A pyrimidine amine nuak inhibitor and its preparation method and use

Abstract

This application provides a pyrimidine amine compound, characterized in that the pyrimidine amine compound is a compound represented by Formula I, or its stereoisomers, tautomers, isotopic derivatives, hydrates, solvates, prodrugs, and pharmaceutically acceptable salts. The pyrimidine amine compound of this application possesses excellent NUAK1 / NUAK2 kinase inhibitory activity, and can be used to prevent or treat the following diseases by inhibiting NUAK1 or NUAK2: neuropsychiatric disorders, metabolic diseases, tumors, visceral fibrosis, and skin fibrosis.

Description

1. Description of a Pyrimidine Amine NUAK Inhibitor, Preparation Method Thereof, and Uses Thereof Cross-Reference to Related Applications This application claims priority to Chinese Patent Application No. 202310866091.6, filed July 13, 2023, the entire contents of which are incorporated herein by reference. Technical Field This invention belongs to the field of small molecule compounds, and specifically relates to a pyrimidine amine NUAK inhibitor, its preparation method, and uses. The compound, by inhibiting NUAK1 or NUAK2, can be used to prevent or treat the following diseases: neuropsychiatric disorders, metabolic diseases, tumors, visceral fibrosis, skin fibrosis, or alone to reduce scarring after trauma and surgery. Background Technology: Protein kinases are a group of important functional proteins involved in regulating cellular metabolism, polarity, growth, division, and differentiation. The human genome encodes more than 500 protein kinases, which can phosphorylate ATP (adenosine triphosphate) by transferring the phosphate group from ATP to specific serine, threonine, or tyrosine residues of substrate proteins. Most protein kinases are serine / threonine kinases, while there are fewer than 100 tyrosine kinases. Adenosine monophosphate-activated protein kinase (AMPK) belongs to the serine / threonine kinases (STKs) and is an important regulator of cellular energy homeostasis in mammals. It regulates glucose and lipid metabolism, cell proliferation, and cell polarity by sensing changes in the intracellular AMP (adenosine monophosphate) / ATP or ADP (adenosine diphosphate) / ATP ratio under metabolic stress (such as hypoxia or heat shock), and can be considered a metabolic sensor protein. AMPK is highly conserved in evolution and is a heterotrimeric protein composed of an α subunit containing a kinase domain (KD), and β and γ subunits that regulate kinase activity. The γ subunit contains four CBS (Cystathionine-β-synthase (CBS) domains) responsible for detecting changes in the intracellular AMP / ATP and ADP / ATP ratios (Hardie DG, Trends in Cell Biology. 2016, 26:190).AMPK dysfunction can lead to various diseases, including obesity, diabetes, inflammatory diseases, and tumors. Therefore, the regulation of AMPK function is crucial. Firstly, AMPK activation requires phosphorylation of the threonine residue (T172) at position 172 of its α subunit by an upstream kinase. Currently, three upstream kinases are known: liver kinase B1 (LKB1), Ca2+ / calmodulin-dependent PK kinase 2 (CaMKK2), and transforming growth factor-β-activated kinase 1 (TAK1). Corresponding to the upstream kinase's activation of AMPK via phosphorylation of the T172 site, three protein phosphatases are known to inhibit AMPK activity by removing the phosphate group at T172, including protein phosphatase 2A (PP2A), protein phosphatase 2C (PP2C), and Mg2+- / Mn2+-dependent protein phosphatase 1E (PPM1E). When cells are in a low-energy state (high AMP / ATP or ADP / ATP ratio), the α subunit KD and γ subunits of AMPK are tightly cross-linked, while the β subunit is myristylated, ensuring that the protein phosphatase cannot access the T172 site and remains activated. When cells are in a high-energy state, the KD and γ subunits loosen, exposing T172 to phosphatases and leading to AMPK inactivation (Steinberg GR, Nature Reviews Drug Discovery. 2019, 18:527).Besides upstream AMPK kinases and protein phosphatases, which can activate and inactivate AMPK respectively, there is another class of AMPK-related kinases (ARKs) involved in regulating AMPK function. Currently, a total of 12 ARKs have been identified (BRSK1, BRSK2, NUAK1, NUAK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4, and MELK), all of which belong to serine / threonine protein kinases. The kinase domains of ARKs have high homology with the α subunit of AMPK. Except for MELK, all of them can be activated by LKB1, and their phosphorylation sites for kinase activation are also comparable to T172 of AMPK. Functionally, they are all involved in the regulation of cell metabolism, proliferation, and polarity. However, unlike AMPK, which has a regulatory subunit, ARKs cannot be directly regulated by the intracellular AMP / ATP ratio (Bright NJ, Acta Physiologica. 2009, 196:15). ARKs are further divided into several ARK subfamilies based on differences in protein structure and function. Among them, the NUAK (Nu (novel) and AMPK-related kinase) ARK subfamily contains two members: NUAK1 (originally named ARK5) and NUAK2 (originally named sucrose nonfermenting-like / AMPK-related kinase, SNARK). The amino acid sequences of the two are approximately 55% homologous. Based on the amino acid sequence of NUAK1, NUAK2 is estimated to have molecular weights of 76 and 69 kDa, respectively. Their protein structures are very similar, with the amino terminus being a kinase domain and the carboxyl terminus being a ubiquitin-associated domain. It is currently unclear whether NUAK, like AMPKs, is also a heterotrimeric structure. NUAK1 and NUAK2 are expressed in most tissues. NUAK1 is expressed significantly higher in organs and tissues such as the brain, skin, muscle, upper digestive tract, and endocrine system than in other parts. NUAK2 is expressed highest in organs and tissues such as the digestive tract, female reproductive system, skin, bone, brain, and endocrine system. NUAK2 expression shows more tissue specificity.It is worth noting that NUAK1 and other ARKs and AMPK proteins are mainly distributed in the cytoplasm, while NUAK2 is mainly distributed in the nucleus, and there are indications that NUAK2 participates in the expression of metabolic stress-related genes as a transcriptional regulator (Sun X, J of Molecular Endocrinology. 2013, 51:R15). As serine / threonine protein kinases, NUAK1 and NUAK2 can phosphorylate a variety of protein substrates, including proteins involved in cell signaling, metabolism, cell proliferation, apoptosis, autophagy, and cytoskeleton organization. NUAK1 is known to phosphorylate AMPK, LATS1 / 2, p53 tumor suppressor protein, and myosin phosphatase target subunit 1 (Mypt1), which regulates actin cytoskeleton organization. NUAK2 can phosphorylate transcription factors Gli3, FoxO1, kinin light chain 1 (KLC1), and Rho GDP dissociation inhibitor α (Rho GDIα) in the Hedghog signaling pathway. The functional regulation of NUAK1 and NUAK2 involves multiple intracellular signaling systems. In addition to being activated by LKB1 phosphorylation (T211, equivalent to AMPK's T172) and by calcium ions / PKC, NUAK1 is the only member of the AMPK-related protein family that can be activated by Akt. Increased NUAK1 activity is also seen in the activation of some growth factors such as insulin-like growth factor 1 (IGF1) signaling pathways. Increased NUAK1 activity is also associated with skeletal muscle cells in a contractile state. Both NUAK1 and NUAK2 can be activated by LKB1 (T211 / NUAK1, T208 / NUAK2, equivalent to AMPK's T172), but NUAK2 can be activated by autophosphorylation. NUAK2 can interact with ubiquitin-specific protease 9 (USP9X) on the X chromosome, a deubiquitinating enzyme that maintains NUAK2 activity. In different cells, stimuli such as low osmotic pressure, DNA damage, oxidation, and nutrient deficiency can all lead to NUAK2 activation. NUAK2 activation is also observed in skeletal muscle cell contraction (Brooks D, Data in Brief. 2022, 43:108482).Multiple studies have shown that NUAK plays an important role in the pathogenesis of metabolic diseases, tumors, neurodegenerative diseases, and fibrotic diseases. Homozygous knockout mice of NUAK1 and NUAK2 gene essentially lead to embryonic death, while heterozygous NUAK1 deletion mice result in maldevelopment of the body and neural tissues (such as the cerebral cortex and peripheral neurons). Heterozygous mutations in the human NUAK1 gene are associated with autism spectrum disorders (ASD), cognitive deficits, attention deficit / hyperactivity disorder (AD / HD), and schizophrenia. Deletion of the human NUAK2 gene leads to anencephaly, a severe neural tube defect that causes fetal developmental defects, and its mechanism is related to the loss of YAP function (Bonnard C, J Exp Med. 2020, 217:e20191561). Specific knockout of the NUAK1 gene in skeletal muscle cells can prevent subclinical diabetes induced by a high-fat diet; while the phenotype exhibited in heterozygous NUAK2-deficient mice is similar to a range of clinical manifestations of type 2 diabetes mellitus with obesity in humans. These phenomena may be related to an imbalance in autophagy mechanisms (Bennison SA, Cellular Signaling. 2022, 100:110472; Blazejewski SM, Scientific Reports. 