WO2018121774A1 - 一种选择性抑制激酶化合物及其用途 - Google Patents

一种选择性抑制激酶化合物及其用途 Download PDF

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WO2018121774A1
WO2018121774A1 PCT/CN2017/120224 CN2017120224W WO2018121774A1 WO 2018121774 A1 WO2018121774 A1 WO 2018121774A1 CN 2017120224 W CN2017120224 W CN 2017120224W WO 2018121774 A1 WO2018121774 A1 WO 2018121774A1
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compound
group
cancer
alkyl
pharmaceutically acceptable
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PCT/CN2017/120224
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English (en)
French (fr)
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刘建余
张海东
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上海喆邺生物科技有限公司
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Priority to EP17887773.4A priority Critical patent/EP3564242B1/en
Priority to ES17887773T priority patent/ES2911183T3/es
Priority to US16/474,991 priority patent/US11046684B2/en
Priority to JP2019556416A priority patent/JP6850361B2/ja
Priority to CN201780080355.8A priority patent/CN110461836B/zh
Publication of WO2018121774A1 publication Critical patent/WO2018121774A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a compound of formula (I) and formula (II) as a selective inhibitor of fibroblast growth factor receptor kinase, a process for the preparation thereof, a pharmaceutical composition and a method for inhibiting kinase activity using said compounds and compositions And its use in medicine.
  • Fibroblast growth factor is a family of intracellular polypeptides consisting of 22 structurally similar members, 150-300 amino acid residues, widely distributed in mammals, promoting cell proliferation, migration, differentiation, It plays an important role in physiological activities such as embryonic development, wound repair, hematopoiesis, angiogenesis, metabolism (Itoh, N.; Ornitz, DM Fibroblast growth factors: From molecular evolution to roles in development, metabolism and disease. J. Biochem. , 149, 121–130). Many studies have confirmed that abnormalities in the FGF family are associated with the development of malignant tumors such as leukemia, sarcoma, pancreatic cancer, bladder cancer, colon cancer, breast cancer and prostate cancer.
  • malignant tumors such as leukemia, sarcoma, pancreatic cancer, bladder cancer, colon cancer, breast cancer and prostate cancer.
  • FGF exerts its physiologically active function by binding to its specific receptor (FGFR).
  • Mammalian FGFR includes four FGFR1-4 receptors and belongs to receptor tyrosine kinase receptors. After binding to FGF, homodimerization occurs in the transmembrane receptor, phosphorylation of the intracellular kinase domain is activated, and activation of the intracellular downstream MAPK or PI3K/AKT signaling pathway activates multiple signaling cascades (Lin, BC, Desnoyers, LRFGF19 and cancer. Adv. Exp. Med. Biol. 2012, 728: 183-94; Powers, CJ et al, Endocr. Relat. Cancer, 2000, 7: 165-197).
  • FGF19 is an important metabolic regulator involved in bile synthesis, glycogen synthesis, gluconeogenesis, and protein synthesis.
  • FXR Farnesoid X Receptor
  • the natural receptor for FGF19 is FGFR4, which has high levels of expression in the liver.
  • FGFR4 After binding to FGF19, under the action of co-factor ⁇ -Klotho (KLB), dimerization and activation of the intracellular kinase domain autophosphorylation are activated, and physiological functions are regulated by downstream cascade signals. .
  • the human FGF19 gene is located at 11q13.1.
  • FGFR4 also has overexpression in a variety of cancers, such as liver cancer (Ho, HK et al, Journal of Hepatology, 2009, 50: 118–127; Sawey, ET et al, Cancer Cell, 2011, 19: 347-358), gastric cancer (Ye, YW, et al, Cancer, 2011, 117: 5304-5313; Ye, Y. et al, Ann. Surg. Oncol.
  • pancreatic cancer Leung, HY et al, Int. J. Cancer , 1994, 59: 667-675
  • renal cell carcinoma Takahashi, A. et al, Biochem. Biophys. Res. Commun. 1999, 257: 855-859
  • rhabdomyosarcoma Taylor VI, JG et al, J. Clin. Invest. Doi: 1o.1172/JCI39703
  • cholangiocarcinoma Xu, Y.-F. et al., Biochem. Biophys. Res. Commun. 2014, 446: 54-60
  • colon cancer Barderas, R.
  • Non-selective FGFR inhibitors cause side effects such as hyperphosphatemia and ectopic calcification.
  • Selective FGFR4 inhibitors are more safe against tumor patients with abnormal FGF19/FGFR4 signaling pathways.
  • PD173074 is a small molecule inhibitor of FGFR4 that inhibits the growth of rhabdomyosarcoma cells and has antitumor activity in vivo (Crose, 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, which can inhibit the growth of human colon cancer xenografts in nude mice and effectively prevent liver cancer in FGF19 transgenic mice (Desnoyers, LR et al, Oncogene, 2008). , 27:85-97). Sawey et al.
  • FGFR4 small molecule inhibitors can induce apoptosis of breast cancer cells and inhibit cancer cell migration (Ho, H. K. et al., Current Medicinal Chemistry, 2013, 20: 1203-1217).
  • the selective FGFR4 small molecule inhibitor BLU9931 is capable of inhibiting the proliferation of hepatoma cells and inhibiting the growth of human hepatocarcinoma xenografts in a dose-dependent manner (Hagel, M. et al., Cancer Discov. 2015, 5(4): 1-14).
  • 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 additional therapeutic agent and, optionally, a pharmaceutically acceptable carrier.
  • the invention further relates to the use or use of these compounds, alone or in combination, with at least one additional therapeutic agent for the prevention or treatment of a disease mediated by FGFR4 or FGF19.
  • the present invention discloses a compound of the formula (I), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,
  • R 2 , R 3 , R 4 are independently N or C(R X );
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, amino, amide, hydroxy, ester, acyl, acyloxy, sulfonyl, sulfinyl, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl Base, heterocyclic group, heterocyclylalkyl group;
  • R 6 is selected from the group consisting of hydrogen, halogen, cyano, amino, amide, hydroxy, ester, acyl, acyloxy, sulfonyl, sulfinyl, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl Base, heterocyclic group, heterocyclylalkyl group;
  • R 7 , R 8 , R 9 are independently N or C(R X );
  • R 10 , R 11 , R 12 are independently hydrogen, halogen, cyano, amino, hydroxy, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, or two substituents R 11 , R 12 Ring synthesis into a cyclic group,
  • R X is independently hydrogen, halogen, cyano, amino, amido, hydroxy, ester, acyl, acyloxy, sulfonyl, sulfinyl, alkyl, alkoxy, aryl, cycloalkyl, hetero Aryl or heterocyclic group,
  • n 1, 2, 3, 4, 5.
  • R 5 is hydrogen, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl,
  • R 11 , R 12 are independently hydrogen, halogen, cyano, amino, hydroxy, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, or R 11 , R 12 ring substituents are synthesized as Cyclic group,
  • n 1, 2, 3, 4, 5,
  • R 6 is selected from the following structures:
  • the method for preparing a compound of the present invention, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R 5 , R 6 , R 11 , R 12 and n are as defined above; R y and R z are selected from C1-C6 alkyl.
  • the base selected therein is selected from the group consisting of lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amine, preferably bis(trimethylsilyl) Alkyl lithium.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the present invention, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier .
  • the medicament or pharmaceutical composition of the invention for use in the treatment of various cancers.
  • various cancers treated include: liver cancer, lung cancer, esophageal cancer, gastric cancer, renal cell carcinoma, sarcoma, cholangiocarcinoma, colon cancer, prostate cancer, ovarian cancer, and breast cancer.
  • halogen refers to -F, -Cl, -Br and -I.
  • fluorine refers to -F.
  • chlorine refers to -Cl.
  • bromine refers to -Br.
  • cyano refers herein to -CN.
  • amino herein refers to -NH 2.
  • hydroxy refers herein to -OH.
  • aryl refers herein to a 6 to 10 membered all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups, a polycyclic ring having a conjugated pi-electron system (ie, a band) a ring having a pair of adjacent carbon atoms).
  • the aryl group can be covalently attached to the defined chemical structure at any carbon atom that results in a stable structure.
  • aryl groups described herein may be optionally substituted by one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, amide Base, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkynyl group and cycloalkoxy group.
  • heteroaryl refers to an aromatic group consisting of 5 to 10 atoms and containing at least one hetero atom 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, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran) , hydrazine, isoindole, etc.), wherein the fused ring may or may not be an aromatic group containing a hetero atom, assuming that the point of attachment is an atom through an aromatic heteroaryl group.
  • heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy Base, amide group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkynyl group and cycloalkoxy group.
  • cycloalkyl refers to a cyclic alkyl group having from 3 to 10 carbon atoms having a single or multiple ring (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, hydroxy, carboxy, amino, alkyl, oxo, alkoxy.
  • heterocyclyl means substituted or unsubstituted saturated or unsaturated and contains at least 1 to 5 aromatic rings selected from N, O or S heteroatoms, non-aromatic rings, aromatic rings, non-aromatic rings may be A 3 to 10 membered monocyclic ring, a 4 to 20 membered spiro ring, a ring or a bridged ring, and optionally substituted N, S in the heterocyclyl ring can be oxidized to various oxidation states.
  • a 3- to 12-membered heterocyclic ring is preferred.
  • Non-limiting examples include oxiranyl, oxetanyl, oxearyl, oxetan, oxacyclohexyl, oxetanyl, aziridine, azetidin , azacyclopentyl, azacyclohexyl, azacyclopropenyl, 1,3-dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3-dioxocyclopentyl, 1 , 3-dioxacyclohexyl, 1,3-dithiocyclohexyl, azepanyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrolyl, pyranyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl,
  • heterocycloalkyl refers 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.
  • Heterocycloalkyl groups can be covalently attached to a 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.
  • heterocycloalkyl group can be oxidized (e.g., morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S, S-dioxide).
  • Heterocycloalkyl groups may also contain one or more oxo groups such as phthalimido, piperidinone, oxazolidinone, 2,4(1H,3H)-dioxo-pyrimidinyl , pyridine-2(1H)-keto group and the like.
  • heterocycloalkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, oxy , acyl, acyloxy, amide, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl or heteroaryl base.
  • substituents include the following structure:
  • alkenyl refers to an alkenyl group having 2 to 8 carbon atoms and having at least one alkenyl unsaturation.
  • alkenyl groups include ethenyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, and the like.
  • alkenyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, oxo, Acyl, acyloxy, amide, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkoxy, aryl or Heteroaryl.
  • substituents fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, oxo, Acyl, acyloxy, amide, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl,
  • alkyl refers herein to a saturated aliphatic hydrocarbyl group having from 1 to 10 carbon atoms, and the term includes both straight chain and branched chain hydrocarbon groups.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and the like.
  • alkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, acyl Oxy, oxo, amide, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocycloalkyloxy, An aryloxy group, a heteroaryloxy group, an aryl group or a heteroaryl group.
  • alkoxy refers to an alkyl group attached to the remainder of the molecule (O-alkyl) through an oxygen atom, wherein the alkyl group is as defined herein.
  • alkoxy groups include methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, positive Pentyloxy and the like.
  • ⁇ refers herein to -NR 30 -C(O)-alkyl, -NR 30 -C(O)-cycloalkyl, -NR 30 -C(O)-cycloalkenyl, -NR 30- C(O)-aryl, -NR 30 -C(O)-heteroaryl and -NR 30 -C(O)-heterocycloalkyl, wherein R 30 is hydrogen, cycloalkyl, cycloalkenyl , aryl, heteroaryl, heterocycloalkyl and alkyl.
  • the groups such as hydrogen, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl and alkyl are as defined herein.
  • acyl refers to HC(O)-, R 31 R 32 NC(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, cycloalkenyl-C ( O)-,heterocycloalkyl-C(O)-, aryl-C(O)-, and heteroaryl-C(O)-, wherein said R 31 and R 32 are each independently selected from hydrogen, hydroxy An alkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a sulfonyl group, a sulfinyl group, a cycloalkenyl group, an acyl group or a cycloalkyl group.
  • the groups such as hydrogen, hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl and cycloalkyl are as defined herein.
  • sulfonyl refers herein to R 33 R 34 NS(O) 2 -, cycloalkyl-S(O) 2 -, cycloalkenyl-S(O) 2 -, aryl-S(O) 2- , heteroaryl-S(O) 2 -, heterocycloalkyl-S(O) 2 - and alkyl-S(O) 2 -, wherein said R 33 and R 34 are each independently selected from hydrogen A hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl group.
  • the groups such as hydrogen, hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl and cycloalkyl are as defined herein.
  • sulfinyl refers herein to R 35 R 36 NS(O)-, cycloalkyl-S(O)-, cycloalkenyl-S(O)-, aryl-S(O)-, a heteroaryl-S(O)-, heterocycloalkyl-S(O)- or alkyl-S(O)- group, wherein said R 35 and R 36 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, Heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl.
  • the groups such as hydrogen, hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl and cycloalkyl are as defined herein.
  • acyloxy refers to -OC(O)-alkyl, -OC(O)-cycloalkyl, -OC(O)-cycloalkenyl, -OC(O)-aryl, - OC(O)-heteroaryl and -OC(O)-heterocycloalkyl, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl groups are as herein Defined in .
  • ester group refers to alkyl-OC(O)-, cycloalkyl-OC(O)-, cycloalkenyl-OC(O)-, heterocycloalkyl-OC(O)-, aryl-OC(O)- and heteroaryl-OC(O)-, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl groups are as herein Defined.
  • substituents as used herein refers to the degree to which a group is mono- or polysubstituted by a given substituent to such a mono- or poly-substitution (including multiple substitutions in the same moiety), each substituent being Located at any available position on the group and may be attached through any available atom on the substituent. "Any position that is available” means that it is chemically obtainable by methods known in the art or as taught herein, and does not create any position on the group of molecules that are excessively unstable. 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.
  • substituents of the compounds of the invention are disclosed in the form of groups or ranges. This specifically means that the invention encompasses subgroups of each of the members or members of such groups and ranges.
  • the term "C 1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • compound of the invention refers herein to compounds of formula (I) and formula (II) and all their pure and mixed stereoisomers, geometric isomers, tautomers.
  • the solvate of the compound of the present invention means a compound or a salt thereof, such as a hydrate, an ethanolate, a methanolate, an acetonate or the like, in combination with a stoichiometric and non-stoichiometric solvent.
  • the compound may also be present in one or more crystalline states, i.e., as a co-crystal, a polymorph, or it may be present as an amorphous solid. All such forms are covered by the claims.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients that make up the formulation and/or the mammal to which it is treated.
  • stereoisomer refers to a chiralally different compound having one or more stereocenters, including the corresponding isomers and diastereomers.
  • tautomer refers to structural isomerizations having different energies that can cross the low energy barrier and thereby transform each other.
  • Valence tautomers include some bond-forming electron recombination for interconversion.
  • prodrug refers to any derivative of a compound of the invention that is capable of providing, directly or indirectly, a compound of the invention, an active metabolite or residue thereof, when administered to a subject. Particularly preferred are those derivatives or prodrugs which increase the bioavailability of the compounds of the invention, increase metabolic stability and tissue targeting.
  • the compound of the present invention can be used in the form of a salt such as a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
  • a salt such as a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
  • a salt such as a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
  • a salt such as a "pharmaceutically acceptable salt” derived from an inorganic or organic acid.
  • basic nitrogen-containing groups can be quaternized with the following reagents to form quaternary ammonium salts: such as lower alkyl halides, including chlorides, bromides and iodines of methyl, ethyl, propyl and butyl groups.
  • a dialkyl sulfate including dimethyl, diethyl, dibutyl, and dipentyl sulfates; such as long chain halides, including sulfhydryl, lauryl, myristyl, and stearyl Chloride, bromide and iodide; such as aralkyl halides, such as benzyl and phenethyl bromide.
  • the invention also includes isotopically-labeled compounds of the invention, i.e., 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.
  • isotopes incorporating compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl and 131 I, etc.
  • the compounds of the present invention are within the scope of the invention.
  • Certain isotopically-labeled compounds of the invention such as those labeled with 3 H or 14 C, can be used in drug tissue distribution assays and, therefore, these 3 H or 14 C isotopes are particularly preferred for their ease of preparation and detection.
  • certain compounds of the invention that are replaced by heavier isotopes such as 2 H have certain therapeutic advantages due to better metabolic stability, such as increased in vivo half-life and lower doses, etc., therefore, 2 H is in some It is also preferred in some cases.
  • the compounds of the present invention have a FGFR4 selective inhibitory action and are useful for the preparation of a pharmaceutical or pharmaceutical composition for human or veterinary use for the treatment of diseases associated with FGFR4 or FGF19 mediated diseases such as cancer.
  • the compounds can be used to treat cancer in humans or animals, including liver cancer, gastric cancer, pancreatic cancer, renal cell carcinoma, sarcoma, cholangiocarcinoma, colon cancer, prostate cancer, ovarian cancer, breast cancer, and the like.
  • Figure 1 shows the results of in vivo efficacy testing using HEP3B cells in a hepatocellular carcinoma model.
  • Compound 1 was administered by oral gavage, solvent blank control, relative tumor volume during the experimental period.
  • Figure 2 shows the results of in vivo efficacy testing using HEP3B cells in a hepatocellular carcinoma model.
  • Compound 2 was administered orally, solvent blanks, relative tumor volume over the experimental period.
  • Figure 3 shows the results of an in vivo efficacy test performed in a hepatocellular carcinoma model using HEP3B cells.
  • Compound 1 (15 mg/kg, bid) and sorafenib (30 mg/kg, qd) were administered orally, solvent blanks, relative tumor volume over the experimental period.
  • the starting material X1 is coupled with the starting material X2 to obtain the compound X3, the compound X3 is reduced to obtain the compound X4, the compound X4 is coupled with the compound X5 to obtain the compound X6, and the compound X6 is exchanged with the compound X7 to obtain the final compound X8.
  • R 5 , R 6 , R 11 , R 12 and n are as defined in claim 2;
  • R y and R z are selected from C1-C6 alkyl groups, or R y and R z are bonded to form a 5- to 7-membered heterocyclic ring. structure,
  • Step 1 in a certain solvent, a certain temperature, the compound Y1 and Y2 are coupled under the action of a base to form a compound Y3;
  • Step 2 in a certain solvent, a certain temperature, the compound Y3 and Y4 reacted under the action of a base to obtain a compound Y5;
  • Step 3 in a certain solvent, at a certain temperature, the compound Y5 is deprotected by the deprotection reagent to obtain the compound (II);
  • the solvent is selected from one or more of tetrahydrofuran, dioxane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, dichloroethane, ethyl acetate, and the solvent is preferably two.
  • Methyl chloride, chloroform temperature selected from -30 to 80 ° C, preferably at -10 to 20 ° C; base used is selected from the group consisting of triethylamine, N,N'-dimethylpropylamine, N,N'-diiso a propyl ethylamine, an aqueous solution of methylamine, preferably N,N'-diisopropylethylamine;
  • the solvent is selected from the group consisting of tert-butyl methyl ether, diethyl ether, tetrahydrofuran, dioxane, dichloromethane, chloroform, acetonitrile, dichloroethane, one or more, the solvent is preferably tetrahydrofuran, dioxane Ring; temperature is selected from -50 to 80 ° C, preferably at -30 to 10 ° C, the selected base is selected from bis(trimethylsilyl)amine lithium, bis(trimethylsilyl)amide sodium, double (Trimethylsilyl)amino potassium, preferably bis(trimethylsilyl)amine lithium;
  • the solvent is selected from the group consisting of tert-butyl methyl ether, diethyl ether, tetrahydrofuran, dioxane, dichloromethane, chloroform, carbon tetrachloride, acetone, methyl ethyl ketone, ethyl acetate, one or more of water;
  • the solvent is preferably tetrahydrofuran, water, or a mixed solution of tetrahydrofuran and water;
  • the temperature is selected from -30 to 80 ° C, preferably at a temperature of -10 to 10 ° C;
  • the selected deprotecting reagent is an acidic substance, preferably from phosphoric acid, sulfuric acid, concentrated hydrochloric acid. , nitric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, more preferably self-concentrating hydrochloric acid, sulfuric acid.
  • the compounds provided herein can be prepared by standard synthetic methods well known in the art, and the present specification provides general methods for preparing the compounds of the invention. Starting materials are usually obtained commercially, for example by It is commercially available from companies such as Suiyuan Chemical, Angie Chemical, etc., or prepared by methods well known to those skilled in the art.
  • Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc) and the like.
  • Suitable hydroxy protecting groups include allyl, acetyl, silane, benzyl, trityl, p-methoxybenzyl and the like.
  • Such protecting groups can be readily determined by those skilled in the art (see, for example, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, Third Edition, 1999).
  • reaction temperature e.g., reaction temperature, time, molar ratio of reactants, reaction solvent, and pressure, etc.
  • Optimum reaction conditions may vary depending on the particular reaction substrate or solvent employed, but such conditions can be determined by one of ordinary skill in the art by routine optimization.
  • the structures of the compounds of the following examples were characterized by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the compound was dissolved in a suitable deuterated reagent using a Bruker Ascend 400 MHz NMR spectrometer and subjected to 1 H-NMR analysis using TMS as an internal standard at ambient temperature.
  • the NMR chemical shift ( ⁇ ) is in ppm and uses the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad singlet.
