CN108341816A

CN108341816A - A kind of selective depression kinases compound

Info

Publication number: CN108341816A
Application number: CN201710895315.0A
Authority: CN
Inventors: 袁昊
Original assignee: Shanghai Zhe Yeh Biological Science And Technology Co Ltd
Current assignee: Shanghai Zhe Yeh Biological Science And Technology Co Ltd
Priority date: 2017-01-25
Filing date: 2017-09-28
Publication date: 2018-07-31

Abstract

A kind of selective depression kinases compound.The present invention provides formula (I) compound, its stereoisomer, tautomer or pharmaceutically acceptable salt, it is as FGFR4 Kinase Selectivities inhibitor and its is preparing treatment by the application in the drug or pharmaceutical composition of FGFR4 or FGF19 associated diseases, compound disclosed by the invention is with a wide range of applications to the selective remarkable inhibiting activities of FGFR4 in therapeutic field of tumor.

Description

Selective kinase inhibition compound

Technical Field

The present invention relates to compounds of formula (I) as selective inhibitors of fibroblast growth factor receptor kinase, processes for their preparation, pharmaceutical compositions and methods of using the compounds and compositions to inhibit kinase activity, and their use in medicine.

Background

Fibroblast Growth Factor (FGF) signaling pathways play important roles in many intracellular processes, such as cell proliferation, differentiation, wound repair, and angiogenesis. Many studies have confirmed that the amplification or overexpression of FGF is associated with the development of malignant tumors, such as leukemia, sarcoma, pancreatic cancer, bladder cancer, colon cancer, breast cancer, prostate cancer, etc., and the relationship between overexpression, polymorphism, ectopic expression of FGF and receptor blockade thereof and many human tumors, such as myeloma, breast cancer, gastric cancer, colon cancer, bladder cancer, cervical cancer, etc., has also been reported. The FGF family includes 22 structurally related polypeptides, which interact with the receptor tyrosine kinase FGFR1-4 to homodimerize and autophosphorylate the receptor, and then recruit membrane-associated proteins and cytoplasmic accessory proteins to activate multiple signaling cascades (Lin, b.c., Desnoyers, l.r.fgf19 and cancer.adv.exp.med.biol.2012,728: 183-94; Powers, c.j. et al, endocr.relat.cancer,2000,7: 165-197). Under normal physiological conditions, FGF19 is an important metabolic regulator; under pathological conditions, FGF19 may be associated with the development of various cancers.

The human FGF19 gene is located at 11q13.1, FGFR4 is the only receptor for FGF19 that shows specificity, FGF19 exerts its activity by binding to FGFR4 and activating FGFR 4. FGFR4 is one of FGFR family members and plays an important role in embryonic development, central nervous control, tissue repair, and even in tumor invasion and angiogenesis (Ho, H.K., et al, Journal of Hepatology,2009,50: 118-127). FGFR4 was found to be overexpressed in a variety of cancers, such as liver Cancer (Ho, H.K. et al, Journal of Hepatology,2009,50: 118-127; Sawey, E.T. et al, Cancer Cell,2011,19:347-358), stomach Cancer (Ye, Y.W. et al, Cancer,2011,117: 5304-5313; Ye, Y. et al, Ann.Surg.Oncol.2010,17:3354-3361), pancreatic Cancer (Leung, H.Y. et al, int.J.cancer,1994,59:667-675), renal Cell carcinoma (Takahashi, A. et al, Inv.Biophys.Res.1999, 257:855-859), rhabdomyosarcoma (Taylor, J.G. et al, J.Clin.1.Bioches.Res.2.Res.1999, 257:855-859), bile duct Cancer (Comber, J.G. J.Clin.2.J.Bioches.2: 03, Inv.J.4655, Bioches.J.4655, Couch.4655, Couch.54, Biochem.J. 4655, Col.4655, Biochem.4675, Bryom.;PLos ONE,2012,8(5): e63695), prostate cancer (Xu, B. et al, BMC cancer 2011,11:84), ovarian cancer (Zaid, T.M. et al, Clin. cancer Res.2013,19(4):809-820), and the like. Therefore, the FGF19-FGFR4 signaling pathway plays an important role in the occurrence and development of various cancers in human.

