WO2017202390A1 - 作为fgfr4抑制剂的杂环化合物 - Google Patents
作为fgfr4抑制剂的杂环化合物 Download PDFInfo
- Publication number
- WO2017202390A1 WO2017202390A1 PCT/CN2017/086445 CN2017086445W WO2017202390A1 WO 2017202390 A1 WO2017202390 A1 WO 2017202390A1 CN 2017086445 W CN2017086445 W CN 2017086445W WO 2017202390 A1 WO2017202390 A1 WO 2017202390A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- group
- substituted
- compound
- alkoxy
- Prior art date
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- 150000002391 heterocyclic compounds Chemical class 0.000 title abstract description 4
- 229940125408 FGFR4 inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 131
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- 230000000694 effects Effects 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 18
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 11
- 239000003112 inhibitor Substances 0.000 claims abstract description 8
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- 229940002612 prodrug Drugs 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 174
- 238000006243 chemical reaction Methods 0.000 claims description 99
- 125000000623 heterocyclic group Chemical group 0.000 claims description 75
- 125000003545 alkoxy group Chemical group 0.000 claims description 59
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- 125000003118 aryl group Chemical group 0.000 claims description 40
- 125000005842 heteroatom Chemical group 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 36
- -1 CHR 3 R 4 Chemical group 0.000 claims description 34
- 125000000304 alkynyl group Chemical group 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 34
- 125000004178 (C1-C4) alkyl group Chemical class 0.000 claims description 30
- 125000003342 alkenyl group Chemical group 0.000 claims description 27
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 25
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000002950 monocyclic group Chemical group 0.000 claims description 21
- 125000004122 cyclic group Chemical group 0.000 claims description 18
- 125000003003 spiro group Chemical group 0.000 claims description 17
- 125000003277 amino group Chemical group 0.000 claims description 16
- 230000005764 inhibitory process Effects 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000003367 polycyclic group Chemical group 0.000 claims description 14
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 13
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- 125000002619 bicyclic group Chemical group 0.000 claims description 9
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- 125000006661 (C4-C6) heterocyclic group Chemical group 0.000 claims description 6
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- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 5
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 4
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- 230000009471 action Effects 0.000 claims description 4
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- 238000000338 in vitro Methods 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
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- 108091008794 FGF receptors Proteins 0.000 description 10
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
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- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- BFDBKMOZYNOTPK-UHFFFAOYSA-N vonoprazan Chemical compound C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F BFDBKMOZYNOTPK-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention provides a novel class of heterocyclic compounds, their synthesis and their use as FGFR4 inhibitors.
- FGFR fibroblast growth factor receptor
- FGFR activating mutation can not only promote malignant tumor cell proliferation and inhibit apoptosis, but also play an important role in tumor neovascularization, tumor invasion and metastasis.
- FGFR is highly expressed in non-small cell lung cancer, liver cancer, breast cancer, bladder cancer and many other cancers. Therefore, FGFR small molecule kinase inhibitor is a promising treatment for tumor patients with abnormal FGFR expression. The development of selective FGFR small molecule inhibitors has received increasing attention.
- Liver cancer is one of the most malignant tumors with the highest morbidity and mortality. There are 466,000 new cases of liver cancer and 422,000 cases of liver cancer deaths in China every year. Studies have shown that the FGFR4-FGF19 signaling system is closely related to hepatocellular carcinoma (HCCs), a FGFR subtype highly expressed in human hepatocytes, and a variety of FGFR4 variants are found in liver cancer patients. Selective inhibition of FGFR4 but not other subtypes of FGFR1, FGFR2, and FGFR3 can avoid certain toxicity and is likely to become an important target for the treatment of liver cancer. Clinical studies have shown that FGFR inhibitors can be used in the treatment of a variety of cancers, but there is an urgent need to develop selective FGFR4 inhibitors for the treatment of a variety of tumors, especially liver cancer.
- HCCs hepatocellular carcinoma
- FGFR4 variants are found in liver cancer patients.
- T 1 is N or CR 1 , wherein R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, cyano, CO 2 NH 2 , halogenated C 1-4 alkane group or a hydroxy-substituted C 1-4 alkyl;
- T 2 is N or CR 2 , wherein R 2 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, hydroxy substituted C 1-4 alkoxy, C 2-4 Alkenyl, C 2-4 alkynyl, CHR 3 R 4 , cyano, CO 2 NH 2 , C 1-4 alkoxy substituted C 1-4 alkyl, C 1-4 alkoxy substituted C 1 -4 alkoxy, C 1-4 alkoxy substituted halo C 1-4 alkoxy, C 1-4 alkoxy substituted C 2-4 alkenyl, C 1-4 alkoxy substituted C 2-4 alkynyl, C 1-4 alkyl fluorenyl, bis(C 1-4 alkyl)amino substituted C 1-4 alkoxy, O(CR 7 R 8 ) n -R 6 , NR 5 (CR 7 R 8 ) n -R 6 or a halogenated C 1-4 alkoxy group (preferably, a
