WO2021115375A1 - 含氮杂环类自分泌运动因子抑制剂及其组合物和用途 - Google Patents
含氮杂环类自分泌运动因子抑制剂及其组合物和用途 Download PDFInfo
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- WO2021115375A1 WO2021115375A1 PCT/CN2020/135220 CN2020135220W WO2021115375A1 WO 2021115375 A1 WO2021115375 A1 WO 2021115375A1 CN 2020135220 W CN2020135220 W CN 2020135220W WO 2021115375 A1 WO2021115375 A1 WO 2021115375A1
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- Prior art keywords
- alkyl
- halogen
- compound
- cycloalkyl
- independently
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims description 93
- 229940122849 Autotaxin inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 242
- -1 nitrogen-containing heterocyclic compound Chemical class 0.000 claims abstract description 182
- 150000003839 salts Chemical class 0.000 claims abstract description 72
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 89
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- 239000013078 crystal Substances 0.000 claims description 67
- 125000000623 heterocyclic group Chemical group 0.000 claims description 57
- 125000003545 alkoxy group Chemical group 0.000 claims description 50
- 125000004432 carbon atom Chemical group C* 0.000 claims description 50
- 229910052757 nitrogen Inorganic materials 0.000 claims description 50
- 150000001721 carbon Chemical group 0.000 claims description 47
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 44
- 125000005843 halogen group Chemical group 0.000 claims description 38
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 36
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 36
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 238000006467 substitution reaction Methods 0.000 claims description 22
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 21
- 125000000304 alkynyl group Chemical group 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 14
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 12
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 11
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 10
- 125000004419 alkynylene group Chemical group 0.000 claims description 10
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
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- 125000004429 atom Chemical group 0.000 claims description 9
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- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 6
- 230000003305 autocrine Effects 0.000 claims description 6
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 206010003246 arthritis Diseases 0.000 claims description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- 229910052805 deuterium Inorganic materials 0.000 claims description 4
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 230000004899 motility Effects 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
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- 102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 abstract description 17
- 230000005496 eutectics Effects 0.000 abstract description 5
- 108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 abstract 1
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 257
- 238000006243 chemical reaction Methods 0.000 description 218
- 239000000243 solution Substances 0.000 description 188
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- 238000003756 stirring Methods 0.000 description 58
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- 239000012153 distilled water Substances 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
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- 239000000047 product Substances 0.000 description 31
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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 24
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- HZSLJFGMNPIAOY-UHFFFAOYSA-N 4,5,6,7-tetrahydro-2H-triazolo[4,5-c]pyridine hydrochloride Chemical compound Cl.C1Cc2n[nH]nc2CN1 HZSLJFGMNPIAOY-UHFFFAOYSA-N 0.000 description 9
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Definitions
- the present invention relates to a nitrogen-containing heterocyclic compound, or its stereoisomer, solvate, deuterium, pharmaceutically acceptable salt, co-crystal or their pharmaceutical composition, and its preparation for the treatment/prevention of autocrine movement Use in medicine for factor-mediated diseases.
- Autocrine motility factor is an enzyme responsible for the increase of lysophosphatidic acid in ascites and plasma, and it is the conversion of lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA) as a biologically active signaling molecule.
- LPC lysophosphatidylcholine
- LPA lysophosphatidic acid
- ATX is a secreted enzyme also known as exonucleotide pyrophosphatase/phosphodiesterase 2 or lysophospholipase D, which is useful for converting lysophosphatidylcholine (LPC) into organisms.
- the active signal molecule lysophosphatidic acid (LPA) is important. ATX plays a role in causing pathological conditions including fibrosis, arthritis, neurodegeneration, neuropathic pain, and cancer.
- LPA is a physiologically active lipid, which has an effect on the migration, proliferation and survival of various types of cells. Since the level of LPA in plasma is highly correlated with the activity of ATX, it is believed that ATX is an important source of extracellular LPA. It has been shown that under pathological conditions, the inhibition of ATX reduces LPA levels. Early experiments with prototype ATX inhibitors have confirmed that such compounds can inhibit LPA synthesis activity in mouse plasma. Early work has proven that LPA can cause a variety of cellular responses: including smooth muscle cell contraction, platelet activation, cell proliferation, chemotaxis, and so on.
- LPA mediates its effects by sending signals to several G protein-coupled receptors (GPCRs); the first members were originally expressed as Edg (endothelial cell differentiation gene) receptors or ventricular region gene-1, but are now called LPA receptor.
- GPCRs G protein-coupled receptors
- the prototype group now consists of LPA1/Edg-2, VZG-1, LPA2/Edg-4 and LPA3/Edg-7.
- LPA4/p2y9/GPR23, LPA5/GPR92, and LPA6/p2y5 have been described, which are more closely related to the nucleotide-selective purine energy than the prototype LPA1-3 receptor. Receptor connection.
- the ATX-LPA signal axis involves a variety of physiological and pathological functions, including, for example, nervous system function, vascular development, cardiovascular physiology, reproduction, immune system function, chronic inflammation, tumor metastasis and progression, organ fibrosis, and obesity. / Or other metabolic diseases such as diabetes.
