Pyrimidopyridine FGFR inhibitors and preparation method and use thereof

Abstract

The present invention discloses a pyrimidine-piperidine-based FGFR inhibitor represented by Formula 1, and its preparation method and uses. The compounds according to the present invention, or pharmaceutically acceptable salts, stereoisomers, prodrug molecules or solvates thereof, exhibit high inhibitory activity against FGFR activating mutants or resistant mutant forms (one or more). The compounds of the present invention have good physicochemical properties and safety and toxicity parameters. Such compounds will have good clinical effects in the treatment of diseases (including cancer) mediated by FGFR activating mutations and / or drug-resistant mutations.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a class of pyrimidine-piperidine compounds or pharmaceutically acceptable salts, stereoisomers, prodrug molecules or solvates thereof, and a preparation method thereof, a pharmaceutical composition containing such compounds, and the use of such compounds in the preparation of drugs for treating and / or preventing FGFR-related diseases, particularly tumors. Background Art

[0002] Fibroblast growth factors (FGFs) bind to their receptors (fibroblast growth factor receptors, FGFRs), activate the downstream signaling pathways they regulate, and play important roles in biological processes such as mitosis (embryogenesis, growth and development, etc.) and non-mitosis (neural regulation, metabolic regulation, etc.). FGFRs are a typical class of receptor tyrosine kinases (RTKs), and its family includes four receptors, namely FGFR1, FGFR2, FGFR3, and FGFR4. They are all composed of three parts: an extracellular region, a transmembrane region, and an intracellular tyrosine kinase region. The extracellular region contains three immunoglobulin-like structures (D1-D3). The D1 region has a self-inhibitory function, and the D2 and D3 regions and the linker region between D2 and D3 bind to ligands. Selective splicing can occur in the D3 of the IIIb or IIIc part of FGFR1, FGFR2, and FGFR3, resulting in two subtypes, FGFRb or FGFRc. The difference in the D3 domain determines the ligand-binding specificity of FGFRs. FGFs need to bind to FGFRs with the assistance of heparan sulphate glycosaminoglycan (HSGAG), causing FGFR dimerization, leading to autophosphorylation and activation of multiple tyrosine residues in its intracellular tyrosine kinase region. The activated FGFRs activate their substrates PLCγ and the signal adapter protein FRS2 through phosphorylation, and their substrates then activate downstream signaling pathways such as MEK / MAPK, PI3K / AKT, PKC, and STATS. When the internal environment is disordered, the overexpression, mutation, etc. of FGFR lead to abnormal activation of its signaling pathways, which is closely related to the occurrence and development of various diseases. Diseases related to tumors include lung cancer, gastric cancer, breast cancer, colorectal cancer, chronic myeloid leukemia, cholangiocarcinoma, glioblastoma multiforme, chondrosarcoma, lipomatosis, bladder cancer, etc.

[0003] It is also related to non-tumor diseases, such as bone diseases (craniosynostosis syndrome, Kallman syndrome, osteoporotic dysplasia, chondrodysplasia), gonadal dysgenesis, hypopigmented spots of Blaschko lines in children, and arthritis. Inhibitor drugs targeting FGFR can inhibit the abnormal activation of the FGF / FGFR signaling pathway and have the potential to treat the above diseases. FGFR inhibitor drugs have become one of the hot spots in drug research in recent years. According to the protein structure of FGFR, its inhibitors can be divided into two types. The first type is to inhibit the catalytic activity or tyrosine autophosphorylation of FGFR by targeting the intramembrane tyrosine kinase domain. These inhibitors are all small molecule compounds. The other type is to target the immunoglobulin domain outside the FGFR membrane, competitively bind to the FGFR extramembrane region with FGFs, and block FGF-FGFR binding and pathway activation. This type of inhibitor includes small molecule compounds, short peptides and antibodies. Summary of the invention

[0004] After extensive and in-depth research, the inventors of the application designed and synthesized a series of small molecule compounds with novel structures through artificial intelligence (AI) technology, which have a good inhibitory effect on multiple mutants of FGFR kinases commonly used in clinical practice.

[0005] According to one aspect of the present invention, an object of the present invention is to provide a pyrimidopiperidine compound represented by the following formula 1 or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate thereof:

[0006]

[0007] wherein R1 and R2 are each independently selected from a hydrogen atom, a hydroxyl group, an amino group, a halogen, a cyano group, a C1 to C6 alkyl group, a halogen-substituted C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen-substituted C1 to C6 alkoxy group, a substituted or unsubstituted C3 to C8 cycloalkyl group, a substituted or unsubstituted C6 to C 14 aryl, a three- to eight-membered substituted or unsubstituted heteroaryl containing 1 to 4 heteroatoms selected from S, N or O, a three- to eight-membered substituted or unsubstituted heterocycloalkyl containing 1 to 4 heteroatoms selected from S, N or O; the substituted or unsubstituted C3 to C8 cycloalkyl, substituted or unsubstituted C6 to C 14 In the aryl group, a three- to eight-membered substituted or unsubstituted heteroaryl group containing 1-4 heteroatoms selected from S, N or O, and a three- to eight-membered substituted or unsubstituted heterocycloalkyl group containing 1-4 heteroatoms selected from S, N or O, the “substituted” refers to each substituent containing 1-3 substituents selected from hydroxyl, amino, halogen, cyano, C1 to C6 alkyl, halogen-substituted C1 to C6 alkyl, C1 to C6 alkoxy, and halogen-substituted C1 to C6 alkoxy;

[0008] R3 is selected from a hydrogen atom, a hydroxyl group, an amino group, a halogen, a cyano group, an alkyl group having 1 to 6 carbon atoms, a halogen-substituted alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen-substituted alkoxy group having 1 to 6 carbon atoms;

[0009] R4 is selected from a hydrogen atom, a hydroxyl group, an amino group, a halogen, a cyano group, an alkyl group having 1 to 6 carbon atoms, a halogen-substituted alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen-substituted alkoxy group having 1 to 6 carbon atoms.

[0010] Preferably, R1 and R2 are each independently selected from a hydrogen atom, a hydroxyl group, an amino group, a halogen, a cyano group, an alkyl group having 1 to 3 carbon atoms, a halogen-substituted alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen-substituted alkoxy group having 1 to 3 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group having 6 to C 10 an aryl group, a substituted or unsubstituted heteroaryl group having 3 to 6 members containing 1 to 3 heteroatoms selected from N or O, a substituted or unsubstituted heterocycloalkyl group having 3 to 6 members containing 1 to 3 heteroatoms selected from N or O; in the substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, the substituted or unsubstituted aryl group having 6 to C 10 an aryl group, a substituted or unsubstituted heteroaryl group having 3 to 6 members containing 1 to 3 heteroatoms selected from N or O, a substituted or unsubstituted heterocycloalkyl group having 3 to 6 members containing 1 to 3 heteroatoms selected from N or O, the "substitution" means that each substituent contains 1 to 3 substituents selected from a hydroxyl group, an amino group, a halogen, a cyano group, an alkyl group having 1 to 3 carbon atoms, and a halogen-substituted alkyl group having 1 to 3 carbon atoms;