It was found that PD173074 is a small molecule inhibitor of FGFR4 that inhibits the growth of rhabdomyosarcoma cells and has in vivo anti-tumor activity (cross, l.e.s. et al, clin.cancer res.2012,18(14): 1-11). Desnoyers et al found that FGF19 monoclonal antibody can selectively block the interaction between FGF19 and FGFR4, and the antibody can inhibit the growth of naked mouse transplanted tumors of human colon cancer and can effectively prevent FGF19 transgenic mice from suffering from liver cancer (Desnoyers, L.R. et al, Oncogene,2008,27: 85-97). Sawey et al found that FGF19 monoclonal antibody significantly inhibited the growth of human hepatoma transplantable tumors (Sawey, E.T. et al, Cancer Cell,2011,19, 347-358). Ho et al found that FGFR4 small molecule inhibitor V4-015 can induce apoptosis of breast cancer cells and inhibit cancer cell migration (Ho, H.K. et al, Current medical Chemistry,2013,20: 1203-1217). A selective FGFR4 small molecule inhibitor BLU9931 can inhibit liver Cancer cell proliferation, and can inhibit the growth of human liver Cancer xenograft tumor at the same time in a dose-dependent manner (Hagel, M. et al, Cancer Discov.2015,5(4): 1-14). These studies indicate that by blocking the interaction between FGF19 and FGFR4, tumor growth can be inhibited, which provides an effective target for molecular targeted therapy of tumors. The selective small molecule inhibitor targeting FGFR4 is likely to become a therapeutic drug for various tumors.

Although a series of compounds having an effect of inhibiting FGFR4 kinase have been disclosed so far, including patents: WO2014011900, WO2014144737, WO2015057938, WO2015057963, WO2015059668, WO2015061572, WO2015108992, WO2016054483, WO2016064960, WO2016134294, WO2016134314, WO2016134320, WO2016151500, WO2016151501, WO2016164703, WO 2016164164754, WO2016168331, the present invention relates to the development of new compounds having a structure of the general formula (I) which have a better pharmacodynamic, pharmacokinetic effect. The compound with the structure shows excellent effect and action, the relation between the structure and the activity and the efficacy is disclosed and clarified more deeply and comprehensively in a larger range, and the compound has important application value.

Disclosure of Invention

The present invention relates to novel FGFR4 selective small molecule inhibitor compounds and pharmaceutically acceptable salts thereof. The invention also relates to compositions of these compounds, alone or in combination with at least one other therapeutic agent and optionally a pharmaceutically acceptable carrier. The invention further relates to methods of using these compounds, alone or in combination with at least one additional therapeutic agent, in the prevention or treatment of diseases mediated by FGFR4 or FGF 19.

The invention discloses a compound of formula (I), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,

wherein,

z is- (CH)₂)_n-，-NR^Y-，-O-；

R¹Selected from the following groups:

R²，R³，R⁴independently is N or C (R)^X)；

R⁵Selected from substituted or unsubstituted alkynyl, alkenyl;

R⁶selected from the group consisting of hydrogen, halogen, cyano, amino, amido, hydroxyl, ester, acyl, acyloxy, sulfonyl, sulfinyl, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl;

R⁷，R⁸，R⁹independently is N or C (R)^X)；

R¹⁰，R¹¹，R¹²Independently is hydrogen, halogen, cyano, amino, hydroxy, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, or R¹¹，R¹²The two substituent rings are synthesized into a cyclic group,

R^X，R^Yindependently hydrogen, halogen, cyano, amino, amidoHydroxyl, ester, acyl, acyloxy, sulfonyl, sulfinyl, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl or heterocyclyl,

n＝0，1，2，3，4，5。

the compound of formula (I), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof comprises a compound of a general formula (II)

Wherein,

z is- (CH)₂)_n-，-NR^Y-，-O-；

R⁵Selected from substituted or unsubstituted alkynyl, alkenyl;

R⁶a structure selected from:

R¹¹，R¹²independently is hydrogen, halogen, cyano, amino, hydroxy, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, or R¹¹，R¹²The two substituent rings are synthesized as cyclic groups.

n＝0，1，2，3，4，5。

The compound of formula (II) according to the invention, wherein,

R¹¹，R¹²independently hydrogen, halogen, cyano, alkyl, cycloalkyl, aryl, heteroaryl, or R¹¹，R¹²The two substituent rings are synthesized into a cyclic group;

R⁵selected from substituted or unsubstituted alkynyl, alkenyl;

R⁶a structure selected from:

n＝0，1，2，3，4，5。

the compound of the present invention, wherein,

R¹¹，R¹²independently hydrogen, fluorine, cyano, C1-C6 alkyl, 3-6 membered cycloalkyl, aryl, heteroaryl, or R¹¹，R¹²The two substituent rings are synthesized into a cyclic group;

R⁵selected from substituted or unsubstituted alkynyl, alkenyl;

R⁶a structure selected from:

n＝0，1，2，3，4，5。

the compound of the present invention, wherein,

R¹¹，R¹²independently hydrogen, fluorine, C1-C6 alkyl, or R¹¹，R¹²The two substituent rings are synthesized into a cyclic group;

R⁵selected from substituted or unsubstituted alkynyl, alkenyl;

R⁶a structure selected from:

n＝0，1，2，3，4，5。

the compound of the present invention, wherein the structural fragment

A structure selected from:

the compounds of formulae (I) and (II) according to the present invention, stereoisomers, tautomers or pharmaceutically acceptable salts thereof, are selected from the group consisting of the following compounds:

the compound, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof can be used as an FGFR4 kinase selective inhibitor for preparing a medicament or a pharmaceutical composition for treating FGFR4 or FGF19 mediated diseases.