2011, 11:8156). NUAK1 activation induced by Akt and other protein kinases can promote tumor cell survival in energy-deficient environments and protect tumor cells from apoptosis. NUAK2 also inhibits TNFα and CD95-induced apoptosis through a similar mechanism. Furthermore, NUAK1 activation promotes tumor cell invasion and metastasis by upregulating metalloproteinases (MMPs), while NUAK2 participates in tumor metastasis by enhancing tumor cell activity (Hou X, Oncogen. 201, 30:2933; Chen Y, Cell Death and Disease. 2020, 11:712; Molina E, Cells. 10:2760; Humbert N, The EMBO Journal. 2010, 29:376).Numerous studies have demonstrated that NUAK1 and NUAK2 play roles in tumor formation and metastasis. Compared to NUAK1, NUAK2 exhibits a stronger promoting effect on tumor formation and metastasis, suggesting that NUAK2 inhibitors are more likely to become novel targeted anti-tumor drugs than NUAK1 inhibitors. Recent research indicates that NUAK plays a crucial role in the development of tissue fibrosis through its interaction with the transforming growth factor-β (TGF-β) signaling pathway. Firstly, TGF-β upregulates the transcription of NUAK1 and NUAK2 genes in various epithelial cells, such as keratinocytes and dermal fibroblasts, while MAPK (ERK1 / 2 and p38) signaling inactivation inhibits TGF-β-dependent NUAK2 expression. Furthermore, NUAK2 inhibits intracellular SMAD3 degradation by binding to the cross-linking domain and MH2 domain of the SMAD3 protein structure, a similar mechanism also exists between NUAK2 and TβRI. The expression of TGF-β-induced profibrotic molecules, such as fibronectin (FN), plasminogen activator inhibitor 1 (PAI1), and tissue inhibitor of metalloproteinase-1 (TIMP1), depends on the presence of NUAK2, indicating that NUAK2 promotes the development of fibrosis. Studies have also shown that NUAK1 promotes kidney, lung, and liver fibrosis by upregulating the TGF-β and YAP signaling pathways. In animal experiments, inhibiting NUAK1 can reduce scarring caused by new trauma and old scar tissue (Gill MK, Nature Communications. 2018. 9:3510). Interestingly, the study found that the expression of the gene encoding FN in keratinocytes with the NUAK1 knockout gene was upregulated. NUAK1 may inhibit fibrosis by affecting TGF-β signaling through a negative feedback mechanism (van de Vis RAJ, Cancers. 2021, 13:3377). Overall, inhibiting NUAK may effectively suppress the fibrotic process involved in tissues and organs.Since kinases have always been ideal targets for small molecule drugs in terms of both structure and function, and NUAK1 and NUAK2 are involved in the development of various diseases, some NUAK inhibitors are currently in the early stages of development, but their efficacy and safety remain questionable (Banerjee S, The Biochemical Journal. 2014, 457:215). Therefore, the development of selective NUAK inhibitors and dual-target inhibitors of NUAK1 / 2 holds promise for providing innovative new directions for the treatment of neuropsychiatric diseases (such as Parkinson's disease and Alzheimer's disease), metabolic diseases (such as diabetes, hyperlipidemia, and obesity), tumors (such as liver cancer, leukemia, lymphoma, and tumor metastasis), visceral fibrosis (such as cirrhosis, renal fibrosis, pulmonary fibrosis, and sequelae of myocarditis), and skin fibrosis (such as scleroderma, keloids, hypertrophic scars, or simply for reducing scars after trauma and surgery). The development of next-generation NUAK inhibitors has enormous potential clinical application value. The present invention aims to obtain an effective NUAK1 / NUAK2 inhibitor that can be used to prepare drugs for the prevention or treatment of the following diseases: neuropsychiatric diseases (such as Parkinson's disease, Alzheimer's disease), metabolic diseases (such as diabetes, hyperlipidemia, obesity), tumors (such as liver cancer, leukemia, lymphoma, tumor metastasis), visceral fibrosis diseases (such as cirrhosis, renal fibrosis, pulmonary fibrosis, and sequelae of myocarditis), and skin fibrosis diseases (such as scleroderma, keloids, hypertrophic scars, or simply for the relief of traumatic and postoperative scars).To achieve the above objectives, in one aspect, the present invention provides a pyrimidine amine compound, which is a compound represented by Formula I as shown below, or a stereoisomer, geometric isomer, tautomer, isotopic derivative, hydrate, solvate, prodrug, or pharmaceutically acceptable salt thereof: HK 20105994 B 6 NNNAX R1 (R3)n (R4)m R5 Formula IN (R7)p R8 Y R5=-N-(R2)-C(O)-R6, wherein A is q(R10) or NN r(R11); X is N or CH, Y is O or NR9; R1, R2, R8, and R9 are each independently H or optionally substituted C1-8 alkyl groups; R3, R4, R7, R10, and R11 are each independently a halogen, amino, hydroxyl, nitro, cyano, mercapto, optionally substituted C1-8 alkyl, optionally substituted C1-8 alkyloxy, optionally substituted C1-8 alkylthio, or optionally substituted C1-8 alkylamino; R6 is an optionally substituted 3-10 membered cycloalkyl or optionally substituted 3-10 membered heterocycloalkyl, wherein the substituent on the cycloalkyl or heterocycloalkyl is selected from one or more of halogen, amino, hydroxyl, nitro, cyano, mercapto, optionally substituted C1-8 alkyl, optionally substituted C1-8 alkyloxy, optionally substituted C1-8 alkylthio, or optionally substituted C1-8 alkylamino; the substituent on the C1-8 alkyl is selected from one or more of halogen, amino, hydroxyl, nitro, cyano, or mercapto; n and r are 0, 1, or 2, and m, p, and q are 0, 1, 2, 3, or 4, respectively. In one set of embodiments, Y is O or NH. In one set of embodiments, R6 is an optionally substituted 3-10 membered cycloalkyl group, preferably an optionally substituted 3-6 membered cycloalkyl group, more preferably a halogen-substituted 3-6 membered cycloalkyl group, and more preferably a fluorine-substituted 3-6 membered cycloalkyl group. In one set of embodiments, R6 is or FF. HK 20105994 B 7 In one set of embodiments, R5 is O NH or FFONH, preferably FFO HN (S). In one set of embodiments, R5 is substituted at the ortho or meta position of Y. In one set of embodiments, the compound represented by Formula I is Formula I-1, NNNAX R1 (R4)m R5 Formula I-1 N (R7)p R8 Y R5=-N-(R2)-C(O)-R6 Cl. In one set of embodiments, X is N, and R8 is H or methyl.In one set of embodiments, the compound represented by Formula I is Formula I-2 or Formula I-3, NNN R1 (R4)m R5 N (R7)p Y Cl O R5=-N-(R2)-C(O)-R6 Formula I-2 or NNN R1 (R4)m R5 N (R7)p Y Cl R5=-N-(R2)-C(O)-R6 Formula I-3. In one set of embodiments, the compound represented by Formula I is one of the following compounds: HK 20105994 B 8 NN NH FFO HN NNO Cl NN NH FFO HN NNNHO Cl NN NH (S) FFO HN NNN Cl O TDM-181120 TDM-181127 TDM-181130 NN NH (S) FFO HN NNN Cl NN HN NNO Cl O HN ONN HN NNO Cl O HN (S) OFF TDM-181131 TDM-181132 TDM-181160 NN HN NNN Cl HN (S) OFF TDM-181168. In one set of embodiments, the pharmaceutically acceptable salt is a formate. In one set of embodiments, the isotope derivative is a deuterated product. On the other hand, this application also provides a method for preparing the pyrimidine amine compound, which includes the following steps: preparing compound I from compound II and compound III; or preparing compound V from compound IV and compound II, and then preparing compound I from compound V; HK 20105994 B 9 NH AX R1 N (R7)p R8 NN (R3)n (R4)m R5 Y R5=-N-(R2)-C(O)-R6 Z Formula II Formula III NNZ (R3)n (R4)m NHR2 Formula IV YNNNAX R1 (R3)n (R4)m NHR2 Formula VN (R7)p R8 Y ; wherein, Z is a leaving group, preferably Z is a halogen, more preferably Z is Cl, and the definitions of other groups are as described above. In one set of embodiments, the amino or imino group on the six-membered nitrogen-containing heterocycle of Formula II is first protected, coupled with a compound of Formula III, and then the protecting group is removed to prepare the compound of Formula I.In one embodiment, the amino or imino group attached to R2 in compound IV is first protected, and optionally the amino or imino group on the six-membered nitrogen-containing heterocycle in formula II is protected. Then, the protected compound IV is coupled with the optionally protected compound II, and the protecting group on the amino or imino group attached to R2 is removed to prepare compound V. Compound V is then reacted with R6-COOH, and the protecting group on ring B is optionally removed to prepare compound I. This application provides a pharmaceutical composition using the pyrimidine amine compounds described above as the active ingredient; the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient. This application also provides the use of the pyrimidine amine compounds in the preparation of NUAK1 or NUAK2 inhibitors. This application also provides the use of the pyrimidine amine compounds in the preparation of medicaments, characterized in that the compounds inhibit NUAK1 or NUAK2 to prevent or treat the following diseases: neuropsychiatric disorders, metabolic diseases, tumors, visceral fibrosis, and skin fibrosis. In one set of embodiments, the disease is Parkinson's disease, Alzheimer's disease, diabetes, hyperlipidemia, obesity, liver cancer, leukemia, lymphoma, tumor metastasis, cirrhosis, renal fibrosis, pulmonary fibrosis, sequelae of myocarditis, scleroderma, keloids, hypertrophic scars, or used alone to reduce scars after trauma and surgery.