[0011] Preferably, R1 and R2 are each independently selected from a hydrogen atom, a hydroxyl group, an amino group, a halogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, a C1 to C3 alkyl group substituted by 1 to 3 fluorine atoms, a C1 to C3 alkyl group substituted by 1 to 3 chlorine atoms, a C1 to C3 alkyl group substituted by 1 to 3 bromine atoms, a substituted or unsubstituted cycloalkyl group having 5 to 6 carbon atoms, a substituted or unsubstituted phenyl group, a substituted or unsubstituted heteroaryl group having 5 to 6 members containing 1 or 2 heteroatoms selected from N or O, a substituted or unsubstituted heterocycloalkyl group having 5 to 6 members containing 1 or 2 heteroatoms selected from N or O; in the substituted or unsubstituted cycloalkyl group having 5 to 6 carbon atoms, the substituted or unsubstituted phenyl group, the substituted or unsubstituted heteroaryl group having 5 to 6 members containing 1 or 2 heteroatoms selected from N or O, the substituted or unsubstituted heterocycloalkyl group having 5 to 6 members containing 1 or 2 heteroatoms selected from N or O, the "substitution" means that each substituent contains 1 to 3 substituents selected from a hydroxyl group, a halogen, a methyl group, an ethyl group, a propyl group, and an isopropyl group.

[0012] More preferably, when R1 and R2 are each independently selected from substituted or unsubstituted C5-C6 cycloalkyl, substituted or unsubstituted phenyl, five- to six-membered substituted or unsubstituted heteroaryl containing 1 or 2 heteroatoms selected from N or O, five- to six-membered substituted or unsubstituted heterocycloalkyl containing 1 or 2 heteroatoms selected from N or O, R1 and R2 are specifically substituents selected from the following:

[0013]

[0014] Preferably, R3 is selected from a hydrogen atom, a hydroxyl group, an amino group, a halogen, a C1-C4 alkyl group, and a halogen-substituted C1-C4 alkyl group.

[0015] Preferably, R3 is selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a C1-C3 alkyl group substituted with 1-3 fluorine atoms, a C1-C3 alkyl group substituted with 1-3 chlorine atoms, and a C1-C3 alkyl group substituted with 1-3 bromine atoms.

[0016] Preferably, R4 is selected from a hydrogen atom, a hydroxyl group, an amino group, a halogen, a C1-C4 alkyl group, and a halogen-substituted C1-C4 alkyl group.

[0017] Preferably, R4 is selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a C1-C3 alkyl group substituted with 1-3 fluorine atoms, a C1-C3 alkyl group substituted with 1-3 chlorine atoms, and a C1-C3 alkyl group substituted with 1-3 bromine atoms.

[0018] Preferably, the pyrimidine-piperidine compound represented by Formula 1 according to the present invention, or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate thereof is represented by the following Formula 2 or Formula 3:

[0019]

[0020] Wherein, the definitions of R1, R2 and R3 are the same as those in Formula 1.

[0021] R5 and R6 are each independently selected from a hydrogen atom, a hydroxyl group, an amino group, a halogen, a cyano group, a C1-C6 alkyl group, a halogen-substituted C1-C6 alkyl group, a C1-C6 alkoxy group, and a halogen-substituted C1-C6 alkoxy group.

[0022] Preferably, R5 and R6 are each independently selected from a hydrogen atom, a hydroxyl group, an amino group, a halogen, a C1-C4 alkyl group, and a halogen-substituted C1-C4 alkyl group.

[0023] Preferably, R5 and R6 are each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a C1-C3 alkyl group substituted with 1-3 fluorine atoms, a C1-C3 alkyl group substituted with 1-3 chlorine atoms, and a C1-C3 alkyl group substituted with 1-3 bromine atoms.

[0024] The pyrimidopiperidine compound or its pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate according to the present invention is selected from the following compounds:

[0025]

[0026]

[0027] According to one aspect of the present invention, an object of the present invention is to provide a method for preparing a pyrimidopiperidine compound represented by Formula 1 to Formula 3 or a pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate thereof, comprising the following steps:

[0028]

[0029] Step 1: 2-methylthio-4-amino-6-hydroxypyrimidine (Compound 1) is reacted with cycloisopropyl malonate (Compound 1A) and methyl glyoxylate (Compound 1B) in toluene under reflux for 3 to 5 hours to obtain methyl 2-(methylthio)-4,7-dioxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carboxylate (Intermediate 2);

[0030]

[0031] Step 2: The intermediate 2 is subjected to oxidation of the methylthio group under the action of an oxidant to obtain 2-(methylsulfonyl)-4,7-dioxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carboxylic acid methyl ester (intermediate 6), wherein the oxidant is selected from potassium permanganate, potassium dichromate, m-chloroperbenzoic acid, periodic acid, perbenzoic acid, peracetic acid, cumene hydroperoxide, and cyclohexanone peroxide;

[0032]

[0033] Step 3: Intermediate 6 undergoes substitution reaction with tetrahydroisoquinoline (compound 2A) with different substituents to obtain intermediate 7a;

[0034]

[0035] Step 4: Intermediate 7a is subjected to esterification under the catalysis of a base such as lithium hydroxide to obtain intermediate 4a;

[0036]

[0037] Step 5: Primary amines (NHR1R2) with different groups react with intermediate 4a, N,N - diisopropylethylamine (DIPEA), and 2-(7 - azabenzotriazol - 1 - yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) in an organic solvent such as DMF at room temperature for 3 - 5 hours to obtain the target compound of formula 1.

[0038] In the above preparation methods, the definitions of the substituents R1, R2, R3, and R4 in each reaction formula are the same as those in formula 1.

[0039] According to one aspect of the present invention, an object of the present invention is to provide the use of the pyrimidine - piperidine compounds represented by formula 1 to formula 3 or pharmaceutically acceptable salts, stereoisomers, prodrug molecules, or solvates thereof in the preparation of drugs for treating diseases or disorders such as lung cancer, gastric cancer, breast cancer, colorectal cancer, chronic myeloid leukemia, cholangiocarcinoma, glioblastoma multiforme, chondrosarcoma, lipomatosis, bladder cancer, skeletal diseases (craniosynostosis syndrome, Kallman syndrome, osteoporotic dysplasia, chondrodysplasia), gonadal dysgenesis, hypopigmented macules along Blaschko lines in children, arthritis, etc.

[0040] According to one aspect of the present invention, an object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the pyrimidine - piperidine compounds represented by formula 1 to formula 3 according to the present invention or pharmaceutically acceptable salts, stereoisomers, prodrug molecules, or solvates thereof and a pharmaceutically acceptable excipient.