- R 3 and R 4 together with the carbon atom to which they are attached form a 4- to 7-membered heterocyclic group containing one or two heteroatoms selected from N, O or S, wherein the heterocyclic group is optionally one or two X 1 is substituted;
- R 5 is hydrogen or C 1-4 alkyl
- R 6 is C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 alkynyl substituted C 1-4 alkyl, C 3-12 cycloalkyl (including monocyclic, bridged, spiro, and cyclo), C 3-8 cycloalkyl substituted C 1-4 alkyl, containing 1 to 3, optionally selected from N, O, and S 4- to 12-membered heterocyclic groups of heteroatoms (including monocyclic, bridged, spiro, and cyclo), 4- to 12-membered heterocyclic substituted C 1-4 alkyl, 6-membered aromatic a 6-membered aryl-substituted C 1-4 alkyl group, a 5- to 6-membered heteroaryl group, a 5- to 6-membered heteroaryl-substituted C 1-4 alkyl group, a halogenated C 1-4 Alkyl, C 1-4 al
- R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocyclic group which may contain an additional one or two heteroatoms selected from N, O or S, wherein the heterocyclic group is optionally Or a plurality of X 3 substitutions;
- R 7 and R 8 are each independently hydrogen, C 1-4 alkyl, or halogen
- Z is CH or N; wherein, when T 1 is N, T 2 and Z are not N; when T 2 is N, T 1 and Z are not N; when Z is N, T 1 and T 2 are not N;
- Y is NR or O, wherein R is hydrogen or C 1-4 alkyl
- W is hydrogen or C 1-4 alkyl
- V is CH 2 , O, CH(OH), CHF, or CF 2 ;
- U is hydrogen, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy substituted C 1-4 alkyl, C 1 -4 alkoxy group, C 2-4 alkenyl group, C 2-4 alkynyl group, (CR 9 R 10 ) p -NR 11 R 12 , (CR 13 R 14 ) q -R 15 , CH 2 CO 2 H, Or C(O)H;
- R 9 and R 10 are each independently hydrogen or C 1-4 alkyl
- R 11 is C 1-4 alkyl, bis(C 1-4 alkyl)amino substituted C 1-4 alkyl, or 4- to 1-2 hetero atom selected from N, O and S 7-membered heterocyclic group;
- R 12 is C 1-4 alkyl, halo C 1-4 alkyl, hydroxy substituted halo C 1-4 alkyl, C(O)C 1-4 alkyl, C(O)-CH 2 - OH, C(O)-CH 2 -OCH 3 , C(O)-CH 2 -N(CH 3 ) 2 , S(O) 2 CH 3 or C(O)C(O)N(R 16 ) 2 ;
- R 11 and R 12 together with the N atom to which they are attached form a monocyclic, bicyclic, or polycyclic 4- to 12-membered ring structure which, in addition to the existing N atom, may Containing an additional 1-2 heteroatoms, optionally selected from N, O, S; moreover, the cyclic structure may be optionally substituted with 1-3 X 4 , the sites of substitution at the C and N atoms, provided that Provided that the structure formed is a reasonably stable structure;
- X 4 is each independently selected from the group consisting of halogen, C 1-4 alkyl, C 3-8 cycloalkyl, 4- to 6-membered heterocyclic, C 1-4 Alkyl-substituted 4- to 6-membered heterocyclic group, 6-membered aryl group, 5- to 6-membered heteroaryl group, hydroxy group, C 1-4 alkoxy group, halogenated C 1-4 alkyl group, hydroxy group Substituted C 1-4 alkyl, C
- R 13 and R 14 are each independently hydrogen, C 1-4 alkyl, or halogen
- R 15 is a C 3-8 cycloalkyl group, a 4- to 12-membered heterocyclic group having 1 to 3 hetero atoms selected from N, O and S, a 6-membered aryl group, or 1 to 3 a 5- to 6-membered heteroaryl group selected from heteroatoms of N, O and S, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted by 1-3 X 4 , The definition of X 4 is as described above;
- R 16 are each independently selected from hydrogen or C 1-4 alkyl
- n 0, 1, 2 or 3;
- n 0, 1, 2 or 3;
- p 0, 1, or 2;
- q 0, 1, or 2.
- T 1 is CR 1 ;
- T 2 is CR 2 ;
- Z is CH; and/or
- Y is NH
- W is hydrogen
- V is CH 2 ;
- n 1;
- U is C 1-4 alkyl, halo C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy substituted C 1-4 alkyl, C 1-4 alkoxy a group, C 2-4 alkenyl, C 2-4 alkynyl, CH 2 -NR 11 R 12 , (CR 13 R 14 ) q -R 15 , CH 2 CO 2 H, or C(O)H;
- R 1 , R 2 , R 11 , R 12 , R 13 , R 14 , R 15 and q are as described above, respectively.
- R 1 is CN
- R 2 is NR 5 (CR 7 R 8 ) n -R 6 or O(CR 7 R 8 ) n -R 6 ; wherein R 5 is hydrogen or C 1-4 alkyl; R 6 Is a C 2-4 alkenyl group, a C 2-4 alkynyl group, a C 2-4 alkynyl substituted C 1-4 alkyl group, a C 3-12 cycloalkyl group (including a monocyclic ring, a bridged ring, a spiro ring, and a cyclic ring).
- a C 3-8 cycloalkyl-substituted C 1-4 alkyl group a 4- to 12-membered heterocyclic group containing 1 to 3 hetero atoms selected from N, O and S (including a single ring, a bridge) Ring, spiro, and cyclo), 4- to 12-membered heterocyclic substituted C 1-4 alkyl, 6-membered aryl, 6-membered aryl substituted C 1-4 alkyl, 5- to a 6-membered heteroaryl, or a 5- to 6-membered heteroaryl-substituted C 1-4 alkyl group, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl
- the base is optionally substituted by 1-3 X 2 , X 2 is as defined above; or R 5 and R 6 taken together with the nitrogen atom to which they are attached may contain an additional 1-2 selected from N, O or S a 4- to 5-
- R 2 is NH(CR 7 R 8 ) n -R 6 or O(CR 7 R 8 ) n -R 6 ;
- R 6 is C 2-4 alkenyl, C 2-4 alkynyl , C 2-4 alkynyl substituted C 1-4 alkyl, C 3-12 cycloalkyl (including monocyclic, bridged, spiro, and cyclic), C 3-8 cycloalkyl substituted C 1- 4- alkyl, 4- to 12-membered heterocyclic group (including monocyclic, bridged, spiro, and cyclic) containing from 1 to 3 heteroatoms selected from N, O and S, inclusive from 4 to 12 a C 1-4 alkyl group of a heterocyclic group, a 6-membered aryl group, a 6-membered aryl-substituted C 1-4 alkyl group, a 5- to 6-membered heteroaryl group, or a 5- to 6-membered member.