The medicine or the pharmaceutical composition is used for treating various cancers.

Various cancers to be treated according to the present invention include: liver cancer, lung cancer, stomach cancer, renal cell carcinoma, sarcoma, cholangiocarcinoma, colon cancer, prostate cancer, ovarian cancer, breast cancer.

Detailed Description

The term "hydrogen" refers herein to-H.

The term "halogen" refers herein to-F, -Cl, -Br, and-I.

The term "fluoro" refers herein to-F.

The term "chloro" refers herein to-Cl.

The term "bromine" refers herein to-Br.

The term "iodine" refers herein to-I.

The term "cyano" refers herein to — CN.

The term "amino" refers herein to the group-NH₂。

The term "hydroxy" refers herein to-OH.

The term "aryl" refers herein to a 6 to 10 membered all carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, polycyclic (i.e., rings with adjacent pairs of carbon atoms) groups having a conjugated pi-electron system. The aryl group may be covalently linked to the defined chemical structure at any carbon atom that results in a stable structure. The aryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

The term "heteroaryl" refers herein to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O or S. The term may have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, and the like) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, and the like), where the fused rings may or may not be aromatic groups containing heteroatoms, provided that the point of attachment is through an atom of an aromatic heteroaryl group. The heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, amino, alkyl, alkoxy, acyl, acyloxy, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

The term "cycloalkyl" refers herein to cyclic alkyl groups having from 3 to 10 carbon atoms, having a single ring or multiple rings, including fused, bridged and spiro ring systems. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, oxo, alkoxy, acyl, acyloxy, amide, ester, amino, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl, or heteroaryl.

The term "heterocyclyl" refers to a substituted or unsubstituted saturated or unsaturated aromatic, non-aromatic ring containing at least 1 to 5 heteroatoms selected from N, O or S, which may be a 3 to 10 membered monocyclic, 4 to 20 membered spiro, fused or bridged ring, optionally substituted N, S in the heterocyclyl ring being oxidizable to various oxidation states. Preferably 3 to 12 membered heterocyclic. Non-limiting examples include oxacyclopropane, oxetanyl, oxocyclopentyl, oxocyclohexyl, oxooctyl, aziridinyl, azetidinyl, azacyclohexyl, azacyclopropenyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxacyclohexyl, 1, 3-dithiocyclohexyl, azepinyl, morpholinyl, piperazinyl, pyridyl, furanyl, thienyl, pyrrolyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyrane, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, 1, 4-dioxacyclohexadienyl, and the like. Non-limiting examples include the following structures:

and so on.

The term "heterocycloalkyl" refers herein to a non-aromatic cycloalkyl group containing at least one heteroatom selected from O, N and S, and optionally containing one or more double or triple bonds. The heterocycloalkyl group as a whole may have 3 to 10 ring atoms. The heterocycloalkyl group can be covalently attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure. Non-limiting examples of heterocycloalkyl groups include: pyrrolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyranyl and the like. One or more of the N or S atoms on the heterocycloalkyl group may be oxidized (e.g., morpholine N-oxide, thiomorpholine S, S-dioxide). Heterocycloalkyl may also contain one or more oxo groups, such as phthalimido, piperidinonyl, oxazolidinonyl, 2,4(1H,3H) -dioxo-pyrimidinyl, pyridine-2 (1H) -keto, and the like. The heterocycloalkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, oxo, acyl, acyloxy, amide, ester, amino, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl, or heteroaryl. Non-limiting examples include the following structures:

and so on.

The term "alkenyl" refers herein to an alkenyl group having 2 to 8 carbon atoms and having at least one site of alkenyl unsaturation. Non-limiting examples of alkenyl groups include ethenyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, and the like. The alkenyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, oxo, acyl, acyloxy, amide, ester, amino, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkoxy, aryl, or heteroaryl.

The term "alkynyl" refers herein to alkynyl groups having 2 to 8 carbon atoms and having at least one site of alkynyl unsaturation. Non-limiting examples of alkynyl groups include ethynyl, propargyl, and the like. The alkynyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, oxo, acyl, acyloxy, amide, ester, amino, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkoxy, aryl, or heteroaryl.

The term "alkyl" refers herein to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, and this term includes both straight and branched chain hydrocarbon groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and the like. The alkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, oxo, amido, ester, amino, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aryl, or heteroaryl.

The term "alkoxy" as used herein means an alkyl group attached to the rest of the molecule through an oxygen atom (-O-alkyl), wherein the alkyl group is as defined herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and the like.

