FAK inhibitor

Abstract

The present invention relates to a new focal adhesion kinase (FAK) inhibitor, and particularly to a compound as represented by formula (I) or a stereoisomer, tautomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof. The present invention further relates to a pharmaceutical composition containing the FAK inhibitor, and the use thereof in the treatment of FAK-mediated diseases.

Description

FAK inhibitors Technical Field

[0001] This invention belongs to the field of medicinal chemistry. Specifically, this invention relates to novel focal adhesion kinase (FAK) inhibitors and pharmaceutical compositions thereof for the treatment of FAK-mediated diseases, such as tumors. Background Technology

[0002] The focal adhesion kinase (FAK) family has two members: FAK1 (Focal Adhesion Kinase 1, also known as protein tyrosine kinase 2, PTK2) and FAK2 (also known as proline-rich tyrosine kinase 2, PYK2).

[0003] FAK is a non-receptor tyrosine kinase and a key protein in the formation of focal adhesion. FAK plays a crucial role in mediating integrin and growth factor signaling to regulate tumor cell invasion, proliferation, and survival. FAK is widely expressed and evolutionarily conserved. Studies over the past two decades have shown that FAK is widely and highly expressed in solid tumors such as uveal melanoma, ovarian cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, esophageal cancer, breast cancer, and gastric cancer. Furthermore, its expression level in these cancer types is negatively correlated with prognosis, suggesting a significant role for FAK in cancer development and progression. Recent studies have also indicated that FAK plays an important role in regulating the tumor microenvironment, suggesting its crucial role in adaptive resistance to immunotherapy and antitumor therapies. FAK is a mechanistic molecule for tumor fibroblast survival, primarily expressed in the nucleus of tumor fibroblasts. It plays a vital role in maintaining the tumor protective umbrella formed by tumor fibroblasts. Research has found that targeting FAK not only affects the escape response of tumor cells themselves but also blocks the escape response that tumor cells may generate through the protective umbrella formed by tumor fibroblasts. It generates broad and durable antitumor activity by influencing the synergistic effect between tumor cells and the tumor microenvironment.

[0004] Currently, there are no FAK inhibitors on the market, and clinical trials have shown that several FAK inhibitors can cause proteinuria. For example, IN10018 (BI853520) exhibits grade 3 proteinuria as a dose-limiting toxicity, especially at doses of 200 mg or higher, requiring discontinuation or dose reduction, which may affect efficacy. Therefore, there is an unmet clinical need for a safer and more effective FAK inhibitor. This invention aims to provide a FAK inhibitor that does not cause proteinuria. Summary of the Invention

[0005] This invention provides, in one aspect, novel FAK inhibitors, which are compounds of formula (I) or stereoisomers, tautomers, or isotopic variants thereof, or pharmaceutically acceptable salts thereof:

[0006] in,

[0007] R1 is selected from H or halogen;

[0008] R2 is selected from OC 1-6 Alkyl or OC 1-6 Halogenated alkyl groups;

[0009] R3 is selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0010] R is selected from OH, NH2, or COOH;

[0011] n = 1, 2, 3 or 4;

[0012] The aforementioned groups may optionally be substituted with 1, 2, 3 or more Ds.

[0013] Another aspect of the present invention provides a pharmaceutical composition comprising the compound described herein or a stereoisomer, tautomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, and optionally, other therapeutic agents, such as IN10018.

[0014] Another aspect of the present invention provides the use of the compounds described herein or their stereoisomers, tautomers or isotopic variants, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described herein in the preparation of medicaments for treating and / or preventing FAK-mediated diseases.

[0015] Another aspect of the present invention provides a method for treating and / or preventing FAK-mediated diseases in a subject, the method comprising administering to the subject a compound of the present invention or a stereoisomer, tautomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0016] Another aspect of the present invention provides the compounds described herein or their stereoisomers, tautomers or isotopic variants, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described herein, for the treatment and / or prevention of FAK-mediated diseases.

