1H-Pyrrolo[2,3-c]pyridine compounds and their uses

Abstract

A series of 1H-pyrrolo[2,3-c]pyridine compounds and uses thereof are disclosed, specifically compounds represented by formula (P) and pharmaceutically acceptable salts thereof: [Formula 1] JPEG2023543006000127.jpg29169

Description

Detailed Description of the Invention

[0001] Claiming priority CN202011023186.4, Application date: September 25, 2020, CN202011253763.9, application date: November 11, 2020.

[0002] [Technical field] The present invention relates to a series of 1H-pyrrolo[2,3-c]pyridine compounds and uses thereof, in particular to compounds of formula (P) and pharma- ceutically acceptable salts thereof:

[0003] [Background technology] Colony stimulating factor 1 (CSF-1, also called macrophage colony stimulating factor, M-CSF) is an important growth factor that controls the growth of bone marrow progenitor cells, monocytes, macrophages, osteoclasts and dendritic cells differentiated from macrophages, and must bind to its unique cell surface receptor, CSF-1R, to exert its biological effects. CSF-1R is also called c-FMS because it is encoded by the proto-oncogene c-FMS. It is a receptor tyrosine kinase. The binding of CSF-1 and CSF-1R at the extracellular domain induces dimerization of CSF-1R, which then causes phosphorylation of the intracellular CSF-1R kinase domain itself. Once phosphorylated, CSF-1R functions as a docking site for multiple cytoplasmic signaling molecules, ultimately inducing a series of signal cascade reactions. For example, phosphorylation of CSF-1R at tyrosine 697 can activate the MAPK signaling pathway, whereas phosphorylation of CSF-1R at tyrosine 721 can activate the PI3K and PLCγ signaling pathways, etc.

[0004] Colony-stimulating factor-1 receptor (CSF-1R) is a key target for regulating tumor-associated macrophages in the tumor microenvironment. Many tumor cells can secrete growth factors such as CSF-1 during growth, and the latter can further recruit macrophages (tumor-associated macrophages, TAMs) to the tumor area. The macrophages can also secrete CSF-1 as tumor cells, and their recruitment promotes the formation of a complex tumor microenvironment, which can induce immune resistance to autoimmune functions in tumor cells and further promote the proliferation, invasion and metastasis of tumor cells in the body. It has been confirmed that blocking the CSF-1 / CSF1R pathway can significantly reduce the infiltration of macrophages at tumor sites, delay the growth of primary tumors, and reduce tumor metastasis. Therefore, inhibiting macrophage survival / activation by inhibiting CSF-1 / CSF1R signaling has already become one of the important countermeasures in cancer immunotherapy.

[0005] Recent studies have shown that CSF-1R inhibitors can be applied in multiple disease treatment fields through multiple pathways, and can be used alone or in combination with multiple anti-cancer therapies, such as antiangiogenesis, adoptive transfer of T cells, radiation therapy, chemotherapy and immune checkpoint therapy. Many drugs on the market have CSF-1R inhibitory activity, such as imatinib, dasatinib and sunitinib, but selective CSF-1R inhibitors have not yet been marketed. Pexidartinib (PLX-3397), researched and developed by Plexxikon and acquired by Daiichi Sankyo, is a dual inhibitor of CSF-1R and c-Kit, and was approved by the FDA in August 2019 for the treatment of tendon sheath giant cell tumor (TGCT).

[0006] [ka]

[0007] Summary of the Invention The present invention provides a compound represented by formula (P) or a pharma- ceutically acceptable salt thereof:

[0008] [ka]

[0009] Among them, R1 is F, Cl, Br, I, C 1-3 Alkyl group, C 1-3 Alkoxy group, -C(=O)-C 1-3 Alkyl groups and -C(=O)-NH-C 1-3 alkyl group, 1-3 Alkyl group, C 1-3 Alkoxy group, -C(=O)-C 1-3 Alkyl groups and -C(=O)-NH-C 1-3 The alkyl group may optionally be one, two or three R a is replaced by R2 is F, Cl, Br, I and C 1-3 alkyl group, 1-3 The alkyl group may optionally be one, two or three R b is replaced by R3 is H, C 1-3 Alkyl group and C 3-5 cycloalkyl group, 1-3 Alkyl groups and C 3-5 The cycloalkyl group may optionally include one, two or three R c is replaced by Ring B is selected from a phenyl group and a 6-membered heteroaryl group; m and n are each independently selected from 0, 1, and 2; L1 is -N(R d )-selected from L2 is a single bond, -O-, -N(R d )-C(=O)- and -N(R d )-C(R e )(R f )-selected from R a , R b and R c are each independently selected from F, Cl, Br, I, and CH3; Rd , R e and R f are each independently selected from H and CH3.

[0010] In some embodiments of the invention, R1 is selected from F, Cl, Br, I, CH3, OCH3, -C(=O)-CH3 and -C(=O)-NH-CH3, and CH3, OCH3, -C(=O)-CH3 and -C(=O)-NH-CH3 are optionally selected from 1, 2 or 3 R a and other variables are as defined herein.

[0011] In some embodiments of the invention, R1 is selected from F, Cl, Br, I, CH3, CHF2, CF3, OCH3, -C(=O)-CH3 and -C(=O)-NH-CH3, and all other variables are as defined herein.

[0012] In some embodiments of the invention, R2 is selected from F, Cl, Br, I, and CH3, and CH3 is optionally selected from 1, 2, or 3 R b and other variables are as defined herein.

[0013] In some embodiments of the invention, R2 is selected from F, Cl, Br, I, CH3, CH2F, CHF2, and CF3, with all other variables being as defined herein.

[0014] In some embodiments of the invention, R is selected from H, CH, CH(CH) and a cyclopropyl group, and the CH, OCH and cyclopropyl groups are optionally joined by 1, 2 or 3 R c and other variables are as defined herein.

[0015] In some embodiments of the invention, R3 is selected from H, CH3, CF3, CH(CH3)2, and a cyclopropyl group, with all other variables being as defined herein.

[0016] In some embodiments of the invention, L1 above is selected from -NH- and -N(CH3)-, with all other variables being as defined herein.

[0017] In some embodiments of the present invention, L2 above is selected from a single bond, -O-, -NH-C(=O)-, -NH-CH2-, and -N(CH3)-CH2-, and all other variables are as defined herein.

[0018] In some aspects of the invention, Ring B is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, with all other variables being as defined herein.

[0019] In some embodiments of the present invention, the structural unit

[0020] [ka]

[0021] teeth,

[0022] [ka]

[0023] and

[0024] [ka]

[0025] and other variables are as defined herein.

[0026] In some embodiments of the present invention, L2 is a structural unit

[0027] [ka]

[0028] Selected from

[0029] [ka]

[0030] ,

[0031] [ka]

[0032] ,

[0033] [ka]

[0034] ,

[0035] [ka]

[0036] and

[0037] [ka]

[0038] and other variables are as defined herein.

[0039] In one embodiment of the present invention, the structural unit

[0040] [ka]

[0041] teeth

[0042] [ka]

[0043] ,

[0044] [ka]

[0045] ,

[0046] [ka]

[0047] ,

[0048] [ka]

[0049] ,

[0050] [ka]

[0051] ,

[0052] [ka]

[0053] ,

[0054] [ka]

[0055] ,

[0056] [ka]

[0057] and

[0058] [ka]

[0059] and other variables are as defined herein.

[0060] The present invention provides a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof,

[0061] [ka]

[0062] Among them, T1 and T2 are each independently selected from N and CH; R1 is F, Cl, Br, I, C 1-3 Alkyl group, C 1-3 Alkoxy group, -C(=O)-C 1-3 Alkyl groups and -C(=O)-NH-C 1-3 alkyl group, 1-3 Alkyl group, C 1-3 Alkoxy group, -C(=O)-C 1-3 Alkyl groups and -C(=O)-NH-C 1-3 The alkyl group may optionally be one, two or three R a is replaced by R2 is F, Cl, Br, I and C 1-3 alkyl group, 1-3 The alkyl group may optionally be one, two or three R b is replaced by R3 is C 1-3 Alkyl groups and C 3-5 cycloalkyl group, 1-3 Alkyl groups and C 3-5 The cycloalkyl group may optionally include one, two or three R c is replaced by m and n are each independently selected from 0, 1, and 2; L1 is -N(R d )-selected from L2 is -O-, -N(Rd )-C(=O)- and -N(R d )-C(R e )(R f )-selected from R a , R b and R c are each independently selected from F, Cl, Br, I, and CH3; R d , R e and R f are each independently selected from H and CH3.

[0063] In some embodiments of the invention, R1 is selected from F, Cl, Br, I, CH3, OCH3, -C(=O)-CH3 and -C(=O)-NH-CH3, and CH3, OCH3, -C(=O)-CH3 and -C(=O)-NH-CH3 are optionally selected from 1, 2 or 3 R a and other variables are as defined herein.