The term "amido" refers herein to the group-NR³⁰-C (O) -alkyl, -NR³⁰-C (O) -cycloalkyl, -NR³⁰-C (O) -cycloalkenyl, -NR³⁰-C (O) -aryl, -NR³⁰-C (O) -heteroaryl and-NR³⁰-C (O) -heterocycloalkyl, wherein R³⁰Are hydrogen, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, and alkyl. Wherein the hydrogen, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, alkyl, and like groups are as defined herein.

The term "acyl" refers herein to H-C (O) -, R³¹R³²N-C (O) -, alkyl-C (O) -, cycloalkyl-C (O) -, cycloalkenyl-C (O) -, heterocycloalkyl-C (O) -, aryl-C (O) -and heteroaryl-C (O) -, wherein said R³¹And R³²Each independently selected from hydrogen, hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, or cycloalkyl. Wherein the hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, cycloalkyl, and like groups are as defined herein.

The term "sulfonyl" refers herein to R³³R³⁴N-S(O)₂-, cycloalkyl-S (O)₂-, cycloalkenyl-S (O)₂-, aryl-S (O)₂-, heteroaryl-S (O)₂-, heterocycloalkyl-S (O)₂And alkyl-S (O)₂-, wherein said R³³And R³⁴Each independently selected from hydrogen, hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, or cycloalkyl. Wherein the hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, cycloalkyl, and like groups are as defined herein.

The term "sulfinyl" refers herein to R³⁵R³⁶N-S (O) -, cycloalkyl-S (O) -, cycloalkenyl-S (O) -, aryl-S (O) -, heteroaryl-S (O) -, heterocycloalkyl-S (O) -or alkyl-S (O) -, wherein said R³⁵And R³⁶Each independently selected from hydrogen, hydroxy, alkylHeterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, or cycloalkyl. Wherein the hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, cycloalkyl, and like groups are as defined herein.

The term "acyloxy" refers herein to-O-C (O) -alkyl, -O-C (O) -cycloalkyl, -O-C (O) -cycloalkenyl, -O-C (O) -aryl, -O-C (O) -heteroaryl, and-O-C (O) -heterocycloalkyl, where the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl groups are as defined herein.

The term "ester group" refers herein to alkyl-O-C (O) -, cycloalkyl-O-C (O) -, cycloalkenyl-O-C (O) -, heterocycloalkyl-O-C (O) -, aryl-O-C (O) -, and heteroaryl-O-C (O) -, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl groups are as defined herein.

The term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The term "optionally substituted with … …" means that the structure is unsubstituted or substituted with one or more substituents described herein. The term "substituted" as used herein means that any group is mono-or polysubstituted with the indicated substituent(s) to the extent that such mono-or polysubstitution is chemically permissible, including multiple substitutions on the same moiety, each substituent may be at any available position on the group and may be attached through any available atom on the substituent. By "any available position" is meant any position on the group that is chemically available by methods known in the art or taught herein, and that does not result in an overly labile molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and thus may be the same or different.

At various positions in this specification, substituents for the compounds of the invention are disclosed in the form of groups or ranges. This specifically means that the invention includes each member of such groups and ranges or subcombinations of each individual member of the members. Such as the term "C_1-6Alkyl "specifically means that methyl, ethyl, C are disclosed separately₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

The term "compounds of the present invention" (unless specifically indicated otherwise) refers herein to compounds of formula (I) and all pure and mixed stereoisomers, geometric isomers, tautomers, solvates, prodrugs and isotopically labeled compounds and any pharmaceutically acceptable salts thereof. Solvates of the compounds of the invention refer to compounds or salts thereof, such as hydrates, ethanolates, methanolates, and the like, in combination with stoichiometric and non-stoichiometric amounts of solvent. The compound may also exist in one or more crystalline states, i.e., as co-crystals, polymorphs, or it may exist as an amorphous solid. All such forms are intended to be covered by the claims.

The term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal being treated therewith.

The term "stereoisomer" refers herein to compounds of different chirality having one or more stereocenters, including the enantiomers and diastereomers.

The term "tautomer" refers herein to structural isomeric forms having different energies that may cross the low energy barrier and thereby interconvert. Such as proton tautomers include tautomers that undergo interconversion by proton migration, such as enol-ketone tautomers and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms attached to ring-NH-moieties and ring-N-moieties, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. Valence tautomers include interconversion by recombination of some of the bond-forming electrons.

The term "prodrug" refers herein to any derivative of a compound of the present invention that, when administered to a subject, is capable of providing, directly or indirectly, a compound of the present invention, an active metabolite or residue thereof. Particularly preferred are those derivatives or prodrugs that increase the bioavailability, metabolic stability and tissue targeting of the compounds of the present invention.