- the present invention first provides a nitrogen-containing heterocyclic compound of formula (I) with ATX inhibitory activity, its stereoisomers, solvates, deuterated compounds, and pharmaceutically acceptable salts Or eutectic,
- X is O, S or NR x , R x is H or cyano;
- Each R 1 to R 6 is independently selected from H, halogen, C 1-4 alkyl or C 3-6 cycloalkyl;
- Each R 7 and R 8 is independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl;
- R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 on the carbon atom together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring, which is optionally substituted by 1- 4 substituents selected from halogen or C 1-4 alkyl;
- a, c and e are independently selected from an integer of 0-5, b and d are independently 0 or 1;
- A is C 3-6 cycloalkylene, C 2-4 alkynylene, -RaC(O)NRa'-, -RaNRa'C(O)-, -RaNRa'-, -RaC(O)-, -Ra(CRa'Ra”) n -or bond ;
- Ra' and Ra" are independently H or C 1-4 alkyl
- n is an integer of 1-2;
- X 1 and X 2 are independently N or CR A1 , and are not CR A1 at the same time, and X 3 is S, O or NR A1 ;
- X 4 , X 5 and X 6 are independently N, NR A1 , S, O or CR A1 , and they are not CR A1 at the same time;
- Each R A1 is independently H, cyano, -R A, halo, -C 1-4 alkyl R A, -NHC (O) R A, -C (O) R A, -C 1-4 alkyl Group -OC 1-4 alkyl, -NHR A , -C(O)NHR A or -OR A ;
- R A is C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy , Or a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, the alkyl group, cycloalkyl group, cycloalkyloxy group, alkoxy group, halogenated alkyl group, halogenated alkoxy group , The heterocyclic group is optionally further selected from C 3-6 cycloalkyl, C 1-4 alkyl, halogen, -S (O) 2 C 1-4 alkyl, -OC 1-4 Alkyl or cyano group substitution;
- Y 1 is O, S or NR B3 ;
- Cy has a structure: among them, Represents a single bond or a double bond, Z 1 is C or N, ring E is a 5-membered heterocyclic ring containing 1-3 heteroatoms selected from N, O or S, and ring D contains 0-3 heteroatoms selected from N, O Or a 6-membered ring of S heteroatom; the 5-membered heterocyclic ring and the 6-membered ring are independently optionally substituted by 1-3 R B2;
- Each R B1 and R B2 is independently selected from H, oxo, OH, halogen, cyano, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkyloxy Or C 3-6 cycloalkyl;
- R B3 is selected from H, C 1-4 alkyl or C 3-6 cycloalkyl;
- the group R A1 on A and the group R B1 on B together with the atoms to which they are attached form a 6-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S and O;
- f is an integer of 0-3;
- L 2 is -O-, -NR 9 -, -C(O)NR 9 -, -NR 9 C(O)NR 9 -, -(CR 10 R 11 ) g -, -NR 9 -(CR 10 R 11 ) g -or bond, g is an integer of 1-3;
- R 9 is H or C 1-4 alkyl
- Each R 10 and R 11 is independently H, halogen, C 1-4 alkyl or C 3-6 cycloalkyl; alternatively, R 10 and R 11 on the same carbon atom and the carbon atom to which they are attached form a 3- 6-membered carbon ring;
- Z 2 and Z 3 are CR M or N, and Z 4 is O, S or NR M1 ;
- Each R M is independently H, C 1-4 alkyl, C 1-4 alkoxyalkyl, cyano, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, -SRm' , -S(O) 2 Rm', -C(O)NRmRm', -NRmC(O)Rm', C 2-6 alkenyl, C 2-6 alkynyl, -NR M1 , containing 1-3 options
- a 3-6 membered heterocyclic group derived from N, O or S heteroatoms, or halogen; the alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally selected from halogen, cyano, C 1-4 alkoxy, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy group substituted, the heterocyclic group is optionally substituted by 1-3 selected from halogen, oxo, Substitution of C 1-4 alkyl groups;
- the two R M on the adjacent ring carbon atoms in M 2 together with the carbon atoms to which they are connected form a 3-6 membered carbon ring or 3-6 membered carbon ring containing 0-3 heteroatoms selected from N, O or S Heterocyclic group;
- Rm is H, C 1-4 alkyl, halogenated C 1-4 alkyl
- Rm' is C 1-4 alkyl, halogenated C 1-4 alkyl
- R M1 is H, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl or C 1-4 alkoxyalkyl;
- R M2 is a halogenated C 1-4 alkoxy group
- Each R 12 is independently H, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, or halo C 1-4 alkyl;
- h is an integer of 0-3;
- i 0, 1 or 2;
- M 1 When M 1 is L 1 is -C(O)-CH 2 -, A is B is L 2 is -NH-, M 2 is When A has at least one substituent R A1 selected from the group consisting of cyano, halogen, C 3-4 cycloalkyloxy, cyclopropylmethyloxy, C 1-4 haloalkoxy, cyclopropylmethyl,- C 1-4 alkyl -OC 1-4 alkyl, -NHC (O) R A, -C (O) NHR A, -C (O) -C 3-6 cycloalkyl,
- M 1 When M 1 is L 1 is -C(O)-CH 2 -, A is B is L 2 is -NH-, M 2 is When, R A1 is not methyl, ethyl, or cyclopropyl.