[0064] In some embodiments of the invention, R1 is selected from F, Cl, Br, I, CH3, CHF2, CF3, OCH3, -C(=O)-CH3 and -C(=O)-NH-CH3, and all other variables are as defined herein.

[0065] In some embodiments of the invention, R2 is selected from F, Cl, Br, I, and CH3, and CH3 is optionally selected from 1, 2, or 3 R b and other variables are as defined herein.

[0066] In some embodiments of the invention, R2 is selected from F, Cl, Br, I, CH3, CH2F, CHF2, and CF3, with all other variables being as defined herein.

[0067] In some embodiments of the invention, R is selected from CH and a cyclopropyl group, and the CH and cyclopropyl groups are optionally selected from 1, 2 or 3 R c and other variables are as defined herein.

[0068] In some embodiments of the present invention, R3 is selected from CH3, CF3, and a cyclopropyl group, with all other variables being as defined herein.

[0069] In some embodiments of the invention, L1 above is selected from -NH- and -N(CH3)-, with all other variables being as defined herein.

[0070] In some embodiments of the present invention, L2 above is selected from -O-, -NH-C(=O)-, and -NH-CH2-, with all other variables being as defined herein.

[0071] In some embodiments of the present invention, the structural unit

[0072] [ka]

[0073] teeth,

[0074] [ka]

[0075] and

[0076] [ka]

[0077] and other variables are as defined herein.

[0078] In some embodiments of the present invention, the structural unit

[0079] [ka]

[0080] teeth,

[0081] [ka]

[0082] and

[0083] [ka]

[0084] and other variables are as defined herein.

[0085] In some embodiments of the present invention, the structural unit

[0086] [ka]

[0087] teeth,

[0088] [ka]

[0089] and

[0090] [ka]

[0091] and other variables are as defined herein.

[0092] The present invention further includes embodiments in which the above variables are combined in any desired manner.

[0093] In some embodiments of the invention, the compound or a pharma- ceutically acceptable salt thereof is

[0094] [ka]

[0095] Selected from Among them, R1, R2, R3, L1 and L2 are as defined in the present invention.

[0096] In some embodiments of the invention, the compound or a pharma- ceutically acceptable salt thereof is

[0097] [ka]

[0098] Selected from Among them, Ring B is

[0099] [ka]

[0100] ,

[0101] [ka]

[0102] ,

[0103] [ka]

[0104] and

[0105] [ka]

[0106] Selected from R3 and L2 are as defined in the present invention.

[0107] The present invention relates to a compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

[0108] [ka]

[0109] Further provided is:

[0110] The present invention further provides the use of the above compound, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating tendon sheath giant cell tumor.

[0111] [Effects of the Invention] The compounds according to the present invention have significant CSF-1R kinase inhibitory activity, and the compounds according to the present invention have a weak inhibitory effect on five CYP isoenzymes, reducing the risks associated with concomitant use of drugs, and the compounds according to the present invention have excellent pharmacokinetic properties and in vivo efficacy.

[0112] (Definitions and Explanations) Unless otherwise specified, the following terms and phrases used herein have the following meanings. A particular term or phrase, unless specifically defined, should not be considered indefinite or unclear, but should be understood in its general sense. When a trade name appears in this specification, it refers to the corresponding product or its active ingredient.

[0113] The term "pharmacologically acceptable" as used herein means those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response or other problem or complication, within the bounds of sound medical judgment, and consistent with a reasonable benefit / disadvantage ratio.

[0114] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from compounds having specific substituents discovered in the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of the compounds with a sufficient amount of alkali in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral forms of the compounds with a sufficient amount of acid in a pure solution or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts including acids such as, for example, acetic acid, propionic acid, isobutanoic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, and further including salts of amino acids (such as, for example, arginic acid), and salts of organic acids such as, for example, glucuronic acid. Certain compounds according to the present invention contain both basic and acidic functional groups and can therefore be converted into either base or acid addition salts.

[0115] The pharma- ceutically acceptable salts of the present invention can be synthesized from the parent compound that contains an acid or base group by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of the compound with a stoichiometrically appropriate base or acid in water or an organic solvent or a mixture of both.

[0116] Unless otherwise specified, the term "isomer" includes geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0117] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof. All mixtures, such as, for example, enantiomer- or diastereomer-enriched mixtures, are within the scope of the present invention. Substituents such as alkyl groups may have other asymmetric carbon atoms. All of these isomers and mixtures thereof are within the scope of the present invention.

[0118] Unless otherwise specified, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.

[0119] Unless otherwise specified, the terms "cis-trans isomers" or "geometric isomers" refer to the inability to freely rotate about double bonds or single bonds of ring carbon atoms.

[0120] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more centers of chirality in the molecules and where the molecules are not mirror images of each other.

[0121] Unless otherwise noted, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemization.

[0122] Unless otherwise noted, solid wedge bonds (

[0123] [ka]

[0124] ) and the wedge-shaped dashed bond (

[0125] [ka]

[0126] ) indicates the absolute configuration of one stereocenter, and a straight solid bond (

[0127] [ka]

[0128] ) and straight dashed bond (

[0129] [ka]

[0130] ) indicates the relative configuration of stereocenters, and the wavy line (

[0131] [ka]

[0132] ) to form a solid wedge connection (

[0133] [ka]

[0134] ) or wedge-shaped dashed bond (

[0135] [ka]

[0136] ) or a wavy line (

[0137] [ka]

[0138] ) is a straight solid line connection (

[0139] [ka]

[0140] ) and straight dashed bond (

[0141] [ka]

[0142] ) is shown.

[0143] Unless otherwise specified, the terms "enriched in one isomer," "enriched in one enantiomer," or "enantiomer-enriched" mean that the amount of one isomer or enantiomer is less than 100% and that the amount of that isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0144] Unless otherwise specified, the term "isomeric excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is present at 90% and the other isomer or enantiomer at 10%, then the isomeric or enantiomeric excess (ee value) is 80%.

[0145] Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. One enantiomer of a compound according to the invention can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, where the resulting mixture of diastereomers is separated and the groups are assisted in the resolution to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxy) functional group, the diastereomeric salt can be formed with an appropriate optically active acid or base, and the diastereomers can be resolved by conventional methods known in the art, followed by recovery to obtain the pure enantiomers. Separation of enantiomers and diastereomers is generally accomplished by chromatography, which utilizes a chiral stationary phase and is optionally combined with chemical derivatization (e.g., forming carbamates from amides).

[0146] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, tritium ( 3 H), Iodine-125 ( 125 I) or C-14( 14 The compound may be labeled with a radioisotope such as 1,2-dihydrogen (1,2,3,4-trimethylphenyl)- ...

[0147] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes cases where the described event or circumstance occurs as well as cases where the event or circumstance does not occur.

[0148] The term "substituted" means that any one or more hydrogen atoms at a particular atom are replaced with a substituent, and can include deuterium and hydrogen variants, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur in aryl groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of the substituents can be any, provided that it is chemically feasible.

[0149] When any variable (e.g., R) occurs more than once in a composition or structure of a compound, each definition is independent. Thus, for example, if a group is substituted with 0-2 R, the group may be optionally substituted with at most 2 R, and each occurrence of R is an independent option. Combinations of substituents and / or variants thereof are permissible only if such combinations produce stable compounds.

[0150] When the number of one linking group is 0, for example, -(CRR)0-, this indicates that the linking group is a single bond.

[0151] When the number of one substituent is 0, it indicates that the substituent is absent, for example, -A-(R)0 indicates that the structure is actually -A.

[0152] The absence of a single substituent indicates that the substituent is not present, for example, the absence of X in AX indicates that the structure is in fact A.

[0153] When one of the variables is selected from a single bond, it indicates that the two groups to be linked are directly linked; for example, when L in ALZ is a single bond, it indicates that the structure is actually AZ.

[0154] When the bond of a substituent can cross-connect more than one atom in a ring, such substituent can be attached to any atom in the ring, e.g., the structural unit

[0155] [ka]

[0156] or

[0157] [ka]

[0158] indicates that the substituent R may be substituted at any one of the positions on the cyclohexyl or cyclohexadienyl group. If a listed substituent does not specify through which atom it is linked to the substituted group, then such substituent may be bonded through any atom thereof, e.g., a pyridinyl group may be linked as a substituent to the substituted group through any carbon atom on the pyridine ring.

[0159] When the linking direction of the listed linking groups is not specified, the linking direction is arbitrary, for example,

[0160] [ka]

[0161] In the formula (I), the linking group L is -MW-, and in this case, -MW- connects ring A and ring B in the same direction as the reading order from left to right.

