and Cs2CO3 (2.7 g, 8.25 mmol, 3.0 eq) were added. The mixture was stirred at 90 °C for 2 hours under nitrogen protection. Water (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (50 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give the target product (0.4 g, 32% yield, yellow solid). LC-MS: 481.45 [M+1] + . d) Preparation of ethyl 3-(4-(cyclopentylamino)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)propionate: Ethyl 3-(4-(cyclopentylamino)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)acrylate (0.4 g, 0.8 mmol, 1.0 eq) and a methanol (10 mL) solution of 10% Pd / C (40.0 mg) were purged with hydrogen and stirred overnight at room temperature. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give the target product (230.0 mg, 58% yield, pale yellow solid). LC-MS: 483.25 [M+1] + . e) Preparation of 3-(4-(cyclopentylamino)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)propionic acid: 2M NaOH solution (1.45 mL, 2.0 eq) was added to a methanol (10 mL) solution of ethyl 3-(4-(cyclopentylamino)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)propionic acid (0.7 g, 1.5 mmol, 1.0 eq). The mixture was stirred overnight at room temperature. After the reaction was complete, the pH was adjusted to 3 with 6M HCl solution, and then the crude product was directly lyophilized to obtain the target product, which could be used directly for the next step without purification. LC-MS: 455.20 [M+1] + . f) Preparation of 8-cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one: 3-(4-(cyclopentylamino)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)propionic acid (0.7 g, 1.5 mmol, 1.0 eq), HATU (1.1 g, 3.0 mmol, 2.0 eq), and DIEA (0.5 g, 3.75 mmol, 2.5 eq) were dissolved in DMF (10 mL) and stirred overnight at room temperature. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (DCM:MeOH = 10:1) and preparative high performance liquid chromatography to obtain the target compound (28.0 mg, 4% yield, yellow solid). Examples 29-30 were prepared using a synthesis method similar to that of Example 28. Example 31 8-Cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-6H-pyrimidino[5,4-b][1,4]oxazine-7(8H)- ketone a) Preparation of 2-chloro-N-cyclopentyl-5-methoxypyrimidine-4-amine: Cyclopentylamine (1.7 g, 20.2 mmol, 1.2 eq) was added to a DCM (30 mL) solution of 2,4-dichloro-5-methoxypyrimidine (3.0 g, 16.9 mmol, 1.0 eq) and TEA (3.4 g, 33.8 mmol, 2.0 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then brought to room temperature and stirred overnight. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give the target product (3.5 g, 93% yield, white solid). LC-MS: 228.00 [M+1] + . b) Preparation of 2-chloro-4-(cyclopentylamino)pyrimidin-5-ol: BBr3 in 1,2-dichloroethane (2M, 34.4mL, 68.8mmol, 4.0eq) was added dropwise to a solution of 2-chloro-N-cyclopentyl-5-methoxypyrimidin-4-amine (3.9g, 17.2mmol, 1.0eq) in 20mL of 1,2-dichloroethane. The reaction mixture was stirred at 0°C for 40 minutes, then heated to 80°C and stirred for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to give the target product (2.9g, 80% yield, off-white solid). LC-MS: 214.05 [M+1] + 211.95 [M-1] - . c) Preparation of 2-chloro-8-cyclopentyl-6H-pyrimidino[5,4-b][1,4]oxazine-7(8H)-one: Ethyl bromoacetate (208.0 mg, 1.3 mmol, 1.2 eq) was added to a solution of 2-chloro-4-(cyclopentylamino)pyrimidin-5-ol (220.0 mg, 1.04 mmol, 1.0 eq) in acetonitrile (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, then heated to room temperature and stirred overnight. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. Water (5 mL) was added to the crude product, and the mixture was extracted with DCM (5 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the target product (222.0 mg, 50% yield, yellow solid). LC-MS: 254.00 [M+1] + . d) Preparation of 8-cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one: Pd(OAc)2 (8.0 mg, 0.04 mmol, 0.1 eq), BINAP (44.3 mg, 0.2 eq, 0.07 mmol), Cs2CO3 (347.1 mg, 1.1 mmol, 3.0 eq) and 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (78.7 mg, 0.36 mmol, 1.0 eq) were added to a solution of 2-chloro-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (90.0 mg, 0.36 mmol, 1.0 eq) in dioxane (1.5 mL). The mixture was stirred at 100°C for 1 hour under nitrogen protection. After the reaction was complete, water (5 mL) was added, and the mixture was extracted with EA (5 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was slurried with EA / PE = 3 / 1 (4 mL) to give the target compound (50.0 mg, yield: 37%, yellow solid). LC-MS: 439.40 [M+1] + . 