  • MS was determined by Waters UPLC-Vevo TM TQ MS mass spectrometer (ESI).
  • reaction starting materials, intermediates, and example compounds can be isolated and purified by conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography (e.g., column chromatography, TLC separation, etc.).
  • TLC was extracted from Yantai Huanghai HSGF254 thin-layer chromatography silica gel plate (0.2 ⁇ 0.03 mm) by TLC.
  • the Yantai Yellow Sea HSGF254 thin layer chromatography thick preparation plate (0.9-1 mm) was purchased from Qingdao Ocean Chemical Plant.
  • Column chromatography was purchased from Qingdao Ocean Chemical Plant using Yantai Yellow Sea 300-400 mesh silica gel as carrier.
  • reaction temperature reaction temperature
  • reaction solvent reactant molar ratio or/and reaction duration
  • the purification conditions of the compound may also vary. Generally, a suitable column chromatography eluent is selected according to the Rf value of TLC, or the corresponding compound is isolated and purified by preparative TLC.
  • N 1 -methyl-N 2 -tert-butoxycarbonylethylenediamine (10.0 g, 57.4 mmol) was dissolved in tetrahydrofuran (100 ml), then triethylamine (8.4 ml, 60 mmol) was added and then cooled to 0 ° C Then, ethyl bromoacetate (6.31 ml, 57.4 mmol) was added dropwise, and the reaction was continued after the dropwise addition. The reaction was monitored by TLC, EtOAc (EtOAc) (EtOAc). The target product (13.4 g) was obtained.
  • the compound 3 of the present invention is prepared according to the published patent document WO2015059668 to obtain the intermediate 3A of the knot, and is identified. 3A and Intermediate 2B were then prepared in a similar manner to Example 2 to give compound 3, ESI-MS m/z: 488.3 [M+H] + .
  • the intermediate 4CD was first prepared according to the similar scheme of Example 1, and the structure was as follows:
  • the intermediate 4CD was first prepared according to the similar scheme of Example 1, and then 4CD and the compound 4-pentyn-1-amine were prepared according to a scheme similar to that of Example 1, and ESI-MS m was obtained. /z:518.1[M+H] + .
  • the compound of the present invention 7 was prepared according to the published patent document WO2015059668 to obtain the key intermediate 3A and identified, and then the compound 3A and the compound 4-pentyn-1-amine were prepared according to the similar scheme of Example 1, to obtain the compound 7, ESI-MS m/ z:502.2[M+H] +
  • the intermediate 8C is first prepared according to the following scheme.
  • the compound of the present invention 9 was prepared according to the published patent document WO2015059668 to obtain the key intermediate 3A and identified, and then the compound 3A and the compound (S)-3-butyn-2-amine were prepared according to the similar scheme of Example 1, to obtain the compound 9, ESI. - MS m/z: 488.2 [M+H] + .
  • FGFR Fibroblast growth factor receptor
  • the kinase inhibitory activity of the test substance on FGFR was determined by the ADP-Glo method.
  • Test was started from 1000nM with FGFR1, FGFR2, FGFR3 or FGFR4 kinase dilutions of the recombinant protein after incubation for 30 minutes with the reaction substrate in the presence of ATP, ADP-Glo TM detected generated ADP, and further generates chemiluminescent signal
  • the wells were read by a microplate reader (Perkin Elmer, Envision) and the IC50 was calculated and analyzed using origin 7.5, the concentration at which 50% inhibition occurred.
  • the above cells are all from the ATCC (American Standard Biological Collection Center).
  • Hep3B, Huh-7, JHH-7 cells all have FGF19 gene amplification (increased copy number) and increased mRNA expression level, as well as high level expression of FGFR4 and KLB mRNA; SK-hep-1, SNU423 cells
  • FGF19 gene amplification increased copy number
  • mRNA expression level as well as high level expression of FGFR4 and KLB mRNA
  • SK-hep-1, SNU423 cells There is no amplification of the FGF19 gene and the level of FGF19 mRNA expression is very low (Barretina J, Caponigro G, et al. Nature 2012; 483: 603-7.).
  • Cell proliferation was measured using the SRB (Sulforhodamine-B, sulforhodamine B) method.
  • the cells were cultured to a degree of fusion of more than 90% and then trypsinized. After counting, the cells were inoculated into 96-well plates at 6000 cells/well. After adherent culture overnight, the test compound was dissolved in DMSO and diluted with complete medium. The culture wells were added to form a 10-fold dilution of 10 concentration gradients from 10 ⁇ M, and after further 72 hours of culture, 50 ⁇ l of 50% trichloroacetic acid was added to each well, and fixed at 4 ° C for 1 hour.
  • the antitumor cell proliferation activity of the compound of the present invention was measured by the above test, and the measured IC50 (nM) value is shown in Table 2.
  • N.D. means not determined.
  • the Hep3B cells in the logarithmic growth phase were cultured and collected, and subcutaneously inoculated into the right side of the nude mice (female Balb/c Nude mice, derived from Beijing Vitalius) at a dose of 1 ⁇ 10 7 cells/subcutaneously.
  • the temperature was 50-300 mm 3
  • the tumor-bearing nude mice were randomly divided into groups of 6 animals. Subsequently, each group of animals was administered at the following dose, and the day of the first dose was defined as the first day of the test.
  • Blank solvent (ultra-pure water) control group, compound 1, compound 2 were set to 50 mg/kg, 100 mg/kg, 150 mg/kg three dose groups, intragastric administration, twice daily (BID), continuous administration 21 day.