[0162] [ka]

[0163] By concatenating ring A and ring B in the reverse left-to-right reading order,

[0164] [ka]

[0165] Combinations of the above linking groups, substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0166] Unless otherwise specified, when a group has one or more linkable sites, any one or more sites of the group can be linked to other groups via a chemical bond. The method of linking the chemical bond is non-site specific, and when there is an H atom at the linkable site, when the chemical bond is linked, the number of H atoms at the site is reduced according to the number of chemical bonds to be linked, resulting in a group with a corresponding valence. The chemical bond linking the site to other groups is a straight solid bond (

[0167] [ka]

[0168] ), straight dashed bond (

[0169] [ka]

[0170] ), or wavy line (

[0171] [ka]

[0172] For example, the straight solid bond in -OCH3 indicates that the group is connected to another group via the oxygen atom in the group,

[0173] [ka]

[0174] The straight broken line bond in represents that the nitrogen atom in the group is linked to another group via both ends thereof,

[0175] [ka]

[0176] The wavy lines in the figure indicate that the phenyl group is linked to other groups via the 1st and 2nd carbon atoms,

[0177] [ka]

[0178] indicates that any linkable site in the piperidinyl group can be linked to another group via one chemical bond, and at least

[0179] [ka]

[0180] ,

[0181] [ka]

[0182] ,

[0183] [ka]

[0184] ,

[0185] [ka]

[0186] Even if an H atom is drawn on -N-,

[0187] [ka]

[0188] is still

[0189] [ka]

[0190] When the linking group contains a linking group of the formula: and is linked to only one chemical bond, the H at that site is correspondingly reduced by one to become the corresponding monovalent piperidinyl group.

[0191] Unless otherwise specified, the number of atoms in a ring is usually defined as the number of members in the ring. For example, a "5- to 7-membered ring" refers to a "ring" in which 5 to 7 atoms are arranged in a ring.

[0192] Unless otherwise noted, "C 1-3 The term "alkyl group" is used to indicate a linear or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups are C 1-2 and C. 2-3 alkyl groups, which may be monovalent (e.g., methyl groups), divalent (e.g., methylene groups) or polyvalent (e.g., methine groups). 1-3 Illustrative examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl) groups, and the like.

[0193] Unless otherwise noted, "C 1-3 The term "alkoxy group" refers to an alkyl group containing 1 to 3 carbon atoms that is linked to the rest of the molecule through an oxygen atom. 1-3 Alkoxy group is C 1-2 , C 2-3 , C3, and C2 alkoxy groups.1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0194] Unless otherwise noted, "C 3-5 "Cycloalkyl group" refers to a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring and is as defined above in the C 3-5 Cycloalkyl groups are C 3-4 and C. 4-5 C includes cycloalkyl groups and may be monovalent, divalent or polyvalent. 3-5 Illustrative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

[0195] Unless otherwise specified, the terms "6-membered heteroaromatic ring" and "6-membered heteroaryl group" according to the present invention are interchangeable, and the term "6-membered heteroaryl group" refers to a monocyclic group consisting of six cyclic atoms and having a conjugated π-electron system, in which one, two, three or four cyclic atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, in which the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p and p is 1 or 2. The 6-membered heteroaryl group can be linked to the rest of the molecule via a heteroatom or a carbon atom. Illustrative examples of the 6-membered heteroaryl group include, but are not limited to, a pyridinyl group (including 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl groups, etc.), a pyrazinyl group, or a pyrimidinyl group (including 2-pyrimidinyl and 4-pyrimidinyl groups, etc.).

[0196] The term "work-up" means that the hydrochloride or trifluoroacetate salt of the compound according to the invention can be obtained in its free form by dissolving it in an organic solvent such as ethyl acetate or dichloromethane, washing with 1 N sodium bicarbonate solution and concentrating the organic phase.

[0197] The compounds according to the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitution forms well known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0198] The solvents used in the present invention are commercially available.

[0199] The present invention uses the following abbreviations: aq stands for water, eq stands for equivalent, DCM stands for dichloromethane, PE stands for petroleum ether, DMF stands for N,N-dimethylformamide, DMSO stands for dimethylsulfoxide, EtOAc stands for ethyl acetate, EtOH stands for ethanol, MeOH stands for methanol, CBz stands for benzyloxycarbonyl group which is an amide protecting group, BOC stands for t-butoxycarbonyl group which is an amide protecting group, and rt stands for room temperature. where O / N stands for overnight standing, THF stands for tetrahydrofuran, Boc2O stands for di-tert-butyl dicarbonate, TFA stands for trifluoroacetic acid, DIPEA stands for diisopropylethylamine, mp stands for melting point, Pd(dppf)Cl2 stands for 1,1'-bisdiphenylphosphinoferrocene palladium dichloride, and Pd(dppf)Cl2CH2Cl2 stands for [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex.

[0200] The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art, and the present invention relates to the absolute configuration of the compound, and the absolute configuration can be confirmed by conventional technical means in this field.For example, in single crystal X-ray diffraction (SXRD), the diffraction intensity data of the cultivated single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning method is φ / ω scanning, and after collecting the relevant data, the crystal structure is further analyzed by direct method (Shelxs97), and the absolute configuration can be confirmed.

[0201] Compounds are named according to conventional naming principles in the art or by ChemDraw® software; commercially available compounds adopt the supplier's catalogue name.

[0202] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a mouse splenomegaly test.

[0203] [Mode for carrying out the invention] The present invention will be described in detail below with reference to examples, which are not intended to be any detrimental limitations on the present invention. Although the present specification has already described the present invention in detail and disclosed specific examples, it is obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0204] (Intermediate I)

[0205] [ka]

[0206] Synthesis Route:

[0207] [ka]

[0208] Step 1: Synthesis of compound IA Compound 1-F (1 g, 3.31 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL) and the reaction was cooled to 0 °C, then sodium hydride (158.90 mg, 3.97 mmol, 60% purity, 1.2 eq) was added and the reaction was stirred at 0 °C for 0.5 h. (2-(chloromethoxy)ethyl)trimethylsilane (717.51 ​​mg, 4.30 mmol, 761.69 μL, 1.3 eq) was then added and the reaction was stirred at 20 °C for 1 h. The reaction was quenched by pouring into 20 mL of water and stirring under a gentle nitrogen stream. 40 mL of ethyl acetate was added for extraction, and the organic phase was washed with saturated brine, dried, and filtered to give intermediate IA.

[0209] MS m / z: 432.9[M+H] + .

[0210] Step 2: Synthesis of Compound I Compound IA (1 g, 2.31 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), and compound IB (495.54 mg, 2.89 mmol), Pd(dppf)Cl2 (169.25 mg, 231.31 μmol), and potassium phosphate (1.47 g, 6.94 mmol) were added thereto, and nitrogen gas was bubbled into the reaction solution for 1 minute, and the reaction was performed in a microwave reaction at 60 °C for 45 minutes (3 batches were added in parallel). After mixing the three reaction solutions, water (50 mL) and ethyl acetate (100 mL) were added thereto, and the liquids were separated. The organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 10: 1 to 4: 1) to obtain compound I.

[0211] MS m / z: 432.1[M+H] + ; 1H NMR (400MHz, CDCl3) δ = 8.40 (d, J=5.3 Hz, 1H), 8.30 (s, 1H), 7.47 (d, J=5.3 Hz, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 5.79 (s, 2H), 4.08 (s, 3H), 3.35 - 3.26 (m, 2H), 2.26 (s, 3H), 0.84 - 0.77 (m, 2H), 0.09 (s, 9H).

[0212] (Intermediate II)

[0213] [ka]

[0214] Synthesis Route:

[0215] [ka]

[0216] Step 1: Synthesis of compound II-B Compound II-A (200 mg, 624.64 μmol) was dissolved in dichloromethane (5 mL), Boc2O (272.65 mg, 1.25 mmol, 287.00 μL) and 4-dimethylaminopyridine (38.16 mg, 312.32 μmol) were added thereto, and the reaction solution was stirred at 25°C to 30°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (ethyl acetate:petroleum ether = 0 to 5 to 10%) to obtain compound II-B.

[0217] MS m / z: 420.1[M+H] + .

[0218] Step 2: Synthesis of Compound II Compound II-B (110 mg, 261.72 μmol) was dissolved in 1,4-dioxane (2 mL), and bisboronic acid pinacol ester (73.11 mg, 287.89 μmol) and potassium acetate (51.37 mg, 523.44 μmol) were added thereto, and nitrogen gas was bubbled into the reaction system for 30 s, and then Pd(dppf)Cl2CH2Cl2 (21.37 mg, 26.17 μmol) was added thereto, and nitrogen gas was bubbled into the reaction system for 30 s, and the reaction solution was subjected to microwave reaction at 130 °C for 2 hours. The reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (ethyl acetate: petroleum ether = 0-10%) to obtain intermediate II.