- R 2 is NHR 6 or OR 6 ;
- R 6 is C 2-4 alkynyl substituted C 1-4 alkyl, C 3-12 cycloalkyl (including monocyclic, bridged, spiky) a ring-and-cyclic ring), a C 3-8 cycloalkyl-substituted C 1-4 alkyl group, a 4- to 12-membered heterocyclic group containing 1-3 hetero atoms selected from N, O and S (including Monocyclic, bridged, spiro, or cyclic), or 4- to 12-membered heterocyclic substituted C 1-4 alkyl, wherein alkyl, alkynyl, cycloalkyl, heterocyclyl is optionally 1-3 X 2 substitutions, X 2 are as described above.
- R 2 is NHR 6 or OR 6 ;
- R 6 is C 3-8 cycloalkyl, 3- to 8-membered with 1-3 heteroatoms selected from N, O and S Heterocycloalkyl, C 1-4 alkoxy substituted C 3-8 cycloalkyl, hydroxy substituted C 3-8 cycloalkyl, C 1-4 alkoxy substituted C 1-4 alkyl, C 3-8 cycloalkyl-substituted C 1-4 alkyl, 3- to 8-membered heterocycloalkyl substituted C 1-4 alkyl, or hydroxy-containing C 3-8 cycloalkyl substituted C 1- 4 alkyl, wherein the alkyl, cycloalkyl, heterocyclyl optionally substituted with 1-3 substituents X 2, X 2 described above.
- R 2 is NHR 6 ;
- R 6 is C 3-8 cycloalkyl, C 3-8 heterocycloalkyl having 1-3 heteroatoms selected from N, O and S, C 1-4 alkoxy-substituted C 3-8 cycloalkyl, hydroxy-substituted C 3-8 cycloalkyl, C 1-4 alkoxy-substituted C 1-4 alkyl, C 1-4 naphthenic a substituted C 1-4 alkyl group or a C 1-4 cycloalkyl group substituted with a C 1-4 alkyl group.
- R 2 is OR 6 ;
- R 6 is C 3-8 cycloalkyl, C 1-4 alkoxy substituted C 3-8 cycloalkyl, hydroxy substituted C 3-8 cycloalkane a C 1-4 alkyl group substituted with a C 1-4 alkoxy group or a C 1-4 alkyl group substituted with a C 1-4 cycloalkyl group.
- the compound has a structure as shown in formula (II).
- R 17 is a group selected from the group consisting of:
- R 17 is a group selected from the group consisting of:
- the compound has a structure as shown in formula (II).
- R 17 is a group selected from the group consisting of:
- U is CH 2 -NR 11 R 12 ; wherein R 11 is C 1-4 alkyl, 4- to 6-membered heterocyclic, or bis(C 1-4 alkyl)amino Substituted C 1-4 alkyl; R 12 is C 1-4 alkyl, halo C 1-4 alkyl, hydroxy halogenated C 1-4 alkyl, C(O)C 1-4 alkyl, C(O)-CH 2 -OH, C(O)-CH 2 -OCH 3 , C(O)-CH 2 -N(CH 3 ) 2 , S(O) 2 CH 3 , or C(O)C (O)N(R 16 ) 2 ; R 11 and R 12 together with the N atom to which they are attached form a monocyclic, bicyclic, or polycyclic 5- to 12-membered ring structure, which In addition to the existing N atom, it may contain an additional 1-2 heteroatoms selected from N, O, S; moreover, the cyclic structure
- U is (CR 13 R 14 ) 0-2 - R 15 ; wherein R 13 and R 14 are each independently hydrogen or C 1-4 alkyl; R 15 is C 3-8 cycloalkyl, 4- to 12 a -heterocyclic group, a 6-membered aryl group, or a 5- to 6-membered heteroaryl group, wherein a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group may be optionally 1-3 X 4 Instead, X 4 is as described above.
- U is CH 2 -NR 11 R 12 ; wherein R 11 and R 12 together with the N atom to which they are attached form a bicyclic, or polycyclic, 8- to 12-membered ring structure,
- the cyclic structure may contain, in addition to the existing N atom, an additional 1-2 heteroatoms selected from N, O, S; moreover, the cyclic structure may optionally be 1-3 X 4 substituted, substituted sites on the C and N atoms, provided that the structure formed is a reasonable stable structure;
- U is CH 2 -R 15 ; wherein R 15 is C 3-8 cycloalkyl, 4- to 12- having 1-3 heteroatoms selected from N, O and S a heterocyclic group, a 6-membered aryl group, or a 5- to 6-membered heteroaryl group, wherein a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group may be optionally substituted by 1 to 3 X 4 , X 4 is as described above.
- U is CH 2 -R 15 ; wherein R 15 is a 4- to 12-membered heterocyclic group containing 1 to 3 hetero atoms selected from N, O and S, wherein the heterocyclic ring
- the base may be optionally substituted by 1-3 X 4 , and X 4 is as described above.
- U is CH 2 -R 15 ; wherein R 15 is a 5- to 9-membered heterocyclic group containing 1-3 hetero atoms selected from N, O and S, wherein the heterocyclic ring
- the base may be optionally substituted by 1-3 X 4 , and X 4 is as described above.
- the R 15 is a 5- to 9-membered heterocyclic group containing 2 hetero atoms selected from N, O and S; preferably, R 15 is a 2 N hetero atom 5- to 9-membered heterocyclic group.
- U is a group selected from the group consisting of:
- U is a group selected from the group consisting of:
- the compound is selected from the group consisting of:
- the disease is a tumor.
- the tumor is selected from the group consisting of lung cancer, bladder cancer, breast cancer, gastric cancer, liver cancer, salivary gland sarcoma, ovarian cancer, prostate cancer, cervical cancer, epithelial cell carcinoma, multiple myeloma, pancreatic cancer. Lymphoma, chronic myelogenous leukemia, lymphocytic leukemia, cutaneous T-cell lymphoma, etc.
- a pharmaceutical composition comprising: (i) an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; and (ii) pharmaceutically Acceptable carrier.