  • the state of the animals was observed daily during the administration; the body weight was measured once a week before the first administration; and the body weight was measured twice a week after the start of the administration.
  • the size of the transplanted tumor was measured every 3 days after the start of administration.
  • Tumor volume (TV) l/2 ⁇ a ⁇ b 2 , where a and b represent the length and width of the tumor, respectively.
  • RTV relative tumor volume
  • Fig. 1 The growth inhibition of the test compound on Hep3b xenografts in nude mice is shown in Fig. 1, Fig. 2.
  • Compound 1 and Compound 2 were administered at a dose of 50 mg/kg, and the growth inhibition of the transplanted tumor was significant after 21 days of BID; all the dose groups of Compound 1 and Compound 2 were fed with normal water, normal activity, and body weight during the administration test period. Normal, no adverse reactions occurred.
  • TGI tumor inhibition rate
  • Compound 1 at 15 mg/kg BID was superior to that of sorafenib 30 mg/kg QD in the Hep3B nude mouse xenograft model.
  • Tumor inhibition rate (%) (last dose) Compound 1 (15mg/kg, bid) +++ Sorafenib (30mg/kg, qd) +
  • mice Female Balb/c Nude mice (derived from Beijing Vitalius), weighing 18-22 g, randomized into groups of 6 rats, were administered orally with the following doses: Compound 1 (50 mg/kg, 100 mg/ Kg, 200 mg/kg, 500 mg/kg); Compound 2 (50 mg/kg, 100 mg/kg, 200 mg/kg, 500 mg/kg). The drug was administered twice a day for 5 days. Animal status was observed daily and body weight and food intake were monitored.
  • Compound 1 50 mg/kg, 100 mg/ Kg, 200 mg/kg, 500 mg/kg
  • Compound 2 50 mg/kg, 100 mg/kg, 200 mg/kg, 500 mg/kg.
  • the drug was administered twice a day for 5 days. Animal status was observed daily and body weight and food intake were monitored.

Abstract

本发明提供式（I）化合物，其立体异构体、互变异构体或药学上可接受的盐，其作为FGFR4激酶选择性抑制剂及其在制备治疗由FGFR4或FGF19所致疾病的药物或药物组合物中的应用，本发明公开的化合物对FGFR4具有选择性的显著抑制活性，在肿瘤治疗领域具有广泛的应用前景。

Description

一种选择性抑制激酶化合物及其用途 技术领域
本发明涉及式(I)和式(II)化合物作为成纤维细胞生长因子受体激酶选择性抑制剂，及其制备方法、药物组合物以及使用所述化合物和组合物用以抑制激酶活性的方法，及其在医学上的用途。
背景技术
成纤维细胞生长因子(Fibroblast growth factor,FGF)是一类包括22个结构相近的成员的细胞内多肽家族，150-300氨基酸残基，在哺乳动物体内广泛分布，促进细胞增殖、迁移、分化，在胚胎发育、创伤修复、造血、血管生成、代谢等生理活动中发挥重要作用(Itoh,N.；Ornitz,D.M.Fibroblast growth factors:From molecular evolution to roles in development,metabolism and disease.J.Biochem.2011,149,121–130)。诸多研究证实FGF家族的异常与恶性肿瘤的发生相关，如白血病、肉瘤、胰腺癌、膀胱癌、结肠癌、乳腺癌和***癌等。
FGF通过结合其特异性受体(FGFR)而发挥其生理活性功能。哺乳动物FGFR包括FGFR1-4四种，属于受体酪氨酸激酶类受体。在结合FGF后，跨膜受体发生同源二聚化，胞内激酶结构域发生磷酸化而活化，进而活化胞内下游MAPK或PI3K/AKT信号通路激活多重信号级联反应(Lin,B.C.,Desnoyers,L.R.FGF19and cancer.Adv.Exp.Med.Biol.2012,728:183–94；Powers,C.J.等,Endocr.Relat.Cancer,2000,7:165-197)。
FGF19是重要的代谢调节因子，参与胆汁合成，糖元合成，糖异生，蛋白合成等。正常生理条件下，分泌至小肠的胆汁酸活化法尼醇－X受体(Farnesoid X Receptor(FXR)，刺激FGF19从回肠表达分泌。FGF19的天然受体为FGFR4，在肝脏具有高水平表达。FGFR4结合FGF19后，在共同作用因子(co-factor)β-Klotho(KLB)的作用下，发生二聚体化和胞内激酶结构域自身磷酸化而活化，通过下游级联信号发挥生理功能调节作用。
人类FGF19基因位于11q13.1。研究发现，在部分肝细胞癌患者中有FGF19基因扩增且与肿瘤发展相关。另有研究发现，～25％肝癌患者肿瘤组织中FGF19蛋白表达升高。FGFR4在多种癌症中也存在过表达现象，如肝癌(Ho,H.K.等，Journal of Hepatology,2009,50:118–127；Sawey,E.T.等,Cancer Cell,2011,19:347-358)、胃癌(Ye,Y.W.等,Cancer,2011,117:5304-5313；Ye,Y.等,Ann.Surg.Oncol.2010,17:3354-3361)、胰腺癌(Leung,H.Y.等,Int.J.Cancer,1994,59:667-675)、肾细胞癌(Takahashi,A.等,Biochem.Biophys.Res.Commun.1999,257:855-859)、横纹肌肉瘤(Taylor VI,J.G.等,J.Clin.Invest.Doi:1o.1172/JCI39703)、胆管癌(Xu,Y.-F.等,Biochem.Biophys.Res.Commun.2014,446:54-60)、结肠癌(Barderas,R.等,J.Proteomics,2012,75:4647-4655；
Figure PCTCN2017120224-appb-000001
A.,PLos ONE,2012,8(5):e63695)、***癌(Xu,B.等,BMC cancer 2011,11:84)、卵巢癌(Zaid,T.M.等,Clin.Cancer Res.2013,19(4):809-820)等。因此，FGF19/FGFR4信号通路异常可能参与了人类多种癌症的发生发展。
鉴于FGF/FGFR信号通路在肿瘤发生发展中的作用，已有多个FGFR抑制剂处于临床研究阶段。非选择性的FGFR抑制剂带来高磷酸血症，异位钙化等副作用。选择性的FGFR4抑制剂针对FGF19/FGFR4信号通路异常的肿瘤患者具有更高的安全性。
研究发现，PD173074为一种FGFR4小分子抑制剂，能够抑制横纹肌肉瘤细胞的生长并具有体内抗肿瘤活性(Crose,L.E.S.等,Clin.Cancer Res.2012,18(14):1-11)。Desnoyers等发现FGF19单克隆抗体能够选择性阻断FGF19与FGFR4的相互作用，该抗体能抑制人结肠癌裸鼠移植瘤生长并能有效防止FGF19转基因小鼠罹患肝癌(Desnoyers,L.R.等,Oncogene,2008,27:85-97)。Sawey等发现FGF19单克隆抗体能显著抑制人肝癌移植瘤生长(Sawey,E.T.等,Cancer Cell,2011,19,347-358)。Ho等发现FGFR4小分子抑制剂能诱导乳腺癌细胞凋亡并抑制癌细胞迁移(Ho,H.K.等,Current Medicinal Chemistry,2013,20:1203-1217)。选择性FGFR4小分子抑制剂BLU9931能够抑制肝癌细胞增殖，同时能够抑制人肝癌异种移植瘤生长并呈剂量依赖性(Hagel,M.等,Cancer Discov.2015,5(4):1-14)。这些研究表明，选择性抑制FGFR4，阻断FGF19/FGFR4信号通路可以抑制肿瘤生长，为肿瘤的分子靶向治疗提供了有效的靶点。
尽管目前已经公开了个别具有抑制FGFR4激酶效果的化合物，但是，仍然需要开发新的具有更好治疗效果和安全窗的化合物，本发明设计具有通式(I)，(II)结构的化合物，并发现具有此类结构的化合物表现出优异的药效和安全窗口，具有显著和重要的应用价值。
发明内容
本发明涉及新型FGFR4选择性小分子抑制剂化合物及其医药学上可接受的盐。本发明也涉及这些化合物单独或组合有至少一种其它治疗剂及视情况医药学上可接受的载剂的组合物。本发明又涉及这些化合物单独或组合有至少一种其它治疗剂在预防或治疗由FGFR4或FGF19介导的疾病中的用途或使用方法。
本发明公开一种式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，
Figure PCTCN2017120224-appb-000002
其中，R 2，R 3，R 4独立地为N或者C(R X)；
R 5选自氢，卤素，氰基，氨基，酰胺基，羟基，酯基，酰基，酰氧基，磺酰基，亚磺酰基，烷基，烷氧基，芳基，环烷基，杂芳基，杂环基，杂环基烷基；
R 6选自氢，卤素，氰基，氨基，酰胺基，羟基，酯基，酰基，酰氧基，磺酰基，亚磺酰基，烷基，烷氧基，芳基，环烷基，杂芳基，杂环基，杂环基烷基；
R 7，R 8，R 9独立地为N或者C(R X)；
R 10，R 11，R 12独立地为氢，卤素，氰基，氨基，羟基，烷基，烷氧基，芳基，环烷基，杂芳基，或者R 11，R 12两个取代基环合成为环状基团，
R X独立地为氢，卤素，氰基，氨基，酰胺基，羟基，酯基，酰基，酰氧基，磺酰基，亚磺酰基，烷基，烷氧基，芳基，环烷基，杂芳基或杂环基，
n＝1，2，3，4，5。
本发明所述的式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，其中包括通式(II)化合物
Figure PCTCN2017120224-appb-000003
其中，R 5为氢，烷基，烷氧基，芳基，环烷基，杂芳基，杂环基，杂环基烷基，
R 11，R 12独立地为氢，卤素，氰基，氨基，羟基，烷基，烷氧基，芳基，环烷基，杂芳基，或者R 11，R 12两个取代基环合成为环状基团，
n＝1，2，3，4，5，
R 6选自以下的结构：
Figure PCTCN2017120224-appb-000004
本发明所述的式(II)化合物，其中结构
Figure PCTCN2017120224-appb-000005
选自以下结构：