[0219] MS m / z: 468.3[M+H] + ; 1H NMR (400MHz, CDCl3) δ = 8.59 (s, 1H), 8.03 (d, J=2.5 Hz, 1H), 7.50 (dd, J=2.8, 8.8 Hz, 1H), 7.41 (s, 1H), 6.77 (d, J=8.8 Hz, 1H), 4.29 - 4.07 (m, 1H), 2.54 (s, 3H), 1.45 (s, 9H), 1.32 (s, 12H), 0.81 - 0.76 (m, 4H).

[0220] Example 1

[0221] [ka]

[0222] Synthesis Route:

[0223] [ka]

[0224] Step 1: Synthesis of compound 1-B Compound 1-A (700 mg, 3.23 mmol), Pd(dppf)Cl2 (236.01 mg, 322.55 μmol) and triethylamine (1.63 g, 16.13 mmol) were mixed in methanol (3 mL) and N,N-dimethylformamide (30 mL) and stirred at 80°C and CO (50 Psi) for 12 hours. After filtering the reaction solution through diatomaceous earth, water (100 mL) was added, extracted with dichloromethane (250 mL), the organic phase was washed with water (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, which was separated by column chromatography (tetrahydrofuran: petroleum ether = 0-10-25%) to obtain compound 1-B.

[0225] MS m / z: 196.9[M+H] + .

[0226] Step 2: Synthesis of compound 1-C Compound 1-B (30 mg, 152.94 μmol) and N,N-dimethylformamide dimethyl acetal (448.50 mg, 3.76 mmol) were mixed in N,N-dimethylformamide (2 mL) and stirred at 100° C. for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (petroleum ether / ethyl acetate=1:1) to obtain compound 1-C.

[0227] 1 H NMR (400MHz, CDCl3) δ = 8.31 (d, J=5.5 Hz, 1H), 7.36 (d, J=5.5 Hz, 1H), 7.23 (d, J=13.1 Hz, 1H), 4.97 (d, J=13.6 Hz, 1H), 3.98 (s, 3H), 3.00 (s, 6H).

[0228] Step 3: Synthesis of compound 1-D Compound 1-C (330 mg, 1.31 mmol) was dissolved in acetic acid (10 mL), iron powder (733.52 mg, 13.13 mmol) was added, and the mixture was stirred at 70° C. for 5 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude product. The crude product was separated by column chromatography (tetrahydrofuran:petroleum ether = 0 to 50%) to obtain compound 1-D.

[0229] MS m / z: 176.8[M+H] + .

[0230] Step 4: Synthesis of compound 1-F Compound 1-D (60 mg, 340.58 μmol) and N-iodosuccinimide (91.95 mg, 408.69 μmol) were dissolved in N,N-dimethylformamide (6 mL) and stirred at 35° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (tetrahydrofuran:petroleum ether = 0 to 50%) to obtain 1-F.

[0231] MS m / z: 302.9[M+H] + .

[0232] Step 5: Synthesis of compound 1-G Compound 1-F (50 mg, 165.53 μmol), intermediate II (77.36 mg, 165.53 μmol), tetrakistriphenylphosphine palladium (19.13 mg, 16.55 μmol) and sodium carbonate (35.09 mg, 331.05 μmol) were dissolved in dioxane (2.5 mL) and water (0.25 mL), and N2 was bubbled into the reaction solution for about 30 seconds, and then the mixture was stirred at 100 ° C. for 30 minutes in a microwave. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL), dried with anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (tetrahydrofuran: petroleum ether = 0 ~ 25 ~ 50%) to obtain compound 1-G.

[0233] Step 6: Synthesis of compound 1-H Compound 1-G (30 mg, 58.19 μmol) was dissolved in a methylamine ethanol solution (20 mL, mass fraction 33%) and stirred at 45° C. for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography (ethyl acetate:petroleum ether=0-10-25%) to obtain compound 1-H.

[0234] MS m / z: 515.1[M+H] + .

[0235] Step 7: Synthesis of the hydrochloride salt of compound 1 Compound 1-H (12 mg, 23.32 μmol) was mixed with ethyl acetate (4 mL) and ethyl acetate hydrochloride (4 M, 20 mL) and stirred for 12 hours at 18° C. The reaction solution was concentrated under reduced pressure, and the crude product was separated by preparative high performance liquid chromatography (HCl, acetonitrile) to obtain the hydrochloride salt of compound 1.

[0236] MS m / z: 415.2[M+H] + ; 1H NMR (400MHz, CD3OD) δ = 8.53 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 8.38 (d, J=6.0 Hz, 1H), 8.21 - 8.13 (m, 2H), 8.02 (s, 1H), 7.46 (d, J=9.0 Hz, 1H), 7.28 (s, 1H), 4.41 - 4.30 (m, 1H), 3.15 (s, 3H), 2.40 (s, 3H), 0.99 - 0.93 (m, 2H), 0.92 - 0.87 (m, 2H).

[0237] Example 2

[0238] [ka]

[0239] Synthesis Route:

[0240] [ka]

[0241] Step 1: Synthesis of compound 2-B Under the condition of 0°C, NaH (314.56 mg, 7.86 mmol, 60% mass fraction) was added to a solution of 2-A (1 g, 6.55 mmol) in THF (30 mL). The reaction mixture was stirred at 0°C for 20 minutes. Then, iodomethane (3.44 g, 24.24 mmol, 1.51 mL) was added, and the reaction solution was stirred at 0°C for 1 hour. After the reaction was completed, 5 mL of water was added to quench the reaction, the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL*3), washed with saturated saline (50 mL*3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (0-20% ethyl acetate / petroleum ether) to obtain compound 2-B.

[0242] MS m / z: 166.9[M+H] + ; 1 H NMR (400MHz, CDCl3) δ = 7.95 (d, J=5.5 Hz, 1H), 7.42 (d, J=5.4 Hz, 1H), 7.16 (d, J=3.1 Hz, 1H), 6.49 (d, J=3.1 Hz, 1H), 4.17 (s, 3H).

[0243] Step 2: Synthesis of compound 2-C A solution of 2-B (500 mg, 3.00 mmol), TEA (1.26 g, 12.45 mmol, 1.73 mL) and Pd(dppf)Cl2CH2Cl2 (122.54 mg, 150.05 μmol) in toluene (40 mL) and methanol (40 mL) was stirred under carbon monoxide (4 MPa) and at 110 °C for 17 h. After the reaction was completed, the mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (0-30% tetrahydrofuran / petroleum ether) to give compound 2-C.

[0244] MS m / z: 190.9 [M+H] + ; 1H NMR (400MHz, CDCl3) δ = 8.30 (d, J=5.0 Hz, 1H), 7.66 (d, J=5.3 Hz, 1H), 7.22 (d, J=3.0 Hz, 1H), 6.57 (d, J=3.0 Hz, 1H), 4.06 (s, 3H), 3.97 (s, 3H).

[0245] Step 3: Synthesis of compound 2-D A solution of N-iodosuccinimide (567.78 mg, 2.52 mmol) in DMF (5 mL) was added to a solution of 2-C (400 mg, 2.10 mmol) in DMF (10 mL), and the reaction solution was stirred at 20°C to 30°C for 2 hours. After the reaction was completed, 5 mL of water was added to quench the reaction, and the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL*3), washed with saturated saline (50 mL*3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (0-20% tetrahydrofuran / petroleum ether) to obtain compound 2-D.

[0246] MS m / z: 316.9 [M+H] + ; 1H NMR (400MHz, CDCl3) δ = 8.39 (d, J=5.3 Hz, 1H), 7.51 (d, J=5.3 Hz, 1H), 7.32 (s, 1H), 4.06 (s, 3H), 3.99 (s, 3H).

[0247] Step 4: Synthesis of compound 2-E Under the protection of N2, a mixture of compound 2-D (150 mg, 474.54 μmol), intermediate II (443.57 mg, 949.08 μmol), tetrakistriphenylphosphine palladium and Na2CO3 (100.59 mg, 949.08 μmol) in dioxane (10 mL) and water (1 mL) was stirred at 85°C to 90°C for 12 hours. After the reaction was completed, 5 mL of water was added to quench the reaction, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL*3), washed with saturated saline (20 mL*3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (0-50% tetrahydrofuran / petroleum ether) to obtain compound 2-E.

[0248] MS m / z: 530.4 [M+H] + .

[0249] Step 5: Synthesis of compound 2-F Besides the corresponding raw materials, compound 2-F was prepared in the same manner as in the preparation of compound 1-H in Example 1.

[0250] MS m / z: 529.3 [M+H] + .