- X is O, S or NR x , R x is H or cyano;
- Each R 1 to R 6 is independently selected from H, halogen, C 1-4 alkyl or C 3-6 cycloalkyl;
- Each R 7 and R 8 is independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl;
- R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 on the carbon atom together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring, which is optionally substituted by 1- 4 substituents selected from halogen or C 1-4 alkyl;
- a, c and e are independently selected from an integer of 0-5, b and d are independently 0 or 1;
- A is C 3-6 cycloalkylene, C 2-4 alkynylene group or bond
- n is an integer of 1-2;
- X 1 and X 2 are independently N or CR A1 , and are not CR A1 at the same time, and X 3 is S, O or NR A1 ;
- Each R A1 is independently H, cyano, -R A, halo, -C 1-4 alkyl R A, -NHC (O) R A, -C (O) R A, -C 1-4 alkyl Group -OC 1-4 alkyl, -NHR A , -C(O)NHR A , or -OR A ;
- R A is C 1-4 alkyl, C 3-6 cycloalkyl, or contain 1-3 heteroatoms selected from N, O or S heteroatom 3-6 membered heterocyclyl, said alkyl, cycloalkyl ,
- the heterocyclic group is optionally further selected from C 3-6 cycloalkyl, C 1-4 alkyl, halogen, -S (O) 2 C 1-4 alkyl, -OC 1-4 Alkyl or cyano group substitution;
- Y 1 is O, S or NR B3 ;
- Cy has a structure: among them, Represents a single bond or a double bond, Z 1 is C or N, ring E is a 5-membered heterocyclic ring containing 1-3 heteroatoms selected from N, O or S, and ring D contains 0-3 heteroatoms selected from N, O Or a 6-membered ring of S heteroatom; the 5-membered heterocyclic ring and the 6-membered ring are independently optionally substituted by 1-3 R B2;
- R B1 and R B2 are independently selected from H, oxo, OH, halo, cyano, C 1-4 alkyl, halo C 1-4 alkyl, C 1- 4 alkyl group or a C 3 -6 cycloalkyl;
- R B3 is selected from H, C 1-4 alkyl or C 3-6 cycloalkyl;
- the group R A1 on A and the group R B1 on B together with the atoms to which they are attached form a 6-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S and O;
- f is an integer of 0-3;
- L 2 is -O-, -NR 9 -, -(CR 10 R 11 ) g -or a bond, and g is an integer of 1-3;
- R 9 is H or C 1-4 alkyl
- Each R 10 and R 11 is independently H, halogen, C 1-4 alkyl or C 3-6 cycloalkyl; alternatively, R 10 and R 11 on the same carbon atom and the carbon atom to which they are attached form a 3- 6-membered carbon ring;
- Z 2 and Z 3 are CR M or N, and Z 4 is O, S or NR M1 ;
- Each R M is independently H, C 1-4 alkyl, cyano, C 3-6 cycloalkyl or halogen; the alkyl, cycloalkyl is optionally selected from 1-3 halogen, cyano Group substitution;
- R M1 is H, C 1-4 alkyl or C 3-6 cycloalkyl
- h is an integer of 0-3;
- M 1 When M 1 is L 1 is -C(O)-CH 2 -, A is B is L 2 is -NH-, M 2 is When A has at least one substituent R A1 selected from cyano, halogen, C 3-4 cycloalkyloxy, cyclopropylmethoxy, C 1-4 haloalkoxy, cyclopropylmethyl, -C 4alkyl -OC 1-4 alkyl, -NHC (O) R A, -C (O) NHR A, -C (O) -C 3-6 cycloalkyl,
- M 1 When M 1 is L 1 is -C(O)-CH 2 -, A is B is L 2 is -NH-, M 2 is When, R A1 is not methyl, ethyl, or cyclopropyl.
- a, c and e are independently selected from an integer of 0-3, b and d are independently 0 or 1;
- Each R 1 to R 6 is independently selected from H, halogen, C 1-4 alkyl, and R 7 and R 8 are independently selected from H or C 1-4 alkyl;
- A is C 3-6 cycloalkylene, C 2-4 alkynylene group or bond
- R A is C 1-4 alkyl, C 3-4 cycloalkyl, containing 1-2 heteroatoms selected from N, 4-6 membered heterocyclyl O heteroatom, said alkyl, heterocyclyl is further optionally substituted with 1-5 substituents selected from C 3-4 cycloalkyl, C 1-4 alkyl, halo, -S (O) 2 C 1-2 alkyl, -OC 1- 2 alkyl or cyano group Group replacement,
- L 1 is -W-(CR 3 R 4 ) c -, where W is a 5-membered heterocyclylene containing 1-2 heteroatoms selected from N or O, and c is an integer of 0-3,
- the nitrogen-containing heterocyclic compound of formula (I), its stereoisomer, solvate, deuterated product, pharmaceutically acceptable salt or co-crystal, said compound has more specific The structure of formula (II):
- the nitrogen-containing heterocyclic compound of formula (I), its stereoisomer, solvate, deuterated product, pharmaceutically acceptable salt or co-crystal L 1 is -W- (CR 3 R 4 ) c -, W is a 5-membered heterocyclylene containing 1-2 heteroatoms selected from N and O, and when c is an integer of 0-3, the 5-membered heterocyclylene is
- M 1 is The remaining groups are as defined in the aforementioned first or second technical solution.
- the nitrogen-containing heterocyclic compound represented by formula (I), its stereoisomer, solvate, deuterated product, pharmaceutically acceptable salt or co-crystal, said compound has more specific The structure of formula (III)
- A is C 3-6 cycloalkylene, C 2-4 alkynylene, RaC(O)NRa'-or X 1 is N or CR A1, X 3 is S, O or NR A1, each of R A1 is independently H, cyano, -R A, halo, -C 1-4 alkyl R A, -NHC (O ) R A, -C (O) R A, -C 1-4 alkyl -OC 1-4 alkyl, -NHR A, -C (O) NHR A or -OR A, Ra is Ra' is H or C 1-4 alkyl, and the remaining groups are as defined in the first or second technical solution;
- R A is n is not 0, and at least one R A1 is selected from cyano, halogen, C 3-4 cycloalkyloxy, cyclopropylmethoxy, halogenated C 1-4 alkoxy, cyclopropylmethyl , -C 1-4 alkyl -OC 1-4 alkyl, -NHC (O) R A, - C (O) NHR A, -C (O) -C 3-6 cycloalkyl, The remaining groups are as defined in the aforementioned first or second technical solution.
- the nitrogen-containing heterocyclic compound represented by formula (I), its stereoisomers, solvates, deuterated compounds, pharmaceutically acceptable salts or co-crystals has more Specific structure of formula (IV)
- L 1 is -C(O)-(CR 5 R 6 ) e -, and the remaining groups are defined as in the tenth technical solution.