The compounds of the present invention may be used in the form of salts, such as "pharmaceutically acceptable salts" derived from inorganic or organic acids. These include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, ethanesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, ethanesulfonate, hydrochloride, 2-naphthalenesulfonate, oxalate, pectinate, sulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and decanoate. In addition, the basic nitrogen-containing groups can be quaternized with the following agents to form quaternary ammonium salts: such as lower alkyl halides including methyl, ethyl, propyl and butyl chlorides, bromides and iodides; such as dialkyl sulfates, including dimethyl, diethyl, dibutyl, and diamyl sulfates; such as long chain halides including decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; such as aralkyl halides, such as benzyl and phenethyl bromides, and the like.

Protecting Groups in relation to hydroxy, amino, mercapto, carboxy and the like are those which protect hydroxy, amino, mercapto, carboxy and the like from undesired reactions by means of functional Groups, and the protecting Groups used are well known to the person skilled in the art, such as those mentioned in Protective Groups in Organic Synthesis (John Wiley & Sons, New York, third edition, 1999).

The invention also includes isotopically-labelled compounds of the invention, i.e. those structures which are identical to those disclosed above, but in which one or more atoms are replaced by an atom having the same number of protons, but a different number of neutrons. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, respectively²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³⁵S、¹⁸F、³⁶Cl and¹³¹i, and the like. The compounds of the present invention, stereoisomers, tautomers or pharmaceutically acceptable salts thereof, as well as the compounds of the above forms containing the above isotopes and/or other atomic isotopes, are within the scope of the present invention. Certain isotopically-labelled compounds of the invention, e.g. by³H or¹⁴Those labeled with C can be used in drug tissue distribution assays, and thus, these³H or¹⁴The C isotope is particularly preferred because of its ease of preparation and detection. In addition, by heavier isotopes such as²Certain compounds of the invention substituted with H have certain therapeutic advantages due to their greater metabolic stability, such as increased in vivo half-life and lower dosages, and, therefore,²h is also preferred in some cases.

The compound has the selective inhibition effect on FGFR4, and can be used for preparing medicaments or pharmaceutical compositions applied to human or veterinary medicine and used for treating FGFR4 or FGF19 mediated diseases such as cancers and other related diseases. In particular, the compounds may be used for the treatment of human or animal cancers, including liver cancer, stomach cancer, pancreatic cancer, renal cell carcinoma, sarcoma, cholangiocarcinoma, colon cancer, prostate cancer, ovarian cancer, breast cancer, and the like.

Detailed Description

Throughout this application, various embodiments of the compounds and methods of the present invention are referenced herein. The embodiments described are intended to provide illustrative examples and should not be construed as descriptions of alternatives. It should also be noted that the embodiments discussed herein (including the various methods and parameters) are merely illustrative of the invention and do not limit the scope of the invention in any way. Specific examples are set forth below to illustrate the invention. It is to be understood that the invention is not limited to these examples, which are provided solely to provide methods of practicing the invention and are not intended to limit the scope of the invention in any way.

The compounds of the general formulae of the invention are prepared according to the following preparation schemes:

the preparation of the compounds of general formula (I) is summarized below:

firstly, a commercially available intermediate X1 and a commercially available intermediate X2 are coupled to prepare a compound X3, the compound X3 is reduced to obtain a compound X4, the compound X4 and the compound X5 are coupled to react to obtain a compound X6, and the compound X6 and the compound X7 are subjected to exchange reaction to obtain a compound X8 with a final general formula.

The compounds provided herein can be prepared by standard synthetic methods well known in the art, and the general methods for preparing the compounds of the invention are provided herein. The starting materials are generally commercially available, for example, via AlfaTCI、Shaoyuan chemical, Annaiji chemical, etc., or by methods well known to those skilled in the art.

The following reaction methods and synthetic steps provide possible routes for the synthesis of the compounds of the invention as well as key intermediates. For a more detailed description of the individual reaction steps, reference is made to the following examples. It will be appreciated by those skilled in the art that the compounds of the invention may also be obtained by other synthetic routes. Although specific starting materials and reagents are used in the reaction schemes below, these starting materials and reagents may be substituted with other similar starting materials or reagents to provide various derivatives. In addition, many of the compounds made by the methods described below may be further modified by conventional chemical methods well known to those skilled in the art, given the benefit of this disclosure.

In the preparation of the compounds of the present invention, it may be desirable to protect certain interfering functional groups (e.g., primary or secondary amines) of the intermediates. The requirements for such protecting groups vary depending on the nature of the particular functional group and the conditions of the preparation process. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), and the like. Suitable hydroxy protecting groups include allyl, acetyl, silyl, benzyl, trityl, p-methoxybenzyl and the like. Such protecting groups can be readily determined by those skilled in the art (see in particular Protective group in Organic Synthesis, John Wiley & Sons, New York, third edition, 1999).