- a fourth aspect of the invention provides a method of inhibiting FGFR4 activity, the method comprising the steps of: administering to a subject, inhibiting an effective amount of a compound of formula (I), or a pharmaceutically acceptable compound thereof, according to the first aspect of the invention
- the salt is accepted, or an inhibitory effective amount of the pharmaceutical composition according to the third aspect of the invention is administered to the subject.
- the inhibition is selective inhibition of FGFR4.
- the inhibition of FGFR4 activity is non-therapeutic inhibition in vitro.
- a process for the preparation of a compound according to the first aspect of the invention which comprises the steps of:
- Ar is an aryl group and X is a halogen, and the other groups are as defined above.
- the inventors have unexpectedly discovered a class of heterocyclic compounds having FGFR4 (fibroblast growth factor receptor 4) inhibitory activity after long-term and intensive research, and thus can be used for the preparation of a disease associated with FGFR4 activity or expression.
- Pharmaceutical composition Based on the above findings, the inventors completed the present invention.
- the present invention provides a compound represented by the formula (I) as described above, including an isomer (enantiomer or diastereomer) which may be present, or a pharmaceutically acceptable salt thereof , prodrugs, deuterated derivatives, hydrates, solvates.
- the compound of the present invention has FGFR4 inhibitory activity and can be used for the prevention or treatment of diseases associated with the activity or expression level of FGFR4, and can also be used in combination with other drugs for the treatment of various related diseases.
- each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
- alkyl refers to a straight-chain (ie, unbranched) or branched-chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched-chain groups. .
- the alkyl group has a carbon number limitation (e.g., C 1-10 ) it means that the alkyl group has 1 to 10 carbon atoms.
- C 1-8 alkyl refers to an alkyl group containing from 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or Similar group.
- alkenyl when used alone or as part of another substituent, refers to a straight or branched, carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When the alkenyl group has a carbon number limitation (e.g., C 2-8 ), it means that the alkenyl group has 2 to 8 carbon atoms. For example, C 2-8 alkenyl refers to an alkenyl group having 2-8 carbon atoms, including ethenyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or the like. group.
- C 2-8 alkenyl refers to an alkenyl group having 2-8 carbon atoms, including ethenyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or the like. group.
- alkynyl when used alone or as part of another substituent, refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
- the alkynyl group can be straight or branched, or a combination thereof.
- the alkynyl group has a carbon number limitation (e.g., C 2-8 alkynyl group), it means that the alkynyl group has 2 to 8 carbon atoms.
- C 2-8 alkynyl refers to a straight or branched alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, A sec-butynyl group, a tert-butynyl group, or the like.
- cycloalkyl refers to a unit ring having a saturated or partially saturated ring, a bicyclic or polycyclic (fused ring, bridged or spiro) ring system. .
- a certain cycloalkyl group has a carbon number limitation (e.g., C 3-10 )
- C 3-8 cycloalkyl refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having from 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentane.
- Spirocycloalkyl refers to a bicyclic or polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have fully conjugated ⁇ electrons. system.
- Fused cycloalkyl means an all-carbon bicyclic or polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more Key, but none of the rings have a fully conjugated ⁇ -electron system.
- “Bridge cycloalkyl” refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system .
- the atoms contained in the cycloalkyl group are all carbon atoms.
- Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a conjugated ⁇ -electron system, such as phenyl and naphthyl.
- the aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but may not contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be in a conjugated pi-electron system.
- the aryl group can be substituted or unsubstituted. as follows
- Heteroaryl refers to a heteroaromatic group containing one to more heteroatoms.
- the heteroatoms referred to herein include oxygen, sulfur, and nitrogen.
- the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring.
- the heteroaryl group can be optionally substituted or unsubstituted.
- the following are some examples of heteroaryl groups, and the present invention is not limited to the following heteroaryl groups. Among them, the last three heteroaryl groups are tricyclic heteroaryl groups, which are the focus of the present invention.
- Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or sulfur and the remaining ring atoms are carbon.
- monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.
- Polycyclic heterocyclic group refers to a heterocyclic group including a spiro ring, a fused ring, and a bridged ring.
- Spirocyclic heterocyclyl refers to a polycyclic heterocyclic group in which each ring of the system shares an atom (referred to as a spiro atom) with other rings in the system, wherein one or more of the ring atoms is selected from the group consisting of nitrogen and oxygen. Or sulfur, the remaining ring atoms are carbon.
- “Fused ring heterocyclyl” refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none One ring has a fully conjugated pi-electron system, and wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
- “Bridged heterocyclyl” refers to a polycyclic heterocyclic group in which any two rings share two atoms which are not directly bonded, these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system And wherein one or more of the ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If a heterocyclic group has both a saturated ring and an aromatic ring (for example, the saturated ring and the aromatic ring are fused together), the point attached to the parent must be on the saturated ring. Note: When the point attached to the parent is on the aromatic ring, it is called a heteroaryl group and is not called a heterocyclic group. Some examples of the heterocyclic group are as follows, and the present invention is not limited to the following heterocyclic group.
- halogen when used alone or as part of another substituent, refers to F, Cl, Br, and I.
- substituted when with or without “optionally” means that one or more hydrogen atoms on a particular group are replaced by a particular substituent.
- Particular substituents are the substituents described above in the corresponding paragraphs, or the substituents which appear in the examples.
- an optionally substituted group may have a substituent selected from a particular group at any substitutable position of the group, and the substituents may be the same or different at each position.
- a cyclic substituent, such as a heterocyclic group may be attached to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, i.e., the two rings have a common carbon atom.
- substituents contemplated by the present invention are those that are stable or chemically achievable.
- the substituents are, for example but not limited to, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic , aryl, heteroaryl, halogen, hydroxy, carboxy (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino.
- a pharmaceutically acceptable salt of a compound of the invention refers to a salt that is suitable for contact with the tissue of a subject (eg, a human) without causing unpleasant side effects.