1 H NMR (400MHz, CDCl3): δ8.13(d,J=8.8Hz,1H),8.00–7.97(m,1H),7.29(s,1H),6.55(s,2H),5.33–5.22(m,1H),4.56–4.52( m,2H),3.92–3.86(m,3H),3.37(s,4H),2.96(s,4H),2.62(s,3H),2.28–2.14(m,2H),2.02–1.82(m,4H),1.71–1.56(m,2H). Examples 32-33 were prepared using a synthesis method similar to that of Example 2. Example 34 8-Cyclopentyl-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrido[4,3-d]pyrimidine-2-amine a) Preparation of 8-iodo-2-(methylsulfinyl)pyrido[4,3-d]pyrimidine: 8-iodo-2-(methylthio)pyrido[4,3-d]pyrimidine (350.0 mg, 1.2 mmol) was dissolved in DCM (15 mL), and m-chloroperoxybenzoic acid (240.0 mg, 1.4 mmol) was added at -20 °C. The reaction was maintained at this temperature for 2 hours. After the reaction was complete, sodium thiosulfate solution (10 mL) was added to quench the reaction, and the mixture was extracted with DCM (10 mL × 3). The organic phase was separated, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (MeOH:DCM = 100:1 to 10:1) to obtain the target compound (200.0 mg, yield: 54%, yellow solid). LC-MS: 319.85 [M+1] + . b) Preparation of 8-iodo-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrido[4,3-d]pyrimidine-2-amine: 8-iodo-2-(methylsulfinyl)pyrido[4,3-d]pyrimidine (200.0 mg, 0.6 mmol) and 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (166.0 mg, 0.7 mmol) were dissolved in acetonitrile (5 mL), and then trifluoroacetic acid (358.0 mg, 3.1 mmol) was added. The mixture was reacted at 85 °C for 12 hours. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (MeOH:DCM = 100:1–20:1) to give the target compound (160.0 mg, yield: 29%, red solid). LC-MS: 477.05 [M+1] + . c) Preparation of 8-(cyclopentyl-1-en-1-yl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrido[4,3-d]pyrimidin-2-amine: 8-iodo-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrido[4,3-d]pyrimidin-2-amine (160.0 mg, 0.3 mmol), 2-(cyclopentyl-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (98.0 mg, 0.5 mmol), NaHCO3 (56.0 mg, 0.7 mmol), and Pd(PPh3)2Cl2 (69.0 mg, 0.1 mmol) were dissolved in dioxane (3 mL) and water (3 mL). The reaction system was purged with nitrogen three times and reacted at 130 °C for 0.5 h. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative thin-layer chromatography (MeOH:DCM = 10:1) to give the target compound (65.0 mg, yield: 55%, yellow solid). LC-MS: 417.15 [M+1] + . d) Preparation of 8-cyclopentyl-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrido[4,3-d]pyrimidine-2-amine: 8-(cyclopent-1-en-1-yl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrido[4,3-d]pyrimidine-2-amine (65.0 mg, 0.2 mmol), p-toluenesulfonyl hydrazine (290.0 mg, 1.6 mmol), and NaOAc (128.0 mg, 1.6 mmol) were dissolved in THF (10 mL) and water (2 mL). The mixture was reacted at 85 °C for 48 hours. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (C18 column, CH3CN / H2O, 10-40%, 0.1% HCOOH) to obtain the target compound (22.0 mg, yield: 33%, yellow solid). Example 35 was prepared using a synthesis method similar to that of Example 34. Example 36 6-Acetyl-8-cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methylpyrido[2,3-d]pyrimidine- 7(8H)-keto a) Preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (500.0 mg, 1.9 mmol) was dissolved in acetonitrile (10 mL), and oxalic acid (35.0 mg, 0.38 mmol), acetic anhydride (250.0 mg, 50% W / W), and NBS (405.0 mg, 2.3 mmol) were added. The mixture was reacted overnight at 60 °C under nitrogen protection. After the reaction was complete, the reaction was quenched by adding sodium thiosulfate solution (10 mL), the mixture was filtered, and the filtrate was concentrated under reduced pressure to give the target compound (410.0 mg, yield: 64%, white solid). LC-MS: 342.15 [M+1] + . b) Preparation of 6-acetyl-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (200.0 mg, 0.6 