[01] The beneficial effects of the present invention are: The present invention provides a class of pyrimidine amine compounds. In vitro kinase activity inhibition assays show that the compounds of the present invention have excellent inhibitory activity against NUAK1 or NUAK2 kinases. The following diseases can be prevented or treated by inhibiting NUAK1 or NUAK2: neuropsychiatric diseases, metabolic diseases, tumors, visceral fibrosis, and skin fibrosis. Detailed embodiments The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described herein are only for illustration and explanation of the present invention and are not intended to limit the present invention. The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein. Before describing the invention in detail, it should be understood that the terminology used herein is only for describing particular embodiments and is not intended to limit the scope of the invention, which is defined only by the appended claims. For a more complete understanding of the invention described herein, the following terms are used, and their definitions are as follows.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art to which this invention pertains. Definitions: Unless otherwise specified, the following terms referred to in this invention have the following definitions. Features described or illustrated as part of one embodiment or set of embodiments may be used in another embodiment or set of embodiments to produce further embodiments. In this invention, (R3)n (R4)m (R7)p (R10)q (R11)r on the ring group indicates that n R3s, m R4s, p R7s, q R10s, and r R11s can be attached to any possible position on the ring group. HK 20105994 B 11 In this invention, “ " in the partially substituents indicates a linking site. For group A, it represents an amino group attached above and an N-containing six-membered heterocycle attached below. Unless otherwise stated, "optional substitution" means that the hydrogen atom on the substituted group is not substituted or that one or more substituted sites of the substituted group are independently substituted by a substituent, which is independently selected from one or more of deuterium, halogen, amino, hydroxyl, nitro, cyano, mercapto, oxo, optionally substituted C1-8 alkyl, optionally substituted C1-8 alkyloxy, optionally substituted C1-8 alkylthio, optionally substituted C1-8 alkylamino; the substituent on the C1-8 alkyl group is selected from one or more of deuterium, halogen, amino, hydroxyl, nitro, cyano, mercapto; when the substituent is selected as "oxo", it means that two hydrogen atoms at the same substitution position are replaced by an oxygen atom. The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic system containing 3-10 carbon atoms, wherein the monocyclic, bicyclic, or tricyclic system does not contain an aromatic ring. Bicyclic groups include bridged cycloalkyl, spirocyclic, and fused cycloalkyl groups. Preferably, it comprises 3-10 carbon atoms (C3-10 cycloalkyl), more preferably 3-8 carbon atoms (C3-8 cycloalkyl), 3-6 carbon atoms (C3-6 cycloalkyl), 4-6 carbon atoms (C4-6 cycloalkyl), or 5-6 carbon atoms (C5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc. The term "heterocyclic alkyl" refers to a saturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon group, preferably comprising 3-10 ring atoms, wherein one, two, three, or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C, including bridged cyclic groups, spirocyclic groups, fused cyclic groups, etc. Preferably, it contains 3 to 8 ring atoms (3-8 membered heterocyclic alkyl), or 3 to 6 ring atoms (3-6 membered heterocyclic alkyl), or 4 to 6 ring atoms (4-6 membered heterocyclic alkyl), or 5 to 6 ring atoms (5-6 membered heterocyclic alkyl).The heteroatoms are preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). The heterocyclic alkyl group may be a 5-6 member monocyclic heterocyclic alkyl group containing 1-2 N atoms. Examples of heterocyclic alkyl groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, pyranyl, azircyclopropane, oxacyclopropane, thiohexane, azircyclobutane, oxacyclobutane, thiohexane, oxacyclohexane, morpholinyl, thiomorpholinyl, dioxalkyl, dithiohexyl, oxazolyl, thiazoalkyl, pyrazolyl, imidazolinidine, etc. The term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, preferably a straight-chain or branched group containing 1-8 carbon atoms (C1-8 alkyl) (the number of carbon atoms is between 1 and 8, specifically 1, 2, 3, 4, 5, 6, 7, or 8), more preferably containing 1-6 carbon atoms (i.e., C1-6 alkyl, the number of carbon atoms is between 1 and 6, specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc. The terms "alkyloxy," "alkylthio," and "alkylamino" refer to -O-alkyl, -S-alkyl, -NH-alkyl, or dialkylamino, respectively, with the alkyl group defined as above. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, etc.; methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, tert-butylthio, etc.; methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, etc. The term "halogen" refers to F, Cl, Br, and I. The active compound described in this invention is interpreted as including the compound and its stereoisomers, tautomers, isotopic derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof. Stereoisomes, tautomers, isotope derivatives, hydrates, solvates, prodrugs, isotope derivatives, or pharmaceutically acceptable salts of the compound are obtained by conventional techniques in the art and exert the same or similar effects in vitro and in vivo through substantially the same mechanism of action as the compound. The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including configurational isomers and conformational isomers. Configurational isomers further include geometric isomers (or cis-trans isomers) and optical isomers (including enantiomers and diastereomers).Geometric isomers may be present in this compound. Optical isomers refer to substances with identical molecular structures and similar physicochemical properties, but different optical rotations. The compounds of the present invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms “R” and “S” are as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds having asymmetrically substituted carbon atoms (having equal numbers of R and S configurations) are racemic at those carbon atoms. Having an excess of one configuration (relative to the other) makes that configuration present in a higher quantity, preferably an excess of about 85%-90%, more preferably an excess of about 9%-99%, and even more preferably an excess of more than about 99%. Accordingly, the present invention includes racemic mixtures, relative and absolute optical isomers, and mixtures of relative and absolute optical isomers. The term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved for the tautomers. For example, proton tautomers (also called proton transfer tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the rearrangement of some bonding electrons. The term "isotope derivative" means that the compounds of this invention can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to: 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36Cl, and 125I. Compounds containing other isotopes of these and / or other atoms are within the scope of this invention. The isotopically labeled compounds of this invention can be prepared using general methods well known to those skilled in the art. The term "hydrate" refers to an association formed by one or more water molecules with a compound of this invention. The term "solvent" refers to an association formed by one or more solvent molecules with a compound of this invention. The term "prodrug" is a derivative of a designed active pharmaceutical ingredient that can improve certain undesirable physical or biological properties.Physical properties are typically related to solubility (too high or too low lipid or water solubility) or stability, while problematic biological properties include metabolism that is too rapid or bioavailability that may itself be related to physicochemical properties. The term "pharmaceutically acceptable salt" means a salt suitable for contact with mammalian, particularly human, tissues without excessive toxicity, irritation, allergic reactions, etc., and in a manner commensurate with a reasonable benefit / risk ratio, within the bounds of reasonable medical judgment. If the compound is basic, pharmaceutically acceptable salts include salts prepared from inorganic acids, as well as salts prepared from organic acids. If the compound is acidic, pharmaceutically acceptable salts include salts prepared from inorganic bases and / or organic bases. The terms "pharmaceutically acceptable carrier" or "pharmaceuticalally acceptable excipient" include, but are not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier, etc., permitted by the relevant governmental regulatory authority for acceptable use in humans or livestock. As used herein, the term "treatment" refers to any application of a therapeutic agent according to a therapeutic regimen that achieves the desired effect, namely, partial or complete reduction, improvement, relief, suppression, delay of onset, reduction of severity, and / or reduction of the incidence of one or more symptoms or features of a particular disease, disorder, and / or condition; in some embodiments, the application of a therapeutic agent according to a therapeutic regimen is associated with the achievement of the desired effect. Such treatment may be directed to subjects who do not exhibit the relevant disease, disorder, and / or condition and / or to subjects who only exhibit early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be directed to subjects exhibiting one or more identified signs of the relevant disease, disorder, and / or condition. In some embodiments, treatment may be directed to subjects who have been diagnosed with the relevant disease, disorder, and / or condition. In some embodiments, treatment may be directed to subjects known to have one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, disorder, and / or condition. According to the present invention, the pharmaceutical preparations made for the pharmaceutical purposes described in this application may contain, in addition to the pyrimidine amine compounds of the present invention as active ingredients, other agents that can be used to prevent or treat related diseases as another active ingredient. When the pharmaceutical preparation contains multiple active ingredients, each active ingredient may be administered simultaneously, sequentially, or separately according to the physician's judgment.