Figure PCTCN2017120224-appb-000006
本发明所述的式(I)和(II)化合物，其立体异构体，互变异构体或药学上可接受的盐，优选自下述化合物：
Figure PCTCN2017120224-appb-000007
Figure PCTCN2017120224-appb-000008
本发明所述化合物，其立体异构体，互变异构体或药学上可接受的盐的制备方法，包括如下步骤：
Figure PCTCN2017120224-appb-000009
其中，R 5，R 6，R 11，R 12和n的定义如前所述；R y和R z选自C1～C6的烷基。其中所选碱选自双(三甲基硅基)胺基锂，双(三甲基硅基)胺基钠，双(三甲基硅基)胺基钾，优选为双(三甲基硅基)胺基锂。
本发明提供一种药物组合物，其包括治疗有效剂量的本发明中任一项所述化合物，或其立体异构体，互变异构体或药学上可接受的盐及可药用的载体。
本发明中任一项所述化合物，其立体异构体，互变异构体或药学上可接受的盐，作为FGFR4激酶选择性抑制剂，在制备治疗由FGFR4或FGF19介导疾病的药物或药物组合物中的应用。
本发明中任一项所述化合物，其立体异构体，互变异构体或药学上可接受的盐，根据本发明所述的药物组合物在制备治疗癌症药物中的应用。
本发明所述的药物或药物组合物，其用于各种癌症的治疗。
本发明所述，治疗的各种癌症包括：肝癌，肺癌，食管癌，胃癌，肾细胞癌，肉瘤，胆管癌，结肠癌，***癌，卵巢癌，乳腺癌。
发明详述
术语“氢”在本文中是指-H。
术语“卤素”在本文中是指-F、-Cl、-Br和-I。
术语“氟”在本文中是指-F。
术语“氯”在本文中是指-Cl。
术语“溴”在本文中是指-Br。
术语“碘”在本文中是指-I。
术语“氰基”在本文中是指-CN。
术语“氨基”在本文中是指-NH 2。
术语“羟基”在本文中是指-OH。
术语“芳基”在本文中是指6至10元全碳单环或稠合多环(即共享相邻碳原子对的环)基团，具有共轭的π电子体系的多环(即带有相邻碳原子对的环)基团。芳基可以在产生稳定结构的任意碳原子上与所定 义的化学结构共价连接。本文所述芳基可以任选地被一个或多个下列取代基所取代：氟、氯、溴、碘、氰基、硝基、羟基、羧基、氨基、烷基、烷氧基、酰基、酰胺基、酯基、胺基、磺酰基、亚磺酰基、环烷基、环烯基、杂环烷基、烯基、炔基和环烷氧基。
术语“杂芳基”在本文中是指由5至10个原子所组成的并且含有至少一个选自N、O或S等杂原子的芳香族基团。该术语可以具有单个环(非限制性实例包括呋喃、噻吩、咪唑、吡唑、吡啶、吡嗪、恶唑、噻唑等)或多个稠环(非限制性实例包括苯并噻吩、苯并呋喃、吲哚、异吲哚等)，其中稠环可以是或者可以不是包含杂原子的芳香族基团，假定连接点是通过芳族杂芳基基团的原子。本文所述杂芳基可以任选地被一个或多个下列取代基所取代：氟、氯、溴、碘、氰基、硝基、羟基、氨基、烷基、烷氧基、酰基、酰氧基、酰胺基、酯基、胺基、磺酰基、亚磺酰基、环烷基、环烯基、杂环烷基、烯基、炔基和环烷氧基。
术语“环烷基”在本文中是指具有3至10个碳原子，具有单环或多环(包括稠环、桥环及螺环***)的环状烷基。环烷基的非限制性实例包括环丙基、环丁基、环戊基、环己基等。本文所述环烷基可以任选地被一个或多个下列取代基所取代：氟、氯、溴、碘、氰基、硝基、羟基、羧基、氨基、烷基、氧代、烷氧基、酰基、酰氧基、酰胺基、酯基、胺基、环烷基、环烯基、杂环烷基、烯基、烯氧基、炔基、环烷氧基、芳基或杂芳基。
术语“杂环基”是指取代的或未取代的饱和或者不饱和且至少含有1至5个选自N、O或S杂原子的芳香环、非芳香环，芳香环、非芳香环可以是3至10元的单环，4至20元的螺环、并环或桥环，杂环基环中选择性取代的N、S可被氧化成各种氧化态。优选3至12元杂环。非限制性实施例包括氧杂环丙烷基、氧杂环丁基、氧杂环戊基、氧杂环己基、氧杂环己基、氧杂环辛基、氮杂环丙烷基、氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环丙烯基、1,3-二氧环戊基、1,4-二氧环戊基、1,3-二氧环戊基、1,3-二氧环己基、1,3-二硫环己基、氮杂环庚烯基、吗啉基、哌嗪基、吡啶基、呋喃基、噻吩基、吡咯基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、硫代吗啉基、二氢吡喃、噻二唑基、噁唑基、噁二唑基、吡唑基、1,4-二氧杂环己二烯基等。非限制性实施例包括如下结构：
Figure PCTCN2017120224-appb-000010
等等。
术语“杂环烷基”在本文中是指至少含有一个选自O、N和S等杂原子且任选含有一条或多条双键或三键的非芳族环烷基。杂环烷基作为整体可以具有3至10个环原子。杂环烷基可以在产生稳定结构的任意杂原子或碳原子上与所定义的化学结构共价连接。杂环烷基的非限制性实例包括：吡咯啉基、哌啶基、哌嗪基、四氢呋喃基、四氢吡喃基、吗啉基、吡喃基等。杂环烷基上的一个或多个N或S原子可以被氧化(例如吗啉N-氧化物、硫吗啉S-氧化物、硫吗啉S，S-二氧化物)。杂环烷基还可以含有一个或多个氧代基团，如邻苯二酰亚氨基、哌啶酮基、恶唑烷酮基、2,4(1H,3H)-二氧代-嘧啶基、吡啶-2(1H)-酮基等。本文所述杂环烷基可以任选地被一个或多个下列取代基所取代：氟、氯、溴、碘、氰基、硝基、羟基、羧基、氨基、烷基、烷氧基、氧代、酰基、酰氧基、酰胺基、酯基、胺基、环烷基、环烯基、杂环烷基、烯基、烯氧基、炔基、环烷氧基、芳基或杂芳基。非限制性实施例包括如下结构：
Figure PCTCN2017120224-appb-000011
等等。
术语“烯基”在本文中是指具有2至8个碳原子并且具有至少一个烯基不饱和位点的烯基基团。烯基的非限制性实例包括乙烯基、丙烯基、烯丙基、异丙烯基、丁烯基、异丁烯基等。本文所述烯基可以任选地被一个或多个下列取代基所取代：氟、氯、溴、碘、氰基、硝基、羟基、羧基、氨基、烷基、烷氧基、氧代、酰基、酰氧基、酰胺基、酯基、胺基、环烷基、环烯基、杂环烷基、烯基、烯氧基、炔基、炔氧基、环烷氧基、芳基或杂芳基。
术语“烷基”在本文中是指具有1至10个碳原子的饱和脂肪族烃基基团，该术语包括直链和支链烃基。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、新戊基、正己基等。本文所述烷基可以任选地被一个或多个下列取代基所取代：氟、氯、溴、碘、氰基、硝基、羟基、羧基、氨基、烷基、烷氧基、酰基、酰氧基、氧代、酰胺基、酯基、胺基、环烷基、环烯基、杂环烷基、烯基、烯氧基、炔基、环烷氧基、杂环烷基氧基、芳氧基、杂芳氧基、芳基或杂芳基。
术语“烷氧基”在本文中是指烷基基团通过氧原子与分子其余部分相连(-O-烷基)，其中所述烷基如本文中所定义。烷氧基的非限制性实例包括甲氧基、乙氧基、三氟甲氧基、二氟甲氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、正戊氧基等。
术语“酰胺基”在本文中是指-NR 30-C(O)-烷基、-NR 30-C(O)-环烷基、-NR 30-C(O)-环烯基、-NR 30-C(O)-芳基、-NR 30-C(O)-杂芳基和-NR 30-C(O)-杂环烷基，其中R 30为氢、环烷基、环烯基、芳基、杂芳基、杂环烷基和烷基。其中所述氢、环烷基、环烯基、芳基、杂芳基、杂环烷基和烷基等基团如本文中所定义。
术语“酰基”在本文中是指H-C(O)-、R 31R 32N-C(O)-、烷基-C(O)-、环烷基-C(O)-、环烯基-C(O)-、杂环烷基-C(O)-、芳基-C(O)-和杂芳基-C(O)-，其中所述R 31和R 32分别独立地选自氢、羟基、烷基、杂环烷基、芳基、杂芳基、磺酰基、亚磺酰基、环烯基、酰基或环烷基。其中所述氢、羟基、烷基、杂环烷基、芳基、杂芳基、磺酰基、亚磺酰基、环烯基、酰基和环烷基等基团如本文中所定义。
术语“磺酰基”在本文中是指R 33R 34N-S(O) 2-、环烷基-S(O) 2-、环烯基-S(O) 2-、芳基-S(O) 2-、杂芳基-S(O) 2-、杂环烷基-S(O) 2-和烷基-S(O) 2-，其中所述R 33和R 34分别独立地选自氢、羟基、烷基、杂环烷基、芳基、杂芳基、磺酰基、亚磺酰基、环烯基、酰基或环烷基。其中所述氢、羟基、烷基、杂环烷基、芳基、杂芳基、磺酰基、亚磺酰基、环烯基、酰基和环烷基等基团如本文中所定义。
术语“亚磺酰基”在本文中是指R 35R 36N-S(O)-、环烷基-S(O)-、环烯基-S(O)-、芳基-S(O)-、杂芳基-S(O)-、杂环烷基-S(O)-或烷基-S(O)-，其中所述R 35和R 36分别独立地选自氢、羟基、烷基、杂环烷基、芳基、杂芳基、磺酰基、亚磺酰基、环烯基、酰基或环烷基。其中所述氢、羟基、烷基、杂环烷基、芳基、杂芳基、磺酰基、亚磺酰基、环烯基、酰基和环烷基等基团如本文中所定义。
术语“酰氧基”在本文中是指-O-C(O)-烷基、-O-C(O)-环烷基、-O-C(O)-环烯基、-O-C(O)-芳基、-O-C(O)-杂芳基和-O-C(O)-杂环烷基，其中所述烷基、环烷基、环烯基、芳基、杂芳基和杂环烷基等基团如本文中所定义。
术语“酯基”在本文中是指烷基-O-C(O)-、环烷基-O-C(O)-、环烯基-O-C(O)-、杂环烷基-O-C(O)-、芳基-O-C(O)-和杂芳基-O-C(O)-，其中所述烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基等基团如本文中所定义。
术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况以及其中它不出现的情况。
术语“任选被……所取代”是指所述结构是未取代的或者被一个或多个本发明所述的取代基取代。术语“取代”在本文中是指任何基团由指定取代基单取代或多取代至这种单取代或多取代(包括在相同部分的多重取代)在化学上允许的程度，每个取代基可以位于该基团上任何可利用的位置，且可以通过所述取代基上任何可利用的原子连接。“任何可利用的位置”是指通过本领域已知的方法或本文教导的方法可化学得到，并且不产生过度不稳定的分子的所述基团上的任何位置。当在任何基团上有两个或多个取代基时，每个取代基独立于任何其它取代基而定义，因此可以是相同或不同的。
在本说明书的各个位置，本发明化合物的取代基以基团或范围的形式进行公开。这具体意味着本发明包括这样的基团和范围的每个成员或成员中的每个个体的亚组合。如术语“C 1-6烷基”具体意味着单独公开 了甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。
术语“本发明化合物”(除非另有具体指明)在本文中是指式(I)和式(II)化合物及其所有纯的和混合的立体异构体、几何异构体、互变异构体、溶剂合物、前药及同位素标记的化合物和任何药学上可接受的盐。本发明化合物的溶剂合物是指与化学计量和非化学计量的溶剂结合的化合物或其盐，如水合物、乙醇合物、甲醇合物，丙酮合物等。化合物也可以一种或多种结晶状态存在，即作为共晶体、多晶型物，或其可以无定形固体存在。所有此种形式均被权利要求所涵盖。
术语“药学上可接受”表示物质或组合物在化学上和/或毒理学上必须与构成制剂的其它成分和/或用其治疗的哺乳动物相容。
术语“立体异构体”在本文中是指具有一个或多个立体中心的手性不同的化合物，包括对应异构体和非对映异构体。
术语“互变异构体”在本文中是指具有不同能量的结构同分异构提可以越过低能垒，从而互相转化。诸如质子互变异构体包括通过质子迁移进行互变，如烯醇-酮互变异构体和亚胺-烯胺互变异构体，或者含有连接到环-NH-部分和环＝N-部分的环原子的杂芳基基团的互变异构形式，如吡唑、咪唑、苯并咪唑、***和四唑。化合价互变异构体包括一些成键电子重组而进行互变。
术语“前药”在本文中是指在对受试者给药时，能够直接或间接地提供本发明的化合物、其活性代谢物或残基的本发明化合物的任何衍生物。尤其优选的是那些能增加本发明化合物生物利用度、提高代谢稳定性及组织靶向性的衍生物或前药。
本发明化合物可以以盐的形式被使用，如从无机酸或有机酸衍生得到的“医药上可接受的盐”。这些包括但并不限于下列所述：乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、乙磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡萄糖酸盐、环戊烷丙酸盐、十二烷基硫酸盐、乙磺酸盐、葡糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、延胡索酸盐、氢氯化物、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、乙磺酸盐、盐酸盐、2-萘磺酸盐、草酸盐、果胶酯酸盐、硫酸盐、3-苯基丙酸盐、苦味酸盐、三甲基乙酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐和癸酸盐。另外，碱性含氮基团可以与以下试剂发生季铵化反应生成季铵盐：如低碳烷基卤化物，包括甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物；如二烷基硫酸盐，包括二甲基、二乙基、二丁基和二戊基的硫酸盐；如长链卤化物，包括癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物；如芳烷基卤化物，如苯甲基和苯乙基的溴化物等。