[0017] Specifically, the FAK-mediated diseases mentioned above are tumors. Attached Figure Description

[0018] Figure 1: Statistical analysis results of albumin in 24-hour urine of test drug compound 11 and positive control drug IN10018. Detailed Implementation

[0019] To make the objectives, technical solutions, and advantages of the embodiments of this disclosure clearer, the technical solutions of this disclosure will be clearly and completely described below in conjunction with the embodiments of this disclosure. Obviously, the described embodiments are only some, not all, of the embodiments of this disclosure. All other embodiments obtained by those skilled in the art based on the described embodiments of this disclosure without creative effort are within the scope of protection of this invention.

[0020] definition

[0021] Chemical definition

[0022] The definitions of specific functional groups and chemical terms are described in more detail below.

[0023] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0024] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl". In some embodiments, C 1-4 Alkyl groups are particularly preferred. Examples of such alkyl groups include, but are not limited to: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Regardless of whether the alkyl group is preceded by "substituted," each alkyl group is optionally substituted independently, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with suitable substituents defined below.

[0025] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.

[0026] Therefore, "C" 1-6 "Halogenated alkyl" refers to the above "C 1-6 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl groups are particularly preferred, and C4 groups are more preferred. 1-2 Alkyl halogens. Exemplary alkyl halogens include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc.

[0027] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(R bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa -OC(=NR) bb )R aa -OC(=NR)bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(ORcc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0028] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace;

[0029] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0030] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(Rcc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0031] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0032] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff)2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee 3. -OSi(R) ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0033] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0034] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0035] R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3, -C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC (=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 carbocyclic, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0036] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc-P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0037] "Deuterated" or "D-substituted" refers to the substitution of one or more hydrogen atoms in a compound or group by deuterium; deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted. The terms "one or more deuterated" and "one or more deuterated" are used interchangeably.

[0038] The term "pharmaceutically acceptable salt" refers to those salts that, within the bounds of reliable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Salts formed using methods conventional in the art are also included, such as ion exchange methods. Other pharmaceutically acceptable salts include: adipic acid salts, alginate salts, ascorbate salts, aspartate salts, benzenesulfonate salts, benzoate salts, bisulfate salts, borate salts, butyrate salts, camphorate salts, camphor sulfonate salts, citrate salts, cyclopentylpropionate salts, diglucuronate salts, dodecyl sulfate salts, ethanesulfonate salts, formate salts, fumarate salts, gluconate salts, glyceryl phosphate salts, glucuronate salts, hemisulfate salts, heptarate salts, hexanoate salts, hydroiodate salts, 2-hydroxy-ethanesulfonate salts, lactobionate salts, lactate salts, laurate salts, lauryl sulfate salts, malate salts, maleate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, oxalate salts, palmitate salts, dihydroxynaphthalate salts, pectin ester salts, persulfate salts, 3-phenylpropionate salts, phosphate salts, picrate salts, p-pentanoate salts, propionate salts, stearate salts, succinate salts, sulfate salts, tartrate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts, if appropriate, include non-toxic ammonium salts, quaternary ammonium salts, and amine cations that form with counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonates, and aryl sulfonates.

[0039] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0040] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0041] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0042] The term "combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, the compounds of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously with another therapeutic agent in a single unit dosage form.

[0043] This invention relates to compounds of formula (I) or their stereoisomers, tautomers, or isotopic variants, or pharmaceutically acceptable salts thereof:

[0044] in,

[0045] R1 is selected from H or halogen;

[0046] R2 is selected from OC 1-6 Alkyl or OC 1-6 Halogenated alkyl groups;

[0047] R3 is selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0048] R is selected from OH, NH2, or COOH;

[0049] n = 1, 2, 3 or 4;

[0050] The aforementioned groups may optionally be substituted with 1, 2, 3 or more Ds.

[0051] R1

[0052] In one embodiment, R1 is H; in another embodiment, R1 is a halogen, such as F or Cl.

[0053] R2

[0054] In one implementation, R2 is OC. 1-6 Alkyl group, such as OCH3; in another embodiment, R2 is OC. 1-6 Halogenated alkyl groups, such as OCF3.