The compounds of the invention and the corresponding preparation processes are further illustrated and exemplified below by means of examples and preparations. It is to be understood that although typical or preferred reaction conditions (e.g., reaction temperature, time, molar ratios of reactants, reaction solvent, and pressure, etc.) are given in the specific examples, other reaction conditions may be used by one skilled in the art. Optimal reaction conditions may vary with the particular reaction substrate or solvent used, but the conditions may be determined by one of skill in the art through routine optimization.

The structures of the compounds of the following examples were characterized by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The compound was dissolved in appropriate deuterated reagents using a Bruker ascend 400MHz NMR spectrometer and performed at ambient temperature using TMS as internal standard¹H-NMR spectroscopyAnd (6) analyzing. NMR chemical shifts (δ) are in ppm and are abbreviated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad singlet. MS by Waters UPLC-Vevo^TMTQ MS mass spectrometry (ESI) measurements.

The starting materials, intermediates and compounds of the examples can be isolated and purified by conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography (e.g., column chromatography, TLC separation and purification).

TLC uses a tobacco yellow sea HSGF254 thin layer chromatography silica gel plate (0.2 +/-0.03 mm), and TLC separation and purification uses a tobacco yellow sea HSGF254 thin layer chromatography thick preparation plate (0.9-1 mm), which are purchased from Qingdao ocean chemical plants.

The column chromatography is carried out by taking 300-400 mesh silica gel of Taiwan Huanghai as a carrier and purchased from Qingdao oceanic chemical plants.

Commercial solvents and reagents used in the test were used without specific indication, and were used without further purification or treatment after purchase. The reaction conditions (reaction temperature, reaction solvent, molar ratio of reactants, or/and reaction duration) may be different when referring to other examples or synthetic methods. In general, the progress of the reaction can be monitored by TLC, whereby the reaction is terminated and worked up at a suitable time. The purification conditions of the compounds may also vary, generally speaking, according to R of TLC_fThe appropriate column chromatography eluent is selected or the corresponding compound is isolated and purified by preparative TLC.

Example 1

Compound 1 of the present invention is prepared according to the above preparation scheme to give compound 1, ESI-MS m/z: 500.0[ M + H]⁺。

Example 2

Compound 2 of the present invention is prepared according to the above preparation scheme to give compound 2, ESI-MS m/z: 514.4[ M + H]⁺。

Example 3

Compound 3 of the present invention was prepared according to the above preparation scheme to give compound 3, ESI-MS m/z: 458.2[ M + H]⁺。

Example 4

Compound 4 of the present invention is prepared according to the above preparation scheme to give compound 4, ESI-MS m/z: 486.3[ M + H]⁺。

Example 5

Compound 5 of the present invention is prepared according to the above preparation scheme to give compound 5, ESI-MS m/z: 514.2[ M + H]⁺。

Example 6

Compound 6 of the present invention is prepared according to the above preparation scheme to give compound 6, ESI-MS m/z: 500.4[ M + H]⁺。

Example 7

Compound 7 of the present invention was prepared according to the above preparation scheme to give compound 7, ESI-MS m/z: 541.3[ M + H]⁺。

Example 8

Compound 8 of the present invention is prepared according to the above preparation scheme to give compound 8, ESI-MS m/z: 515.1[ M + H]⁺。

Example 9

Compound 9 of the present invention is prepared according to the above preparation scheme to give compound 9, ESI-MS m/z: 541.2[ M + H]⁺。

Example 10

Compound 10 of the present invention is prepared according to the above preparation scheme to give compound 10, ESI-MS m/z: 527.4[ M + H]⁺。

Example 11

Compound 11 of the present invention is prepared according to the above preparation scheme to give compound 11, ESI-MS m/z: 529.2[ M + H]⁺。

Example 12

Compound 12 of the present invention is prepared according to the above preparation scheme to give compound 12, ESI-MS m/z: 529.0[ M + H]⁺。

Example 13

Compound 13 of the present invention was prepared according to the above preparation scheme to give compound 13, ESI-MS m/z: 488.3[ M + H]⁺。

Example 14

Compound 14 of the present invention is prepared according to the above preparation scheme to give compound 14, ESI-MS m/z: 502.2[ M + H]⁺。

Example 15

Compound 15 of the present invention was prepared according to the above preparation scheme to give compound 15, ESI-MS m/z: 502.4[ M + H]⁺。

Example 16

Compound 16 of the present invention is prepared according to the above preparation scheme to give compound 16, ESI-MS m/z: 542.0[ M + H]⁺。

Example 17

Compound 17 of the present invention is prepared according to the above preparation scheme to give compound 17, ESI-MS m/z: 490.3[ M + H]⁺。

Example 18

Compound 18 of the present invention was prepared according to the above preparation scheme to give compound 18, ESI-MS m/z: 504.4[ M + H]⁺。

Example 19

Compound 19 of the present invention is prepared according to the above preparation scheme to give compound 19, ESI-MS m/z: 528.1[ M + H]⁺。