- R B is Wherein at least one of R B1 and R B2 is selected from OH, halogen, cyano, halogenated C 1-4 alkyl, C 1-4 alkyloxy, C 3-6 cycloalkyl, or the group on A
- R A1 and the group R B1 on the group B together with the atoms to which they are connected form a 6-8 membered heterocyclic ring containing 1 O atom, and the remaining groups are as defined in the first or second technical solution; or
- R B2 is halogen or cyano, f is 1, 2 or 3, and the remaining groups are as defined in the first or second technical solution; or
- the nitrogen-containing heterocyclic compound represented by formula (I), its stereoisomers, solvates, deuterated products, pharmaceutically acceptable salts or co-crystals has more Specific structure of formula (V)
- R B is R B1 and R B2 at least one group selected from OH, halogen, cyano, halo C 1-4 alkyl, C 1- 4 alkyl group, C 3-6 cycloalkyl group such as the remainder of the Twelve definitions of technical solutions; or
- R B2 is halogen or cyano, f is 1, 2 or 3, and the remaining groups are as defined in the twelfth technical solution; or
- the nitrogen-containing heterocyclic compound represented by formula (I), its stereoisomers, solvates, deuterated compounds, pharmaceutically acceptable salts or co-crystals has more Specific structure of formula (VI)
- Cy has a structure: among them, Represents a single bond or a double bond, Z 1 is C or N, ring E is a 5-membered heterocyclic ring containing 1-3 heteroatoms selected from N, O or S, and ring D is saturated or unsaturated and contains 0-3 A 6-membered ring selected from N, O or S heteroatoms; the 5-membered heterocyclic ring and the 6-membered ring are independently optionally substituted with 1-3 R B2;
- Each R B2 is independently selected from H, halogen, cyano, C 1-4 alkyl, halo C 1-4 alkyl;
- L 2 is -NH-or bond
- R M is a halogenated C 1-4 alkyl, cyano, C 3-6 cycloalkyl, C 2-6 alkynyl or contains 1-3 selected from N, O or S heteroatom 3-6 membered heterocyclic group; the alkyl group is optionally substituted by 1-3 groups selected from halogen or cyano, and the heterocyclic group is optionally substituted by 1-3 groups Substitution by a group selected from halogen, oxo or C 1-4 alkyl; or, alternatively, two R M on adjacent ring carbon atoms in M 2 together with the carbon atom to which they are attached form a group containing 0-3 A 3-6 membered carbocyclic or 3-6 membered heterocyclic group derived from N, O or S heteroatoms; the remaining groups are as defined in the first or second technical solution; preferably, M 2 is Wherein R M is trifluoromethyl, difluoromethyl, cyclopropyl, e
- the nitrogen-containing heterocyclic compound represented by formula (I), its stereoisomers, solvates, deuterated products, pharmaceutically acceptable salts or co-crystals has More specific structure of formula (VII)
- M 2 is as defined in the aforementioned sixteenth technical solution.
- the nitrogen-containing heterocyclic compound represented by formula (I) its stereoisomers, solvates, deuterated products, pharmaceutically acceptable salts or co-crystals,
- L 1 is -(CR 1 R 2 ) a -(NR 7 ) b -W-(CR 3 R 4 ) c -(NR 8 ) d -(CR 5 R 6 ) e -;
- a and b are 0, c is 1 or 2, and d and e are 0;
- Each R 3 , R 4 is independently selected from H, halogen, C 1-4 alkyl, and is not H at the same time;
- R B is R B1 and R B2 are both H;
- L 2 is -NR 9 -, R 9 is H;
- M 2 is Z 2 and Z 3 are CR M , and Z 4 is O or S;
- Each R 12 is independently H, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, or halo C 1-4 alkyl;
- h 0, 1 or 2;
- Each R M is independently H or C 1-4 alkyl, which alkyl is optionally substituted with 1-3 halogens;
- the nitrogen-containing heterocyclic compound represented by formula (I) its stereoisomers, solvates, deuterated products, pharmaceutically acceptable salts or co-crystals,
- L 1 is a bond or -(CR 1 R 2 ) a -(NR 7 ) b -W-(CR 3 R 4 ) c -(NR 8 ) d -(CR 5 R 6 ) e -;
- X is O, S or NR x , R x is H or cyano;
- Each R 1 to R 6 is independently selected from H, halogen, C 1-4 alkyl or C 3-6 cycloalkyl;
- Each R 7 and R 8 is independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl;
- R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 on the carbon atom together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring, which is optionally substituted by 1- 4 substituents selected from halogen or C 1-4 alkyl;
- a, c and e are independently selected from 0, 1, 2 and 3, and b and d are independently 0 or 1;
- A is -RaC(O)NRa'-, -RaNRa'C(O)-, -RaNRa'-, -RaC(O)-, or -Ra(CRa'Ra”) n -;
- Ra' and Ra" are H or C 1-4 alkyl
- n 1 or 2;
- X 1 and X 2 are independently N, NR A1 or CR A1 , and are not CR A1 at the same time;
- X 4 , X 5 and X 6 are independently N, NR A1 , S, O or CR A1 , and they are not CR A1 at the same time;
- Each R A1 is independently H, cyano, -R A, halo, -C 1-4 alkyl R A, -NHC (O) R A, -C (O) R A, -C 1-4 alkyl Substituents of -OC 1-4 alkyl, -NHR A , -C(O)NHR A , -OR A;
- R A is C 1-4 alkyl, C 3-6 cycloalkyl, or contain 1-3 heteroatoms selected from N, O or S heteroatom 3-6 membered heterocyclyl, said alkyl, cycloalkyl ,
- the heterocyclic group is optionally further selected from C 3-6 cycloalkyl, C 1-4 alkyl, halogen, -S (O) 2 C 1-4 alkyl, -OC 1-4 Alkyl or cyano group substitution;
- Each R B1 and R B2 is independently selected from H, OH, halogen, cyano, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkyloxy or C 3-6 ring alkyl;
- L 2 is -O-, -NR 9 -, -(CR 10 R 11 ) g -, -NR 9 -(CR 10 R 11 ) g -or bond, g is an integer of 1-3;
- R 9 is H or C 1-4 alkyl