[0251] Step 6: Synthesis of the hydrochloride salt of compound 2 A solution of compound 2-F (100 mg, 189.18 μmol) in hydrochloric acid / ethyl acetate (4 M, 5 mL) and MeOH (2 mL) was stirred for 12 hours at 40° C. After the reaction was completed, the product was obtained by filtration and dried to obtain the hydrochloride salt of compound 2.

[0252] MS m / z: 429.2 [M+H] + ; 1H NMR (400MHz, CD3OD) δ = 8.49 (d, J=2.3 Hz, 1H), 8.39 (s, 1H), 8.32 (d, J=6.5 Hz, 1H), 8.13 - 8.06 (m, 2H), 7.98 (s, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.24 (s, 1H), 4.38 - 4.25 (m, 1H), 4.13 (s, 3H), 3.13 (s, 3H), 2.37 (s, 3H), 0.98 - 0.80 (m, 4H).

[0253] Example 3

[0254] [ka]

[0255] Synthesis Route:

[0256] [ka]

[0257] Step 1: Synthesis of compound 3-A Under nitrogen gas protection, intermediate I (100 mg, 231.49 μmol), 4-isopropoxyaniline (38.50 mg, 254.64 μmol), cesium carbonate (150.85 mg, 462.98 μmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaanthracene (26.79 mg, 46.30 μmol) and tris(dibenzylideneacetone)dipalladium (21.20 mg, 23.15 μmol) were added to a solution of dioxane (10 mL). The reaction mixture was stirred at 100° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (0-50% ethyl acetate / petroleum ether) to obtain compound 3-A.

[0258] MS m / z: 547.3[M+H] + .

[0259] Step 2: Synthesis of compound 3-B To a solution of methylamine (5 mL, purity 33%) in ethanol was added 3-A (85 mg, 155.47 μmol). The reaction mixture was stirred at 50° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 3-B.

[0260] MS m / z: 546.3[M+H] + .

[0261] Step 3: Synthesis of the hydrochloride salt of compound 3 3-B (85 mg, 155.47 μmol) was added to a solution of tetrabutylammonium fluoride (1 M, 10 mL) in tetrahydrofuran. The reaction mixture was stirred at 80°C for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and water (50 mL) and ethyl acetate (50 mL) were added for extraction. The organic phase was washed with water (200 mL, 50 mL x 4), and the organic phase was concentrated to obtain the crude product. Under the condition of 10°C to 20°C, the crude product (70 mg, 168.48 μmol) was dissolved in ethyl acetate (10 mL), and HCl / EtOAc (4 M, 421.19 μL) was added. The reaction mixture was stirred at 40°C for 12 hours. After the reaction was completed, the reaction mixture was filtered to obtain a filter cake, which was then vacuum dried (45°C, -0.1 MPa, 2 h) to obtain the hydrochloride salt of compound 3.

[0262] MS m / z: 416.2[M+H] + ; 1 H NMR (400MHz, CD3OD) δ = 8.37 - 8.30 (m, 2H), 8.09 (d, J=6.3 Hz, 1H), 7.83 (s, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.16 (s, 1H), 7.10 (d, J=8.8 Hz, 2H), 4.68 (spt, J=6.0 Hz, 1H), 3.12 (s, 3H), 2.34 (s, 3H), 1.36 (d, J=6.0 Hz, 6H).

[0263] Example 4

[0264] [ka]

[0265] Synthesis Route:

[0266] [ka]

[0267] Step 1: Synthesis of compound 4-A Under nitrogen gas protection, intermediate I (100 mg, 231.49 μmol), 4-isopropylaniline (34.43 mg, 254.64 μmol), cesium carbonate (150.85 mg, 462.98 μmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaanthracene (26.79 mg, 46.30 μmol) and tris(dibenzylideneacetone)dipalladium (21.20 mg, 23.15 μmol) were added to a solution of dioxane (10 mL). The reaction mixture was stirred at 100° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (0-50% ethyl acetate / petroleum ether) to obtain compound 4-A.

[0268] MS m / z: 531.3 [M+H] + .

[0269] Step 2: Synthesis of compound 4-B 4-A (81 mg, 152.62 μmol) was added to a solution of methylamine (5 mL, 33% purity) in ethanol. The reaction mixture was stirred at 50° C. for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 4-B.

[0270] MS m / z: 530.1 [M+H] + .

[0271] Step 3: Synthesis of the hydrochloride salt of compound 4 4-B (81 mg, 152.90 μmol) was added to a solution of tetrabutylammonium fluoride (1 M, 15.45 mL) in tetrahydrofuran. The reaction mixture was stirred at 80°C for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and water (50 mL) and ethyl acetate (50 mL) were added for extraction. The organic phase was washed with water (200 mL, 50 mL x 4), and the organic phase was concentrated to obtain the crude product. Under the condition of 10°C to 20°C, the crude product (69 mg, 172.72 μmol) was dissolved in ethyl acetate (10 mL), and HCl / EtOAc (4 M, 431.80 μL) was added. The reaction mixture was stirred at 40°C for 12 hours. After the reaction was completed, the reaction mixture was filtered to obtain a filter cake, which was then vacuum dried (45°C, -0.1 MPa, 2 h) to obtain the hydrochloride salt of compound 4.

[0272] MS m / z: 400.2 [M+H] + ; 1 H NMR (400MHz, CD3OD) δ = 8.42 - 8.31 (m, 2H), 8.11 (br s, 1H), 7.86 (s, 1H), 7.49 - 7.34 (m, 4H), 7.21 (s, 1H), 3.12 (s, 3H), 3.06 - 2.96 (m, 1H), 2.35 (s, 3H), 1.30 (d, J=7.0 Hz, 6H).

[0273] Example 5

[0274] [ka]

[0275] Synthesis Route:

[0276] [ka]

[0277] Step 1: Synthesis of compound 5-A Under nitrogen gas protection, intermediate I (100 mg, 231.49 μmol), N,N-dimethyl-p-phenylenediamine (34.68 mg, 254.64 μmol), cesium carbonate (150.85 mg, 462.98 μmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaanthracene (26.79 mg, 46.30 μmol) and tris(dibenzylideneacetone)dipalladium (21.20 mg, 23.15 μmol) were added to a solution of dioxane (10 mL). The reaction mixture was stirred at 100° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (0-50% ethyl acetate / petroleum ether) to obtain compound 5-A.

[0278] MS m / z: 532.3 [M+H] + .

[0279] Step 2: Synthesis of compound 5-B 5-A (90 mg, 169.26 μmol) was added to a solution of methylamine (5 mL, purity 33%) in ethanol. The reaction mixture was stirred at 50° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 5-B.

[0280] MS m / z: 531.1 [M+H] + .

[0281] Step 3: Synthesis of the hydrochloride salt of compound 5 5-B (89 mg, 167.69 μmol) was added to a solution of tetrabutylammonium fluoride (1 M, 16.95 mL) in tetrahydrofuran. The reaction mixture was stirred at 80°C for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and water (50 mL) and ethyl acetate (50 mL) were added for extraction. The organic phase was washed with water (200 mL, 50 mL x 4), and the organic phase was concentrated to obtain the crude product. Under the condition of 10°C to 20°C, the crude product (65 mg, 162.31 μmol) was dissolved in ethyl acetate (10 mL), and hydrochloric acid / ethyl acetate (4 M, 405.77 μL) was added. The reaction mixture was stirred at 40°C for 16 hours. After the reaction was completed, the reaction mixture was filtered to obtain a filter cake, which was then vacuum dried (45°C, -0.1 MPa, 2 h) to obtain the hydrochloride salt of compound 5.

[0282] MS m / z: 401.2 [M+H] + ; 1 H NMR (400MHz, CD3OD) δ = 8.45 - 8.33 (m, 2H), 8.22 - 8.06 (m, 1H), 8.04 (s, 1H), 7.84 (br d, J=8.8 Hz, 2H), 7.73 - 7.66 (m, J=8.8 Hz, 2H), 7.35 (s, 1H), 3.34 (s, 6H), 3.12 (s, 3H), 2.40 (s, 3H).

[0283] Example 6

[0284] [ka]

[0285] Synthesis Route:

[0286] [ka]

[0287] Step 1: Synthesis of compound 6-A Under nitrogen gas protection, intermediate I (100 mg, 231.49 μmol), 3-amino-6-methylpyridine (27.54 mg, 254.64 μmol), cesium carbonate (150.85 mg, 462.98 μmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaanthracene (26.79 mg, 46.30 μmol) and tris(dibenzylideneacetone)dipalladium (21.20 mg, 23.15 μmol) were added to a solution of dioxane (10 mL). The reaction mixture was stirred at 100° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (0-60% ethyl acetate / petroleum ether) to obtain compound 6-A.

[0288] MS m / z: 504.2 [M+H] + .