[0055] R3

[0056] In one implementation, R3 is C 1-6 Alkyl; in another embodiment, R3 is C 1-6 Haloalkyl, such as C 1-4 Halogenated alkyl groups, such as trifluoromethyl.

[0057] R

[0058] In one embodiment, R is OH; in another embodiment, R is NH2; in yet another embodiment, R is COOH.

[0059] n

[0060] In one implementation, n = 1; in another implementation, n = 2; in yet another implementation, n = 3; and in yet another implementation, n = 4.

[0061] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. This invention aims to include combinations of all such technical solutions; however, due to space limitations, they are not listed individually.

[0062] This application specifically involves the following technical solutions:

[0063] 1. The compound represented by formula (I) or its stereoisomers, tautomers or isotopic variants, or pharmaceutically acceptable salts thereof:

[0064] in,

[0065] R1 is selected from H or halogen;

[0066] R2 is selected from OC 1-6 Alkyl or OC 1-6 Halogenated alkyl groups;

[0067] R3 is selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0068] R is selected from OH, NH2, or COOH;

[0069] n = 1, 2, 3 or 4;

[0070] The aforementioned groups may optionally be substituted with 1, 2, 3 or more Ds.

[0071] 2. The compound of technical solution 1 or its stereoisomers, tautomers or isotopic variants, or pharmaceutically acceptable salts thereof, having the structure shown in formula (II):

[0072] in,

[0073] R1 is selected from H or halogen;

[0074] R2 is selected from OC 1-6 Alkyl or OC 1-6 Halogenated alkyl groups;

[0075] R3 is selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0076] R is selected from OH, NH2, or COOH;

[0077] The aforementioned groups may optionally be substituted with 1, 2, 3 or more Ds.

[0078] 3. The compound of technical solution 1 or its stereoisomers, tautomers or isotopic variants, or pharmaceutically acceptable salts thereof, having the structure shown in formula (III):

[0079] in,

[0080] R is selected from OH, NH2, or COOH.

[0081] 4. The compound of technical solution 1 or its stereoisomers, tautomers, or isotopic variants, or pharmaceutically acceptable salts thereof, wherein the compound is one of the following:

[0082] 5. A pharmaceutical composition comprising a compound of any one of claims 1-4 or a stereoisomer, tautomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, and optionally, other therapeutic agents.

[0083] 6. The pharmaceutical composition of technical solution 5, wherein the other therapeutic agent is IN10018 or its tartrate salt, preferably the tartrate salt of IN10018.

[0084] 7. The pharmaceutical composition of technical solution 6, wherein the compound of any one of technical solutions 1-4 or its stereoisomer, tautomer or isotopic variant, or pharmaceutically acceptable salt thereof constitutes no more than 0.2% by mass relative to other therapeutic agents.

[0085] 8. Use of any compound of any one of technical claims 1-4 or its stereoisomers, tautomers or isotopic variants, or pharmaceutically acceptable salts thereof, or any pharmaceutical composition of any one of technical claims 5-7 in the preparation of a medicament for the treatment and / or prevention of FAK-mediated diseases.

[0086] 9. A method for treating and / or preventing FAK-mediated disease in a subject, the method comprising administering to the subject a compound of any one of technical solutions 1-4 or a stereoisomer, tautomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of technical solutions 5-7.

[0087] 10. A compound of any one of technical solutions 1-4 or a stereoisomer, tautomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of technical solutions 5-7, for the treatment and / or prevention of FAK-mediated diseases.

[0088] 11. The use of technical solution 8, or the method of technical solution 9, or the use of the compound or composition of technical solution 10, wherein the FAK-mediated disease is a tumor.

[0089] 12. A method for preparing the compound shown in formula (II):

[0090] Wherein, R is OH, and the R1-R3 groups are as defined in claim 2;

[0091] The step includes reacting the compound shown in formula (II-b) with dipotassium osmium tetroxide and sodium periodate.

[0092] 13. The method of technical solution 12, wherein the reaction is carried out in a mixed solvent of an organic solvent and water (preferably, the organic solvent is such as THF and dioxane); preferably, the reaction is carried out in THF and H2O.