本发明还包括同位素标记的本发明化合物，即与上述所公开的结构相同，但该结构中一个或多个原子被与其具有相同质子数但不同中子数的原子所替代。结合本发明化合物的同位素实施例包括氢、碳、氮、氧、硫、氟、氯、碘的同位素，分别如 2H、 3H、 13C、 14C、 15N、 18O、 17O、 35S、 18F、 36Cl和 131I等。本发明的化合物，其立体异构体、互变异构体或医药上可接受的盐，以及含有上述同位素和/或其他原子同位素的所述以上形式的化合物，均在本发明范围内。某些同位素标记的本发明化合物，如被 3H或 14C所标记的那些化合物可以用于药物组织分布试验中，因此，这些 3H或 14C同位素由于其容易制备和检测是特别优选的。此外，被较重的同位素如 2H所替代的某些本发明化合物由于具有更好的代谢稳定性而具有某些治疗优势，如可以增加体内半衰期和较少剂量等，因此， 2H在某些情况下也是优选的。
本发明化合物具有FGFR4选择性抑制作用，可用于制备应用于人类或兽医的药物或药物组合物，用于治疗FGFR4或FGF19介导的疾病例如癌症等相关疾病。具体地，所述化合物可以用于治疗人类或动物的癌症，包括肝癌、胃癌、胰腺癌、肾细胞癌、肉瘤、胆管癌、结肠癌、***癌、卵巢癌、乳腺癌等。
附图说明：
图1表示使用HEP3B细胞在肝细胞癌模型中进行体内功效测试的结果。通过口服灌胃化合物1，溶剂空白对照，实验周期内相对肿瘤体积。
图2表示使用HEP3B细胞在肝细胞癌模型中进行体内功效测试的结果。通过口服灌胃化合物2，溶剂空白对照，实验周期内相对肿瘤体积。
图3表示使用HEP3B细胞在肝细胞癌模型中进行体内功效测试的结果。通过口服灌胃化合物1(15mg/kg，bid)和索拉非尼(30mg/kg，qd)，溶剂空白对照，实验周期内相对肿瘤体积。
具体实施方式
贯穿本申请，本文提及本发明的化合物和方法的多个实施例。所述的多个实施例旨在提供多个说明性实例，不应将其解释为替代物的描述。同时应注意，本文中所论述的实施例(包括各种方法和参数)仅为了说明本发明，并不以任何方式限制本发明的保护范围。为描述本发明，以下列出了具体实施例。但需要理解，本发明不限于这些实施例，以下实施例只是提供实践本发明的方法，并不以任何方式限制本发明的范畴。
本发明各通式化合物按照以下的制备方案进行制备：
通式(I)化合物的制备方法总结如下：
Figure PCTCN2017120224-appb-000012
首先起始物料X1与起始物料X2偶联制备得到化合物X3，化合物X3还原得到化合物X4，化合物X4与化合物X5偶联反应得到化合物X6，化合物X6与化合物X7交换反应得到最终通式化合物X8。
更具体地，通式(II)化合物制备方法总结如下：
Figure PCTCN2017120224-appb-000013
其中，R 5，R 6，R 11，R 12和n的定义如权利要求2；R y和R z选自C1～C6的烷基，或者R y和R z连接构成5～7元杂环结构，
包括以下步骤：
步骤1，在一定的溶剂中，一定温度下，化合物Y1与Y2在碱作用下偶联成为化合物Y3；
步骤2，在一定的溶剂中，一定温度下，化合物Y3与Y4在碱的作用下反应得到化合物Y5；
步骤3，在一定的溶剂中，一定温度下，化合物Y5在脱保护试剂作用下，脱保护得到化合物(II)；
其中，步骤1，溶剂选自四氢呋喃，二氧六环，二氯甲烷，三氯甲烷，四氯化碳，乙腈，二氯乙烷，乙酸乙酯中的一种或多种，溶剂优选为二氯甲烷，三氯甲烷；温度选自–30～80℃，优选温度为–10～20℃；所用碱选自三乙胺，N,N'-二甲基丙胺，N,N'-二异丙基乙胺，甲胺水溶液，优选为N,N'-二异丙基乙胺；
步骤2，溶剂选自叔丁基甲基醚，***，四氢呋喃，二氧六环，二氯甲烷，三氯甲烷，乙腈，二氯乙烷中的一种或多种，溶剂优选为四氢呋喃，二氧六环；温度选自–50～80℃，优选温度为–30～10℃，所选碱选自双(三甲基硅基)胺基锂，双(三甲基硅基)胺基钠，双(三甲基硅基)胺基钾，优选为双(三甲基硅基)胺基锂；
步骤3，溶剂选自叔丁基甲基醚，***，四氢呋喃，二氧六环，二氯甲烷，三氯甲烷，四氯化碳，丙 酮，丁酮，乙酸乙酯，水中的一种或多种；溶剂优选为四氢呋喃，水，或者四氢呋喃和水的混合溶液；温度选自–30～80℃，优选温度为–10～10℃；所选脱保护试剂为酸性物质，优选自磷酸，硫酸，浓盐酸，硝酸，柠檬酸，甲磺酸，对甲基苯磺酸，更优选自浓盐酸，硫酸。
本发明提供的化合物可以通过本领域公知的标准合成方法来制备，本说明书提供了制备本发明化合物的一般方法。起始原料通常可通过商业化获得，例如通过
Figure PCTCN2017120224-appb-000014
韶远化学、安耐吉化学等公司购买得到，或者通过本领域技术人员所熟知的方法进行制备。
在本发明化合物的制备中，可能需要保护中间体的某些干扰官能团(例如，伯胺或仲胺)。对于此类保护基的要求视具体官能团的性质及制备方法的条件而改变。适当的氨基保护基包括乙酰基、三氟乙酰基、叔丁氧羰基(Boc)、苄氧羰基(Cbz)、9-芴亚甲氧羰基(Fmoc)等。适当的羟基保护基包括烯丙基、乙酰基、硅烷基、苯甲基、三苯甲基、对甲氧基苯甲基等。对于此类保护基可由本领域技术人员容易地决定(具体可参考Protective Groups in Organic Synthesis，John Wiley&Sons，New York，第三版，1999)。
下文通过实施例与制备进一步解释并列举本发明化合物及相应的制备方法。应了解，尽管具体实施例中给出了典型或优选的反应条件(如反应温度、时间、反应物的摩尔比、反应溶剂以及压力等)，但是本领域技术人员也可以使用其它反应条件。最佳反应条件可随所用的特定反应底物或溶剂而发生改变，但所述条件可由所属领域的技术人员通过常规优化而确定。
下述实施例化合物的结构通过核磁共振(NMR)和/或质谱(MS)来表征。使用Bruker Ascend 400MHz NMR波谱仪，将化合物溶于适当的氘代试剂中，环境温度下以TMS为内标进行 1H-NMR分析。NMR化学位移(δ)以ppm为单位，并使用以下简称：s，单峰；d，双重峰；t，三重峰；q，四重峰；m，多重峰；brs，宽单峰。MS通过Waters UPLC-Vevo TM TQ MS质谱仪(ESI)测定。
反应起始原料、中间体以及实施例化合物可以通过沉淀、过滤、结晶、蒸发、蒸馏以及色谱法(如柱层析法、TLC分离纯化等)等常规技术进行分离与纯化。
TLC使用烟台黄海HSGF254薄层层析硅胶板(0.2±0.03mm)，TLC分离纯化使用烟台黄海HSGF254薄层层析厚制备板(0.9～1mm)，均购自青岛海洋化工厂。柱层析以烟台黄海300～400目硅胶为载体，购自青岛海洋化工厂。
试验中使用的商品化溶剂及试剂如无特殊说明，购买后均无需进一步纯化或处理直接使用。参考其它实施例或合成方法时，反应条件(反应温度、反应溶剂、反应物摩尔比或/和反应持续时间)可能不同。一般而言，可通过TLC监测反应进程，据此选择合适的时间终止反应并进行后处理。化合物的纯化条件也可能发生变化，一般而言，依据TLC的R f值选择合适柱层析洗脱剂，或通过制备TLC分离纯化相应化合物。
实施例1
Figure PCTCN2017120224-appb-000015
Figure PCTCN2017120224-appb-000016
化合物N 1-甲基-N 2-叔丁氧羰基乙二胺(10.0g，57.4mmol)溶于四氢呋喃(100ml)中，然后加入三乙胺(8.4ml，60mmol)，将其冷却至0℃，然后滴加溴乙酸乙酯(6.31ml，57.4mmol)，滴加完毕后继续反应。经薄层层析监测反应完全，浓缩，加入水用二氯甲烷萃取两次，有机相分别用饱和氯化铵水溶液、水和饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，柱层析得到目标产物(13.4g)。将产物溶于二氯甲烷(20ml)中，加入三氟乙酸(10ml)，室温反应8小时后，减压浓缩得到化合物1A的粗品三氟乙酸盐(20.5g)。
将化合物1B(4.73g，20mmol)(按照公开专利文献WO2015059668制备并鉴定)和化合物1A的三氟乙酸盐(5.43g，18.8mmol)溶于1,2-二氯乙烷(50ml)中，然后加入三乙胺(8.36ml，60mmol)搅拌0.5小时后，分批加入三乙酰氧基硼氢化钠(8.48g，40mmol)，继续搅拌反应。经薄层层析监测反应完全，加入饱和氯化铵水溶液淬灭，用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到化合物1C(4.5g)， 1H NMR(400MHz,CDCl 3)δ7.09(s,1H),5.19(s,1H),4.95(s,1H),4.70(s,2H),3.41–3.37(m,8H),3.22–3.18(m,4H),2.70–2.67(m,2H),2.59–2.56(m,2H),2.23(s,3H),1.91–1.85(m,2H)；ESI-MS m/z：335.2[M+H] +。
将化合物1C(1.0g，3.0mmol)溶于二氯甲烷(10ml)中，然后加入DIPEA(744μl，4.5mmol)，冷却至0℃，滴入氯甲酸对硝基苯酯(907mg，4.5mmol)的二氯甲烷(5ml)溶液，恢复至室温反应，反应完全后，加入饱和氯化铵水溶液，二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析得到化合物1D(989mg)，按照以上方案大量制备1D备用。1D化合物的核磁共振数据： 1H NMR(400MHz,CDCl 3)δ8.28–8.26(d,J＝8Hz,2H),7.39–7.37(d,J＝8Hz,2H),5.19(s,1H),4.88(s,2H),3.95–3.92(m,2H),3.38(s,6H),3.30–3.27(m,2H),3.22(s,2H),2.85–2.81(m,2H),2.64–2.61(m,2H),2.36(s,3H),2.08–2.01(m,2H)。
在1L圆底烧瓶中，加入原料1E化合物50g(388.9mmol)溶于500mlDMF中，冰浴冷却至0℃，缓慢分批加入87.5g(388.9mmol)原料N-碘代丁二酰亚胺，反应液透明澄清，10min后恢复室温，搅拌反应过夜。TLC监控反应进程，反应完全后，将反应液在搅拌下缓慢倒入5L冰水中，析出大量土黄色固体，过滤，水洗涤，干燥，得到土黄色固体产物1F投入下一步反应，ESI-MS m/z：255.4[M+H] +。
单口圆底烧瓶中，加入1F化合物90.7g(357.1mmol)溶于500mlNMP中，加入Zn(CN) 2共21.4g(182.1mmol)，再快速加入41g(35.7mmol)Pd(PPh 3) 4，135℃反应5h。反应完全，得到褐色油状液体，将反应液在搅拌下缓慢倒入3L冰水中，析出大量黄褐色固体，过滤，水洗涤，干燥，得到化合物1G，ESI-MS m/z：154.2[M+H] +。
在1L的圆底三口烧瓶中，加入24g(156.3mmol)原料1G溶于400ml无水THF中，在0℃和N 2保护下，加入117ml(234.4mmol)LiHMDS(浓度2mol/L)，0℃搅拌反应2h，加入40.9g(187.5mmol)Boc 2O升温至室温，反应过夜。反应完全后，加入20ml水淬灭反应，旋蒸除去THF，加入水，用乙酸乙酯萃取，再用水洗涤，MgSO4干燥，过滤，旋干，硅胶柱层析得到产物1H，ESI-MS m/z：254.2[M+H] +。
单口圆底烧瓶中，加入原料1H化合物10g(39.5mmol)，溶于30mlDMSO中，依次加入DIPEA共计11.2g(86.9mmol)、炔丙胺10.9g(197.5mmol)，70℃反应过夜。反应完全后，将反应液冷却，有大量白色固体析出，过滤，水洗，干燥得到产物1J， 1H NMR(400MHz,CDCl 3)δ8.24(s,1H),7.39(s,1H),4.12–4.10(m,2H),2.36–2.35(m,1H),1.55(s,9H)。
反应容器中，加入1J化合物5g(18.4mmol)，溶于30ml二氯甲烷中，加入三氟乙酸30ml，40℃反应，0.5h后，旋干，用饱和NaHCO 3溶液调pH＝8，用乙酸乙酯萃取，水洗涤，MgSO 4干燥，过滤，旋干得到白色产物1K， 1H NMR(400MHz,CD 3OD)δ7.93(s,1H),5.85(s,1H),3.99(s,2H),3.31–3.30(m,1H)。