[0289] Step 2: Synthesis of compound 6-B To a solution of methylamine (5 mL, purity 33%) in ethanol was added 6-A (80 mg, 158.84 μmol). The reaction mixture was stirred at 50° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 6-B.

[0290] MS m / z: 503.3 [M+H] + .

[0291] Step 3: Synthesis of the hydrochloride salt of compound 6 6-B (84 mg, 167.10 μmol) was added to a solution of tetrabutylammonium fluoride (1 M, 16.89 mL) in tetrahydrofuran. The reaction mixture was stirred at 80°C for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and water (50 mL) and ethyl acetate (50 mL) were added for extraction. The organic phase was washed with water (200 mL, 50 mL x 4), and the organic phase was concentrated to obtain the crude product. Under conditions of 20°C to 30°C, the crude product (60 mg, 161.11 μmol) was dissolved in EtOH (3 mL) and HCl (12 M, 14.10 μL) was added. The reaction mixture was stirred at 20°C to 30°C for 2 hours. After the reaction was completed, the reaction mixture was filtered to obtain a filter cake, which was then vacuum dried (45°C, -0.1 MPa, 2 h) to obtain the hydrochloride salt of compound 6.

[0292] MS m / z: 373.2 [M+H] + ; 1 H NMR (400MHz, CD3OD) δ = 9.47 (d, J=2.3 Hz, 1H), 8.47 (dd, J=2.5, 8.8 Hz, 1H), 8.41 (s, 1H), 8.33 (d, J=6.3 Hz, 1H), 8.28 (s, 1H), 8.11 (d, J=6.5 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.18 (s, 1H), 3.14 (s, 3H), 2.76 (s, 3H), 2.35 (s, 3H).

[0293] Example 7

[0294] [ka]

[0295] Synthesis Route:

[0296] [ka]

[0297] Step 1: Synthesis of compound 7-A Under nitrogen gas protection, intermediate I (100 mg, 231.49 μmol), 2-amino-5-methoxypyrazine (28.97 mg, 231.49 μmol), cesium carbonate (150.85 mg, 462.98 μmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaanthracene (26.79 mg, 46.30 μmol) and tris(dibenzylideneacetone)dipalladium (21.20 mg, 23.15 μmol) were added to a solution of dioxane (10 mL). The reaction mixture was stirred at 100° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (0-50% THF / DCM) to obtain compound 7-A.

[0298] MS m / z: 521.2 [M+H] + .

[0299] Step 2: Synthesis of compound 7-B To a solution of methylamine (5 mL, purity 33%) in ethanol was added 7-A (86 mg, 165.18 μmol). The reaction mixture was stirred at 50° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 7-B.

[0300] MS m / z: 520.3 [M+H] + .

[0301] Step 3: Synthesis of the hydrochloride salt of compound 7 7-B (82 mg, 157.79 μmol) was added to a solution of tetrabutylammonium fluoride (1 M, 15.95 mL) in tetrahydrofuran. The reaction mixture was stirred at 80°C for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and water (50 mL) and ethyl acetate (50 mL) were added for extraction. The organic phase was washed with water (200 mL, 50 mL x 4), and the organic phase was concentrated to obtain the crude product. Under conditions of 20°C to 30°C, the crude product (70 mg, 179.76 μmol) was dissolved in EtOH (3 mL) and HCl (12 M, 15.73 μL) was added. The reaction mixture was stirred at 20°C to 30°C for 2 hours. After the reaction was completed, the reaction mixture was filtered to obtain a filter cake, which was then vacuum dried (45°C, -0.1 MPa, 2 h) to obtain the hydrochloride salt of compound 7.

[0302] MS m / z: 390.2 [M+H] + ; 1 H NMR (400MHz, CD3OD) δ = 8.42 (s, 1H), 8.36 (d, J=6.3 Hz, 1H), 8.24 (d, J=4.6 Hz, 2H), 8.14 (s, 1H), 8.12 (d, J=5.9 Hz, 1H), 7.42 (s, 1H), 4.02 (s, 3H), 3.13 (s, 3H), 2.46 (s, 3H).

[0303] Example 8

[0304] [ka]

[0305] Synthesis Route:

[0306] [ka]

[0307] Step 1: Synthesis of compound 8-A Intermediate I (100 mg, 231.49 μmol), p-methoxyaniline (31.36 mg, 254.64 μmol), cesium carbonate (150.85 mg, 462.98 μmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaanthracene (26.79 mg, 46.30 μmol) and tris(dibenzylideneacetone)dipalladium (21.20 mg, 23.15 μmol) were dissolved in dioxane (10 mL), heated to 100°C under nitrogen gas protection, and stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain the crude product, which was purified by column chromatography (0-50% ethyl acetate / petroleum ether) to obtain compound 8-A.

[0308] MS m / z: 519.3 [M+H] + .

[0309] Step 2: Synthesis of compound 8-B Compound 8-A (75 mg, 144.60 μmol, 1 eq) was dissolved in ethanol (5 mL), to which was added a solution of methylamine in ethanol (3.5 g, 37.19 mmol, 5 mL, 33% purity), and the reaction was stirred in an oil bath at 45°C to 50°C for 16 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, yielding compound 8-B.

[0310] MS m / z: 518.2 [M+H] + .

[0311] Step 3: Synthesis of the hydrochloride salt of compound 8 Compound 8-B (83 mg, 160.33 μmol) was dissolved in tetrahydrofuran (5 mL), and anhydrous ethylenediamine (144.53 mg, 2.40 mmol, 160.95 μL) and tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 801.63 μL) were added thereto, and the reaction solution was stirred in an oil bath at an external temperature of 85°C to 90°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent to obtain a crude product, and the obtained residue was purified by preparative HPLC (column model number: Phenomenex Synergi C18 (150*30 mm*4 μm), mobile phase: [0.05% hydrochloric acid aqueous solution-acetonitrile], gradient: 12% to 42%) to obtain the hydrochloride salt of 8.

[0312] MS m / z: 388.3[M+H] + ; 1H NMR (400MHz, CD3OD) δ = 8.36 (br d, J=10.0 Hz, 2H), 8.11 (br s, 1H), 7.85 (s, 1H), 7.39 (br d, J=8.0 Hz, 2H), 7.17 (s, 1H), 7.13 (br d, J=7.8 Hz, 2H), 3.87 (s, 3H), 3.12 (s, 3H), 2.35 (s, 3H).

[0313] Example 9

[0314] [ka]

[0315] Synthesis Route:

[0316] [ka]

[0317] Step 1: Synthesis of compound 9-A Intermediate I (100 mg, 231.49 μmol), 2-amino-5-methylpyridine (27.54 mg, 254.64 μmol), cesium carbonate (98.28 mg, 301.63 μmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaanthracene (26.79 mg, 46.30 μmol) and tris(dibenzylideneacetone)dipalladium (21.20 mg, 23.15 μmol) were dissolved in dioxane (10 mL), heated to 100°C under nitrogen gas protection and stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain the crude product, which was purified by column chromatography (0-10% methanol / dichloromethane) to obtain compound 9-A.

[0318] MS m / z: 504.3 [M+H] + .

[0319] Step 2: Synthesis of compound 9-B Compound 9-A (95 mg, 188.62 μmol) was dissolved in ethanol (5 mL), to which was added a solution of methylamine in ethanol (3.5 g, 37.19 mmol, 5 mL, 33% purity), and the reaction was stirred in an oil bath at 45° C. to 50° C. for 16 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and compound 9-B was obtained.

[0320] MS m / z: 503.1[M+H] + .

[0321] Step 3: Synthesis of the hydrochloride salt of compound 9 Compound 9-B (97 mg, 192.96 μmol) was dissolved in tetrahydrofuran (5 mL), and anhydrous ethylenediamine (173.95 mg, 2.89 mmol, 193.71 μL) and tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 964.82 μL) were added thereto, and the reaction solution was stirred in an oil bath at an external temperature of 85°C to 90°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent to obtain a crude product, and the obtained residue was purified by preparative HPLC (column model number: Phenomenex Synergi C18 (150*30 mm*4 μm), mobile phase: [0.05% hydrochloric acid aqueous solution-acetonitrile], gradient: 26% to 56%) to obtain the hydrochloride salt of 9.

[0322] MS m / z: 373.2[M+H] + ; 1H NMR (400MHz, CD3OD) = 8.48 (s, 1H), 8.43 (br s, 1H), 8.36 (br s, 1H), 8.22 (br s, 1H), 8.16 (br s, 1H), 8.04 (br d, J=8.8 Hz, 1H), 7.35 (br d, J=8.8 Hz, 1H), 7.31 (s, 1H), 3.14 (s, 3H), 2.41 (s, 6H).