[0041] According to one aspect of the present invention, an object of the present invention is to provide a method for treating and / or preventing diseases mediated by FGFR activating mutations and / or drug - resistant mutations in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pyrimidine - piperidine compounds represented by formula 1 to formula 3 according to the present invention or pharmaceutically acceptable salts, stereoisomers, prodrug molecules, or solvates thereof or the pharmaceutical composition comprising the same. The diseases mediated by FGFR activating mutations and / or drug - resistant mutations include diseases or disorders such as lung cancer, gastric cancer, breast cancer, colorectal cancer, chronic myeloid leukemia, cholangiocarcinoma, glioblastoma multiforme, chondrosarcoma, lipomatosis, bladder cancer, skeletal diseases (craniosynostosis syndrome, Kallman syndrome, osteoporotic dysplasia, chondrodysplasia), gonadal dysgenesis, hypopigmented macules along Blaschko lines in children, arthritis, etc.

[0042] Beneficial effects

[0043] The pyrimidopiperidine compound represented by Formula 1 to Formula 3 of the present invention or its pharmaceutically acceptable salt, stereoisomer, prodrug molecule or solvate shows high inhibitory activity against FGFR activation mutant or resistance mutant form (one or more). The compound of the present invention has good physicochemical properties and safety toxicity parameters. Such compounds have good clinical effects in the treatment of diseases (including cancer) mediated by FGFR activation mutations and / or drug resistance mutations. DETAILED DESCRIPTION

[0044] Hereinafter, the present invention will be described in detail. Before describing, it should be understood that the terms used in this specification and the appended claims should not be interpreted as being limited to the general meaning and dictionary meaning, but should be interpreted according to the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that the inventor is allowed to appropriately define the terms for the best interpretation. Therefore, the descriptions presented here are only preferred examples for illustrative purposes and are not intended to limit the scope of the present invention, so that it should be understood that other equivalents or improvements can be obtained therefrom without departing from the spirit and scope of the present invention.

[0045] As used herein, the terms "include", "comprising", "having", "containing" or any other similar terms are open-ended transitional phrases, which are intended to cover non-exclusive inclusions. For example, a composition or article containing multiple elements is not limited to the elements listed herein, but may also include other elements that are not explicitly listed but are generally inherent to the composition or article. In addition, unless otherwise expressly stated, the term "or" refers to an inclusive "or" rather than an exclusive "or". For example, any of the following situations satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist). In addition, as used herein, the terms "include", "comprising", "having", and "containing" should be interpreted as having been specifically disclosed and simultaneously covering closed or semi-closed transitional phrases such as "consisting of" and "consisting essentially of".

[0046] In this text, all features or conditions defined in the form of numerical ranges or percentage ranges are only for the sake of brevity and convenience. Accordingly, the description of a numerical range or percentage range should be regarded as having covered and specifically disclosed all possible sub-ranges and individual numerical values within the range, especially integer numerical values. For example, the description of the range "1 to 8" should be regarded as having specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., especially the sub-ranges defined by all integer numerical values, and should be regarded as having specifically disclosed individual numerical values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. Unless otherwise specified, the foregoing interpretation method applies to all contents of the present invention, regardless of the breadth of the range.

[0047] If a quantity or other numerical value or parameter is expressed in the form of a range, a preferred range, or a series of upper and lower limits, it should be understood that all ranges constituted by any pair of the upper limit or preferred value of the range and the lower limit or preferred value of the range have been specifically disclosed herein, regardless of whether these ranges are separately disclosed. In addition, when a numerical range is mentioned in this text, unless otherwise stated, the range should include its endpoints and all integers and fractions within the range.

[0048] In this text, on the premise that the purpose of the invention can be achieved, a numerical value should be understood as having the precision of the significant digits of that numerical value. For example, the number 40.0 should be understood as covering the range from 39.50 to 40.49.

[0049] In this text, for the case of using a Markush group or alternative terms to describe the features or examples of the present invention, those skilled in the art should understand that all sub-groups or any individual elements within the Markush group or alternative list can also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3", it also means that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, for the case of using a Markush group or alternative terms to describe the features or examples of the present invention, those skilled in the art should understand that any combination of all sub-groups or individual elements within the Markush group or alternative list can also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3", and Y is described as "selected from the group consisting of Y1, Y2, and Y3", it means that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0050] Definition

[0051] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are determined according to the periodic table of the elements on the inside front cover of the CAS version, Handbook of Chemistry and Physics, 75th Edition, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry as well as specific functional moieties and reactivity are described in the following books: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999 (Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999); Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001 (Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001); Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989 (Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989); and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987 (Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987). The present invention is not intended to be limited in any way by the exemplary lists of substituents described herein.

[0052] The compounds described herein may contain one or more asymmetric centers and, thus, may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and formation and crystallization of chiral salts; or the preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (E.L. Eliel, editor, University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein: as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0053] The term “alkyl” refers to a group of straight-chain or branched-chain saturated hydrocarbon groups having 1 to 6 carbon atoms (“C 1–6 alkyl”). In some embodiments, alkyl has 1 to 5 carbon atoms (“C 1–5 alkyl”). In some embodiments, alkyl has 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, alkyl has 1 to 3 carbon atoms (“C 1-3 alkyl”). In some embodiments, alkyl has 1 to 2 carbon atoms (“C 1-2 alkyl”). In some embodiments, alkyl has 1 carbon atom (“C1 alkyl”). In some embodiments, alkyl has 2 to 6 carbon atoms (“C 2-6 alkyl”). C 1–6Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n - propyl, isopropyl), butyl (C4) (e.g., n - butyl, tert - butyl, sec - butyl, isobutyl), pentyl (C5) (e.g., n - pentyl, 3 - pentyl, neopentyl, 3 - methyl - 2 - butyl, tert - pentyl) and hexyl (C6) (e.g., n - hexyl). Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents (e.g., halogen, such as F) (“substituted alkyl”). In certain embodiments, the alkyl group is unsubstituted C 1-10 alkyl (e.g., unsubstituted C 1-6 alkyl, such as - CH3). In certain embodiments, the alkyl group is substituted C 1-10 alkyl (e.g., substituted C 1-6 alkyl, such as - CF3).

[0054] The term “alkoxy,” when used alone or as part of another group, refers to a group of the formula OR a1 , where R a1 is an alkyl group.

[0055] The term “cycloalkyl” refers to a group of a non - aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms (“C 3-8 carbocyclic group”) and zero heteroatoms in a non - aromatic ring system. In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclic group”). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclic group”). In some embodiments, the carbocyclic group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclic group”). Exemplary C 3-6 carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C 3-8 carbocyclic groups include, but are not limited to, the above - mentioned C 3-6Carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. As shown in the foregoing examples, in certain embodiments, the cycloalkyl group is monocyclic or contains fused, bridged, or spiro ring systems, such as bicyclic systems (“bicyclic cycloalkyls”) and can be saturated or can be partially unsaturated. “Cycloalkyl” also includes ring systems in which the carbocyclic ring as defined above is fused to one or more aryl or heteroaryl groups at a point of attachment on the carbocyclic ring, and in such cases, the carbon number continues to refer to the number of carbons in the cycloalkyl group. Unless otherwise specified, each instance of the cycloalkyl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”).