[0093] 14. The method of technical solution 12, wherein the reaction is carried out at -5 to 15 degrees Celsius, preferably 0 degrees Celsius.

[0094] 15. The method of any one of technical solutions 12-14, further comprising the step of reacting the compound represented by formula (II-a) with potassium trifluoro(vinyl)borate in the presence of a palladium catalyst (e.g., palladium acetate, palladium triphenylphosphine dichloride, Pd(dppf)Cl2, etc.), preferably in the presence of Pd(dppf)Cl2:

[0095] Wherein, the R1-R3 groups are as defined in claim 2.

[0096] 16. The method of technical solution 15, wherein the reaction is carried out in a mixed solvent of organic solvent and water (preferably, the organic solvent is such as acetonitrile, THF, dioxane, etc.), preferably in dioxane and H2O, in the presence of a base (e.g., potassium carbonate, cesium carbonate, sodium carbonate, etc.), preferably in the presence of Na2CO3.

[0097] 17. The method of technical solution 15, wherein the reaction is carried out at 80-100 degrees Celsius, preferably 100 degrees Celsius.

[0098] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0099] "Tautomers" refer to compounds in which one functional group changes its structure to become another functional group isomer, and can rapidly interconvert to each other, becoming two isomers in dynamic equilibrium. These two isomers are called tautomers.

[0100] The present invention also includes isotopically labeled compounds that are equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P,32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0101] Pharmaceutical compositions, formulations and kits

[0102] In another aspect, the present invention provides pharmaceutical compositions comprising the compound of the present invention (also referred to as the "active ingredient") and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the active ingredient.

[0103] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0104] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0105] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0106] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0107] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0108] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0109] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to rapidly increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active ingredient, while a bolus dose delivered directly to a vein (e.g., via IV infusion) allows for a more rapid delivery, causing the concentration of the active ingredient in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV infusion, thereby providing a steady-state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0110] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, the compositions are provided in unit dose form for the purpose of precise dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients useful for forming the desired dosage form, as well as processing aids.

[0111] For oral dosage, a typical regimen is one to five oral doses daily, particularly two to four oral doses, typically three oral doses. Using these dosage regimens, each dose provides approximately 0.01 to approximately 20 mg / kg of the compound of the invention, with preferred doses each providing approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0112] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0113] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0114] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[0115] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0116] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and generally include other components to enhance stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of this invention.

[0117] The compounds of this invention can also be administered via transdermal devices. Therefore, transdermal drug delivery can be achieved using reservoirs or porous membrane types, or patches with various solid matrices.

[0118] The above-described components for oral, injectable, or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0119] The compounds of this invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[0120] This invention also relates to pharmaceutically acceptable formulations of the compounds of this invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfonyl ether substituted groups. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0121] Example

[0122] The following embodiments are provided to further illustrate the invention. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0123] Unless otherwise specified, the experimental methods described in the following examples can be performed under the standard conditions for such reactions or under the conditions recommended by the manufacturer.

[0124] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.

[0125] Example 1: Preparation of the target compound - Compound 11

[0126] 1. Synthetic route

[0127] 2.1 Synthesis of Compound 2

[0128] DMF (5 L) was added to the reaction flask, followed by compound 1 (500 g, 2.16 mol), methylamine hydrochloride (292 g, 4.32 mol), HOBt (350 g, 2.59 mol), EDCI (497 g, 2.59 mol), and DIPEA (836 g, 6.48 mol) under stirring at room temperature. After the addition was complete, the mixture was stirred at room temperature for 16 h. The reaction solution was poured into 15 L of water and extracted with 15 L of ethyl acetate. The combined organic phases were washed with 10 L of water and 10 L of saturated brine, respectively. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was pulped with 3 L of methyl tert-butyl ether and filtered. The filter cake was washed with 1 L of methyl tert-butyl ether and dried to obtain compound 2 (400 g, 75.9% yield), a white solid.

[0129] MS[M+H] + =244.0,246.0.