mmol), tributyl(1-ethoxyethylene)tin (264.7 mg, 0.7 mmol), and di(tri-tert-butylphosphine)palladium (14.9 mg, 0.02 mmol) were dissolved in NMP. The mixture was reacted overnight at room temperature under nitrogen protection. After the reaction was complete, 1N HCl (3.5 mL) was added and the mixture was stirred for 30 minutes. The pH of the solution was then adjusted to >7 with saturated sodium carbonate solution. The mixture was extracted with EA (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EtOAc = 4:1) to give the target compound (93.3 mg, yield: 36%, white solid). LC-MS: 306.05 [M+1] + . c) Preparation of 6-acetyl-8-cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one: 200.0 mg (0.6 mmol), 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (145.1 mg, 0.6 mmol), Pd-G3 (110.9 mg, 0.1 mmol), and Cs2CO3 (481.7 mg, 1.5 mmol) were dissolved in dioxane (5 mL). The reaction was carried out overnight at 100 °C under nitrogen protection. After the reaction was complete, the mixture was diluted with water and extracted with DCM (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) and preparative high-performance liquid chromatography (C18 column, CH3CN / H2O, 10-40%, 0.1% HCOOH) to obtain the target compound (11.2 mg, yield: 4%, brown solid). Example 37 was prepared using a synthesis method similar to that of Example 36. Examples 38-40 Examples 38-40 were prepared using a synthesis method similar to that of Example 19. Example 41 8-Cycloheptyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one The compounds in this embodiment were prepared using a synthetic method similar to that in Example 19. Example 42 Determining the inhibitory effect of the compound of the present invention on NUAK1. The assay of the compound of this invention against the NUAK1 enzyme activity was performed at Eurofins Discovery. The method was as follows: the test compound, NUAK1(h) enzyme, and 8 mM MOPS (pH 7.0), 0.2 mM EDTA, and 300 μM KKVSRSGLYRSPSMPENLNRPR substrate were incubated together. The reaction was initiated by adding a Mg / ATP mixture of 10 mM magnesium acetate and 45 μM [γ-33P]-ATP. After incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphate. Then, 10 μL of the reaction mixture was spotted onto P30 filter paper, washed four times with 0.425% phosphate for 4 minutes each time, followed by one wash with methanol, and then dried and subjected to liquid scintillation counting. The obtained values ​​were plotted against the drug concentration, and the IC50 was calculated. 50 . Table 1 summarizes the inhibitory effects (IC50) of the compounds of this invention on NUAK1 enzyme activity. 50 ). Where ++++ represents IC. 50 ≤10nM; +++ indicates 10nM <IC 50 ≤100nM; ++ indicates 100nM <IC 50 ≤1μM; + indicates IC 50 >1μM. Table 1 <![CDATA[IC 50 ]]> + +++ ++ ++ ++ ++ Example 7 8 9 10 11 12 <![CDATA[IC 50 ]]> + + + ++ ++ ++ Example 13 14 15 16 19 20 <![CDATA[IC 50 ]]> + ++ ++ + +++ +++ Example 21 22 23 24 25 26 <![CDATA[IC 50 ]]> +++ ++++ +++ ++ + +++ Example 27 28 29 30 31 32 <![CDATA[IC 50 ]]> ++ ++ +++ ++ ++ +++ Example 33 34 35 36 37 HTH-02-006 <![CDATA[IC 50 ]]> ++ +++ +++ + + +++ Therefore, the compound of the present invention has a good inhibitory effect on NUAK1 enzyme, as determined by NUAK1 enzyme experiments. Example 43 Determining the inhibitory effect of the compound of the present invention on NUAK2. The assay of the compound of this invention against NUAK2 enzyme activity was performed at Eurofins Discovery. The method was as follows: The compound, NUAK2(h) enzyme, and substrate were incubated together with 8 mM MOPS (pH 7.0), 0.2 mM EDTA, and 300 μM KKVSRSGLYRSPSMPENLNRPR. The reaction was initiated by adding a Mg / ATP mixture of 10 mM magnesium acetate and 15 μM [γ-33P]-ATP. After incubation at room temperature for 40 minutes, the reaction was terminated by adding 0.5% phosphate. Then, 10 μL of the reaction mixture was spotted onto P30 filter paper, washed four times with 0.425% phosphate solution for 4 minutes each time, followed by one wash with methanol. After drying, liquid scintillation counting was performed. The obtained values ​​were plotted against drug concentration, and the IC50 was calculated. 