[0056] The term “heterocycloalkyl” refers to a group of 3- to 8-membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-8 membered heterocyclic group”). In heterocyclic groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as long as the valence allows. The heterocyclic group can be monocyclic (“monocyclic heterocycloalkyl”) or a fused, bridged, or spiro ring system, such as a bicyclic system (“bicyclic heterocycloalkyl”), and can be saturated or can be partially unsaturated. The bicyclic heterocycloalkyl system can contain one or more heteroatoms in one or both rings. “Heterocycloalkyl” also includes ring systems in which the heterocyclic ring as defined above is fused to one or more cycloalkyl groups at a point of attachment on the cycloalkyl or heterocycloalkyl, or the heterocyclic ring as defined above is fused to one or more aryl or heteroaryl groups at a point of attachment on the heterocyclic ring, and in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclic system. Unless otherwise specified, each instance of the heterocycloalkyl is independently optionally substituted, i.e., unsubstituted (“unsubstituted heterocycloalkyl”) or substituted with one or more substituents (“substituted heterocycloalkyl”).

[0057] The term “aryl” refers to a group of monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”). In some embodiments, the aryl has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, the aryl has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl has 14 ring carbon atoms (“C 14"Aryl"; for example, anthryl). "Aryl" also includes ring systems in which the aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups and the group or point of attachment is on the aromatic ring, and in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise specified, each instance of aryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted by one or more substituents ("substituted aryl"). In certain embodiments, aryl is unsubstituted C 6-14 aryl. In certain embodiments, aryl is substituted C 6-14 aryl.

[0058] The term "heteroaryl" refers to a group having a 5- to 8-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) with ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In heteroaryl containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as long as the valence allows. The bicyclic heteroaryl system can contain one or more heteroatoms in one or two rings. "Heteroaryl" includes ring systems in which the heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups and the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which the heteroaryl ring as defined above is fused to one or more aryl groups and the point of attachment is on the aryl or heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl in which one ring contains no heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with heteroatoms (e.g., 2-indolyl) or the ring without heteroatoms (e.g., 5-indolyl).

[0059] The term "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0060] The term "pharmaceutically acceptable salts" refers to those salts that are suitable, within the scope of reasonable medical judgment, for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic acids, organic acids, and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, dodecyl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, trimethylacetates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4 (alkyl)4-salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide ions, hydroxide ions, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0061] As used herein, the term "subject" (which may alternatively be referred to herein as "patient") refers to an animal that has been made the object of treatment, observation, or experiment, preferably a mammal, and most preferably a human.

[0062] As used herein, the term "treatment" refers to the elimination, reduction, or amelioration of a disease or disorder and / or one or more symptoms associated therewith. Although not excluded, treating a disease or disorder does not require complete elimination of the disease, disorder, or one or more symptoms associated therewith. As used herein, the term "treatment" and the like can include "preventive treatment", which refers to reducing the likelihood of recurrence or re-development of a disease or disorder in a subject who does not have recurrence or re-development of the disease or disorder, but is at risk of or has a tendency to recurrence or re-development of the disease or disorder. The terms "treatment" and synonyms refer to administering a therapeutically effective amount of the compounds described herein to a subject in need of such treatment.

[0063] A "therapeutically effective amount" of the compounds described herein is an amount sufficient to provide a therapeutic benefit in treating a disorder or to delay or minimize one or more symptoms associated with the disorder. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent that provides a therapeutic benefit in treating the disorder, either alone or in combination with other therapies. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes, and / or enhances the therapeutic efficacy of another therapeutic agent.

[0064] The compounds of the present disclosure may exist in isotopically labeled or isotope-enriched forms, which contain one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Isotopes can be radioactive isotopes or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 I. Compounds containing these and / or other isotopes of atoms are within the scope of the present invention.

[0065] The following examples are merely listed as examples of the embodiments of the present invention and do not constitute any limitation to the present invention. Those skilled in the art can understand that modifications within the scope of the essence and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following examples are commercially available products.

[0066] Examples

[0067] Example 1: Synthesis of Intermediate 2

[0068]

[0069] 2-Methylthio-4-amino-6-hydroxypyrimidine 1 (70.0 g, 445 mmol), propanediol cyclic (isopropylidene) carbonate 1A (64.1 g, 445 mmol), and methyl glyoxylate 1B (39.2 g, 445 mmol) were dissolved in toluene (490 mL), and the mixture was refluxed and stirred for 3 hours. After rotary evaporation under reduced pressure, the crude product was purified by silica gel column (SiO2, dichloromethane:methanol = 30:1 to 3:1) to obtain the yellow target product methyl 2-(methylthio)-4,7-dioxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carboxylate, Compound 2 (7.00 g, yield: 5.63%).

[0070] EI-MS (m / z): 270.05 ([M+H] + )

[0071] Example 2: Synthesis of Intermediate 6

[0072]

[0073] Methyl 2-(methylthio)-4,7-dioxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carboxylate 2 (7.00 g, 26.0 mmol) was dissolved in dichloromethane (40.0 mL), and m-CPBA (meta-chloroperoxybenzoic acid) (13.7 g, 67.5 mmol) was added. The reaction was carried out at room temperature for 16 hours. After filtration and rotary evaporation, the crude product was separated and purified by a preparative high-performance liquid chromatography silica gel column (TFA conditions) to obtain the white solid methyl 2-(methylsulfonyl)-4,7-dioxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carboxylate 6 (3.90 g, yield 49.80%).

[0074] EI-MS (m / z): 302.04 ([M+H] + )

[0075] Example 3: Synthesis of Intermediate 7

[0076]

[0077] Methyl 2-(methylsulfonyl)-4,7-dioxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carboxylate 6 (4.20 g, 13.9 mmol) and tetrahydroisoquinoline 2A (2.23 g, 16.7 mmol, 2.10 mL) were dissolved in dimethyl sulfoxide (20.0 mL), and DIPEA (N,N-diisopropylethylamine) (5.41 g, 41.8 mmol) was added. The mixture was stirred at 100 °C for 16 hours. After cooling to room temperature, the reaction solution was poured into 20.0 mL of ice water, stirred for 15 minutes, filtered, washed with water, and dried to obtain the yellow solid intermediate 7 (1.50 g, yield 28.4%).

[0078] EI-MS (m / z): 355.13 ([M+H] + )

[0079] Example 4: Synthesis of Intermediate 4

[0080]

[0081] To a solution of intermediate 7 (1.45 g, 4.09 mmol) in tetrahydrofuran (7.00 mL) at 0 °C was added an aqueous LiOH solution (1 M, 12.2 mL). The reaction solution was stirred at room temperature for 2 hours, and the pH was adjusted to 3 with 1 N HCl. Stirring was continued for 5 minutes, and the mixture was filtered by suction to obtain the yellow solid intermediate 4 (1.50 g).

[0082] EI-MS (m / z): 341.12 ([M+H] + )

[0083] Example 5: Synthesis of Intermediate 8

[0084]

[0085] Intermediate 6 (300 mg, 996 μmol) and 6-hydroxy-1,2,3,4-tetrahydroisoquinoline 8A (178 mg, 1.19 mmol) were dissolved in DMSO (500 μL), and DIPEA (386 mg, 2.99 mmol, 520 μL) was added. The mixture was reacted at 100 °C for 16 hours. Water (3 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (2 mL × 3), washed with saturated brine (1 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain the yellow crude intermediate 8 (150 mg, crude product).