- a pharmaceutically acceptable salt of a compound of the invention includes a salt (eg, a potassium salt, a sodium salt, a magnesium salt, a calcium salt) of a compound of the invention having an acidic group or is basic A salt of a compound of the invention (e.g., a sulfate, a hydrochloride, a phosphate, a nitrate, a carbonate).
- the compound of the formula (I) of the present invention can be produced by the following method, however, the conditions of the method, such as the reactant, the solvent, the base, the amount of the compound used, the reaction temperature, the time required for the reaction, and the like are not limited to the following explanations. .
- the compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.
- each reaction is usually carried out in an inert solvent at a reaction temperature of -78 ° C to 150 ° C (preferably 20 to 120 ° C).
- the reaction time in each step is usually 0.5 to 48 hours, preferably 2 to 12 hours. Time.
- Reaction Scheme A1 describes another general synthetic method for Compound A6:
- Reaction Scheme A2 describes another general synthetic method for Compound A6:
- NHR 11 R 12 is secondary ammonia
- R A is C 1-3 alkyl, -CH 2 -OH, -CH 2 -OCH 3 , -CH 2 -N(CH 3 ) 2 or C(O)N(CH 3 ) 2 .
- Y is C 1-3 alkyl or CH 2 OH.
- R B -E- is selected from the group consisting of:
- Scheme F describes another method of synthesis of intermediate E4.
- the following synthesis method is a preferred method.
- R B -E- is taken from the following groups:
- Ar is an aryl group
- X is a halogen
- the other groups are as defined above.
- pharmaceutically acceptable salt refers to a salt of a compound of the invention and a pharmaceutically acceptable inorganic and organic acid, wherein preferred inorganic acids include, but are not limited to, hydrochloric acid, hydrogen Bromic acid, phosphoric acid, nitric acid, sulfuric acid; preferred organic acids include, but are not limited to: formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid (1, 5), asiamic acid, oxalic acid, tartaric acid, lactic acid , salicylic acid, benzoic acid, valeric acid, diethyl acetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, Gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic
- pharmaceutically acceptable solvate refers to a compound of the invention that forms a solvate with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes, but is not limited to, water , ethanol, methanol, isopropanol, tetrahydrofuran, dichloromethane.
- pharmaceutically acceptable stereoisomer means that the chiral carbon atom to which the compound of the invention relates may be in the R configuration, in the S configuration, or a combination thereof.
- the compound of the present invention has excellent inhibitory activity against FGFR4, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are main active ingredients.
- the pharmaceutical composition can be used to treat, prevent, and alleviate diseases associated with FGFR4 activity or expression levels.
- the compounds of the present invention are useful for treating (but not limited to) various diseases such as lung cancer, bladder cancer, breast cancer, gastric cancer, liver cancer, salivary gland sarcoma, ovarian cancer, prostate cancer, cervical cancer, Epithelial cell carcinoma, multiple myeloma, pancreatic cancer, lymphoma, chronic myelogenous leukemia, lymphocytic leukemia, cutaneous T-cell lymphoma, etc.; bone-related diseases such as bone dysplasia, dysplasia, dwarfism, Crouzon syndrome; T cell-mediated inflammation and autoimmune diseases such as rheumatoid arthritis, collagen II arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, juvenile diabetes, Sjogren's syndrome , thyroid disease, sarcoidosis, inflammatory bowel disease, celiac disease and so on.
- various diseases such as lung cancer, bladder cancer, breast cancer, gastric cancer, liver cancer, salivary gland s
- compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
- safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
- the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent.
- the "one dose” is a capsule or tablet.
- “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
- pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
- magnesium stearate magnesium stearate
- calcium sulfate vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting Agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
- vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
- polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
- emulsifiers such as Tween
- wetting Agents such as sodium lauryl sulfate
- colorants such as sodium lauryl sulfate
- flavoring agents such as pepperminophen, sorbitol, etc
- the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, Portuguese Glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) an absorption accelerator, for example a quaternary amine compound; (g) a wetting agent
- Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
- the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
- inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
- compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
- the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
- suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
- compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
- Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
- Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
- the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
- the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
- a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kilogram body weight person,
- the daily dose is usually from 1 to 2000 mg, preferably from 5 to 500 mg.
- specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
- a class of pharmaceutical compositions for treating diseases associated with FGFR4 activity is provided.
- reaction was completed by a thin-plate chromatography, and the reaction mixture was added with a saturated aqueous solution of sodium carbonate, and extracted with ethyl acetate (25 mL), and the organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate
- Compound 14a was prepared according to the following literature: (1) Journal of the American Chemical Society, 1970, 92(6), 1582-6; (2) Helvetica Chimica Acta, 1979, 62(8), 2802-16. Compound 14a and compound 13b are reacted to give compound 14b, which is then protected under acidic conditions to afford compound 14c. Compound 14c and compound 1f are reacted to give urea, followed by protection under acidic conditions to give compound 14. The specific experimental procedure is shown in the synthesis of compound 13. MS 574.2 [M+H] + .
- FGFR1, FGFR2, FGFR3 and FGFR4 protein kinase activities were determined using the Caliper mobility shift assay.
- the compound was dissolved in DMSO and diluted with kinase buffer, and 5 ⁇ L of a 5-fold final concentration of the compound (10% DMSO) was added to a 384-well plate. After adding 10 ⁇ L of 2.5-fold enzyme (FGFR1 and FGFR4, respectively) solution, incubate for 10 minutes at room temperature, and then add 10 ⁇ L of FAM-labeled peptide and ATP solution. Incubate at 28 ° C for 30-60 minutes and then stop the reaction by adding 25 ⁇ L of stop solution.
- the Huh7 cell suspension was adjusted to 5x10e4/mL or 2x 10e4/mL with DMEM + 2Mm Glutamine + 10% FBS medium. 100 ⁇ L of the cell suspension was added to each well in a 96-well cell culture plate to a final cell concentration of 5000 cells/well (72 hours) or 2000 cells/well (168 hours). The test compound was dissolved in DMSO as a 10 mM stock solution. Compounds at a final concentration of 200X were prepared using stock solutions and DMSO, and 3X series gradient dilutions were prepared and then diluted 20-fold with each medium. Finally, 10 ⁇ L of the corresponding 10-fold solution was added to each well of each cell, and each drug concentration was single-well.