50 . Table 2 summarizes the inhibitory effects (IC50) of the compounds of this invention on NUAK2 enzyme activity. 50 ). Where ++++ represents IC. 50≤10nM; +++ indicates 10nM <IC 50 ≤100nM; ++ indicates 100nM <IC 50 ≤1μM; + indicates IC 50 >1μM. Table 2 <![CDATA[IC 50 ]]> ++ +++ + ++ ++++ +++ Example 7 8 9 10 11 12 <![CDATA[IC 50 ]]> ++ + + +++ ++ ++ Example 13 14 15 16 19 20 <![CDATA[IC 50 ]]> + ++ + ++ ++++ +++ Example 21 22 23 24 25 26 <![CDATA[IC 50 ]]> ++ ++++ ++ +++ ++ +++ Example 27 28 29 30 31 32 <![CDATA[IC 50 ]]> ++ +++ +++ + ++ +++ Example 33 34 35 36 37 HTH-02-006 <![CDATA[IC 50 ]]> ++ +++ +++ ++ ++ ++ Therefore, the compound of the present invention has a good inhibitory effect on NUAK2 enzyme, as determined by NUAK2 enzyme experiments. Example 44 The inhibitory effect of the compound of this invention on human endometrial cancer cells HEC-1-B was determined using the CTG assay. Human endometrial cancer cells HEC-1-B were resuscitated and passaged in complete culture medium (MEM medium + 10% FBS). When cell confluence reached approximately 80%, cells were gently aspirated from the bottom of the culture dish using a 1 mL pipette, and the cell suspension was collected and centrifuged at 500 rpm for 3 min. The supernatant was discarded, and the cells were resuspended in complete culture medium. The cells were then seeded into culture dishes at an appropriate ratio and incubated statically at 37°C in a 5% CO2 incubator. Cells were passaged until they reached good growth and approximately 80% confluence and were then used for experiments. Cells in the logarithmic growth phase were gently aspirated from the well using a 1 mL pipette, centrifuged at 500 rpm for 3 min, and the supernatant was discarded. The cells were resuspended in fresh culture medium, dispersed into single cells, and counted. Cells were seeded at a density of 1000 cells per well into 96-well cell culture plates (the first column was empty) and incubated overnight at 37°C in a 5% CO2 incubator. The following day, the stock solution of the compound was serially diluted with DMSO at a ratio of 1:3 to obtain nine concentrations. 2 μL of each concentration was added to 98 μL of medium (10-fold dilution). A DMSO control well was also prepared. Cells were removed from the CO2 incubator, and the old medium in the wells was discarded. 135 μL of fresh medium was added to each well, followed by 15 μL of the corresponding concentration of the compound diluted in medium. The plate was then incubated at 37°C in a 5% CO2 incubator for 7 days. After 7 days, 100 μL of CellTiter-Glo reagent was added to each well, and the plate was shaken on a track-mounted shaker for 2 minutes to induce complete cell lysis. The plate was then incubated at room temperature for 10 minutes, and the chemiluminescence values ​​were read using a plate reader. The inhibitory activity of the compound on cell proliferation was plotted on a graph as the compound's inhibition rate against cell proliferation and the compound's concentration. Cell inhibition rate (%) = (chemiluminescence value) / (…) 待测药 - Chemiluminescence value DMSO对照孔 ) / (chemiluminescence value) 培养液对照 - Chemiluminescence value DMSO对照孔 )×100%. The dose-response curve was obtained by fitting a nonlinear S-curve regression using XL Fit software, and the IC was calculated from the curve. 50 The curve equation is: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) × slope)), where Y is the cell inhibition rate, X is the compound concentration, Bottom refers to the minimum inhibition rate, and Top refers to the maximum inhibition rate. Table 3 summarizes the inhibitory effects of the compounds of this invention on the proliferation of Hec-1B cells (IC50). 50 (Where, + indicates 100nM) <IC 50 ≤500nM; ++ indicates 500nM <IC 50 ≤1μM; +++ indicates 1μM <IC 50 ≤10μM; ++++ indicates IC 50 >10μM. Table 3 <![CDATA[IC 50 ]]> ++ +++ +++ +++ +++ + Example 21 22 23 24 26 27 <![CDATA[IC 50 ]]> ++++ + ++++ +++ +++ ++ Example 28 29 32 <![CDATA[IC 50 ]]> ++ +++ ++ Therefore, as determined by CTG detection method, the compound of the present invention has a good inhibitory effect on the growth of human endometrial cancer cells HEC-1-B.