[0086] EI-MS (m / z): 371.13 ([M+H] + )

[0087] Example 6: Synthesis of Intermediate 9

[0088]

[0089] Intermediate 8 (150 mg, 405 μmol) was dissolved in tetrahydrofuran (THF, 1.00 mL). An aqueous solution of LiOH (1 M, 1.22 mL) was added dropwise at 0 °C, and the reaction was carried out at room temperature for 2 hours. The pH was adjusted to 3 with 1 N hydrochloric acid solution, filtered, and concentrated under reduced pressure to obtain yellow solid Intermediate 9 (135 mg, yield: 80.09%).

[0090] EI-MS (m / z): 357.11 ([M+H] + )

[0091] Example 7: Synthesis of Intermediate 10

[0092]

[0093] Intermediate 6 (500 mg, 1.66 mmol) and 2-methyl-1,2,3,4-tetrahydroisoquinoline 10A (293 mg, 1.99 mmol) were dissolved in DMSO (0.200 mL), and then DIPEA (643 mg, 4.98 mmol, 867 μL) was added. The reaction solution was reacted at 100 °C for 16 hours. The reaction solution was poured into water (2 mL), stirred for 5 minutes, filtered, washed with water, and dried to obtain brown solid 10 (0.150 g, yield 24.5%).

[0094] EI-MS (m / z): 369.15 ([M+H] + )

[0095] Example 8: Synthesis of Intermediate 11

[0096]

[0097] Intermediate 10 (145 mg, 394 μmol) was dissolved in tetrahydrofuran (THF, 1.00 mL). At 0 °C, an aqueous solution of LiOH (1 M, 1.57 mL) was added dropwise, and the reaction solution was reacted at room temperature for 2 hours. The pH was adjusted to 5 with 1 N hydrochloric acid, filtered, and concentrated under reduced pressure to obtain yellow solid 11 (80.0 mg, crude product).

[0098] EI-MS (m / z): 355.13 ([M+H] + )

[0099] Example 9: Synthesis of Intermediate 12

[0100]

[0101] Intermediate 6 (300 mg, 996 μmol) and 5-amino-1,2,3,4-tetrahydroisoquinoline 12A (177 mg, 1.19 mmol) were dissolved in DMSO (0.200 mL), and then DIPEA (386 mg, 2.99 mmol, 520 μL) was added. The reaction mixture was reacted at 100 °C for 16 h. After the reaction was completed, the reaction mixture was poured into water (10 mL), stirred for 5 min, filtered by suction, washed with water, and dried to obtain brown solid 12 (300 mg, yield: 81.6%).

[0102] EI-MS (m / z): 370.14 ([M+H] + )

[0103] Example 10: Synthesis of Intermediate 13

[0104]

[0105] Intermediate 12 (270 mg, 731 μmol) was dissolved in tetrahydrofuran THF (3.00 mL), and an aqueous solution of LiOH (1 M, 4.39 mL) was added dropwise at 0 °C. The reaction was carried out at room temperature for 12 h, adjusted to pH = 5 with 1 N hydrochloric acid, filtered, and concentrated to obtain yellow Intermediate 13 (180 mg, crude product).

[0106] EI-MS (m / z): 356.13 ([M+H] + )

[0107] Intermediate 14

[0108]

[0109] For the synthesis method, refer to Intermediate 4. After Intermediate 6 reacts with 7-bromo-1,2,3,4-tetrahydroisoquinoline and is hydrolyzed under the action of lithium hydroxide, Intermediate 14 is obtained.

[0110] EI-MS (m / z): 419.03 ([M+H] + )

[0111] Intermediate 15

[0112]

[0113] For the synthesis method, refer to Intermediate 4. After Intermediate 6 reacts with 8-methoxy-1,2,3,4-tetrahydroisoquinoline and the resulting product is hydrolyzed under the action of lithium hydroxide, Intermediate 15 is obtained.

[0114] EI-MS (m / z): 371.13 ([M+H] + )

[0115] Example 11: Synthesis of HD-0001

[0116]

[0117] Intermediate 4 (150 mg, 440 μmol), 3-aminopyridine A (49.7 mg, 528 μmol) and DIPEA (85.4 mg, 661 μmol) were dissolved in DMF (200 μL), and HATU (201 mg, 528 μmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction product was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 1%-30%, 8 min) to give white solid HD-0001 (50.0 mg, yield: 25.0%).

[0118] 1 H NMR (400 MHz, DMSO)

[0119] δ 11.2 (s, 1H), 10.6 (s, 1H), 10.1 (s, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.19 - 7.24 (m, 3H), 7.14 (t, J = 4.0 Hz, 1H), 4.78 (s, 2H), 3.93 (dd, J = 8.0, 1.6 Hz, 1H), 3.85 (t, J = 6.0 Hz, 3H), 2.80 - 2.92 (m, 3H), 2.62 (d, J = 15.6 Hz, 1H).

[0120] EI-MS (m / z): 417.16 ([M + H] + )

[0121] Example 12: Synthesis of HD-0002

[0122]

[0123] Intermediate 4 (150 mg, 440 μmol), 4-aminopyrimidine B (50.3 mg, 528 μmol) and DIPEA (85.4 mg, 661 μmol) were dissolved in DMF (200 μL), and then HATU (201 mg, 528 μmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction product was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 25%-55%, 8 min) to give yellow solid HD-0002 (35.1 mg, yield: 19.0%).

[0124] 1 1H NMR (400 MHz, DMSO)

[0125] δ 10.3 (s, 1H), 10.1 (s, 1H), 8.96 (s, 2H), 8.87 (s, 1H), 7.24 - 7.18 (m, 3H), 7.14 (t, J = 3.9 Hz, 1H), 4.78 (s, 2H), 3.95 - 3.81 (m, 3H), 2.91 - 2.77 (m, 3H), 2.63 (d, J = 15.2 Hz, 1H).

[0126] EI-MS (m / z): 418.15 ([M + H] + )

[0127] Example 13: Synthesis of HD-0003

[0128]

[0129] Intermediate 4 (150 mg, 440 μmol), m-aminophenol C (57.7 mg, 528 μmol) and DIPEA (85.4 mg, 661 μmol) were dissolved in DMF (200 μL), and then HATU (201 mg, 528 μmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and the reactants were purified by preparative high performance liquid chromatography (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 15% - 45%, 8 min) to obtain white solid HD-0003 (35.9 mg, yield: 18.8%).

[0130] 1 1H NMR (400 MHz, DMSO)

[0131] δ 11.2 (s, 1H), 10.1 (s, 1H), 9.71 (s, 1H), 9.37 (s, 1H), 7.25 - 7.18 (m, 3H), 7.14 (t, J = 4.0 Hz, 1H), 7.09 - 7.01 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.42 (dd, J = 1.6, 8.0 Hz, 1H), 4.77 (s, 2H), 3.90 - 3.79 (m, 3H), 2.88 (t, J = 5.6 Hz, 2H), 2.78 - 2.69 (m, 1H), 2.59 (d, J = 16.0 Hz, 1H).