将1D(5.8g,11.6mmol)和1K(2.5g,14.5mmol)用无水THF溶解，充入氮气保护。然后置于-25℃的冷阱中搅拌，取LiHMDS(30ml,1mol/L in THF,30mmol)在该温度下缓慢滴加到反应液中，该温度搅拌反应两小时，然后自然恢复至室温过夜。薄层层析板监测反应，反应完全后加入饱和NH 4Cl溶液淬灭，乙酸乙酯萃取，干燥，浓缩，柱层析纯化得到化合物1N。 1H NMR(400MHz,CDCl 3)δ13.83(s,1H),8.26(s,1H),7.69(s,1H),7.49(s,1H),5.14–5.12(m,1H),4.87(s,2H),4.15–4.13(m,2H),4.07–4.04(m,2H),3.51(s,6H),3.32–3.30(m,2H),3.26(s,2H),2.86–2.83(m,2H),2.69–2.67(m,2H),2.41(s,3H),2.39–2.37(m,1H),2.01–1.99(m,2H)。
将化合物1N(4g)溶于THF中，然后缓慢加入3N的HCl溶液。室温搅拌反应两小时，薄层层析板监测反应。反应完全后用饱和NaHCO 3溶液调节pH至碱性，此时析出大量白色固体，过滤，干燥后，收集固体即为化合物1。 1H NMR(400MHz,CDCl 3)δ13.68(s,1H),10.23(s,1H),8.22(s,1H),7.68(s,1H),7.63(s,1H),5.29–5.26(m,1H),5.09(s,2H),4.15–4.13(m,2H),4.11–4.08(m,2H),3.37–3.35(m,2H),3.21(s,2H),2.95–2.92(m,2H),2.68–2.65(m,2H),2.38–2.36(m,4H),2.06–2.03(m,2H)； 13C NMR(100MHz,CDCl 3)δ193.6,167.6,156.0,154.9,152.68,152.61,150.9,143.9,140.2,128.5,128.2,116.3,93.5,90.6,78.1,73.1,59.2,51.8,47.2,45.1,44.0,43.8,32.5,28.4,20.9；ESI-MS m/z：487.4[M+H] +。
实施例2
Figure PCTCN2017120224-appb-000017
单口圆底烧瓶中，加入原料1H 10g(39.5mmol)，溶于30ml DMSO中，依次加入DIPEA 16.3g(126.4mmol)、丁炔胺盐酸盐20.8g(197.5mmol)，70℃反应过夜。TLC显示反应完全后，将反应液冷却，有大量白色固体析出，过滤，水洗，得到产物2A，投入下一步反应。ESI-MS m/z：287.2[M+H] +。
单口圆底烧瓶中，加入2A原料5g(17.5mmol)，溶于30ml二氯甲烷中，加入三氟乙酸30ml，40℃反应，0.5h后，旋干，用饱和NaHCO 3溶液调pH＝8，用乙酸乙酯萃取，水洗涤，MgSO 4干燥，过滤，浓缩得到白色的纯产物2B，ESI-MS m/z：187.1[M+H] +。
将1D(5.8g,11.6mmol)和2B(2.5g,13.4mmol)用无水THF溶解，充入氮气保护。然后置于-25℃的冷阱中搅拌，取LiHMDS(30ml,1mol/L in THF,30mmol)在该温度下缓慢滴加到反应液中，该温度搅拌反应两小时，然后自然恢复至室温过夜。薄层层析板监测反应，反应完全后加入饱和NH 4Cl溶液淬灭，乙酸乙酯萃取，干燥，浓缩，柱层析纯化得到化合物2C，ESI-MS m/z：547.3[M+H] +。
将化合物2C(3.5g)溶于THF中，然后缓慢加入3N的HCl溶液。室温搅拌反应两小时，薄层层析板监测反应。反应完全后用饱和NaHCO 3溶液调节pH至碱性，此时析出大量白色固体，过滤，固体真空干燥过夜，收集固体即为化合物2。 1H NMR(400MHz,CDCl 3)δ13.64(s,1H),10.24(s,1H),8.20(s,1H),7.63(s,1H),7.28(s,1H),5.28–5.26(m,1H),5.10(s,2H),4.10–4.07(m,2H),3.55–3.52(m,2H),3.38–3.35(m,2H),3.21(s,2H),2.95–2.92(m,2H),2.68–2.66(m,2H),2.62–2.58(m,2H),2.36(s,3H),2.13–2.12(m,1H),2.07–2.01(m,2H)； 13C NMR(100MHz,CDCl 3)δ193.6,167.6,155.9,155.4,152.74,152.73,150.9,143.9, 140.2,128.5,128.2,116.5,93.1,89.9,80.2,71.2,59.3,51.8,47.2,45.1,43.9,43.7,41.1,28.5,20.9,18.8；ESI-MS m/z：501.3[M+H] +。
实施例3
Figure PCTCN2017120224-appb-000018
本发明化合物3按照公开专利文献WO2015059668制备得到结的中间体3A并鉴定，
Figure PCTCN2017120224-appb-000019
然后3A与中间体2B，按照实施例2类似的方案制备得到化合物3，ESI-MS m/z：488.3[M+H] +。
实施例4
Figure PCTCN2017120224-appb-000020
本发明化合物4的制备，首先按照实施例1的类似方案制备得到中间体4CD，结构如下：
Figure PCTCN2017120224-appb-000021
1H NMR(400MHz,CDCl 3)δ7.09(s,1H),5.18(s,1H),5.03(s,1H),4.70(s,2H),3.40–3.37(m,8H),3.22–3.17(m,4H),2.70–2.67(m,2H),2.58–2.55(m,2H),1.91–1.85(m,2H)；ESI-MS m/z：338.1[M+H] +。然后4CD与中间体2B，按照实施例2类似的方案制备得到化合物4，ESI-MS m/z：504.1[M+H] +。
实施例5
Figure PCTCN2017120224-appb-000022
本发明化合物5的制备，首先按照实施例1的类似方案制备得到中间体4CD，然后4CD与化合物4-戊炔-1-胺，按照实施例1类似的方案制备得到化合物5，ESI-MS m/z：518.1[M+H] +。
实施例6
Figure PCTCN2017120224-appb-000023
本发明化合物6的制备，首先按照实施例1的制备方案制备中间体1C，然后1C与化合物4-戊炔-1- 胺，按照实施例1的类似制备方案，制备得到化合物6，ESI-MS m/z：515.1[M+H] +。
实施例7
Figure PCTCN2017120224-appb-000024
本发明化合物7按照公开专利文献WO2015059668制备得到关键的中间体3A并鉴定，然后化合物3A和化合物4-戊炔-1-胺，按照实施例1类似的方案制备得到化合物7，ESI-MS m/z：502.2[M+H] +
实施例8
Figure PCTCN2017120224-appb-000025
本发明化合物8的制备，首先按照以下的方案制备得到中间体8C，
Figure PCTCN2017120224-appb-000026
将化合物1B(按照公开专利文献WO2015059668制备并鉴定)(5.9g，25.0mmol)溶于1,2-二氯乙烷(100ml)中，然后加入甲胺(2.0M in THF，50ml，100.0mmol)，于0℃下分批加入三乙酰氧基硼氢化钠(10.6g，50.0mmol)，恢复至室温反应，经薄层层析监测反应完全，加入饱和氯化铵水溶液淬灭，浓缩除去有机溶剂，用乙酸乙酯萃取除去杂质，并用水萃取出乙酸乙酯中的目标产物，合并水相，并加入饱和碳酸氢钠水溶液使水相调至弱碱，用二氯甲烷萃取三次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物8A，ESI-MS m/z：252.2[M+H] +。
将化合物8A(4.46g，17.8mmol)和化合物8B(2.30g，17.8mmol)溶于二氯甲烷(50ml)中，于0℃下分别加入EDCI(3.41g，17.8mmol)、HOBt(2.41g，17.8mmol)和三乙胺(3.72ml，26.7mmol)，升至室温反应。经薄层层析监测反应完全，减压浓缩，加入饱和碳酸氢钠水溶液，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩得到化合物8C，ESI-MS m/z：363.1[M+H] +。
然后8C与中间体2B，按照实施例2类似的方案制备得到化合物8，ESI-MS m/z：529.1[M+H] +。
实施例9
Figure PCTCN2017120224-appb-000027
本发明化合物9按照公开专利文献WO2015059668制备得到关键的中间体3A并鉴定，然后化合物3A和化合物(S)-3-丁炔-2-胺，按照实施例1类似的方案制备得到化合物9，ESI-MS m/z：488.2[M+H] +。
实施例10
Figure PCTCN2017120224-appb-000028
本发明化合物10的制备，首先按照实施例1的制备方案制备中间体1C，然后1C与化合物(S)-3-丁炔-2-胺，按照实施例1的类似制备方案，制备得到化合物10，ESI-MS m/z：501.2[M+H] +。
生物测试
生物测试例1.成纤维细胞生长因子受体(FGFR)激酶活性抑制测试
采用ADP-Glo方法测定受试物对FGFR的激酶抑制活性。人源FGFR1，FGFR2及FGFR4激酶重组蛋白及激酶活性测定试剂盒ADP-Glo TM采购自Promega,FGFR3激酶重组蛋白采购自BPS Bioscience。受试物从1000nM开始，梯度稀释后与FGFR1，FGFR2，FGFR3或FGFR4激酶重组蛋白孵育30分钟，在ATP存在条件下与底物反应，ADP-Glo TM检测生成的ADP，并进一步产生化学发光信号，酶标仪(Perkin Elmer，Envision)测定各孔读数，使用origin7.5计算和分析IC50，即发生50％抑制时的浓度。
本发明化合物对FGFR1-4的激酶活性抑制通过以上的试验进行测定，测得的IC50(nM)值见表1。
表1
化合物编号 FGFR4 FGFR1 FGFR2 FGFR3
化合物1 0.41 >1000 >1000 >1000
化合物2 0.33 >1000 >1000 >1000
化合物3 0.62 >1000 >1000 >1000
化合物4 0.37 >1000 >1000 >1000
化合物6 0.59 >1000 >1000 >1000
生物测试例2.肝细胞癌(HCC)细胞株的增殖抑制活性测试
采用5种肝细胞癌细胞株测试实施例化合物对细胞体外增殖的抑制活性：Hep3B,Huh7,JHH-7,SK-hep-1,SNU423。以上细胞均来自ATCC(美国标准生物品收藏中心)。其中Hep3B,Huh-7,JHH-7三种细胞均有FGF19基因扩增(拷贝数增加)且mRNA表达水平升高，以及FGFR4、KLB基因mRNA的高水平表达；SK-hep-1、SNU423细胞则没有FGF19基因的扩增，且FGF19mRNA表达水平很低(Barretina J,Caponigro G,et al.Nature 2012；483:603-7.)。
采用SRB(Sulforhodamine-B，磺酰罗丹明B)法测定细胞增殖。细胞培养至融合度达90％以上后采用胰蛋白酶消化，计数后按6000个细胞/孔接种至96孔板，过夜贴壁培养后，将受试化合物溶于DMSO，再用完全培养基稀释后加入培养孔，形成从10μM开始5倍稀释10个浓度梯度，继续培养72小时后每孔加入50μl 50％三氯乙酸，4℃下固定1小时。将各孔中的三氯乙酸弃去，用300μl双蒸水洗5次。室温干燥后，每孔加入50μl 0.4％SRB染料溶液(1％乙酸/0.4％SRB)，反应15min。弃去各孔的染料溶液，用1％乙酸洗6-7次，室温干燥。各孔加入200μl 10mM Tris溶液(PH＝10.5)，振荡至溶解澄清。用酶标仪测定各孔490nm下吸光度。以待测化合物浓度为0的孔的读数作为对照，用Origin 7.5软件拟合，计算受试物抑制细胞增殖的IC50值(nM)。
本发明化合物的抗肿瘤细胞增殖活性通过以上的试验进行测定，测得的IC50(nM)值见表2。
表2
化合物编号 Hep3B HUH-7 JHH-7 SNU387 SK-hep-1
化合物1 0.35 4.0 3.0 >1000 >1000
化合物2 0.40 2.9 2.6 >1000 >1000
化合物3 0.62 5.7 N.D. >1000 N.D.