- Each R 10 and R 11 is independently H, halogen, C 1-4 alkyl or C 3-6 cycloalkyl; alternatively, R 10 and R 11 on the same carbon atom and the carbon atom to which they are attached form a 3- 6-membered carbon ring;
- Z 2 and Z 3 are CR M or N, and Z 4 is O, S or NR M1 ;
- Each R M is independently H, C 1-4 alkyl, cyano, C 3-6 cycloalkyl, -SRm', -S(O) 2 Rm', -C(O)NRmRm', -NRmC (O) Rm', C 2-6 alkynyl, or a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, or halogen; the alkyl, alkynyl, cycloalkane The group is optionally substituted with 1-3 groups selected from halogen, cyano, C 1-4 alkoxy, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy, the hetero cycloalkyl group optionally substituted with 1-3 substituents selected from halo, oxo, C 1- 4 alkyl group;
- Rm is H, C 1-4 alkyl, halogenated C 1-4 alkyl, Rm' is C 1-4 alkyl, halogenated C 1-4 alkyl;
- R M1 is H, C 1-4 alkyl or C 3-6 cycloalkyl
- R M2 is a halogenated C 1-4 alkoxy group
- Each R 12 is independently H, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, or halo C 1-4 alkyl;
- h is an integer of 0-3;
- i 0, 1 or 2;
- the nitrogen-containing heterocyclic compound represented by formula (I) its stereoisomers, solvates, deuterated products, pharmaceutically acceptable salts or co-crystals,
- L 1 is a bond or -W-(CR 3 R 4 ) c -;
- X is O or S
- Each R 3 and R 4 is independently selected from H, halogen or C 1-4 alkyl
- R 3 and R 4 on the same carbon atom and the carbon atom to which they are attached form a 3-6 membered carbocyclic ring;
- c is selected from 0, 1 and 2;
- A is -RaC(O)NRa'-, -RaNRa'C(O)-, -RaC(O)-, or -Ra(CRa'Ra”) n -;
- Ra' and Ra" are H or C 1-4 alkyl
- n 1 or 2;
- X 1 and X 2 are independently N, NR A1 or CR A1 , and are not CR A1 at the same time;
- X 4 , X 5 and X 6 are independently N, NR A1 , S, O or CR A1 , and they are not CR A1 at the same time;
- Each R A1 is independently H;
- R B1 and R B2 are both H;
- L 2 is -NR 9 -or -NR 9 -(CR 10 R 11 ) g -, g is an integer of 1-3;
- R 9 is H
- R 10 and R 11 are independently H;
- Z 2 and Z 3 are CR M , and Z 4 is O or S;
- Each R M is independently H, C 1-4 alkyl, C 3-6 cycloalkyl, -SRm', -S(O) 2 Rm', -C(O)NRmRm', -NRmC(O) Rm', C 2-6 alkynyl, 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S or halogen; the alkyl, alkynyl, cycloalkyl are optionally One to three groups selected from the group consisting of halogen, C 1-4 alkoxy, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy, the heterocyclic group is optionally substituted by 1- Substitution with 3 groups selected from halogen, oxo, and C 1-4 alkyl;
- Rm is H or C 1-4 alkyl, Rm' is C 1-4 alkyl;
- R M2 is a halogenated C 1-4 alkoxy group
- h 0, 1 or 2;
- i 0, 1 or 2;
- the nitrogen-containing heterocyclic compound represented by formula (I) its stereoisomers, solvates, deuterated products, pharmaceutically acceptable salts or co-crystals,
- h 1 or 2
- R M is C 1-4 alkyl, C 3-6 cycloalkyl, -SRm', -S(O) 2 Rm', -C(O)NRmRm', -NRmC(O)Rm', C 2- 6- alkynyl group, or 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, the alkyl group is optionally substituted by 1-3 selected from halogen, C 1-4 alkoxy Group or a halo C 1-4 alkoxy group, the heterocyclic group is optionally substituted with 1-3 groups selected from halogen, oxo, and C 1-2 alkyl;
- the nitrogen-containing heterocyclic compound represented by formula (I) its stereoisomers, solvates, deuterated products, pharmaceutically acceptable salts or co-crystals,
- M2 is The remaining groups are as defined in the aforementioned twentieth technical solution.
- the nitrogen-containing heterocyclic compound represented by formula (I), its stereoisomer, solvate, deuterated product, pharmaceutically acceptable salt or co-crystal, wherein c is 1 or 2, the R 3 and R 4 on the carbon atom together with the carbon atom to which they are connected form a 3-6 membered carbocyclic ring, and the remaining groups are as defined in the twentieth technical solution mentioned above.
- L 1 is -W-(CR 3 R 4 ) c -or -W-(NR 8 ) d -(CR 5 R 6 ) e -;
- X is O or S
- R 3 , R 4 , R 5 and R 6 is independently selected from H, halogen or C 1-4 alkyl
- Each R 8 is independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl;
- c and e are independently selected from 0 or 1, and d is 1;
- X 1 and X 2 are independently N or CR A1 , and are not CR A1 at the same time;
- R A1 is cyano, C 1-4 alkyl, -R A or halogen
- R A is C 3-6 cycloalkyl, C 3-6 cycloalkyl group, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, a cycloalkyl group, Cycloalkyloxy, alkoxy, haloalkyl, and haloalkoxy are optionally further substituted with 1 to 3 groups selected from C 1-4 alkyl, halogen, and cyano;
- R B1 and R B2 are both H;
- L 2 is -NR 9 -;
- R 9 is H or C 1-4 alkyl
- Z 2 and Z 3 are CR M or N, and Z 4 is O or S;
- Each R M is independently H, C 1-4 alkyl, C 1-4 alkoxyalkyl, cyano, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 2- 6 alkenyl, C 2-6 alkynyl, -NR M1 , or a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S; the alkyl, alkenyl, alkynyl, The cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen and cyano, and the heterocyclic group is optionally substituted with 1 to 3 groups selected from halogen or C 1-4 alkyl;
- the two R M on adjacent ring carbon atoms in M 2 together with the carbon atoms to which they are connected form a 3-6 membered carbon ring or 3-6 membered carbon ring containing 0-3 heteroatoms selected from N, O or S Membered heterocyclic group;
- R M1 is H, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl or C 1-4 alkoxyalkyl;
- Each R 12 is independently H, halogen or C 1-4 alkyl
- h is an integer of 0-3;
- i 0, 1, or 2.