[01] Hereinafter, the effects of specific compounds of the present invention will be described in detail through examples.Example Example 1 General method for synthesizing compound 518 (TDM-181118) Step 1 Step 2 NN NH O (S) F FCl HCl / dioxane DCM / MeOH / rt / ON NN NH (S) FF OHN NNNHNN NH (S) FF OHN NNN Boc H2N BocNN N Pd(OAc)2 / Xantphos / Cs2CO3 / dioxane / 100 oC / 2h 518a 518b 518c 518 HK 20105994 B 15

[02] Step 1: Compound 518c tert-butyl(S)-4-(4-((4-(4-(2,2-difluorocyclopropane-1-carbamoyl)phenyl)pyrimidine- Dioxane (2 mL) was added to a mixture of compounds 518a (20 mg, 0.065 mmol), 518b (26 mg, 0.097 mmol), palladium acetate, xantphos (37 mg, 0.065 mmol), and cesium carbonate (42 mg, 0.129 mmol). The mixture was degassed under vacuum, purged several times with argon, heated to 100 °C, and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (10% methanol / dichloromethane = 0–27 / 73) to give a yellow solid product (compound 518c, 17.3 mg, yield 49.3%). LCMS [M+1]+ = 540. Step 2: Compound 518 (S)-2,2-difluoro-N-(4-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)cyclopropane-1-carboxamide was added to a solution of compound 518c (17.3 mg, 0.028 mmol) in methanol (0.5 mL) and dichloromethane (2 mL). A 4M dioxane hydrochloride solution (0.07 mL) was added, and the mixture was stirred overnight at room temperature. The reactants were concentrated under reduced pressure, and the residue was purified by preparative HPLC (formic acid) to give a white solid product (compound 518, TDM-181118, 13.5 mg, yield 33%). LCMS [M+1]+ = 440.1H NMR (400 MHz, DMSO) δ 10.76 (s, 1H), 9.47 (s, 1H), 8.45 (d, J = 5.1 Hz, 1H), 8.35 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.98 (s, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.62 (s, 1H), 7.24 (d, J = 5.2 Hz, 1H), 4.33 (s, 1H), 3.21 (d, J = 12.5 Hz, 2H), 2.93-2.75 (m, 3H), 2.13-1.87 (m, 6H).