[0110] While the invention has been fully described, those skilled in the art will understand that the same practices can be carried out under broad and equivalent conditions, formulations, and other parameters without affecting the scope of the invention or any embodiments thereof. All patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety.

Claims

1. A compound of formula IIb, or a pharmaceutically acceptable salt or racemate thereof: (IIb) in, R0 is an optionally substituted cycloalkyl group or an optionally substituted 3-7-membered heterocyclic group, wherein each of the cycloalkyl group and the 3-7-membered heterocyclic group is optionally substituted by one, two or three substituents selected from halogens, C1-C6 alkyl groups and halo-C1-C6 alkyl groups; wherein the cycloalkyl group is selected from cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. B1 is N; B2 is N; B3 is CR3; D1 is CR4; D2 is CR5; D3 is CR6; R3, R4, R5 and R6 are each independently selected from H, halogens, C1-C4 alkyl and C1-C4 alkoxy groups; R7 is selected from halogens, C1-C6 alkyl groups optionally substituted with 1, 2, 3, 4 or 5 halogens, and C1-C6 alkoxy groups optionally substituted with 1, 2, 3, 4 or 5 halogens. R8 is a 4-7 membered heterocyclic group optionally substituted with 1-4 substituents selected from C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl and halo-C1-C6 alkyl; A3 is selected from O, S, and CR. 13 R' 13 ; A4 is selected from NR 12 and CR 14 R' 14 ; R 12 H or optionally 1, 2, 3, 4 or 5 selected from halogens, hydroxyl groups and -NR a R b The substituents are optionally substituted C1-C6 alkyl groups, wherein R a and R b Each is independently H or C1-C4 alkyl; R 13 、R' 13 R 14 and R' 14 Each of the following is an H, a C1-C6 alkyl group optionally substituted with 1, 2, 3, 4 or 5 halogens, or a C1-C6 alkoxy group optionally substituted with 1, 2, 3, 4 or 5 halogens; The compound of formula IIb is not: and .

2. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, The 3-7 membered heterocyclic group is a 3-6 membered heterocyclic group containing nitrogen and / or oxygen.

3. The compound of formula IIb as claimed in claim 2, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, The 3-7 membered heterocyclic groups are selected from azirrobutyl, oxoheterobutyl, oxopropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazineyl, and piperidinyl.

4. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, R3 is H, halogen, or C1-C4 alkyl.

5. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, R3 is H or a C1-C4 alkyl group.

6. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, B1 is N; B2 is N; B3 is CH.

7. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, R4, R5, and R6 are each independently H, halogen, and C1-C4 alkyl.

8. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, D1, D2 and D3 are all CH.

9. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, A3 is selected from O and CR. 13 R' 13 .

10. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, R 12 R 13 、R' 13 R 14 and R' 14 Each is independently an H or C1-C3 alkyl group.

11. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, R 12 For H, R 13 and R' 13 At least one of them is H, R 14 and R' 14 At least one of them is H.

12. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, A3 is O or CH2; and / or, A4 is NH or CH2.

13. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, R7 is a halogen or a methoxy group optionally substituted with one, two or three halogens.

14. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, R7 is a methoxy group.

15. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, R7 is a halogen, a C1-C3 alkoxy group, or a halogenated C1-C3 alkoxy group.

16. The compound of formula IIb as claimed in claim 15, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, The C1-C3 alkoxy group is selected from methoxy, ethoxy, and propoxy; and / or, the halogenated C1-C3 alkoxy group is trifluoromethoxy.

17. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, The 4-7 membered heterocyclic groups in R8 are 4-6 membered heterocyclic groups containing nitrogen and / or oxygen.

18. The compound of formula IIb as claimed in claim 17, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, The 4-6 nitrogen- and / or oxygen-containing heterocyclic groups are selected from azirrobutyl, oxoheterobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazine, 1,4-diazacycloheptyl, and piperidinyl.

19. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, The substituents on R8 are 1, 2, or 3 substituents selected from C1-C4 alkyl and halo-C1-C4 alkyl groups.

20. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, R8 is a 4-7 member nitrogen-containing heterocyclic group optionally substituted with one or two substituents selected from C1-C4 alkyl and halo-C1-C4 alkyl groups, wherein the 4-7 member nitrogen-containing heterocyclic group is selected from aziridine, pyrrolidinyl, piperazine, 1,4-diazacycloheptyl and piperidinyl.

21. The compound of formula IIb as claimed in claim 18 or 20, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, The 1,4-diazacycloheptane group is 1,4-diazacycloheptane-1-yl.

22. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, The fused bicyclic rings containing A3 and A4 and rings containing B1-B3 are selected from: , and , in, 1 and 2 indicates the connection position of the group with the remaining parts of the compound, R0 and -NH; R 12 It is H or C1-C3 alkyl.

23. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, The compound of formula IIb has the following structural formula: (IIIc) and (IIId), Among them, in each structural formula, R0, B1, B2, B3, R7 and R 12 The definition is as described in any one of claims 1-22; Cy is a 4-7 membered heterocyclic group optionally substituted with 1, 2 or 3 substituents selected from C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl and halo-C1-C6 alkyl.

24. The compound of formula IIb as claimed in claim 23, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, Cy is an optionally substituted 4-7 member nitrogen- and / or oxygen-containing heterocyclic group, wherein the heterocyclic group is selected from azirrobutyl, oxoheterobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazine, 1,4-diazacycloheptane-1-yl, and piperidinyl.

25. The compound of formula IIb as claimed in claim 23, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, Cy is a piperazine group optionally substituted with 1 to 3 substituents of C1-C6 alkyl groups selected from C1-C6 alkyl and hydroxyl groups.

26. The compound of formula IIb as claimed in claim 1, or a pharmaceutically acceptable salt or racemic mixture thereof, wherein, The compound is selected from: 1-Cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino )- 3,4-Dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one; 1-Cyclopentyl-7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-3-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one; 8-Cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one; 8-Cyclohexyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one; 8-Cyclopentyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-6H-pyrimidino[5,4-b][1,4]oxazine-7(8H)-one; 7-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-cyclopentyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one; 7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrimidine[4,5-d]pyrimidine-2(1H)-one.

27. Use of the compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt or racemate thereof, in the preparation of a medicament for the treatment or prevention of NUAK1 / 2-mediated diseases, disorders and conditions.

28. The use as described in claim 27, characterized in that, The disease, disorder, and ailment mentioned are cancer or cervical hyperplasia.

29. The use as described in claim 28, characterized in that, The cancers mentioned are selected from liver cancer, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, soft tissue sarcoma, primary macroglobulinemia, chronic myeloid leukemia, primary brain cancer, non-small cell lung cancer, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, urogenital tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, polycythemia vera, idiopathic thrombocytosis, adrenocortical carcinoma, and skin cancer.

30. The use as described in claim 29, characterized in that, The skin cancers mentioned are selected from melanoma, mycosis fungoides, and Kaposi's sarcoma.