[0132] EI-MS (m / z): 432.16 ([M + H] + )

[0133] Example 14: Synthesis of HD-0004

[0134]

[0135] Intermediate 4 (150 mg, 440 μmol), m-phenylenediamine D (57.2 mg, 528 μmol) and DIPEA (85.4 mg, 661 μmol) were dissolved in DMF (200 μL), and then HATU (201 mg, 528 μmol) was added. The reaction mixture was stirred at room temperature for 2 h, and the reaction product was purified by preparative high performance liquid chromatography (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 10%-35%, 8 min) to obtain gray solid HD-0004 (35.1 mg, yield: 18.5%).

[0136] 1 1H NMR (400 MHz, DMSO)

[0137] δ 10.1 (s, 1H), 10.1 (s, 1H), 7.67 (s, 1H), 7.38 - 7.27 (m, 2H), 7.24 - 7.18 (m, 3H), 7.14 (t, J = 4.0 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 4.78 (s, 2H), 3.93 - 3.82 (m, 3H), 2.88 (t, J = 6.0 Hz, 2H), 2.79 (dd, J = 8.0, 16.4 Hz, 1H), 2.59 (d, J = 16.0 Hz, 1H).

[0138] EI-MS (m / z): 431.18 ([M + H] + )

[0139] Example 15: Synthesis of HD-0005

[0140]

[0141] Intermediate 4 (150 mg, 440 μmol), aniline E (49.2 mg, 528 μmol) and DIPEA (85.4 mg, 661 μmol) were dissolved in DMF (200 μL), and then HATU (201 mg, 528 μmol) was added. The reaction mixture was stirred at room temperature for 2 h, and the reaction product was purified by preparative high performance liquid chromatography (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 20%-50%, 8 min) to obtain off-white solid HD-0005 (35 mg, yield: 19.1%).

[0142] 1 1H NMR (400 MHz, DMSO)

[0143] δ 10.12 (s, 1H), 9.85 (s, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.29 (t, J = 8.0 Hz, 2H), 7.24 - 7.18 (m, 3H), 7.14 (t, J = 4.0 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 4.78 (s, 2H), 3.90 (dd, J = 1.2, 7.6 Hz, 1H), 3.84 (t, J = 7.6 Hz, 2H), 2.88 (t, J = 6.0 Hz, 2H), 2.80 - 2.71 (m, 1H), 2.61 (d, J = 15.6 Hz, 1H).

[0144] EI-MS (m / z): 416.16 ([M + H] + )

[0145] Example 16: Synthesis of HD-0006

[0146]

[0147] Intermediate 14 (183.9 mg, 440 μmol), m-fluoroaniline F (58.7 mg, 528 μmol) and DIPEA (85.4 mg, 661 μmol) were dissolved in DMF (200 mL), and HATU (201 mg, 528 μmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction product was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 20% - 50%, 8 min) to give yellow solid HD-0006 (129.3 mg, yield: 25.3%).

[0148] 1 1H NMR (400 MHz, DMSO)

[0149] δ 10.1 (s, 1H), 7.53 (d, J = 2.2, 11.6 Hz, 1H), 7.36 - 7.27 (m, 1H), 7.23 - 7.17 (m, 3H), 7.14 (t, J = 4.0 Hz, 1H), 6.83 (d, J = 2.4, 8.4 Hz, 1H), 4.75 (s, 2H), 3.94 - 3.77 (m, 3H), 2.88 (t, J = 6.0 Hz, 2H), 2.78 (dd, J = 8.0, 16.4 Hz, 1H), 2.54 (d, J = 16.4 Hz, 1H).

[0150] EI-MS (m / z): 512.07 ([M+H] + )

[0151] Example 17: Synthesis of HD-0007

[0152]

[0153] Intermediate 15 (162.8 mg, 440 μmol), m-fluoroaniline F (58.7 mg, 528 μmol) and DIPEA (85.4 mg, 661 μmol) were dissolved in DMF (200 mL), and then HATU (201 mg, 528 μmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction product was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 20%-50%, 8 min) to give yellow solid HD-0007 (72.7 mg, yield: 15.7%).

[0154] 1 1H NMR (400 MHz, DMSO)

[0155] δ 10.2 (s, 1H), 7.50 (d, J = 2.2, 11.6 Hz, 1H), 7.35 - 7.27 (m, 1H), 7.22 - 7.16 (m, 3H), 7.13 (t, J = 4.0 Hz, 1H), 6.86 (d, J = 2.4, 8.4 Hz, 1H), 4.77 (s, 2H), 3.94 - 3.77 (m, 6H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (dd, J = 8.0, 16.4 Hz, 1H), 2.60 (d, J = 16.4 Hz, 1H).

[0156] EI-MS (m / z): 464.17 ([M+H] + )

[0157] Example 18: Synthesis of HD-0008

[0158]

[0159] Intermediate 4 (150 mg, 440 μmol), 3-fluoroaniline F (58.7 mg, 528 μmol) and DIPEA (85.4 mg, 661 μmol) were dissolved in DMF (200 mL), and then HATU (201 mg, 528 μmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction product was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 30%-50%, 8 min) to give yellow solid HD-0008 (35.7 mg, yield: 7.7%).

[0160] 1 1H NMR (400 MHz, DMSO)

[0161] δ 10.0 (s, 1H), 7.53 (d, J = 2.2, 11.6 Hz, 1H), 7.36 - 7.27 (m, 1H), 7.23 - 7.17 (m, 4H), 7.14 (t, J = 4.0 Hz, 1H), 6.86 (d, J = 2.4, 8.4 Hz, 1H), 4.77 (s, 2H), 3.94 - 3.77 (m, 3H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (dd, J = 8.0, 16.4 Hz, 1H), 2.59 (d, J = 16.4 Hz, 1H).

[0162] EI-MS (m / z): 434.16 ([M + H] + )

[0163] Example 19: Synthesis of HD-0009

[0164]

[0165] Intermediate 4 (150 mg, 440 μmol), 3,5-difluoroaniline G (68.2 mg, 528 μmol) and DIPEA (85.4 mg, 661 μmol) were dissolved in DMF (200 μL), and then HATU (201 mg, 528 μmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction product was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 35%-55%, 8 min) to give yellow solid HD-0009 (32.0 mg, yield: 14.8%).

[0166] 1 1H NMR (400 MHz, DMSO)

[0167] δ 10.28 (s, 1H), 10.15 (s, 1H), 7.29 - 7.18 (m, 5H), 7.14 (t, J = 3.8 Hz, 1H), 6.94 - 6.82 (m, 1H), 4.77 (s, 2H), 3.89 - 3.79 (m, 3H), 2.87 (t, J = 6.0 Hz, 2H), 2.80 (dd, J = 8.0, 16.4 Hz, 1H), 2.58 (d, J = 16.4 Hz, 2H).