- the final treatment concentrations of each compound were 3000 nM, 1000 nM, 333.3 nM, 111.1 nM, 37.04 nM, 12.35 nM, 4.12 nM, 1.37 nM, and the final concentration of DMSO per well was 0.5%.
- After 72 or 168 hours of drug treatment, according to the CTG instructions add 100 ⁇ L of CellTiter Glo detection reagent per well, pre-melt and equilibrate to room temperature CTG solution, mix with a microplate shaker for 2 minutes, and let stand at room temperature for 10 minutes.
- the EnSpire plate reader measures chemiluminescence signal values.
- Table 2 inhibits Huh7 tumor cell proliferation (IC 50 , nM)
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Abstract
Description
FGFR4 | FGFR1 | |
化合物1 | <5 | >10,000 |
化合物2 | <5 | >10,000 |
化合物3 | <20 | |
化合物4 | <20 | |
化合物5 | <5 | |
化合物6 | <5 | |
化合物7 | <20 | |
化合物8 | <5 | |
化合物9 | <5 | |
化合物10 | <5 | |
化合物11 | <5 | |
化合物12 | <5 |
Huh7 | |
化合物1 | <50 |
化合物2 | <50 |
化合物3 | <50 |
化合物4 | <500 |
化合物5 | <50 |
化合物6 | <500 |
化合物7 | <500 |
Claims (21)
- 一种如式(I)所示的化合物,或其药学上可接受的盐、前药、氘代衍生物、水合物、或溶剂合物:其中:T1为N或CR1,其中R1选自下组:氢、卤素、C1-6烷基、C3-6环烷基、氰基、CO2NH2、卤代C1-4烷基或羟基取代的C1-4烷基;T2为N或CR2,其中R2选自下组:氢、卤素、C1-4烷基、C1-4烷氧基、羟基取代的C1-4烷氧基、C2-4烯基、C2-4炔基、CHR3R4、氰基、CO2NH2、C1-4烷氧基取代的C1-4烷基、C1-4烷氧基取代的C1-4烷氧基、C1-4烷氧基取代的卤代C1-4烷氧基、C1-4烷氧基取代的C2-4烯基、C1-4烷氧基取代的C2-4炔基、C1-4烷巯基、双(C1-4烷基)氨基取代的C1-4烷氧基、O(CR7R8)n-R6、NR5(CR7R8)n-R6、或卤代的C1-4烷氧基(优选地,卤代的C1-4烷氧基任选地被羟基取代);R3和R4与其相连的碳原子共同形成含有一或两个选自N、O或S的杂原子的4-至7-元杂环基,其中杂环基任选地被一或两个X1取代;X1各自独立地选自卤素、C1-4烷基、羟基、C3-8环烷基、4-至8-元杂环基、C1-4烷氧基、C1-4烷氧基取代的C1-4烷氧基、C(O)C1-4烷基、氰基、CO2NH2、氨基、C1-4烷基氨基、双(C1-4烷基)氨基、或=O;R5为氢或C1-4烷基;R6为C1-4烷基、羟基取代的C1-4烷基、C2-4烯基、C2-4炔基、C2-4炔基取代的C1-4烷基,C3-12环烷基(包括单环、桥环、螺环、并环)、C3-8环烷基取代的C1-4烷基、含有1至3个任选自N、O和S的杂原子的4-至12-元杂环基(包括单环、桥环、螺环、并环)、4-至12-元杂环基取代的C1-4烷基、6-元芳基、6-元芳基取代的C1-4烷基、5-至6-元杂芳基、5-至6-元杂芳基取代的C1-4烷基、卤代C1-4烷基、C1-4烷氧基取代的C1-4烷基、卤代C1-4烷氧基取代的C1-4烷基、双(C1-4烷基)氨基取代的C1-4烷基,其中烷基、烯基、炔基、环烷基、杂环基、芳基、和杂芳基,任选地被1-3 个X2取代;X2各自独立地选自氢、卤素、C1-4烷基、羟基、C1-4烷氧基、C3-8环烷基、4-至8-元杂环基、C1-4烷氧基取代的C1-4烷基、C1-4烷氧基取代的C1-4烷氧基、C(O)C1-4烷基、C(O)OC1-4烷基、OC(O)C1-4烷基、氨基、C1-4烷基氨基、双(C1-4烷基)氨基、或=O;或R5和R6与其相连的氮原子共同形成可能含有额外的一或两个选自N、O或S杂原子的4-至12-元杂环基,其中杂环基任选地被一或多个X3取代;X3各自独立地选自氢、卤素、C1-4烷基、羟基、C1-4烷氧基、C3-8环烷基、4-至8-元杂环基、C1-4烷氧基取代的C1-4烷氧基、C(O)C1-4烷基、氨基、C1-4烷基氨基、双(C1-4烷基)氨基、双(C1-4烷基)氨基取代的C1-4烷基、或=O;R7和R8各自独立地为氢、C1-4烷基、或卤素;Z为CH或N;其中,当T1为N,T2和Z不是N;当T2为N,T1和Z不是N;当Z为N,T1和T2不是N;Y为NR或O,其中R为氢或C1-4烷基;W为氢或C1-4烷基;V为CH2、O、CH(OH)、CHF、或CF2;U为氢、卤素、C1-4烷基、卤代C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基取代的C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、(CR9R10)p-NR11R12、(CR13R14)q-R15、CH2CO2H、或C(O)H;R9和R10各自独立地为氢或C1-4烷基;R11为C1-4烷基、双(C1-4烷基)氨基取代的C1-4烷基、或含有1-2个任选自N、O和S的杂原子的4-至7-元杂环基;R12为C1-4烷基、卤代C1-4烷基、羟基取代的卤代C1-4烷基、C(O)C1-4烷基、C(O)-CH2-OH、C(O)-CH2-OCH3、C(O)-CH2-N(CH3)2