[0130] 1 H NMR (400MHz, DMSO-d6) δ8.22(d,J=4.0Hz,1H),7.27(t,J=8.4Hz,1H),7.18-7.16(m,1H),7.07(d,J=8.0Hz,1H),3.76(s,3H),2.71(d,J=4.8Hz,3H).

[0131] 2.2 Synthesis of Compound 3

[0132] Add 4 L of DCM to the reaction flask, then add compound 2 (400 g, 1.64 mol) with stirring at room temperature. Under nitrogen protection, cool to -70°C, then add BBr3 (1.23 kg, 4.92 mol). After the addition is complete, stir the reaction mixture at -50°C for 6 h. Pour the reaction mixture into 12 L of ice water and extract with 12 L of dichloromethane. Combine the organic phases and wash with 8 L of water and 8 L of saturated brine, respectively. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give compound 3 (300 g, 79.3% yield) as a white solid.

[0133] MS[M+H] + =230.1,232.1.

[0134] 1 H NMR (400MHz, DMSO_d6) δ10.01(s,1H),8.14(d,J=4.4Hz,1H),7.09(t,J=8.0Hz,1H),7.00(d,J=8.0Hz,1H),6.84(d,J=8.4Hz,1H),2.70(d,J=4.4Hz,3H).

[0135] 2.3 Synthesis of Compound 4

[0136] IPA (1 L) was added to the reaction flask, and compound 3 (100 g, 435 mmol) was added with stirring at room temperature. The mixture was cooled to 0°C, and KOH (26.8 g, 479 mmol) was dissolved in 1 L of water and added to the reaction solution. Then, 2,4-dichloro-5-(trifluoromethyl)pyrimidine (104 g, 479 mmol) was added to the reaction solution in portions. After the addition was complete, the mixture was stirred at 0°C for 2 h, with three parallel reactions occurring simultaneously. The reaction solution was poured into 6 L of water and extracted with 6 L of dichloromethane. The organic phases were combined and washed with 4 L of water and 4 L of saturated brine, respectively. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1), and the product was collected and concentrated under reduced pressure to obtain compound 4 (300 g, 56.0% yield), a white solid.

[0137] MS[M+H] + =409.9,411.9.

[0138] 1 H NMR (400MHz, DMSO_d6) δ9.08 (s, 1H), 8.49 (d, J = 4.8Hz, 1H), 7.67 (dd, J = 7.2, 2.0Hz, 1H), 7.53-7.47 (m, 2H), 2.63 (d, J = 4.8Hz, 3H).

[0139] 2.4 Synthesis of Compound 6

[0140] DMF (500 mL) and MeOH (500 mL) were added to a reaction flask. Compound 5 (100 g, 493 mmol) and Cs₂CO₃ (482 g, 1.48 mol) were added under stirring at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 16 h, with three parallel reactions occurring simultaneously. The reaction mixture was poured into 10 L of ice water, and the pH was adjusted to 3 with concentrated hydrochloric acid. Extraction was performed with 6 L of ethyl acetate. The combined organic phases were washed with 4 L of water and 3 L of saturated brine, respectively. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 6 (250 g, 78.4% yield) as a yellow solid.

[0141] MS[M+H] + =214.1.

[0142] 1H NMR (400MHz, DMSO_d6) δ13.94(s,1H),8.01(d,J=9.2Hz,1H),7.66(d,J=6.0Hz,1H),3.96(s,3H).

[0143] 2.5 Synthesis of Compound 7

[0144] DMF (1.25 L) was added to the reaction flask, followed by compound 6 (125 g, 581 mmol), 1-methylpiperidin-4-amine (66.2 g, 581 mmol), HOBt (94.1 g, 697 mmol), EDCI (134 g, 697 mmol), and DIEA (225 g, 1.74 mol) under stirring at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 16 h, with two parallel reactions occurring simultaneously. The reaction mixture was poured into 8 L of water and extracted with 10 L of ethyl acetate. The combined organic phases were washed with 4 L of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 7 (220 g, 60.9% yield) as a yellow solid.

[0145] MS[M+H] + =312.1.