[03] N-(3-((5-chloro-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)oxyphenyl)-2,2-difluorocyclopropane-1-carboxamide (TDM-181120) was synthesized using a method similar to that in Example 1. It was a white solid (19.5 mg, yield 13.7%).TDM NO. Structure LCMS [M+1]+ 1H-NMR HK 20105994 B 16 TDM-181120 NN NH FFO HN NNO Cl 515.2 1H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 9.50 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.57-7.49 (m, 2H), 7.44 (t, J = 8.0 Hz, 1H), 7.21 (s, 2H), 7.05-6.94 (m, 1H), 6.65 (s, 2H), 3.02-.94 (m, 4H), 2.86-2.76 (m, 1H), 2.47- 2.40 (m, 4H), 2.22 (s, 3H), 2.07-1.91 (m, 2H).

[04] Example 2 General method for synthesizing compound 527 (TDM-181127) 527a NN Cl Cl HCl / dioxane DCM / MeOH / rt NNN Boc H2N Cl NN NH FFO HN NNNHO Cl HO NO2 NN NO2 O Cl Cl K2CO3 / DMF / rt / 2 h NN NH2 O Cl Cl HATU / DIPEA / DMF / 50oC / 2h OFF HO NN NH FF OO Cl Cl NN NH FFO HN NNNO Cl Boc Fe / NH4Cl / THF / H2O / 65oC / ON Pd(OAc)2 / Xantphos / Cs2CO3 / dioxane / 100oC / 2h 527b 527c 527d 527e 527f 527g 527h 527 Step 1 Step 2 Step 3 Step 4 Step 5 Step 1: Compound 527c 2,5-dichloro-4-(3-nitrophenoxy)pyrimidine HK 20105994 B 17 Potassium carbonate (904 mg, 6.542 mmol) was added to a solution of compound 527a (1000 mg, 5.452 mmol) and compound 527b (758 mg, 5.452 mmol) in N,N-dimethylformamide (40 mL), and the mixture was stirred at room temperature for 2 hours.The mixture was then added to water (250 mL) and extracted with ethyl acetate (80 mL * 3). The organic layers were combined, washed with brine, dried over sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was slurried with dichloromethane and methanol and filtered to give a white solid product (compound 527c, 1.34 g, 85.9% yield). LCMS [M+1]+ = 286. Step 2: Compound 527d 3-((2,5-dichloropyrimidin-4-yl)oxy)aniline Ammonium chloride (145 mg, 2.622 mmol) and iron powder (148 mg, 2.622 mmol) were added to a mixture of compound 527c (150 mg, 0.524 mmol) in tetrahydrofuran (10 mL) and water (10 mL). The mixture was heated to 65 °C and stirred overnight. The mixture was then filtered and the filtrate was concentrated under reduced pressure to remove tetrahydrofuran. The residue was neutralized with an aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL x 3), the organic layers were combined, washed with brine, dried over sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% methanol / dichloromethane = 0–1 / 99) to give a white solid product (compound 527d, 80 mg, 59.6% yield). LCMS [M+1]+ = 256. Step 3: Compound 527f N-(3-(((2,5-dichloropyrimidin-4-yl)oxy)phenyl)-2,2-difluorocyclopropane-1-carboxamide was added to a solution of compound 527d (80 mg, 0.312 mmol), compound 527e (57 mg, 0.469 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (178 mg, 0.469 mmol) in N,N-dimethylformamide (8 mL). The mixture was heated to 50 °C and stirred for 2 hours. The mixture was added to water (80 mL), then extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine, dried over sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% methanol / dichloromethane = 0–1 / 99) to give a yellow solid product (compound 527f, 70 mg, 62.3% yield). LCMS [M+1]+ = 360.Step 4: Compound 527h tert-butyl 4-(4-((5-chloro-4-(3-(2,2-difluorocyclopropane-1-carbamate)phenoxy)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate was added to a mixture of compound 527f (70 mg, 0.194 mmol), compound 527g (62 mg, 0.233 mmol), palladium acetate (8.8 mg, 0.039 mmol), xantphos (45 mg, 0.078 mmol), and cesium carbonate (126 mg, 0.388 mmol). Dioxane (7 mL) was added to the mixture. The mixture was degassed under vacuum, purged several times with argon, heated to 100°C, and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (10% methanol / dichloromethane = 0–30 / 70) to give a yellow solid product (compound 527h, 55 mg, 48% yield). LCMS [M+1]+ = 590. Step 5: Compound 527N-(3-((5-chloro-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)-2,2-difluorocyclopropane-1-carboxamide) was added to a methanol (1 mL) and dichloromethane (5 mL) solution of compound 527h (55 mg, 0.093 mmol) and 0.35 mL of dioxane hydrochloride solution was added, and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (formic acid) to give a white solid product (compound 527, TDM-181127, 25 mg, 54.9% yield). LCMS [M+1]+ = 490. 1H NMR (400 MHz, MeOD) δ 8.55 (s, 1H), 8.26 (s, 1H), 7.99 (s, 1H), 7.53 (s, 1H), 7.23 (d, J = 30.0 Hz, 2H), 7.10 – 6.81 (m, 2H), 4.01 (s, 1H), 3.52-3.40 (m, 2H), 3.15 (dd, J = 20.8, 7.9 Hz, 2H), 2.71 (ddd, J = 13.2, 10.8, 7.8 Hz, 1H), 2.20-1.81 (m, 6H).Example 3 General method for synthesizing compound 530 (TDM-181130) Step 1 530a NN Cl Cl Cl HN NO2 NN NO2 N Cl Cl NN NH2 N Cl Cl OFF HO NN NH FF ON Cl Cl Iron / NH4Cl THF / H2O / 65oC / 8h Py / POCl3 / 0oC~rt / 1h TsOH / n-BuOH / 110oC / 4h NN NH (S) FFO HN NNN Cl O DMF / NaH / 0oC~rt / 3 h NH2N ON 530b 530c 530d 530f 530g 530 Step 2 Step 3 Step 4 530e Step 1: Compound 530c HK 20105994 B 19 2,5-Dichloro-N-methyl-N-(3-nitrophenyl)pyrimidin-4-amine was reacted with sodium hydroxide (384 mg, 9.6 mmol) in a solution of compound 530b (730 mg, 4.8 mmol) in N,N-dimethylformamide (40 mL) at 0 °C. The mixture was allowed to warm naturally to room temperature and stirred for one hour. Then, compound 530a (1232 mg, 6.72 mmol) was added, and the mixture was stirred at room temperature for two hours. The reaction was checked for completeness. Post-treatment: The reaction mixture was poured into water, and the aqueous phase was extracted three times with ethyl acetate (3 x 150 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was column chromatography [eluent: EA / PE = 0–10%] to give a yellow solid target compound (compound 530c, 708.6 mg, yield 49.35%). LCMS [M+1]+ = 299, 301. Step 2: To a solution of compound 530d N1-(2,5-dichloropyrimidin-4-yl)-N1-methylbenzene-1,3-diamine in tetrahydrofuran (60 mL) and water (60 mL), iron powder (565.3 mg, 10.12 mmol) and ammonium chloride (541.3 mg, 10.12 mmol) were added. The reaction solution was heated to 65°C and stirred for 8 hours. The reaction was then checked to confirm its completeness.Post-processing: The reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate. The filtrate was extracted three times with ethyl acetate. The organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and dried. The crude product was passed through a column [eluent: (dichloromethane / methanol = 10:1, ) / DCM = 0~40%] to give a yellow solid target compound (compound 530d, 603 mg, yield 95%). LCMS [M+1]+ = 269, 271. Step 3: Compound 530f (S)-N-(3-((2,5-dichloropyrimidin-4-yl)(methyl)amino)phenyl)-2,2-difluorocyclopropane-1-carboxamide) was added to a pyridine (20 mL) solution of compound 530d (537.4 mg, 2 mmol). After cooling the reaction solution to 0°C, phosphorus oxychloride (0.28 mL, 3 mmol) was added, and the mixture was stirred for one hour. The reaction was then checked for completeness. Post-processing: The reaction solution was poured into ice water (30 mL), and the aqueous phase was extracted twice with ethyl acetate (2*50 mL). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was passed through a column with eluent of EA / PE = 0~40% to give a yellow solid target compound (compound 530f, 273.5 mg, yield 36.6%). LCMS [M+1]+ = 373,375. Step 4: Compound 530 (S)-N-(3-(5-chloro-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)-2,2-difluorocyclopropane-1-carboxamide HK 20105994 B 20 Compound 530f (52 mg, 0.14 mmol) was added to a solution of compound 530f (52 mg, 0.14 mmol) in n-butanol (5 mL) with compound 530g (31 mg, 0.14 mmol) and p-toluenesulfonic acid (53.3 mg, 0.28 mmol). The reaction solution was heated to 110 °C and stirred for 4 hours. The reaction was then checked for completeness. Post-processing: The reaction solution was poured into water, and the aqueous phase was extracted twice with ethyl acetate (2*150 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified to obtain a yellow solid target compound (compound 530, 15.4 mg, yield 19.7%), LCMS [M+1]+ = 558.1H NMR (400 MHz, DMSO) δ10.46 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.40 (dd, J = 8.0, 5.0 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 9.1 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 6.47 (dd, J = 8.8, 2.5 Hz, 1H), 3.83 (s, 3H), 3.36 (s, 3H), 3.15-3.07 (m, 4H), 2.77 (ddd, J = 13.6, 10.9, 8.1 Hz, 1H), 2.47–2.43 (m, 4H), 2.22 (s, 3H), 2.06–1.90 (m, 2H). (S)-N-(3-(5-chloro-2-(4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)-2,2-difluorocyclopropane-1-carboxamide (compound 531, TDM-181131), an off-white solid (9.4 mg, yield 10%), was synthesized by a method similar to that in Example 3.TDM NO. Structure LCMS [M+1]+ 1H-NMR TDM-181131 529.2 1H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 9.29 (s, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.55 (d, J = 9.1 Hz, 2H), 7.41 (t, J = 4.2 Hz, 2H), 7.31 (t, J = 8.2 Hz, 1H), 6.96-6.82 (m, 3H), 3.41 (s, 3H), 3.08-3.01 (m, 4H), 2.77 (ddd, J = 13.7, 10.9, 8.1 Hz, 1H), 2.47 (s, 4H), 2.23 (s, 3H), 1.98 (dd, J = 13.9, 6.6 Hz, 2H).