- Z 2 is CR M
- Each R M is independently H, C 1-4 alkyl, C 1-4 alkoxyalkyl, C 3-6 cycloalkyloxy, C 2-6 alkenyl, C 2-4 alkynyl , -NR M1 , or a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S; the alkyl group, alkenyl group, alkynyl group are optionally substituted by 1-3 halogen, cyano Substitution;
- the two R M on adjacent ring carbon atoms in M 2 together with the carbon atoms to which they are connected form a 3-6 membered carbon ring or 3-6 membered carbon ring containing 0-3 heteroatoms selected from N, O or S Membered heterocyclic group;
- R M1 is H, C 1-4 alkyl or C 3-6 cycloalkyl
- h is 1 or 2;
- R 3 and R 4 are independently selected from H, halogen and C 1-4 alkyl
- L 2 is NH
- h is 1 or 2;
- Each R M is independently H, C 1-4 alkyl or C 2-4 alkynyl; said alkyl or alkynyl is optionally substituted with 1-3 groups selected from halogen and cyano;
- R 3 , R 4 and R M are not H at the same time.
- the present invention also provides a pharmaceutical composition, which contains a pharmaceutically effective amount of the nitrogen-containing heterocyclic compound according to any one of the preceding embodiments, or a stereoisomer, solvate, deuterium, or pharmaceutically acceptable Salts or co-crystals, and pharmaceutically acceptable excipients and/or carriers.
- the present invention also provides the nitrogen-containing heterocyclic compound according to any one of the foregoing embodiments, or its stereoisomers, solvates, deuterated compounds, pharmaceutically acceptable salts or co-crystals, or combinations thereof Use in the preparation of medicines for the treatment/prevention of diseases mediated by autocrine motility factors; and
- the nitrogen-containing heterocyclic compound according to any one of the foregoing embodiments, or its stereoisomers, solvates, deuterated compounds, pharmaceutically acceptable salts or co-crystals, or a combination thereof, is useful in the treatment or prevention of autocrine motility factors Use in mediated diseases.
- autocrine motor factor-mediated disease is selected from cardiovascular disease, cancer, metabolic disorder, kidney disease, liver disease, inflammatory disease, nervous system disease, respiratory system disease, fibrotic disease , Eye disorders, cholestasis and other forms of chronic pruritus, and acute or chronic organ transplant rejection.
- the inflammatory conditions include but are not limited to arthritis, atopic dermatitis, arthritis and asthma.
- M 1 is In some embodiments, M 1 is In some embodiments, M 1 is
- X is O, S, or NR x , and R x is H or cyano; in some embodiments, X is O, S, or NR x , and R x is cyano; in some embodiments, X is O or S;
- each R 1 to R 6 is independently selected from H, halogen, C 1-4 alkyl, or C 3-6 cycloalkyl; in some embodiments, each R 1 to R 6 is independently Ground is selected from H, halogen or C 1-4 alkyl;
- R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 on the carbon atom together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring, which is optionally Substituted by 1-4 substituents selected from halogen or C 1-4 alkyl; in some embodiments, R 3 and R 4 , or R 5 and R 6 on the same carbon atom are formed together with the carbon atom to which they are attached 3-4 membered carbocyclic ring, said carbocyclic ring is optionally substituted by 1-2 substituents selected from halogen or C 1-2 alkyl;
- each R 7 and R 8 is independently selected from H, C 1-4 alkyl, or C 3-6 cycloalkyl;
- a, c, and e are independently selected from integers from 0 to 5, in some embodiments, a, c, and e are independently selected from integers from 0 to 3, in some embodiments, a, c and e are independently 0 or 1;
- b and d are independently 0 or 1;
- L 1 is -C(O)-CF 2 -, -C(O)-CHF-, -C(O)-C(CH 3 )F-, -C(O)-CH 2 -, -C(O)-, -C(O)-CH 2 CH 2 -, -C(O)-CH 2 CH 2 -N(CH 3 )-
- A is C 3-6 cycloalkylene, C 2-4 alkynylene, -RaC(O)NRa'-, -RaNRa'C(O)-, -RaNRa'-, -RaC(O)-, -Ra(CRa'Ra”) n -or bond ; In some embodiments, A is C 3-6 cycloalkylene, C 2-4 alkynylene, In some embodiments, A is Ra is In some embodiments, Ra is In some embodiments, A is In some embodiments, A is
- Ra' and Ra" are independently H or C 1-4 alkyl
- n is an integer of 1-2;
- X 1 and X 2 are independently N or CR A1 , in some embodiments, X 1 and X 2 are not CR A1 at the same time, and in some embodiments, X 3 is S, O, or NR A1 ;
- X 4 , X 5, and X 6 are independently N, NR A1 , S, O, or CR A1 , and are not CR A1 at the same time;
- each of R A1 is independently H, cyano, -R A, halo, -C 1-4 alkyl R A, -NHC (O) R A, -C (O) R A, -C 1-4 alkyl-OC 1-4 alkyl, -NHR A , -C(O)NHR A , or -OR A ;
- R A is C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy or 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, the alkyl, cycloalkyl, cycloalkyloxy, alkoxy, haloalkane Group, halogenated alkoxy group, heterocyclic group is optionally further selected from 1-6 C 3-6 cycloalkyl, C 1-4 alkyl, halogen, -S (O) 2 C 1-4 alkyl, -OC 1-4 alkyl or cyano groups; in some embodiments, R a is C 1-4 alkyl, C 3-6 cycloalkyl, or containing 1-3 heteroatoms selected from N, O or S heteroatom 3-6 membered heterocyclic group, the alkyl, cycloalkyl, hetero
- A is Cyclopropylene, ethynylene, In a preferred embodiment, A is
- B is In some embodiments, B is At least one of R B1 and R B2 is selected from OH, halogen, cyano, halogenated C 1-4 alkyl, C 1-4 alkyloxy, C 3-6 cycloalkyl, or the group R on A
- Y 1 is O, S, or NR B3 ;
- Cy has the structure: among them, Represents a single bond or a double bond, Z 1 is C or N, ring E is a 5-membered heterocyclic ring containing 1-3 heteroatoms selected from N, O or S, and ring D contains 0-3 heteroatoms selected from N, O Or a 6-membered ring of S heteroatom; the 5-membered heterocycle and 6-membered ring are independently optionally substituted with 1-3 R B2 ; in some embodiments, Cy is selected from one of the following structures:
- each R B1 and R B2 is independently selected from H, oxo, OH, halogen, cyano, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkane Oxy, C 3-6 cycloalkyl
- R B3 is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, in some embodiments, the group R A1 on A and the group R A1 on B
- f is an integer from 0 to 3;
- B is
- L 2 is -O-, -C(O)NR 9 -, -NR 9 C(O)NR 9 -, -NR 9 -, -(CR 10 R 11 ) g -, -NR 9 -(CR 10 R 11 ) g -or bond, g is an integer of 1-3;
- L 2 is -O- or -CR 10 R 11 -, wherein at least one of R 10 and R 11 is halogen or C 1-4 alkyl, or the carbon to which R 10 and R 11 are attached Atoms form a 3-4 membered carbocyclic ring, such as cyclopropyl;
- L 2 is -NR 9 -and R 9 is H or C 1-4 alkyl
- each of R 10 and R 11 is independently H, halogen, C 1-4 alkyl, or C 3-6 cycloalkyl; alternatively, R 10 and R 11 on the same carbon atom are connected to it The carbon atoms form a 3-6 membered carbon ring;
- L2 is -NH-, -O-, -CF2-, -C(CH3)2-, -NHC(O)NH- or -C(O)NH-;
- M 2 is In some embodiments, M 2 is In some embodiments, M 2 is In some embodiments, M 2 is In some embodiments, M 2 is In some embodiments, Z 2, Z 3 is CR M or N, Z 4 is O, S or NR M1; In some embodiments, Z 2 is CR M;
- each R M is independently H, C 1-4 alkyl, C 1-4 alkoxyalkyl, cyano, C 3-6 cycloalkyl, C 3-6 cycloalkyl Oxy, -SRm', -S(O) 2 Rm', -C(O)NRmRm', -NRmC(O)Rm', C 2-6 alkenyl, C 2-6 alkynyl, -NR M1 , A 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, or halogen; the alkyl, alkenyl, alkynyl, and cycloalkyl are optionally selected from 1-3 Halogen, cyano, C 1-4 alkoxy, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy group substituted, the heterocyclic group is optionally selected from 1-3 Substitution from halogen, oxo, C 1-4 alkyl groups; in some embodiments
- the two R M on the adjacent ring carbon atoms in M 2 together with the carbon atoms to which they are connected form a 3-6 membered carbon ring or 3-6 membered carbon ring containing 0-3 heteroatoms selected from N, O or S Heterocyclic group; further, the two R M on the adjacent ring carbon atoms in M 2 together with the carbon atoms they are connected to form a 3-5 membered carbocyclic ring containing 0-3 heteroatoms selected from N, O or S or A 3-5 membered heterocyclic group; further, the two R M on the adjacent ring carbon atoms in M 2 together with the carbon atoms to which they are connected form a 4- 5-membered carbocyclic or 4-5 membered heterocyclic group; further, two R M on adjacent ring carbon atoms in M 2 form cyclobutane together with the carbon atoms to which they are connected, or contain 1-2 selected from N , O or S heteroatom 5-membered heterocyclic group;
- Rm is H, C 1-4 alkyl or halogenated C 1-4 alkyl
- Rm' is C 1-4 alkyl or halo C 1-4 alkyl; in some embodiments, M 2 is Wherein R M is trifluoromethyl, difluoromethyl, cyclopropyl, ethynyl, furan-3-yl, methylaminocarbonyl, azetidin-1-yl, oxetan-3-yl, 3,3-Difluoro-azetidin-1-yl, acetamido, 1-methyl-1H-pyrazol-4-yl, tetrahydrofuran-3-yl, methylthio, 4-methyl-5- Oxo-1,2,4-triazol-1-yl, 2-oxo-pyrrolidin-1-yl, methanesulfonyl, methoxymethyl, difluoromethoxymethyl or trifluoromethyl Ethynyl
- M 2 is Wherein R M is a C 1-4 alkyl group, the alkyl group is substituted by 1-3 halogens (preferably F); preferably trifluoromethyl or difluoromethyl;
- M 2 is
- H C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, or C 1-4 alkoxyalkyl; in some embodiments, R M1 is H , C 1-4 alkyl or C 3-6 cycloalkyl;
- each R 12 is independently H, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, or halo C 1-4 alkyl; in some embodiments, each R 12 is independently H;
- h is an integer from 0 to 3; in some embodiments, h is 1 or 2;
- i 0, 1 or 2;
- M 1 When M 1 is L 1 is -C(O)-CH 2 -, A is B is L 2 is -NH-, M 2 is When A has at least one substituent R A1 selected from cyano, halogen, C 3-4 cycloalkyloxy, cyclopropylmethoxy, C 1-4 haloalkoxy, cyclopropylmethyl, -C 4alkyl -OC 1-4 alkyl, -NHC (O) R A, -C (O) NHR A, -C (O) -C 3-6 cycloalkyl,
- M 1 When M 1 is L 1 is -C(O)-CH 2 -, A is B is L 2 is -NH-, M 2 is When, R A1 is not methyl, ethyl, or cyclopropyl.
- Patent document CN109476664A introduces a method for preparing a class of ATX inhibitors.
- the starting materials are commercially available chemicals and (or) chemicals. Compounds described in the literature. "Commercially available chemicals" are obtained from formal commercial sources. Suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Medicine Stone, WuXi AppTec and Bellingway Technology, etc. the company.
- references books and monographs in the field detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide articles describing the preparation methods for reference.
- These reference books and monographs include: “Synthetic Organic Chemistry”, John Wiley&Sons, Inc., New York; SRSandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; HOHouse, "Modern Synthetic Reactions", 2nd Ed., WABenjamin, Inc. Menlo Park, Calif. 1972; TLGilchrist, “Heterocyclic Chemistry", 2nd Ed., John Wiley&Sons, New York, 1992; J.
- Halogen herein refers to F, Cl, Br, I, or their isotopes.
- Halo or halogen substitution refers to substitution by more than one selected from F, Cl, Br, I, or their isotopes.
- the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted by the substituted group, Without special limitation, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they can be substituted with the same or different halogens.