[0146] 1 H NMR (400MHz, DMSO_d6) δ8.48(d,J=8.0Hz,1H),7.97(s,1H),7.41(d,J=5.6Hz,1H),3.94(s,3H),3.69(d,J=7.6H z,1H),2.70(t,J=11.6Hz,2H),2.15(s,3H),1.96(t,J=10.8Hz,2H),1.79(d,J=10.4Hz,2H),1.57-1.48(m,2H).

[0147] 2.6 Synthesis of Compound 8

[0148] The high-pressure reactor was first purged with nitrogen three times, and then MeOH (1.1 L), compound 7 (110 g, 354 mmol) and Raney-Ni (22 g) were added to the reactor. After the addition was complete, hydrogen gas was introduced at 0.5 MPa and purged three times. The reactor was stirred at room temperature for 4 h, and two parallel reactions were carried out simultaneously. The reaction solution was filtered, the filter cake was washed with 500 mL of methanol, and the filtrate was concentrated under reduced pressure to obtain compound 8 (180 g, 90.7% yield), a white solid.

[0149] MS[M+H] + =282.1.

[0150] 1H NMR(400MHz, DMSO_d6)δ7.37(t,J=6.8Hz,1H),7.02(d,J=6.9Hz,1H),6.36(d,J=13.0Hz,1H),5.57(s,2H),3.77- 3.68(m,4H),2.73-2.68(m,2H),2.15(s,3H),1.95(t,J=10.8Hz,2H),1.74(d,J=10.4Hz,2H),1.58-1.48(m,2H).

[0151] 2.7 Synthesis of Compound 9

[0152] Anhydrous NMP (500 mL) was added to the reaction flask, followed by compound 4 (50 g, 122 mmol) with stirring at room temperature. Then, 30.5 mL of 4N HCl dioxane solution (122 mmol) was added to the reaction mixture. After the addition was complete, the mixture was stirred at 55°C for 1 h. Compound 8 (34.3 g, 122 mmol) was added in portions. After the addition was complete, the mixture was stirred at 85°C for 16 h. Six parallel reactions were carried out simultaneously. The reaction mixture was cooled to room temperature, poured into 10 L of water, and extracted with 6 L of ethyl acetate. The combined organic phases were washed with 4 L of water and 4 L of saturated brine, respectively. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 20 / 1), and the product was collected and concentrated under reduced pressure to obtain compound 9 (210 g, 43.8% yield), a white solid.

[0153] MS[M+H] + =655.1,657.1.

[0154] 1 H NMR(400MHz,DMSO_d6)δ8.94(s,1H),8.74(s,1H),8.42-8.40(m,1H),7.98(d ,J=7.2Hz,1H),7.63(d,J=7.8Hz,1H),7.47-7.43(m,3H),7.11(d,J=6.4Hz,1 H),3.84(s,3H),3.70-3.66(m,1H),2.73-2.70(m,2H),2.64(d,J=4.8Hz,3H) ,2.18(s,3H),1.96(t,J=10.4Hz,2H),1.80-1.76(m,2H),1.56-1.51(m,2H).

[0155] 2.8 Synthesis of Compound 10

[0156] Dioxane (400 mL) and H₂O (100 mL) were added to a reaction flask. Compound 9 (35 g, 53.4 mmol), potassium trifluoro(vinyl)borate (21.5 g, 160 mmol), and Na₂CO₃ (17.0 g, 160 mmol) were added at room temperature. Pd(dppf)Cl₂ (3.91 g, 5.34 mmol) was added under nitrogen protection. After the addition was complete, the mixture was stirred at 100 °C for 16 h, with six parallel reactions occurring simultaneously. The reaction mixture was cooled to room temperature, poured into 10 L of water, and extracted with 10 L of ethyl acetate. The combined organic phases were washed with 4 L of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 15 / 1), and the product was collected and concentrated under reduced pressure to give compound 10 (120 g, 62.2% yield), a yellow solid.

[0157] MS[M+H] + =603.3.