[05] HK 20105994 B 21 Example 4 General method for synthesizing compound 532 (TDM-181132) Step 1 532a 532c 532d 532e 532f Step 2 Step 3 Step 4 NN Cl Cl Cl HO NNO Cl Cl K2CO3 / DMF / rt / 2 h NNO Cl Cl Py / POCl3 / 0oC / 1 h O HO NNO Cl Cl Pd(OAc)2 / Xantphos / Cs2 CO3 / dioxane / 100oC / 2h NN HN NNO Cl O HN O Iron / NH4Cl / THF / H2O / 65oC / ON NH2NN O O2N NO2 NH2 HN O 532b 532g 532 Step 1: Compound 532c 2,5-dichloro-4-(2-nitrophenoxy)pyrimidine was added to a solution of compound 532b (421 mg, 3.03 mmol) in N,N-dimethylformamide (20 mL) along with compound 532a (550 mg, 3.03 mmol) and potassium carbonate (502 mg, 3.63 mmol). The reaction mixture was stirred at room temperature for two hours, and the reaction was checked for completeness.Post-processing: The reaction solution was poured into water, and the aqueous phase was extracted with ethyl acetate (3*50 mL). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was passed through a column [eluent: PE / EA = 0~15%] to give a white solid target compound (compound 532c, 800 mg, yield 92.4%). LCMS [M+1]+ = 286, 288. Step 2: Iron powder (1.51 g, 27 mmol) and ammonium chloride (1.44 g, 27 mmol) were added to a solution of compound 532c (1.54 g, 5.4 mmol) in tetrahydrofuran (150 mL) and water (150 mL). The reaction solution was heated to 65 °C and stirred for 3 hours. The reaction was checked for completeness. Post-processing: The reaction solution was cooled to room temperature and filtered. The filtrate was dried and then extracted three times with water and ethyl acetate (20 mL). The organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and dried. The crude product was passed through a column with the following eluent: (dichloromethane / methanol = 10:1) / DCM = 0~40%, yielding a yellow solid target compound (compound 532d, 476 mg, yield 34%). LCMS [M+1]+ = 256, 258. HK 20105994 B 22 Step 3: Compound 532f N-(2-((2,5-dichloropyrimidin-4-yl)oxy)phenyl)cyclopropane formamide was added to a pyridine (25 mL) solution of compound 532d (408 mg, 1.59 mmol) and compound 532e (194.5 mg, 1.59 mmol) was added. The reaction solution was cooled to 0°C and phosphorus oxychloride (0.22 mL, 2.39 mmol) was added. The mixture was kept warm and stirred for one hour. The reaction was then checked to confirm its completeness. Post-processing: The reaction solution was poured into ice water (30 mL), and the aqueous phase was extracted twice with ethyl acetate (2*50 mL). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was passed through a column with eluent of EA / PE = 0~40% to obtain a yellow solid target compound (compound 532f, 396.8 mg, yield 59%), LCMS [M+1]+ = 325.Step 4: Compound 532N-(2-(5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)oxy)phenyl)cyclopropane formamide was added to a 100 mL three-necked flask. The following compounds were added: compound 532f (30 mg, 0.12 mmol), compound 532g (30.5 mg, 0.14 mmol), palladium acetate (5.16 mg, 0.02 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (26.6 mg, 0.05 mmol), cesium carbonate (75 mg, 0.23 mmol), and 1,4-dioxane (6 mL). The reaction mixture was purged with argon several times, heated to 100 °C, and stirred for two hours. The reaction was then checked for completeness. Post-processing: The reaction solution was poured into ice water (30 mL), and the aqueous phase was extracted twice with ethyl acetate (2*50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to obtain the crude product. The target compound (compound 532, 14.3 mg, yield 19.7%) was obtained as a yellow solid. The LCMS [M+1]+ = 255, 509. 1H NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 8.07 (s, 1H), 7.72-7.64 (m, 1H), 7.56 (s, 2H), 7.23 (d, J = 5.9 Hz, 3H), 6.58 (d, J = 2.2 Hz, 1H), 6.32 (d, J = 8.4 Hz, 1H), 3.77 (s, 3H), 3.08 (s, 4H), 2.45 (s, 4H), 2.22 (s, 3H), 1.76 (d, J = 5.0 Hz, 1H), 1.00-0.86 (m, 4H).Example 5 General method for synthesizing compound 560 (TDM-181160) HK 20105994 B 23 560a step1 NN Cl Cl Cl HO NNO Cl Cl K2CO3 / DMF / rt / 2 h NNO Cl Cl NNO Cl Cl TsOH / n-BuOH / 110oC / 4h Iron / NH4Cl / THF / H2O / 65oC / 3 h O2N NO2 NH2 HN (S) ONN HN NNO Cl O HN (S) OO FF HO Py / POCl3 / 0oC~rt / 30 min FFFF NH2N ON step2 step3 step4 560b 560c 560d 560e 560f 560g 560 Step 1: Compound 560c 2,5-dichloro-4-(2-nitrophenoxy)pyrimidine to compound 560b Compound 560a (550 mg, 3.03 mmol) and potassium carbonate (502 mg, 3.63 mmol) were added to a solution of N,N-dimethylformamide (20 mL). The reaction mixture was stirred at room temperature for 2 hours, and the reaction was checked for completeness. Post-treatment: The reaction mixture was poured into water, and ethyl acetate (3 x 50 mL) was added for three-layer extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was passed through a column chromatography with PE / EA = 0-15% to give a white solid target compound (compound 560c, 800 mg, yield 92.4%). LCMS [M+1]+ = 286, 288. Step 2: Iron powder (1.51 g, 27 mmol) and ammonium chloride (1.44 g, 27 mmol) were added to a solution of compound 560c (1.54 g, 5.4 mmol) in tetrahydrofuran (150 mL) and water (150 mL). The reaction mixture was heated to 65 °C and stirred for 3 hours. The reaction was then checked for completeness. Post-treatment: The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filtrate was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was passed through a column chromatography with PE / EA = 0–50% to obtain a yellow solid target compound (compound 560d, 476 mg, yield 34%). LCMS [M+1]+ = 256, 258.Step 3: Compound 560f (S)-N-(2-((2,5-dichloropyrimidin-4-yl)oxy)phenyl)-2,2-difluorocyclopropane-1-carboxamide was added to a pyridine (25 mL) solution of compound 560d (408 mg, 1.59 mmol). After cooling the reaction solution to 0°C, phosphorus oxychloride (0.22 mL, 2.39 HK 20105994 B 24 mmol) was added, and the mixture was kept at this temperature for 30 minutes. The reaction was then checked to confirm its completeness. Post-processing: The reaction solution was poured into ice water (30 mL), and the aqueous phase was extracted twice with ethyl acetate (2*50 mL). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was passed through a column with PE / EA = 0~20% as eluent to obtain a yellow solid target compound (compound 560f, 396.8 mg, yield 59%). LCMS [M+1]+ = 360, 362. Step 4: Compound 560 (S)-N-(2-((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)oxy)benzene)-2,2-difluorocyclopropane-1-carboxamide was added to a solution of compound 560f (339 mg, 0.94 mmol) in n-butanol (24 mL) with compound 560g (208 mg, 0.94 mmol) and p-toluenesulfonic acid monohydrate (357 mg, 1.88 mmol). The reaction solution was heated to 110 °C and stirred for 4 hours. The reaction was then checked to confirm its completeness. Post-processing: The reaction solution was poured into water, and the aqueous phase was extracted with ethyl acetate (2*150 mL). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was passed through a column with the following eluent: (dichloromethane:methanol = 10:1 / DCM = 0~50%). The crude product was purified to obtain a white solid target compound (compound 560, 12.7 mg, yield 17%), with LCMS [M+1]+ = 545.2.1H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 8.06 (s, 1H), 7.70 (dd, J = 7.0, 3.0 Hz, 1H), 7.55 (d, J = 12.4 Hz, 2H), 7.26 (dd, J = 6.3, 3.7 Hz, 3H), 6.58 (d, J = 2.5 Hz, 1H), 6.31 (d, J = 8.7 Hz, 1H), 3.77 (s, 3H), 3.11-3.07 (m, 4H), 2.99-2.89 (m, 1H), 2.49-2.44 (m, 4H), 2.25 (s, 3H), 2.13 (dt, J = 9.4, 5.8 Hz, 1H), 2.02 (td, J = 14.1, 7.9 Hz, 1H). Example 6 General method for synthesizing compound 568 (TDM-181168) NNN Cl Cl NO2 NNN Cl Cl OFF HO NNN Cl Cl Iron / NH4Cl THF / H2O / 65oC / 8h Py / POCl3 / 0oC / 1h TsOH / n-BuOH / 110oC / 6h NN HN NNN Cl HN (S) O NH2 HN (S) OFFFF NH2N N 568a 568b 568c 568d 568e 568 Step 1 Step 2 Step 3 Step 1: Compound 568b N1-(2,5-dichloropyrimidin-4-yl)-N1-methylphenyl-1,2-diamine HK 20105994 B 25 Compound 568a (243 mg, 0.813 mmol) was added to tetrahydrofuran (2.5 Iron powder (28 mg, 0.502 mmol) and ammonium chloride (26.8 mg, 0.502 mmol) were added to a solution of water (2.5 mL). The mixture was heated to 65 °C and stirred. The mixture was filtered and the filtrate was concentrated under reduced pressure to remove some tetrahydrofuran. The residue was neutralized with aqueous sodium carbonate solution and extracted with ethyl acetate (40 mL * 3). The organic layers were combined, washed with brine, dried over sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% dichloromethane) to give a yellow solid product (compound 568b, 112.3 mg, 45.7% yield). LCMS [M+1]+ = 269, 271.Step 2: Compound 568d (S)-N-(2-(((2,5-dichloropyrimidin-4-yl)(methyl)amino)phenyl)-2,2-difluorocyclopropane-1-carboxamide) was mixed with phosphorus oxychloride (96 mg, 0.626 mmol) in a pyridine (5 mL) solution of compound 568b (112.3 mg, 0.417 mmol) and compound 568c (61 mg, 0.501 mmol) under an argon atmosphere at 0 °C. The mixture was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (100% dichloromethane) to give a yellow solid product (compound 568d, 141 mg, 90.6% yield). LCMS [M+1]+ = 373, 375. Step 3: Compound 568 (S)-N-(2-((5-chloro-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)-2,2-difluorocyclopropane-1-carboxamide was added to a n-butanol (5 mL) solution of compound 568d (70 mg, 0.188 mmol) and compound 568e (53.8 mg, 0.288 mmol). The mixture was heated to 110 °C and stirred for 6 hours. The mixture was added to water (50 mL) and extracted with ethyl acetate (25 mL * 3). The organic layers were combined, washed with brine, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid) to give a white solid product (compound 568, TDM-181168, 73.9 mg, yield 58%) with LCMS [M+1]+ = 528.1H NMR (400 MHz, DMSO) δ 9.86 (s, 1H), 9.23 (s, 1H), 8.16 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.93 (s, 1H), 7.59 (d, J = 9.0 Hz, 2H), 7.32-7.23 (m, 1H), 7.09 (d, J = 4.1 Hz, 2H), 6.89 (s, 2H), 3.23 (s, 3H), 3.20 – 3.11 (m, 1H), 3.09-3.02 (m, 4H), 2.49- 2.43 (m, 4H), 2.23 (s, 3H), 2.09-1.87 (m, 2H). HK 20105994 B 26 Test Example: Enzyme Activity Inhibition Detection of NUAK1 / NUAK2 Kinase Inhibitors. The effect of pyrimidine amine small molecules involved in this application on the inhibitory activity of NUAK1 and NUAK2 kinases was tested using a kinase activity assay method based on P81 filter paper combined with hotspot technology (Nat Biotechnol. 2011, 29:1039), which is briefly described as follows: The test buffer system contained 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35 (L23 polyoxyethylene lauryl ether), 0.02 mg / ml BSA (fetal bovine serum albumin), 0.1 mM Na3VO4, 2 mM DTT, and 1% DMSO. Test Procedure: 1. Prepare a 20 µM substrate solution using freshly prepared test buffer. The substrate is a CHKtide peptide fragment (Sanchez Y. Science. 1997, 277: 1497-1501); 2. Add the kinase and mix gently (final concentration of NUAK1: 10 nM; final concentration of NUAK2: 50 nM); 3. Using ultrasonic pipetting (Echo550; nanoliter), add the test compound dissolved in 100% DMSO to the above kinase reaction mixture and incubate at room temperature for 5 minutes; 4. Add 33P-labeled ATP (unlabeled ATP / labeled ATP ratio of 25:1 or 2.5:1); 5. Incubate at room temperature for 2 hours; 6. Detect kinase activity using P81 filter paper combined with hotspot technology. Calculate the IC50 of the test compound against NUAK1 / NUAK2 based on the above detection results. See Table 1 for specific results.IC50 calculation uses the formula obtained from the S-shaped dose-response curve (variable slope): Y=Bottom + (Top-Bottom) / (1+10^((LogEC50-X)*slope), where X is the Log value of the compound concentration, Y is the response (inhibition rate of kinase activity), and Y increases from bottom to top along the S-shaped curve as the concentration increases. Table 1 IC50 (nM) of the test compounds for NUAK1 / NUAK2 in this application