[0323] Example 10

[0324] [ka]

[0325] Synthesis Route:

[0326] [ka]

[0327] Step 1: Synthesis of compound 10-A Under nitrogen gas protection, intermediate I (100 mg, 231.49 μmol), 2-methoxy-5-aminopyrimidine (31.86 mg, 254.64 μmol), cesium carbonate (98.28 mg, 301.63 μmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaanthracene (26.79 mg, 46.30 μmol) and tris(dibenzylideneacetone)dipalladium (21.20 mg, 23.15 μmol) were added to a solution of dioxane (10 mL). The reaction mixture was stirred at 100° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (0-50% tetrahydrofuran / petroleum ether) to obtain compound 10-A.

[0328] MS m / z: 521.2[M+H] + .

[0329] Step 2: Synthesis of compound 10-B 10-A (90 mg, 172.86 μmol) was added to a solution of methylamine (5 mL, purity 33%) in ethanol. The reaction mixture was stirred at 50° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 10-B.

[0330] MS m / z: 520.3[M+H] + .

[0331] Step 3: Synthesis of the hydrochloride salt of compound 10 10-B (120 mg, 230.92 μmol) was added to a solution of tetrabutylammonium fluoride (1 M, 10 mL) in tetrahydrofuran. The reaction mixture was stirred at 80°C for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and water (50 mL) and ethyl acetate (50 mL) were added for extraction. The organic phase was washed with water (200 mL, 50 mL x 4), and the organic phase was concentrated to obtain the crude product. Under the condition of 10°C to 20°C, the crude product (90 mg, 231.12 μmol) was dissolved in EtOH (3 mL) and HCl (12 M, 20.22 μL) was added. The reaction mixture was stirred at 40°C for 12 hours. After the reaction was completed, the reaction mixture was filtered to obtain a filter cake, which was then vacuum dried (45°C, -0.1 MPa, 2 h) to obtain compound 10.

[0332] MS m / z: 390.1 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ = 8.78 (s, 2 H), 8.35 (d, J=5.75 Hz, 1 H), 8.12 (s, 1 H), 7.99 (s, 1 H), 7.88 (d, J=5.75 Hz, 1 H), 7.25 (s, 1 H), 4.09 (s, 3H), 3.07 (s, 3H), 2.39 (s, 3H).

[0333] Experimental Example 1: In vitro enzymatic inhibitory activity of the compounds according to the present invention Experimental Reagents: Basic reaction buffer: 20 mM hydroxyethylpiperazineethanesulfonic acid (pH 7.5), 10 mM magnesium chloride, 1 mM EGTA, 0.02% Brij35, 0.02 mg / mL bovine serum albumin, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO The required cofactors were added alone to the CSF-1R kinase reaction.

[0334] Enzyme:CSF-1R concentration is 2.5 nM Compound processing: Compounds to be measured were prepared in solution at specific concentrations in 100% DMSO and serial dilutions were performed in DMSO with the intelligent pipetting assistant Integra Viaflo Assist.

[0335] Testing Procedure: 1. Prepare fresh Matrix Placement Reaction Buffer 2. Add all of the required cofactors to the reaction buffer; 3. Add the kinase to the matrix solution and shake gently. 4. Add the compound in DMSO solution to the kinase reaction mixture by acoustic techniques (Echo550, nanoliter range) and incubate for 20 min at room temperature. 5. Reaction Mixture 33 The reaction was excited by adding P-ATP (specific activity, 10 μCi / μL). 6. Incubate at room temperature for 2 hours. 7. Detect kinase activity by filter-binding method; 8. Kinase activity was measured by comparing the remaining kinases in the test sample with the solvent (DMSO) group and calculating the IC 50 The values ​​and curves were obtained by Prism (GraphPad software). The measurement results are shown in Table 1.

[0336] [Table 1]

[0337] Experimental conclusion: The compounds according to the present invention have significant inhibitory effects on CSF-1R kinase.

[0338] [Experimental Example 2: Penetration Study (MDR1-MDCK)] Purpose of the experiment: The bidirectional permeability of the test articles was measured using a Caco-2 monolayer cell model.

[0339] Testing Method: Caco-2 cells were seeded into Transwell-96 well plates at a seeding density of 1 × 10 5 cells / cm 2The cells were cultured in a carbon dioxide incubator for 28 days before use in the transport experiment, during which the medium was changed once every 4 to 5 days.

[0340] The buffer was 10 mM HEPES in Hank's balanced salt buffer (pH 7.40±0.05). Test articles were diluted to 2 μM in the buffer. The medium in the culture plate was removed and the cells were rinsed twice with pre-warmed transport buffer. The dosing solution and buffer were added to the corresponding cell plate wells (75 μL and 250 μL sample in each apical and basolateral well, respectively, n=2) to initiate the bidirectional transport experiment. After sample addition, the cell plate was placed at 37±1°C and incubated under 5% CO2 and saturated humidity conditions for 120 min.

[0341] The initial dosing solution was the TO sample, and after the sample was added, it was taken and mixed with a transport buffer (Hank's balanced salt buffer) and a stop solution (acetonitrile solution containing 250 ng / mL tolbutamide) in a fixed ratio. After 120 minutes of incubation, the final samples were collected from the dosing end and the receiving end, and were similarly mixed with a transport buffer and a stop solution in a fixed ratio.

[0342] All samples were vortexed and centrifuged at 4000 rpm at 20°C for 20 min. The supernatants were diluted 1:1 (v:v) with ultrapure water and stored at 2°C to 8°C. They were then analyzed and measured by liquid chromatography tandem mass spectrometry (LC / MS / MS).

[0343] The integrity of the Caco-2 cell layer was measured by the Lucifer Yellow Rejection Assay. Six cell wells were randomly selected in each cell plate, and 75 μL of 100 μM Lucifer Yellow was added to the apical end, and 250 μL of transport buffer was added to the basal end. After 120 min of incubation, a 20 μL sample was taken from the apical end and mixed with 60 μL of transport buffer, and an 80 μL sample was taken from the basal end. The relative fluorescence intensity (RFU) of Lucifer Yellow in the samples was detected by an M2e plate reader at 425 / 528 nm (excitation / emission) spectrum.

[0344] Processing of data: The apparent permeability coefficient (P app The flow rate (cm / s), rejection rate (efflux ratio, ER), and solution recovery rate (%Solution Recovery) were calculated.

[0345]

number

[0346] V R is the volume of the receiving solution (0.075 mL for side A and 0.25 mL for side B), and Area is the relative surface area of ​​the cell monolayer (0.0804 cm 2 ), Time is the incubation time (7200 s), C0 is the ratio of the peak area of ​​the test article at the dosing end, and V D is the volume of the dosing end (side A is 0.075 mL, side B is 0.25 mL), and C D and C. R are the ratios of the peak areas of the test samples at the dosing end and the receiving end, respectively.

[0347] The percentage of Lucifer Yellow penetrating through the basolateral end was calculated using the following formula:

[0348]

number

[0349] RFU Apical and RFU Basolateral are the relative fluorescence intensities of Lucifer Yellow at the apical and basolateral ends, respectively. V Apical and V Basolateral are the loading volumes at the apical and basal ends (0.075 mL and 0.25 mL, respectively).

[0350] [Table 2]

[0351] Conclusion: The permeability of the hydrochloride salt of compound 1 is superior to that of PLX-3397.

[0352] [Experimental Example 3: Cytochrome Enzyme Inhibition Study (CYP Inhibition)] Objective of the experiment: The inhibitory activity of the test article against human hepatic microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) was evaluated using a mixed probe substrate for CYP isoenzymes.

[0353] Testing Method: Test articles were prepared as 10 mM stock solutions in DMSO. 178 μL of the mixture of human liver microsomes and substrate was added to the no inhibitor control (NIC) and test article sample wells of the reaction plate and placed on ice. 2 μL of blank solvent and test article working solution were taken from the dilution plate and added to the reaction plate (final concentrations: 0.05 μM to 50 μM). The reaction plate was preheated in a water bath at 37±0.2°C for 10 minutes. 20 μL of cofactor solution was taken and added to the reaction plate using a liquid handling workstation to start the reaction.

[0354] After 10 minutes, 400 μL of stop solution was added to the reaction plate to stop the reaction, and the reaction plate was placed on ice for 5 minutes. The plate was shaken for 10 minutes to homogenize the solution, and centrifuged at 4000 rpm for 20 minutes, after which the supernatant was removed and ultrapure water was added in an appropriate ratio. The peak areas of the substrate and product were detected by liquid chromatography tandem mass spectrometry (LC / MS / MS). The samples were stored at 2°C to 8°C before detection.

[0355] The ratio of the peak areas of metabolites generated by the probe substrate and the internal standard was measured by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The retention times of the analytes and the internal standard, the collection of the chromatograms and the integration of the chromatograms were processed by the software Analyst (AB Sciex, Framingham, Massachusetts, USA).