[0158] 1 H NMR(400MHz, DMSO_d6)δ8.85(s,1H),8.73(s,1H),8.32(d,J=4.4Hz,1H),8.05(d,J=6.8Hz,1H),7.68(d, J=7.6Hz,1H),7.62-7.56(m,1H),7.47(t,J=8.2Hz,1H),7.35(d,J=8.0Hz,1H),7.10(d,J=6.4Hz,1H),6. 61(dd,J=17.6,11.2Hz,1H),5.91(d,J=17.6Hz,1H),5.37(d,J=11.2Hz,1H),3.84(s,3H),3.76-3.75(m, 1H),2.89-2.87(m,2H),2.63(d,J=4.4Hz,3H),2.29-2.24(m,5H),1.83-1.80(m,2H),1.63-1.58(m,2H).

[0159] 2.9 Synthesis of Compound 11

[0160] THF (200 mL) and H₂O (200 mL) were added to the reaction flask, along with compound 10 (20 g, 33.2 mmol). The system was cooled to 0°C, and dipotassium osmium tetroxide (578 mg, 1.66 mmol) was added, followed by sodium periodate (21.5 g, 99.6 mmol) in portions. After the addition was complete, the mixture was stirred at 0°C for 4 h, with six parallel reactions occurring simultaneously. The reaction solution was poured into 2 L of water and extracted with 2 L of ethyl acetate. The combined organic phases were washed with 1 L of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 10 / 1), and the product was collected and concentrated under reduced pressure to obtain target compound 11 (21 g, 17.5% yield), an off-white solid.

[0161] MS[M+H] + =605.0.

[0162] 1 H NMR(400MHz,DMSO_d6)δ8.78(d,J=6.8Hz,1H),7.95(d,J=6.9Hz,1H),7.74(t,J=7.8Hz,1 H),7.57(d,J=7.4Hz,1H),7.37(d,J=8.0Hz,1H),7.26(brs,0H),7.07(d,J=6.4Hz,1H),6. 72(d,J=8.4Hz,1H),5.72(d,J=7.6Hz,1H),3.79(s,1H),3.71-3.67(m,1H),2.83(s,3H), 2.78-2.75(m,2H),2.19(s,3H),2.02-1.99(m,2H),1.79-1.76(m,2H),1.60-1.51(m,2H).

[0163] 13 C NMR(100MHz,DMSO_d6)δ166.38,163.26,162.52,160.20,157.81,154.06,151.66,147.33,146.66,144.98,133.79,129.95, 129.83,124.67,122.90,122.76,121.98,121.75,117.66,117.50,111.00,81.55,56.30,54.05,46.26,45.64,31.06,25.53.

[0164] Experimental Example

[0165] Experimental Example 1: Study of Proteinuria in Wistar Rats

[0166] Objective: To evaluate the effect of compound 11 on proteinuria induced by Wistar rats.

[0167] Methods: Six-week-old female Wistar rats, weighing approximately 180g, were used, with three animals per group. The positive control group consisted of compound IN10018, and the test compound was compound 11. The dosage of both compounds IN10018 and compound 11 was 80 mg / kg. Administration was via oral gavage once daily for 28 consecutive days. The solvent for the compound preparations was 0.5% hydroxyethyl cellulose. During the experiment, 24-hour urine samples were collected three times: before administration, 2 weeks after administration, and 4 weeks after administration. Urine was collected from each animal using a metabolic cage at the specified time points. Albumin (ALB) in the urine was detected using an automated biochemical analyzer with appropriate reagent kits. At the end of the experiment, the animals were euthanized under 5% isoflurane anesthesia and grossly dissected. Data processing was performed using Office Excel 2013 and GraphPad Prism 9.0, and data are expressed as Mean ± SEM (mean ± standard error). For statistical analysis, the experimental and control groups were compared. ANOVA was first used for analysis, followed by Tukey's test for significance of differences between groups. A two-tailed t-test was used to compare the two groups, and a p-value < 0.05 was considered statistically significant between the two groups.

[0168] Results: The statistical analysis results of albumin in urine three times a day (before administration, 2 weeks after administration, and 4 weeks after administration) of compound 11 in the experimental group and IN10018 in the positive control group are shown in Figure 1.