[0168] EI-MS (m / z): 452.15 ([M + H] + )

[0169] Example 20: Synthesis of HD-0010

[0170]

[0171] Intermediate 4 (150 mg, 440 μmol), cyclohexylamine H (52.4 mg, 528 μmol) and DIPEA (85.4 mg, 661 μmol) were dissolved in DMF (200 μL), and then HATU (201 mg, 528 μmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction product was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 30% - 55%, 8 min) to give yellow solid HD-0010 (35.8 mg, yield: 19.0%).

[0172] 1 1H NMR (400 MHz, DMSO)

[0173] δ 11.18 (s, 1H), 9.99 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.24 - 7.18 (m, 3H), 7.14 (t, J = 4.0 Hz, 1H), 4.76 (s, 2H), 3.83 (t, J = 5.6 Hz, 2H), 3.62 (dd, J = 1.6, 7.6 Hz, 1H), 2.87 (t, J = 6.0 Hz, 2H), 2.64 - 2.55 (m, 1H), 1.75 - 1.42 (m, 5H), 1.32 - 1.01 (m, 5H).

[0174] EI-MS (m / z): 422.21 ([M + H] + )

[0175] Example 21: Synthesis of HD-0011

[0176]

[0177] Intermediate 4 (150 mg, 440 μmol), dimethylamine I (31.2 mg, 528 μmol) and DIPEA (85.4 mg, 661 μmol) were dissolved in DMF (200 μL), and then HATU (201 mg, 528 μmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction product was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 20%-40%, 8 min) to afford white solid HD-0011 (35.7 mg, yield: 21.0%).

[0178] 1 H NMR (400 MHz, DMSO)

[0179] δ 11.16 (s, 1H), 9.98 (s, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.24 - 7.18 (m, 3H), 7.16 - 7.11 (m, 1H), 4.76 (s, 2H), 3.83 (t, J = 5.6 Hz, 2H), 3.72 (dt, J = 6.8, 13.6 Hz, 2H), 3.58 (d, J = 7.5 Hz, 1H), 2.87 (t, J = 5.6 Hz, 2H), 1.03 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 6.4 Hz, 3H)

[0180] EI-MS (m / z): 368.18 ([M + H] + )

[0181] Example 22: Synthesis of HD-0012

[0182]

[0183] Intermediate 4 (150 mg, 440 μmol), 3-aminopyrrole J (62.7 mg, 528 μmol, HCl) and HATU (201 mg, 528 μmol) were dissolved in DMF (300 μL), and then DIPEA (85.4 mg, 661 μmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction product was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 20%-40%, 8 min) to afford black solid HD-0012 (25.0 mg, yield: 13.7%).

[0184] 1 H NMR (400 MHz, DMSO)

[0185] δ 11.17 (s, 1H), 10.41 (s, 1H), 10.05 (s, 1H), 9.45 (s, 1H), 7.24 - 7.17 (m, 3H), 7.16 - 7.10 (m, 1H), 6.97 - 6.89 (m, 1H), 6.55 (q, J = 2.8 Hz, 1H), 5.96 - 5.84 (m, 1H), 4.77 (s, 2H), 3.90 - 3.72 (m, 3H), 2.87 (t, J = 5.6 Hz, 3H), 2.74 - 2.66 (m, 2H).

[0186] EI-MS (m / z): 405.16 ([M + H] + )

[0187] Example 23: Synthesis of HD-0013

[0188]

[0189] To a solution of intermediate 9 (130 mg, 365 μmol) in DMF (1.00 mL) was added m-fluoroaniline F (48.7 mg, 438 μmol, 42.0 μL), DIPEA (70.7 mg, 547 μmol, 95.3 μL), and HATU (166 mg, 438 μmol). The reaction mixture was stirred at room temperature for 6 hours, concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl) - ACN]; B%: 15% - 45%, 8 min) to give yellow solid HD-0013 (31.2 mg, yield: 18.5%).

[0190] 1 1H NMR (400 MHz, DMSO)

[0191] δ 11.16 (br d, J = 1.6 Hz, 1H), 10.11 (br d, J = 10.4 Hz, 2H), 9.29 (br d, J = 4.0 Hz, 1H), 7.53 (td, J = 2.0, 11.7 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.21 (br d, J = 8.0 Hz, 1H), 6.95 - 6.83 (m, 2H), 6.64 - 6.57 (m, 2H), 4.64 (s, 2H), 3.88 (dd, J = 1.2, 7.8 Hz, 1H), 3.84 - 3.72 (m, 2H), 2.83 - 2.72 (m, 4H), 2.62 - 2.56 (m, 2H).

[0192] EI-MS (m / z): 450.15 ([M + H]+ )

[0193] Example 24: Synthesis of HD-0014

[0194]

[0195] To a solution of intermediate 13 (180 mg, 507 μmol) in DMF (1 mL) was added m-fluoroaniline F (84.4 mg, 760 μmol, 72.8 μL), DIPEA (98.2 mg, 760 μmol, 132 μL), and HATU (231 mg, 608 μmol). The reaction was carried out at room temperature for 2 hours, concentrated under reduced pressure, and the reaction product was purified by preparative high-performance liquid chromatography (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 1%-35%, 8 min) to obtain yellow solid HD-0014 (25.0 mg, yield: 11.0%).

[0196] 1 H NMR (400 MHz, DMSO)

[0197] δ 11.39 - 11.11 (m, 1H), 10.13 (s, 1H), 10.09 (s, 1H), 7.52 (td, J = 2.0, 11.6 Hz, 1H), 7.35 - 7.27 (m, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.16 - 7.06 (m, 1H), 6.94 - 6.73 (m, 3H), 4.76 (s, 2H), 3.96 - 3.79 (m, 4H), 2.82 - 2.68 (m, 3H), 2.62 - 2.53 (m, 2H), 2.53 - 2.52 (m, 1H)

[0198] EI-MS (m / z): 449.17 ([M+H] + )

[0199] Example 25: Synthesis of HD-0015

[0200]

[0201] To a solution of intermediate 11 (75.0 mg, 212 μmol) in DMF (1.00 mL) were added m-fluoroaniline F (28.2 mg, 254 μmol, 24.3 μL), DIPEA (41.0 mg, 317 μmol, 55.3 μL) and HATU (96.6 mg, 254 μmol). The reaction was carried out at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 25%-55%, 8 min) to obtain brown solid HD-0015 (15.3 mg, yield: 15.9%).

[0202] 1 H NMR (400 MHz, DMSO)

[0203] δ 11.24 - 11.17 (m, 1H), 10.11 (br d, J = 6.0 Hz, 2H), 7.53 (br d, J = 12.4 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.23 - 7.13 (m, 5H), 6.87 (t, J = 8.0 Hz, 1H), 5.67 - 5.61 (m, 1H), 3.89 - 3.86 (m, 1H), 2.94 - 2.69 (m, 4H), 2.64 - 2.56 (m, 2H), 2.53 - 2.53 (m, 7H), 1.44 (d, J = 6.4 Hz, 3H).