[06] Test compound

[07] NUAK1

[08] NUAK2

[09] TDM-181120

[10] 21 311 HK 20105994 B 27

[11] TDM-181127

[12] 161 352

[13] TDM-181131

[14] 81 635

[15] TDM-181132

[16] 24 37

[17] TDM-181160

[18] 4 13 As can be seen from the results in Table 1, the pyrimidine amine compounds of this application have excellent inhibitory activity against NUAK1 / NUAK2 and are dual-target small molecule kinase inhibitors. The IC50 of the compounds against NUAK1 / NUAK2 can reach several nM or tens of nM. Therefore, the above experiments have proven that the pyrimidine amine compounds of this application can be used as NUAK1 / NUAK2 inhibitors. The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention. These simple modifications are all within the protection scope of the present invention. It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable way without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

[19] In addition, various different embodiments of the present invention can also be combined arbitrarily. As long as they do not violate the spirit of the present invention, they should also be regarded as the content disclosed by the present invention.HK 20105994 B 1 Claim 1. A pyrimidine amine compound, characterized in that the pyrimidine amine compound is a compound represented by formula I-1, or an isotopic derivative thereof, and a pharmaceutically acceptable salt thereof; NNNAX R1 (R4)m R5 Formula I-1 N (R7)p R8 Y R5=-N-(R2)-C(O)-R6 Cl, wherein A is q(R10) or NN r(R11); X is N or CH, Y is O or NR9; R1, R2, R8, R9 are each independently H, or optionally substituted C1-8 alkyl; R4, R7, R10, R11 are each independently halogen, amino, hydroxyl, nitro, cyano, mercapto, optionally substituted C1-8 alkyl, optionally substituted C1-8 alkyloxy, optionally substituted C1-8 alkylthio, optionally substituted C1-8 Alkylamino; R6 is an optionally substituted 3-10 membered cycloalkyl group, wherein the substituent on the cycloalkyl group is selected from one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted C1-8 alkyl, optionally substituted C1-8 alkyloxy, optionally substituted C1-8 alkylthio, and optionally substituted C1-8 alkylamino; the substituent on the C1-8 alkyl group is selected from one or more of halogen, amino, hydroxy, nitro, cyano, and mercapto; r is 0, 1, or 2, and m, p, and q are 0, 1, 2, 3, or 4, respectively; HK 20105994 B 2 The pyrimidineamine compound is not. 2. The compound according to claim 1, wherein Y is O or NH. 3. The compound according to claim 1, wherein R6 is an optionally substituted 3-6 membered cycloalkyl group. 4. The compound according to claim 3, wherein R6 is a halogen-substituted 3-6 membered cycloalkyl group. 5. The compound according to claim 4, wherein R6 is a fluorine-substituted 3-6 membered cycloalkyl group. 6. The compound according to claim 3, wherein R6 is or FF. 7. The compound according to claim 6, wherein R5 is ONH or FFONH. 8. The compound according to claim 7, wherein R5 is FFOHN(S). 9. The compound according to any one of claims 1-8, wherein R5 is substituted at the ortho or meta position of Y. 10. The compound according to any one of claims 1-8, wherein X is N, and R8 is H or methyl.11. The compound according to claim 10, characterized in that the compound represented by formula I-1 is HK 20105994 B 3 NNNN R1 (R4)m R5 N (R7)p Y Cl O R5=-N-(R2)-C(O)-R6 Formula I-2 or NNNN R1 (R4)m R5 N (R7)p Y Cl R5=-N-(R2)-C(O)-R6 Formula I-3. 12. The compound according to claim 1, characterized in that the compound represented by formula I is one of the following compounds: NN NH FFO HN NNO Cl NN NH FFO HN NNNHO Cl NN NH (S) FFO HN NNN Cl O TDM-181120 TDM-181127 TDM-181130 NN NH (S) FFO HN NNN Cl NN HN NNO Cl O HN ONN HN NNO Cl O HN (S) OFF TDM-181131 TDM-181132 TDM-181160 HK 20105994 B 4 NN HN NNN Cl HN (S) OFF TDM-181168. 13. The compound according to claim 1 or 12, wherein the pharmaceutically acceptable salt is a formate. 14. The compound according to claim 1 or 12, wherein the isotope derivative is a deuterated product. 15. A method for preparing a compound according to any one of claims 1-14, comprising the following steps: preparing compound I-1 from compound II and compound III; or preparing compound V from compound IV and compound II, and then preparing compound I-1 from compound V; optionally, the preparation process includes a protecting and deprotecting step; wherein Z is a leaving group, and the definitions of other groups are the same as those defined in claims 1-14. HK 20105994 B 5 16. The preparation method according to claim 15, wherein Z is a halogen. 17. The preparation method according to claim 16, wherein Z is Cl. 18. A pharmaceutical composition, characterized in that the compound according to any one of claims 1-14 is the active ingredient. 19. The pharmaceutical composition according to claim 18, characterized in that it comprises a pharmaceutically acceptable carrier or excipient.20. Use of the compound according to any one of claims 1-14 for the preparation of a NUAK1 or NUAK2 inhibitor. 21. Use of the compound according to any one of claims 1-14 for the preparation of a medicament, characterized in that the compound, by inhibiting NUAK1 or NUAK2, is used to prevent or treat the following diseases: neuropsychiatric diseases, metabolic diseases, tumors, visceral fibrosis, and skin fibrosis. 22. Use according to claim 21, characterized in that the disease is Parkinson's disease, Alzheimer's disease, diabetes, hyperlipidemia, obesity, liver cancer, leukemia, lymphoma, tumor metastasis, cirrhosis, renal fibrosis, pulmonary fibrosis, sequelae of myocarditis, scleroderma, keloids, hypertrophic scars, or used alone to reduce scars after trauma and surgery. HK 20105994 B.