[0169] Conclusion: Under the conditions of this experiment, Wistar rats did not develop proteinuria after being orally administered 80 mg / kg of compound 11 daily for 28 consecutive days.

Claims

1. The compound represented by formula (I) or its stereoisomers, tautomers or isotopic variants, or pharmaceutically acceptable salts thereof: in, R1 is selected from H or halogen; R2 is selected from OC 1-6 Alkyl or OC 1-6 Halogenated alkyl groups; R3is selected from C 1-6 alkyl or C 1-6 haloalkyl; R is selected from OH, NH2, or COOH; n = 1, 2, 3 or 4; The aforementioned groups may optionally be substituted with 1, 2, 3 or more Ds.

2. The compound of claim 1 or a stereoisomer, tautomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, having the structure shown in formula (II): in, R1 is selected from H or halogen; R2is selected from OC 1-6 alkyl or OC 1-6 haloalkyl; R3is selected from C 1-6 alkyl or C 1-6 haloalkyl; R is selected from OH, NH2, or COOH; The aforementioned groups may optionally be substituted with 1, 2, 3 or more Ds.

3. The compound of claim 1 having the structure according to Formula (III): ###0003### or a stereoisomer, tautomer, or isotopolog thereof, or a pharmaceutically acceptable salt thereof. in, R is selected from OH, NH2, or COOH.

4. The compound of claim 1, or a stereoisomer, tautomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is one of the following:

5. A pharmaceutical composition comprising a compound of any one of claims 1-4 or a stereoisomer, tautomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, and optionally, other therapeutic agents.

6. The pharmaceutical composition of claim 5, wherein the other therapeutic agent is IN10018 or its tartrate salt, preferably the tartrate salt of IN10018.

7. The pharmaceutical composition of claim 6, wherein the compound of any one of claims 1-4 or its stereoisomer, tautomer or isotopic variant, or pharmaceutically acceptable salt thereof constitutes no more than 0.2% by mass relative to the other therapeutic agent.

8. Use of any compound of claims 1-4 or a stereoisomer, tautomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, or any pharmaceutical composition of claims 5-7 in the preparation of a medicament for the treatment and / or prevention of FAK-mediated diseases.

9. A method for treating and / or preventing FAK-mediated disease in a subject, the method comprising administering to the subject a compound of any one of claims 1-4 or a stereoisomer, tautomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 5-7.

10. The compound of any one of claims 1-4 or its stereoisomers, tautomers or isotopic variants, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of any one of claims 5-7, for the treatment and / or prevention of FAK-mediated diseases.

11. The use of claim 8, the method of claim 9, or the use of the compound or composition of claim 10, wherein the FAK-mediated disease is a tumor.

12. A process for the preparation of a compound of formula (II): in, R is OH, and the R1-R3 groups are as defined in claim 2; The step includes reacting the compound shown in formula (II-b) with dipotassium osmium tetroxide and sodium periodate.

13. The method of claim 12, wherein the reaction is carried out in a mixed solvent of an organic solvent and water (preferably, the organic solvent is, for example, THF and dioxane); preferably, the reaction is carried out in THF and H2O.

14. The method of claim 12, wherein the reaction is carried out at -5 to 15 degrees Celsius, preferably 0 degrees Celsius.

15. The method of any one of claims 12-14, further comprising the step of reacting the compound represented by formula (II-a) with potassium trifluoro(vinyl)borate in the presence of a palladium catalyst (e.g., palladium acetate, palladium triphenylphosphine dichloride, Pd(dppf)Cl2), preferably in the presence of Pd(dppf)Cl2: wherein, The R1-R3 groups are as defined in claim 2.

16. The method of claim 15, wherein the reaction is carried out in a mixed solvent of an organic solvent and water (preferably, the organic solvent is such as acetonitrile, THF, or dioxane), preferably in dioxane and H2O, in the presence of a base (e.g., potassium carbonate, cesium carbonate, or sodium carbonate), and more preferably in the presence of Na2CO3.

17. The process of claim 15, wherein the reaction is carried out at 80-100 degrees Celsius, preferably 100 degrees Celsius.

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