[0356] Processing of data: Nonlinear regression analysis was performed using SigmaPlot (V.11) to plot the mean percentage activity versus test article concentration. IC was calculated using a three-parameter or four-parameter recursive logarithmic equation. 50 When the percentage activity of CYP was greater than 50% under the action of the highest concentration of the test substance (50 μM), the IC 50 Values ​​were labeled ">50 μM."

[0357] Three-parameter inflexible logarithm equation:

[0358]

number

[0359] 4-parameter inflexible logarithm equation:

[0360]

number

[0361] max: maximum enzyme activity.

[0362] min: minimum enzyme activity.

[0363] x: concentration of test article or positive control inhibitor.

[0364] y: enzyme activity at the corresponding concentration, hillslope: slope.

[0365] I C 50 : Half inhibitory concentration.

[0366] If the minimum enzyme activity was within ±10%, a four-parameter inverse logarithmic equation was used, otherwise a three-parameter equation was used.

[0367] [Table 3]

[0368] Conclusion: The compounds according to the present invention have a weak inhibition level against five CYP isoenzymes, and thus reduce the risk of concomitant use of drugs.

[0369] [Experimental Example 4: Pharmacokinetic Study (PK)] Purpose of the experiment: This study was conducted to study the pharmacokinetic profile of the test article in plasma of male C57BL / 6J mice and SD rats after intravenous and oral administration.

[0370] Testing Method: The animals were randomly divided into two groups, with 3 males per group. The compounds were prepared in a given formulation (solvent was 0.5% MC), the intravenous formulation was a clear solution, and the oral formulation may be a clear or homogenous suspension.

[0371] Animals were punctured via the jugular vein or had whole blood samples taken from the saphenous vein at 5, 15, 30 min, 1, 2, 4, 6, and 8 h after dosing. Whole blood samples were placed in centrifuge tubes containing anticoagulant and centrifuged at 3000 g for 15 min at 4°C. The supernatant plasma was taken and flash frozen on dry ice, then stored in a refrigerator at -70±10°C until LC-MS / MS analysis.

[0372] Processing of data: WinNonlin TM The plasma concentration data of the compounds were processed using a non-compartmental model with Version 6.3.0 (Pharsight, Mountain View, CA) pharmacokinetic software. Peak concentration (C max ) and peak arrival time (T max ) and the last quantifiable time were obtained directly from the plasma drug concentration-time diagram.

[0373] The following pharmacokinetic parameters were calculated using the log-linear trapezoidal method: plasma clearance (CL), volume of distribution (Vd), elimination half-life (T 1 / 2 ), mean residence time of the drug in the body from 0 to the end point (MRT 0-last ), mean residence time of the drug in the body from 0 to infinity (MRT 0-inf ), the area under the time-plasma concentration curve from 0 to the end (AUC 0-last ), the area under the time-plasma concentration curve from 0 to infinity (AUC 0-inf ) and bioavailability (F).

[0374] Test Results:

[0375] [Table 4]

[0376] Conclusion: The compounds according to the present invention can significantly improve pharmacokinetic indices such as half-life and exposure.

[0377] [Experimental Example 5: In vivo pharmacodynamics study of the hydrochloride salt of compound 1 in a nu / nu nude mouse model with orthotopic transplantation of Ba / F3-TEL-CSF1R cells] (Purpose of the experiment) The in vivo efficacy of the test compound 1 hydrochloride was evaluated in a Ba / F3-TEL-CSF1R cell orthotopic transplant aneurysm model.

[0378] (Experimental Design) Cell culture: Ba / F3-TEL-CSF1R cell line was cultured in 1640 medium (Biological Industries) + 10% fetal bovine serum (BI) + 1% double antibiotics (Penicillin Streptomycin solution, Corning, USA) at 37°C, 5% CO2 and passaged twice a week. When the cell saturation reached 80%-90% and the quantity reached the required level, the cells were collected, counted, and inoculated.

[0379] <Animals>: A total of 28 female nu / nu mice, aged 6 to 8 weeks and weighing 18 to 22 grams, were required and were provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.

[0380] <Tumor inoculation>: 0.2 mL (2 × 10 6 ) The Ba / F3-TEL-CSF1R cell suspension was inoculated into each mouse via tail vein injection, and on day 10, the mice were randomly divided into groups based on their body weight.

[0381] <Animal experiment grouping and administration schedule>

[0382] [Table 5]

[0383] <Animal care>: After the animals arrived, they were kept in isolation and quarantine in a laboratory environment for seven days before the experiment could begin.

[0384] Animals were housed in individually ventilated cages in an SPF-grade animal room with no more than five animals per cage. ·Temperature: 20℃~26℃ ·Humidity: 35%~75% Lighting: 12 hours light, 12 hours dark Corn cob bedding, changed weekly Diet: Free access to dry pelleted feed was sterilized by irradiation. Water: Water was available ad libitum and drinking water was sterilized by acidification. Animal Signs: Ear punch.

[0385] <Animal grouping>: After the inoculation was completed, the subcutaneous tumor-bearing state was observed every day, and before grouping, the animals were weighed and the tumor volume was measured, and the animals were randomly grouped according to the data.

[0386] Observation: The preparation of this experimental protocol and any modifications were evaluated and approved by the Experimental Animal Welfare Ethics Committee of Hefei Zhongke Pu Ruisheng Biomedical Technology Co., Ltd. Daily monitoring of the health and mortality of animals, routine inspections included tumor growth, activity, eating and drinking, weight, eyes, hair and other abnormal behavior, external signs and other abnormal behaviors of animals. The number of animal deaths and side effects within groups were recorded based on the number of animals in each group.

[0387] <Experimental parameters>: The animals were weighed every day and their survival status was observed. At the end of the experiment (4 hours after the last administration), the mice were euthanized and their spleens and livers were taken, weighed, and photographed.

[0388] The results of the experiment are shown in Figure 1. Conclusion: In the TEL-CSF1R-BaF3 cell splenomegaly experiment, compound 1 hydrochloride at a dose of 10 mpk showed overwhelmingly superior effects! The three doses of high, medium, and low showed clear dose correlation, and the 1 mpk dose showed significant efficacy, which was equivalent to and statistically superior to PLX-3397. [Brief description of the drawings]

[0389] [Figure 1] This is a mouse splenomegaly test.

Claims

1. A compound represented by any one of the group consisting of formulas (I-1), (I-2), (P-1), (P-2) and (P-3) or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 Among them, R 1 is -C(=O)-NH-C 1-3 alkyl group, and the -C(=O)-NH-C 1-3 The alkyl group may optionally be one, two or three R a is replaced by R 2 is C 1-3 alkyl group, 1-3 The alkyl group may optionally be one, two or three R b is replaced by R 3 , H, C 1-3 Alkyl group and C 3-5 cycloalkyl groups, 1-3 Alkyl groups and C 3-5 The cycloalkyl group may optionally include one, two or three R c is replaced by L 1 -N(R d )-selected from L 2 is a single bond, -O-, -N (R d )-C(=O)- and -N(R d )-C(R e ) (R f )-selected from R a , R b and R c each independently represents F, Cl, Br, I, or CH 3 Selected from R d , R e and R f are independently H and CH 3 Selected from A compound represented by any one of the formulae (I-1), (I-2), (P-1), (P-2) and (P-3) or a pharma- ceutically acceptable salt thereof.

2. R 1 is -C(=O)-NH-CH 3 and the -C(=O)-NH-CH 3 optionally 1, 2 or 3 R a is replaced by 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

3. R 1 is -C(=O)-NH-CH 3 Selected from 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

4. R 2 is CH 3 wherein said CH 3 optionally 1, 2 or 3 R b is replaced by 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

5. R 2 is CH 3 , C.H. 2 F, CHF 2 and CF 3 Selected from 5. The compound according to claim 4 or a pharma- ceutically acceptable salt thereof.

6. R 3 H, CH 3 , CH(CH 3 ) 2 and a cyclopropyl group, 3 , CH(CH 3 ) 2 and the cyclopropyl group optionally has 1, 2 or 3 R c is replaced by 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

7. R 3 H, CH 3 , C.F. 3 , CH(CH 3 ) 2 and a cyclopropyl group; 7. The compound according to claim 6 or a pharma- ceutically acceptable salt thereof.

8. L 1 -NH- and -N(CH 3 )-selected from 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

9. L 2 is a single bond, -O-, -NH-C(=O)-, -NH-CH 2 - and -N(CH 3 )-CH 2 - selected from 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

10. Structural Units 【Chemistry 2】 teeth, 【Chemistry 3】 are each independently selected from 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

11. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof: 【Chemistry 4】 。

12. 12. Use of the compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating tendon sheath giant cell tumor.

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