Example 20

Compound 20 of the present invention was prepared according to the above preparation scheme to give compound 20, ESI-MS m/z: 530.3[ M + H]⁺。

Example 21

Compound 21 of the present invention was prepared according to the above preparation scheme to give compound 21, ESI-MS m/z: 530.2[ M + H]⁺。

Practice ofExample 22

Compound 22 of the present invention is prepared according to the above preparation scheme to give compound 22, ESI-MS m/z: 555.5[ M + H]⁺。

Example 23

Compound 23 of the present invention was prepared according to the above preparation scheme to give compound 23, ESI-MS m/z: 544.1[ M + H]⁺。

Example 24

Compound 24 of the present invention is prepared according to the above preparation scheme to give compound 24, ESI-MS m/z: 528.3[ M + H]⁺。

Example 25

Compound 25 of the present invention was prepared according to the above preparation scheme to give compound 25, ESI-MS m/z: 460.2[ M + H]⁺。

Example 26

Compound 26 of the present invention was prepared according to the above preparation scheme to give compound 26, ESI-MS m/z: 474.1[ M + H]⁺。

Example 27

Compound 27 of the present invention is prepared according to the above preparation scheme to give compound 27, ESI-MS m/z: 502.3[ M + H]⁺。

Example 28

Compound 27 of the present invention is prepared according to the above-described preparation to give compound 28, by the following specific steps:

compound 28G (prepared according to the method disclosed in patent WO 2015059668) amounting to 686mg, 5.0mmol), N-methyl-2-methoxyethylamine (1.074ml, 10.0mmol), N-dimethylacetamide (12ml) and diisopropylethylamine (3.3ml, 20.0mmol) were placed in a sealed tube and reacted at 80 ℃, the completion of the reaction was monitored by thin layer chromatography, concentrated at 75 ℃ under reduced pressure, slurried with petroleum ether/ethyl acetate (2/1), filtered and dried to give compound 28H (222 mg).¹H NMR(400MHz,CDCl₃)δ8.06(s,1H),5.59～5.83(m,1H),5.58(s,1H),5.27～5.24(m,2H),3.85～3.82(m,2H)。

Compound 28B (prepared according to the method disclosed in WO 2015059668) (1.0g, 3.0mmol) was dissolved in dichloromethane (10ml), DIPEA (744. mu.l, 4.5mmol) was added, cooled to 0 ℃ and a solution of p-nitrophenylchloroformate (907mg, 4.5mmol) in dichloromethane (5ml) was added dropwise, and the reaction was allowed to return to room temperature. The completion of the reaction was monitored by thin layer chromatography, and saturated aqueous ammonium chloride was added, followed by extraction with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (dichloromethane: methanol: 30:1) to obtain compound 28C (667 mg).

Dissolving compound 28C (100mg, 0.2mmol) and compound 28H (52mg, 0.3mmol) in anhydrous tetrahydrofuran (10ml), cooling to-15 ℃, then adding LiHMDS (1.0M in THF, 300 μ l, 0.3mmol) dropwise under nitrogen protection, reacting at that temperature, monitoring the reaction completion by thin layer chromatography, adding an aqueous ammonium chloride solution to quench the reaction, extracting with ethyl acetate, combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating, and performing silica gel column chromatography (ethyl acetate: methanol 500: 1-50: 1) to obtain compound 28D (67 mg).

Compound 28D (67mg) was dissolved in tetrahydrofuran (2ml) and water (2ml), followed by addition of concentrated hydrochloric acid (0.4ml), reaction at room temperature for 2 hours, followed by addition of saturated sodium bicarbonate for neutralization, extraction with ethyl acetate, combination of organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, concentration, beating with petroleum ether/ethyl acetate (2/1), filtration and drying to give compound 28(25 mg).¹H NMR(400MHz,CDCl₃)δ13.62(s,1H),10.25(s,1H),8.21(s,1H),7.64(s,1H),7.60(s,1H),6.00～5.91(m,1H),5.39～5.29(m,2H),5.15～5.12(m,1H),5.11(s,2H),4.11～4.08(m,2H),4.01～3.98(m,2H),3.38～3.35(m,2H),3.22(s,2H),2.95～2.92(m,2H),2.69～2.66(m,2H),2.37(s,3H),2.06～2.03(m,2H)；ESI-MS m/z：489.3[M+H]⁺。

Biological assay

1. In vitro biochemical kinase assay

Recombinant FGFR4 and substrate Poly (Glu4, Tyr1) were incubated in 1 XBuffer (40mM Tris, pH 7.5; 20mM MgCl)₂；0.1mg/ml BSA；2mM MnCl₂(ii) a 50 μ M DTT). The compound is added to a mixed enzyme/substrate system, mixed and pre-incubated, and then ATP is added to start the reaction. Reacting at room temperature for 60min, and adding ADP-Glo Reagent; the reaction was then continued at 23 ℃ for 40min and a Kinase Detection Reagent was added to continue the reaction for 30 min. Fluorescence values were detected for each reaction well. The inhibition rate was calculated from the chemiluminescence intensity L value, which was [1- (L sample-L blank)/(L negative-L blank)]X 100%. IC of compound was calculated from sample inhibition using 4Parameter Logistic Model in XLFit software₅₀。