31. The use as described in claim 29, characterized in that, The urogenital system tumors are selected from renal cell carcinoma, bladder cancer, Wilms' tumor, testicular cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, and choriocarcinoma.

32. The use as described in claim 27, wherein the drug is used in combination with radiotherapy.

33. The use as described in claim 27, wherein, The drug also includes at least one known anticancer drug or a pharmaceutically acceptable salt of the anticancer drug.

34. The use as described in claim 33, characterized in that, The anticancer drugs are selected from one or more of the following groups: busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyrosine, mentholtoporp, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nerabine, cytarabine, pralatrexate, pemetrexed. Xylurea, hydroxyurea, thioguanine, colchicine, vincristine, vinorelbine, paclitaxel, ixapril, cabazitaxel, docetaxel, monoclonal antibodies, panitumumab, nezotuzumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, oxetuzumab, ofamumab, rituximab, alemtuzumab, tiimomab, tosimob, daratumumab, erlotuzumab, T-DM1, offatumumab Dinutuximab, Blinatumomab, Iprimimab, Avastin, Herceptin, Rituxan, Imatinib, Gefitinib, Erlotinib, Ostinib, Afatinib, Celitinib, Alectinib, Crizotinib, Erlotinib, Lapatinib, Sorafenib, Sunitinib, Nilotinib, Dasatinib, Pazopanib, Tetracycline, Everolimus, Vorinostat, Romidhizine, Papilstat, Belipista, Tamoxifen, Letrozole, Fulvestrant, Mitoguanidine, Octreotide, Retinoic Acid, Arsenic Zoledronic acid, bortezomib, carfilzomib, Ixazomib, vemodilamide, sinedazole, denosumab, thalidomide, lenalidomide, venetoclax, Aldesleukin (recombinant human interleukin-2), Sipueucel-T (prostate cancer treatment vaccine), palbociclib, olaparib, niraparib, rucaparib, talazoparib, pamiparib, fluzoparib, and Senaparib.

35. A pharmaceutical composition comprising a compound of formula IIb as claimed in any one of claims 1 to 26, or a pharmaceutically acceptable salt or racemic mixture thereof, and a pharmaceutically acceptable carrier.

36. The pharmaceutical composition according to claim 35, characterized in that, The pharmaceutical composition further contains at least one known anticancer drug or a pharmaceutically acceptable salt of the anticancer drug.

37. The pharmaceutical composition according to claim 36, characterized in that, The at least one known anticancer drug is selected from the group consisting of: busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyrosine, mentholtoporp, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nerabine, cytarabine, and pralatrexate. Sa, Pemetrexed, Hydroxyurea, Thioguanine, Colchicine, Vincristine, Vincristine, Vinorelbine, Paclitaxel, Ixapiron, Cabazitaxel, Docetaxel, Monoclonal Antibody, Panitumumab, Nezotuzumab, Nivolumab, Pembrolizumab, Ramucirumab, Bevacizumab, Pertuzumab, Trastuzumab, Cetuximab, Obinutuzumab, Ofamumab, Rituximab, Alemumab, Teimozumab, Tosimozumab, Bentuximab, Daremumab, Erotozumab, T-DM1, O fatumumab, Dinutuximab, Blinatumomab, Iprimumab, Avastin, Herceptin, Rituxan, Imatinib, Gefitinib, Erlotinib, Ostinib, Afatinib, Celitinib, Alectinib, Crizotinib, Erlotinib, Lapatinib, Sorafenib, Sunitinib, Nilotinib, Dasatinib, Pazopanib, Tetracycline, Everolimus, Vorinostat, Romidhizine, Pabbilstat, Belipista, Tamoxifen, Letrozole, Fulvestrant Mitoguanidine, Octreotide, Retinoic acid, Arsenic, Zoledronic acid, Bortezomib, Carfilzomib, Ixazomib, Vemodil, Sonicil, Dinosema, Salidone, Lenalidomide, Venetoclax, Aldesleukin, Sipueucel-T, Palbociclib, Olaparib, Niraparib, Rucaparib, Talazoparib, Pamiparib, Fluzoparib, and Senaparib.

Images