化合物4 0.36 2.8 N.D. >1000 N.D.
化合物6 0.53 4.9 N.D. >1000 N.D.
N.D.表示未测定。
以上数据表明，本发明化合物1，2，3，4，6对FGF19基因扩增的HCC细胞具有显著的选择性抑制作用。
生物测试例3.HCC细胞裸鼠皮下移植瘤生长抑制测试
培养并收集对数生长期的Hep3B细胞，按1×10 7个细胞/只皮下接种于裸鼠(雌性Balb/c Nude小鼠，来源于北京维通利华)的右侧背部皮下，待肿瘤长至50-300mm 3时，对荷瘤裸鼠进行随机分组，每组6只动物。随后，对每组动物按下述剂量给药，并将首次给药当天定义为试验第1天。
空白溶剂(超纯水)对照组，化合物1，化合物2分别设定50mg/kg，100mg/kg，150mg/kg三个剂量组，灌胃给药，每天两次(BID)，连续给药21天。给药期间每天观察动物状态；首次给药前每周测量1次体重；开始给药后每周测定2次体重。开始给药后每3天测量1次移植瘤大小。肿瘤体积(TV)＝l/2×a×b 2，其中，a、b分别表示肿瘤长、宽。根据测量的结果计算出相对肿瘤体积(RTV)，RTV＝V t/V 0×100，其中V 0为分笼当天(即第0天)测量所得肿瘤体积，V t为每一次测量时的肿瘤体积。
受试化合物对Hep3b裸鼠移植瘤的生长抑制如图1，图2。
化合物1和化合物2给药剂量50mg/kg，BID 21天后对移植瘤生长抑制显著；化合物1和化合物2的所有的剂量组动物，在给药试验周期中，进水进食正常，活动正常，体重正常，未出现不良反应。
按上述方法建立Hep3B裸鼠移植瘤模型后，分3组，分别灌胃给予空白溶剂(超纯水)对照，化合物1(15mg/kg，BID)，索拉非尼(按照文献CN1721397A记载的方法制备得到并鉴定，30mg/kg，每天一次(QD))，连续给药21天，按上述相同方法评估受试物对移植瘤的生长抑制及动物状态、体重。各组移植瘤生长曲线见图3。测得肿瘤体积(TV)按照抑瘤率(TGI)＝(1-T/C)×100％计算抑瘤率。C：对照组平均肿瘤体积；T：给药组平均肿瘤体积。结果见表3。“+”表示抑瘤率40％～60％；“++”表示抑瘤率60％～80％；“+++”表示抑瘤率80％～100％。
化合物1的剂量15mg/kg BID对Hep3B裸鼠移植瘤模型药效优于索拉非尼30mg/kg QD。
表3
抑瘤率(％)(末次给药)
化合物1(15mg/kg，bid) +++
索拉非尼(30mg/kg，qd) +
生物测试例4.受试化合物小鼠耐受剂量探索实验
雌性Balb/c Nude小鼠(来源于北京维通利华)，体重18-22克，随机分组，每组6只，按以下剂量灌胃给予受试物：化合物1(50mg/kg，100mg/kg，200mg/kg，500mg/kg)；化合物2(50mg/kg，100mg/kg，200mg/kg，500mg/kg)。每天给药2次，连续给药5天。每天观察动物状态并监测体重、摄食量。
在给药周期内，受试化合物所有剂量组动物进水进食正常，活动正常，体重正常，无明显不良反应。
生物测试例3和4提示，化合物1及化合物2具有较好的抑瘤效果和较高的耐受剂量，具有较大的安全窗。

Claims (13)

  1. 一种式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，
    Figure PCTCN2017120224-appb-100001
    其中，R 2，R 3，R 4独立地为N或者C(R X)；
    R 5选自氢，卤素，氰基，氨基，酰胺基，羟基，酯基，酰基，酰氧基，磺酰基，亚磺酰基，烷基，烷氧基，芳基，环烷基，杂芳基，杂环基，杂环基烷基，
    R 6选自氢，卤素，氰基，氨基，酰胺基，羟基，酯基，酰基，酰氧基，磺酰基，亚磺酰基，烷基，烷氧基，芳基，环烷基，杂芳基，杂环基，杂环基烷基；
    R 7，R 8，R 9独立地为N或者C(R X)；
    R 10，R 11，R 12独立地为氢，卤素，氰基，氨基，羟基，烷基，烷氧基，芳基，环烷基，杂芳基，或者R 11，R 12两个取代基环合成为环状基团，
    R X独立地为氢，卤素，氰基，氨基，酰胺基，羟基，酯基，酰基，酰氧基，磺酰基，亚磺酰基，烷基，烷氧基，芳基，环烷基，杂芳基或杂环基，
    n＝1，2，3，4，5。
  2. 如权利要求1所述的式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，其中包括通式(II)化合物
    Figure PCTCN2017120224-appb-100002
    其中，R 5为氢，烷基，烷氧基，芳基，环烷基，杂芳基，杂环基，杂环基烷基，
    R 11，R 12独立地为氢，卤素，氰基，氨基，羟基，烷基，烷氧基，芳基，环烷基，杂芳基，或者R 11，R 12两个取代基环合成为环状基团，
    n＝1，2，3，4，5，
    R 6选自以下的结构：
    Figure PCTCN2017120224-appb-100003
  3. 如权利要求2所述的式(I)化合物，其中结构片段
    Figure PCTCN2017120224-appb-100004
    选自以下结构：
    Figure PCTCN2017120224-appb-100005
  4. 如权利要求1至3所述的式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，其选自下述化合物：
    Figure PCTCN2017120224-appb-100006
    Figure PCTCN2017120224-appb-100007
  5. 如权利要求1至4所述的式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，其选自下述化合物：
    Figure PCTCN2017120224-appb-100008
  6. 如权利要求1至5所述的式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，其选自下述化合物：
    Figure PCTCN2017120224-appb-100009
  7. 如权利要求2至4中任一项所述化合物，其立体异构体，互变异构体或药学上可接受的盐的制备方法，包括如下步骤：
    Figure PCTCN2017120224-appb-100010
    其中，R 5，R 6，R 11，R 12和n的定义如权利要求2；R y和R z选自C1～C6的烷基，或者R y和R z连接构成5～7元杂环结构，
    包括以下步骤：
    步骤1，在一定的溶剂中，一定温度下，化合物Y1与Y2在碱作用下偶联成为化合物Y3；
    步骤2，在一定的溶剂中，一定温度下，化合物Y3与Y4在碱的作用下反应得到化合物Y5；
    步骤3，在一定的溶剂中，一定温度下，化合物Y5在脱保护试剂作用下，脱保护得到化合物(II)。
  8. 如权利要求7所述的制备方法，其中，步骤1中，溶剂选自四氢呋喃，二氧六环，二氯甲烷，三氯甲烷，四氯化碳，乙腈，二氯乙烷，乙酸乙酯中的一种或多种，溶剂优选为二氯甲烷，三氯甲烷；温度选自–30～80℃，优选温度为–10～20℃；所用碱选自三乙胺，N,N'-二甲基丙胺，N,N'-二异丙基乙胺，甲胺水溶液，优选为N,N'-二异丙基乙胺；
    步骤2中，溶剂选自叔丁基甲基醚，***，四氢呋喃，二氧六环，二氯甲烷，三氯甲烷，乙腈，二氯乙烷中的一种或多种，溶剂优选为四氢呋喃，二氧六环；温度选自–50～80℃，优选温度为–30～10℃；所选碱选自双(三甲基硅基)胺基锂，双(三甲基硅基)胺基钠，双(三甲基硅基)胺基钾，优选为双(三甲基硅基)胺基锂；
    步骤3中，溶剂选自叔丁基甲基醚，***，四氢呋喃，二氧六环，二氯甲烷，三氯甲烷，四氯化碳，丙酮，丁酮，乙酸乙酯，水中的一种或多种；溶剂优选为四氢呋喃，水，或者四氢呋喃和水的混合溶液；温度选自–30～80℃，优选温度为–10～10℃；所选脱保护试剂为酸性物质，优选自磷酸，硫酸，浓盐酸，硝酸，柠檬酸，甲磺酸，对甲基苯磺酸，更优选自浓盐酸，硫酸。
  9. 一种药物组合物，其包括治疗有效剂量的权利要求1至6中任一项所述化合物或其立体异构体，互变异构体或药学上可接受的盐及可药用的载体。
  10. 如权利要求9所述的药物组合物，其用于各种癌症的治疗，优选所述癌症包括：肝癌，肺癌，食管癌，胃癌，肾细胞癌，肉瘤，胆管癌，结肠癌，***癌，卵巢癌，乳腺癌。
  11. 如权利要求1至6中任一项所述化合物，其立体异构体，互变异构体或药学上可接受的盐，作为FGFR4激酶选择性抑制剂，在制备治疗由FGFR4或FGF19介导疾病的药物或药物组合物中的应用。
  12. 如权利要求1至6中任一项所述化合物，其立体异构体，互变异构体或药学上可接受的盐，根据权利要求9所述的药物组合物在制备治疗癌症药物中的应用。
  13. 如权利要求12所述的应用，治疗的各种癌症包括：肝癌，肺癌，食管癌，胃癌，肾细胞癌，肉瘤，胆管癌，结肠癌，***癌，卵巢癌，乳腺癌。
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