Compound numbering	FGFR4(IC50)(nM)	FGFR1(IC50)(μM)
			1	0.05	>10
3	0.07	>10
			5	0.01	>10
10	0.03	>10
			17	0.06	>10
27	0.04	>10
			28	0.01	>10

The data show that the compound has a remarkable inhibitory effect on FGFR4, the inhibitory activity on FGFR1 is not high, and the compound has a selective remarkable inhibitory activity on FGFR4 as can be seen from the ratio of the FGFR1(IC50) value to the FGFR4(IC50) value.

2. In vitro cell inhibition assay

Human liver cancer cell: HepG2, Hep3B (FGFR4 mutant) and HuH-7(FGFR4 mutant) were inoculated in 96-well plates at 37 ℃ with 5% CO₂Culturing under the condition. The next day, sample (T) was added, along with no sample control (C) and pre-dosing control (T0). Cells of the control (T0) were fixed with TCA and left for use before dosing. Cells with sample (T) and no sample control (C) were incubated for an additional 48 hours and then fixed. All fixed cells are dyed by SRB dye solution, free dye is washed away by acetic acid solution, Tris alkali is added after air drying, and the OD value is measured at 490nm after shaking, dissolving and mixing. Calculating the growth rate according to the OD value, and if T is more than or equal to T0, the growth rate is (T-T0)/(C-T0). times.100%; if T < T0, (T-T0)/T0X 100. GI50(μ M) was calculated from growth rate using a 4Parameter Logistic Model in Xlfit software.

Compound numbering	Hep3B	HuH-7	HepG2
				1	0.0001	0.0001	>10
3	0.0002	0.0002	>10
				5	0.0002	0.0001	>10
10	0.0001	0.0002	>10
				17	0.0002	0.0003	>10
27	0.0003	0.0004	>10
				28	0.0001	0.0002	>10

The data show that the compound has obvious selective inhibition effect on liver cancer cell strains Hep3B and HuH-7.

Claims

1. A compound of formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,

wherein,

z is- (CH)₂)_n-，-NR^Y-，-O-，

R¹Selected from the following groups:

R²，R³，R⁴independently is N or C (R)^X)，

R⁵Selected from substituted or unsubstituted alkynyl, alkenyl,

R⁶selected from the group consisting of hydrogen, halogen, cyano, amino, amido, hydroxy, ester, acyl, acyloxy, sulfonyl, sulfinyl, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl,

R⁷，R⁸，R⁹independently is N or C (R)^X)，

R^X，R^Yindependently hydrogen, halogen, cyano, amino, amido, hydroxyl, ester, acyl, acyloxy, sulfonyl, sulfinyl, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl or heterocyclyl,

n＝0，1，2，3，4，5。

2. a compound of formula (I), its stereoisomers, tautomers or pharmaceutically acceptable salts thereof according to claim 1, comprising a compound of general formula (II)

Wherein Z is- (CH)₂)_n-，-NR^Y-，-O-；

R⁵Selected from substituted or unsubstituted alkynyl, alkenyl;

R⁶a structure selected from:

n＝0，1，2，3，4，5。

3. The compound of formula (II) according to claim 2, wherein,

R⁵selected from substituted or unsubstituted alkynyl, alkenyl;

R⁶a structure selected from:

n＝0，1，2，3，4，5。

4. the compound of claim 3, wherein,

R⁵selected from substituted or unsubstituted alkynyl, alkenyl;

R⁶a structure selected from:

n＝0，1，2，3，4，5。

5. the compound of claim 4, wherein,

R⁵selected from substituted or unsubstituted alkynyl, alkenyl;

R⁶a structure selected from:

n＝0，1，2，3，4，5。

6. the compound of claim 5, wherein the structural fragment

A structure selected from:

7. a compound of formula (I) and (II), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, according to claims 1 to 6, selected from the group consisting of the following compounds:

8. use of a compound according to any one of claims 1 to 7, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, as a selective inhibitor of FGFR4 kinase, for the preparation of a medicament or pharmaceutical composition for the treatment of a disease mediated by FGFR4 or FGF 19.

9. The medicament or pharmaceutical composition of claim 8, which is used for the treatment of various cancers.

10. The method of claim 9, wherein the various cancers treated comprise: liver cancer, lung cancer, esophageal cancer, stomach cancer, renal cell carcinoma, sarcoma, cholangiocarcinoma, colon cancer, prostate cancer, ovarian cancer, breast cancer.