[0204] EI-MS (m / z): 448.17 ([M + H] + )

[0205] Test Example 1: Enzyme Activity Test

[0206] Experimental Procedure for Enzyme Activity

[0207] 1. Preparation of 1x kinase reaction buffer:

[0208] 1 volume of 5X kinase reaction buffer and 4 volumes of water; 5 mM MgCl2; 1 mM DTT.

[0209] 2. Reaction conditions:

[0210] Kinase ATP Km [μM] ATP onset condition [μM] Substrate TK [μM] EPHA2 3.703 5 1 EPHA8 3.4 5 1 FGFR1 / 50 1 FGFR2 / 50 1 FGFR3 / 50 1 FGFR4 / 50 1

[0211] 3. Compound screening:

[0212] 1) Dilute the compound 4-fold with DMSO in a dilution plate, and the initial concentration of the compound is 10000 nM.

[0213] 2) Dilute the compound 40-fold in 1X kinase reaction buffer and shake on an oscillator for 20 minutes.

[0214] 3) Prepare 2X kinase using 1X enzyme reaction buffer.

[0215] 4) Add 2 μl of kinase (prepared in step 3) to each well of the reaction plate.

[0216] 5) Add 1 μl of the compound diluted in buffer to each well, seal the plate with a sealing film, centrifuge at 1000 g for 30 seconds, and incubate at room temperature for 10 minutes.

[0217] 6) Prepare a 2.5x TK-substrate-biotin and ATP mixture using 1X enzyme reaction buffer and add 2 μl of the K-substrate-biotin / ATP mixture to the reaction plate.

[0218] 7) Seal the plate with a sealing film, centrifuge at 1000 g for 30 seconds, and react at room temperature for 50 minutes.

[0219] 8) Prepare 4X Sa-XL 665 (250 nM) using HTRF detection buffer.

[0220] 9) Add 5 μl of Sa-XL 665 and 5 μl of TK-antibody-Cryptate to each well, centrifuge at 1000 g for 30 seconds, and react at room temperature for 40 min.

[0221] 10) Read the fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665) using Biotek.

[0222] 4. Data Analysis

[0223] 1) Calculate the ratio (Ratio_665 / 615 nm) for each well

[0224] 2) The inhibition rate is calculated as follows:

[0225] Compound inhibition rate (% inh) = 100% - (Compound - Positive control) / (Negative control - Positive control) * 100%

[0226] Positive control: 10000 nM positive drug (Staurosporine (antibiotic AM-2282 or STS))

[0227] Negative control: 0.5% aqueous DMSO solution

[0228] X: Log value of compound concentration Y: Inhibition rate (% inhibition)

[0229] The ratio was converted into the inhibition rate, and the IC50 was calculated by Prism GraphPad 6.0 based on the inhibition rate.

[0230] IC 50 The results were recalculated using the ratio to verify the accuracy.

[0231]

[0232] As described above, the above are only specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention can easily think of changes or substitutions, which should all be covered within the protection scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope of the claims.

Claims

1. A pyrimido[1,2 - a]piperidine compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: Among them, R1 and R2 are each independently selected from a hydrogen atom or the following substituents: Provided that one of R1 and R2 is a hydrogen atom; R3 is selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms; R4 is selected from a hydrogen atom, a hydroxyl group, an amino group, a halogen, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms.

2. The pyrimido[4,5-d]piperidine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R3 is selected from a hydrogen atom, an alkyl group having 1 to 4 carbon atoms.

3. The pyrimidine-piperidine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R3 is selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group.

4. The pyrimidine-piperidine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R4 is selected from a hydrogen atom, a hydroxyl group, an amino group, a halogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 6 carbon atoms.

5. The pyrimidine-piperidine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R4 is selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group.

6. The pyrimidine-piperidine compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein The pyrimido[1,2 - a]piperidine compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is represented by the following Formula 2 or Formula 3: Wherein, the definitions of R1, R2 and R3 are the same as those in Claim 1; R5 and R6 are each independently selected from a hydrogen atom, a hydroxyl group, an amino group, a halogen, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms.

7. The pyrimidine-piperidine compound or a pharmaceutically acceptable salt thereof according to claim 6, wherein R5 and R6 are each independently selected from a hydrogen atom, a hydroxyl group, an amino group, a halogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 6 carbon atoms.

8. The pyrimidine-piperidine compound or a pharmaceutically acceptable salt thereof according to claim 6, wherein R5 and R6 are each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group.

9. The pyrimidine-piperidine compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The pyrimido[1,2 - a]piperidine compound or a pharmaceutically acceptable salt thereof is selected from the following compounds:

10. A method for preparing the pyrimido[1,2 - a]piperidine compound or a pharmaceutically acceptable salt thereof according to Claim 1, comprising the following steps: Step 1: 2 - (Methylthio)-4 - amino - 6 - hydroxypyrimidine (Compound 1) reacts with malonic acid cyclo(isopropylidene) ester (Compound 1A) and methyl glyoxylate (Compound 1B) by refluxing in toluene for 3 - 5 hours to obtain methyl 2 - (methylthio)-4,7 - dioxo - 3,4,5,6,7,8 - hexahydropyrido[2,3 - d]pyrimidine - 5 - carboxylate (Intermediate 2); Step 2: Under the action of an oxidant, the methylthio group of Intermediate 2 is oxidized to obtain methyl 2 - (methylsulfonyl)-4,7 - dioxo - 3,4,5,6,7,8 - hexahydropyrido[2,3 - d]pyrimidine - 5 - carboxylate (Intermediate 6), wherein the oxidant is selected from potassium permanganate, potassium dichromate, m - chloroperoxybenzoic acid, periodic acid, peroxybenzoic acid, peracetic acid, cumene hydroperoxide, cyclohexanone peroxide; Step 3: Intermediate 6 undergoes a substitution reaction with Compound 2A to obtain Intermediate 7a; Step 4: Intermediate 7a undergoes ester hydrolysis under the catalysis of lithium hydroxide to obtain Intermediate 4a; Step 5: A primary amine NHR1R2 with different groups reacts with Intermediate 4a, N,N - diisopropylethylamine and 2 - (7 - azabenzotriazole)-N,N,N',N' - tetramethyluronium hexafluorophosphate in DMF organic solvent at room temperature for 3 - 5 hours to obtain the target compound of Formula 1; In the above steps, the definitions of the substituents R1, R2, R3 and R4 in each reaction formula are the same as those in Claim 1.

11. Use of a pyrimido[1,2 - a]piperidine compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating lung cancer, gastric cancer, breast cancer, colorectal cancer, chronic myeloid leukemia, cholangiocarcinoma, glioblastoma multiforme, chondrosarcoma, lipomatosis, bladder cancer, skeletal diseases, gonadal dysgenesis, hypopigmented macules along Blaschko lines in children, arthritis diseases or disorders.

12. The use according to claim 11, wherein The skeletal diseases are selected from craniosynostosis syndrome, Kallman syndrome, osteoporotic dysplasia, chondrodysplasia.

13. A pharmaceutical composition comprising a therapeutically effective amount of a pyrimido[1,2 - a]piperidine compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

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