、S(O)2CH3或C(O)C(O)N(R16)2;或者R11和R12与和它们连接的N原子一起形成单环、双环、或多环的4-至12-元的环状结构,该环状结构除了含有已有的N原子外,还可以含有额外的1-2个任选自N、O、S的杂原子;而且,该环状结构可以任选地被1-3个X4取代,取代的位点在C和N原子上,前提条件是所形成的结构是合理的稳定结构;X4各自独立地选自卤素、C1-4烷基、C3-8环烷基、4-至6-元杂环基、C1-4烷基取代的4-至6-元杂环基、6-元芳基、5-至6-元杂芳基、羟基、C1-4烷氧基、卤代C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基取代的C1-4烷基、C(O)C1-4烷基、C(O)CH2OH、C(O)OC1-4烷基、OC(O)C1-4烷基、氨基、C1-4烷基氨基、双(C1-4烷基)氨基、双(C1-4烷基)氨基取代的C1-4烷基、或=O;R13和R14各自独立地为氢、C1-4烷基、或卤素;R15为C3-8环烷基、含有1-3个任选自N、O和S的杂原子的4-至12-元杂环基、6-元芳基、或含有1-3个任选自N、O和S的杂原子的5-至6-元杂芳基,其中环烷基、杂环基、芳基、或杂芳基任选地被1-3个X4取代,X4的定义如上所 述;R16各自独立地选自氢或C1-4烷基;m为0、1、2或3;n为0、1、2或3;p为0、1、或2;q为0、1、或2。
- 如权利要求1所述的化合物,其特征在于,T1为CR1;和/或T2为CR2;和/或Z为CH;和/或Y为NH;和/或W为氢;和/或V为CH2;和/或m为1;和/或U为C1-4烷基、卤代C1-4烷基、羟基取代的C1-4烷基、C1-4烷氧基取代的C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、CH2-NR11R12、(CR13R14)q-R15、CH2CO2H、或C(O)H;其中R1、R2、R11、R12、R13、R14、R15和q分别如上所述。
- 如权利要求1-2任一所述的化合物,其特征在于,R1为CN。
- 如权利要求1-3任一所述的化合物,其特征在于,R2为NR5(CR7R8)n-R6或O(CR7R8)n-R6;其中R5为氢或C1-4烷基;R6为C2-4烯基、C2-4炔基、C2-4炔基取代的C1-4烷基、C3-12环烷基(包括单环、桥环、螺环、并环)、C3-8环烷基取代的C1-4烷基、含有1至3个任选自N、O和S的杂原子的4-至12-元杂环基(包括单环、桥环、螺环、并环)、4-至12-元杂环基取代的C1-4烷基、6-元芳基、6-元芳基取代的C1-4烷基、5-至6-元杂芳基、或5-至6-元杂芳基取代的C1-4烷基,其中烷基、烯基、炔基、环烷基、杂环基、芳基、或杂芳基任选地被1-3个X2取代,X2如上所述;或R5和R6与其相连的氮原子一起共同形成可能含有额外的1-2个任选自N、O或S杂原子的4-元至5-元杂环基或7-至12-元杂环基,其中杂环基任选地被1-2个X3取代,X3如上所述,其中n、R7和R8的定义如上所述。
- 如权利要求1-4任一所述的化合物,其特征在于,R2为NH(CR7R8)n-R6或O(CR7R8)n-R6;R6为C2-4烯基、C2-4炔基、C2-4炔基取代的C1-4烷基、C3-12环烷基(包括单环、桥环、螺环、并环)、C3-8环烷基取代的C1-4烷基、含有1至3个任选自N、O和S的杂原子的4-至12-元杂环基(包括单环、桥环、螺环、并环)、含4-至12-元杂环基的C1-4烷基、6-元芳基、6-元芳基取代的C1-4烷基、5-至6-元杂芳基、或5-至6-元杂芳基取代的C1-4烷基,其中烷基、烯基、炔基、环烷基、杂环基、芳基、或杂芳基任选地被1-3个X2取代,X2如上所述;其中n、R7和R8的定义如上所述。
- 如权利要求1-5任一所述的化合物,其特征在于,R2为NHR6或OR6;R6为C2-4炔基取代的C1-4烷基、C3-12环烷基(包括单环、桥环、螺环、并环)、C3-8环烷基取代的C1-4烷基、含有1-3个任选自N、O和S的杂原子的4-至12-元杂环基(包括单环、桥环、螺环、并环),4-至12-元杂环基取代的C1-4烷基,其中烷基、炔基、环烷基、杂环基任选地被1-3个X2取代,X2如上所述。
- 如权利要求1-6任一所述的化合物,其特征在于,R2为NHR6或OR6;R6为C3-8环烷基、含有1-3个任选自N、O和S的杂原子的3-至8-元杂环烷基、C1-4烷氧基取代的C3-8环烷基、羟基取代的C3-8环烷基、C1-4烷氧基取代的C1-4烷基、C3-8环烷基取代的C1-4烷基、3-至8-元杂环烷基取代的C1-4烷基、含羟基的C3-8环烷基取代的C1-4烷基,其中烷基、环烷基、杂环基任选地被1-3个X2取代,X2如上所述。
- 如权利要求1-9任一所述的化合物,其特征在于,U为CH2-NR11R12;其中,R11为C1-4烷基、4-至6-元杂环基、或双(C1-4烷基)氨基取代的C1-4烷基;R12为C1-4烷基、卤代C1-4烷基、羟基卤代的C1-4烷基、C(O)C1-4烷基、C(O)-CH2-OH、C(O)-CH2-OCH3、C(O)-CH2-N(CH3)2、S(O)2CH3、或C(O)C(O)N(R16)2;R11和R12与和它们连接的N原子一起形成单环、双环、或多环的5-至12-元的环状结构,该环状结构除了含有 已有的N原子外,还可以含有额外的1-2个任选自N、O、S的杂原子;而且,该环状结构可以任选地被1-3个X4取代,取代的位点在C和N原子上,前提条件是所形成的结构是合理的稳定结构;或者U为(CR13R14)0-2-R15;其中,R13和R14各自独立地为氢或C1-4烷基;R15为C3-8环烷基、4-至12-元杂环基、6-元芳基、或5-至6-元杂芳基,其中环烷基、杂环基、芳基、或杂芳基可任选地被1-3个X4取代,X4如上所述。
- 如权利要求1-10任一所述的化合物,其特征在于,U为CH2-NR11R12;其中,R11和R12与和它们连接的N原子一起形成双环、或多环的8-至12-元的环状结构,该环状结构除了含有已有的N原子外,还可以含有额外的1-2个任选自N、O、S的杂原子;而且,该环状结构可以任选地被1-3个X4取代,取代的位点在C和N原子上,前提条件是所形成的结构是合理的稳定结构。
- 如权利要求1-10任一所述的化合物,其特征在于,U为CH2-R15;其中,R15为C3-8环烷基、含有1-3个任选自N、O和S的杂原子的4-至12-元杂环基、6-元芳基、或5-至6-元杂芳基,其中环烷基、杂环基、芳基、或杂芳基可任选地被1-3个X4取代,X4如上所述。
- 如权利要求1-10和12任一所述的化合物,其特征在于,U为CH2-R15;其中,R15为含有1-3个任选自N、O和S的杂原子的4-至12-元杂环基,其中杂环基可任选地被1-3个X4取代,X4如上所述。
- 如权利要求1-10和12-13任一所述的化合物,其特征在于,U为CH2-R15;其中,R15为含有1-3个任选自N、O和S的杂原子的5-至9-元杂环基,其中杂环基可任选地被1-3个X4取代,X4如上所述。
- 一种如权利要求1所述的式(I)化合物的用途,其特征在于,用于:(a)制备治疗与FGFR4活性或表达相关的疾病的药物;和/或(b)制备FGFR4靶向抑制剂;和/或(c)体外非治疗性地抑制FGFR4的活性。
- 一种药物组合物,其特征在于,所述的药物组合物包括:(i)有效量的权利要求1所述的化合物,或其药学上可接受的盐;和(ii)药学上可接受的载体。
- 一种抑制FGFR4活性的方法,其特征在于,所述方法包括步骤:对抑制对象施用抑制有效量的如权利要求1所述的式(I)化合物或其药学上可接受的盐,或对抑制对象施用抑制有效量的如权利要求19所述的药物组合物。
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JP2019527701A (ja) * | 2016-08-12 | 2019-10-03 | 江▲蘇▼豪森▲薬▼▲業▼集▲団▼有限公司 | Fgfr4阻害剤並びにその製造方法及び使用 |
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JP7088906B2 (ja) | 2016-08-12 | 2022-06-21 | 江▲蘇▼豪森▲薬▼▲業▼集▲団▼有限公司 | Fgfr4阻害剤並びにその製造方法及び使用 |
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CN112313207B (zh) * | 2018-06-22 | 2023-02-14 | 北京赛特明强医药科技有限公司 | 一种氰基取代吡啶及氰基取代嘧啶类化合物、制备方法及其应用 |
CN112313207A (zh) * | 2018-06-22 | 2021-02-02 | 北京赛特明强医药科技有限公司 | 一种氰基取代吡啶及氰基取代嘧啶类化合物、制备方法及其应用 |
JP2021532147A (ja) * | 2018-07-27 | 2021-11-25 | ジャコバイオ ファーマスーティカルズ カンパニー リミテッドJacobio Pharmaceuticals Co., Ltd. | Fgfr4阻害剤として使用される縮環誘導体 |
US11136320B2 (en) | 2018-07-27 | 2021-10-05 | Jacobio Pharmaceuticals Co., Ltd. | Fused ring derivative used as FGFR4 inhibitor |
EP3831827A4 (en) * | 2018-07-27 | 2022-04-13 | Jacobio Pharmaceuticals Co., Ltd. | CONDENSED RING DERIVATIVE AS FGFR4 INHIBITOR |
CN112513037A (zh) * | 2018-07-27 | 2021-03-16 | 北京加科思新药研发有限公司 | 用作fgfr4抑制剂的稠环衍生物 |
JP7129728B2 (ja) | 2018-07-27 | 2022-09-02 | ジャコバイオ ファーマスーティカルズ カンパニー リミテッド | Fgfr4阻害剤として使用される縮環誘導体 |
WO2020020377A1 (zh) * | 2018-07-27 | 2020-01-30 | 北京加科思新药研发有限公司 | 用作fgfr4抑制剂的稠环衍生物 |
WO2021014365A1 (en) | 2019-07-22 | 2021-01-28 | Lupin Limited | Macrocyclic compounds as sting agonists and methods and uses thereof |
WO2022089648A1 (en) * | 2020-11-02 | 2022-05-05 | Jacobio Pharmaceuticals Co., Ltd. | Crystalline forms of salts of fgfr4 inhibitor |
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KR102499780B1 (ko) | 2023-02-16 |
EP3483158B1 (en) | 2022-08-10 |
CN111689959A (zh) | 2020-09-22 |
CN109153678B (zh) | 2020-04-14 |
JP2019518077A (ja) | 2019-06-27 |
EP3483158A1 (en) | 2019-05-15 |
KR20190038485A (ko) | 2019-04-08 |
EP3483158A4 (en) | 2020-07-29 |
US11352353B2 (en) | 2022-06-07 |
CN108948004B (zh) | 2020-11-10 |
CN111689959B (zh) | 2022-04-01 |
CN108948004A (zh) | 2018-12-07 |
US20200199120A1 (en) | 2020-06-25 |
KR20210092804A (ko) | 2021-07-26 |
CN109153678A (zh) | 2019-01-04 |
JP7008064B2 (ja) | 2022-01-25 |
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