- Alkyl refers to a monovalent linear or branched saturated aliphatic hydrocarbon group. Unless otherwise specified, it is an alkyl group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, and more preferably The alkyl group of 1 to 6 carbon atoms is more preferably an alkyl group of 1 to 4 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And its various branched chain isomers.
- Alkylene refers to divalent linear and branched saturated alkyl groups. Examples of alkylene include, but are not limited to, methylene, ethylene, and the like.
- ring includes carbocyclic and heterocyclic rings. Unless otherwise specified, it is usually a 3-12 membered monocyclic ring containing 0 to 3 heteroatoms selected from N, O or S, preferably a 4-7 membered ring, and more preferably a five-membered ring or a six-membered ring.
- Cycloalkyl refers to a monovalent saturated, substituted or unsubstituted carbocyclic hydrocarbon group. Unless otherwise specified, it usually has 3 to 10 carbon atoms, preferably 3-6 carbon atoms, and more preferably 3-4 Carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl and the like.
- Cycloalkylene refers to a divalent saturated, substituted or unsubstituted cycloalkyl group, non-limiting examples include
- Carbocyclic or “carbocyclic group” refers to a substituted or unsubstituted, saturated or unsaturated carbocyclic group, including monocyclic carbocyclic ring, bicyclic bridged ring, bicyclic ring and bicyclic spiro ring, etc., usually 3 to 12 carbon atoms, preferably 3-10 carbon atoms, more preferably 3-6 carbon atoms.
- monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl, etc.
- bicyclic bridged rings include And so on, the double ring and the ring include Etc., the bicyclic spiro ring includes Wait.
- Heterocycle or “heterocyclic group” refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring, and when not specifically limited, it contains 1 to 3 heteroatoms selected from N, O or S, Including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles and bicyclic spiro heterocycles, etc., preferably 3 to 12 membered heterocycles, more preferably 4-12 membered heterocycles, and more preferably 4-10 membered heterocycles.
- the selectively substituted N and S in the heterocyclic ring can be oxidized to various oxidation states.
- the heterocyclic group can be attached to a hetero atom or a carbon atom.
- Non-limiting examples include oxirane ethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolane Group, 1,4-dioxolane, 1,3-dioxanyl, piperazinyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrole Group, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiol, dihydrofuranyl , Dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl
- Heterocyclylene refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic divalent heterocyclic group. Non-limiting examples include Wait.
- Alkynyl refers to a linear or branched monovalent unsaturated hydrocarbon group containing carbon-carbon triple bonds. Unless otherwise specified, an alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms, without limitation. Sexual examples include ethynyl. "Alkynylene” refers to a straight or branched divalent unsaturated hydrocarbon group containing a carbon-carbon triple bond.
- Alkoxy or "alkyloxy” refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyl Oxy and cyclobutoxy, etc.
- “Optional” or “optionally” means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur.
- “Alkyl group optionally substituted by F” means that the alkyl group may but need not be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
- “Pharmaceutically acceptable salt” means that the compound of the present invention maintains the biological effectiveness and characteristics of the free acid or free base, and the free acid is combined with a non-toxic inorganic or organic base, and the free base is combined with Non-toxic inorganic acid or organic acid reaction salt.
- Deuteride refers to the replacement of one or more hydrogen atoms in a compound with a corresponding number of deuterium atoms.
- “Pharmaceutical composition” means a mixture of one or more of the compounds described herein or its stereoisomers, solvates, deuterated products, pharmaceutically acceptable salts or co-crystals, and other components, wherein the other components include Physiologically/pharmaceutically acceptable carriers and/excipients.
- Carrier refers to: it will not cause obvious stimulation to the organism and will not eliminate the biological activity and characteristics of the administered compound, and can change the way the drug enters the human body and the distribution in the body, control the release rate of the drug, and
- Non-limiting examples of systems for delivery to targeted organs include microcapsules and microspheres, nanoparticles, liposomes, and the like.
- Excipient refers to: it is not a therapeutic agent itself, used as a diluent, adjuvant, binder and/or vehicle, used to add to a pharmaceutical composition to improve its handling or storage properties or to allow or promote The compound or pharmaceutical composition forms a unit dosage form for administration.
- pharmaceutical excipients can provide various functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives , Surface active agent, coloring agent, flavoring agent and sweetening agent.
- Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxymethyl Sodium cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose and croscarmellose (e.g.
- croscarmellose sodium (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oil, such as peanut oil, cottonseed oil, red Flower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as oil (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; ( 18) Ringer's solution; (19) ethanol; (20) pH buffer solution; (21) polyester, polycarbonate and/or polyanhydride; and (22) other non-toxic used in pharmaceutical preparations Compatible substances.
- excipients such as cocoa butter and s
- Stepoisomers refer to isomers produced by the different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
- the compounds of the present invention also include their tautomers.
- the present invention describes the compounds on the left side where the pyrimidine ring is substituted by OH, it also includes the tautomer compounds on the right side.
- Solvate refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric solvent that binds non-covalently between molecules.
- the solvent is water, it is a hydrate.
- Co-crystal refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds.
- API active pharmaceutical ingredient
- CCF co-crystal former
- the pure state of API and CCF are both at room temperature. Solid, and there is a fixed stoichiometric ratio between the components.
- a eutectic is a multi-component crystal, which includes both a binary eutectic formed between two neutral solids and a multi-element eutectic formed between a neutral solid and a salt or solvate.
- the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
- NMR nuclear magnetic resonance
- MS mass spectrometry
- the NMR shift ( ⁇ ) is given in units of 10-6 (ppm).
- the NMR measurement was carried out with (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetometers, and the measurement solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) ), the internal standard is tetramethylsilane (TMS); MS is used for determination (Agilent 6120B (ESI) and Agilent 6120B (APCI)); HPLC is determined by Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6 mm,3.5 ⁇ M); Thin-layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingda
- Example 1 2-(3-Cyclopropoxy-4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazole- 1-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one( Compound 1)
- the fifth step 2-(3-cyclopropoxy-4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazole- 1-yl)acetic acid (1h)
- the sixth step 2-(3-cyclopropoxy-4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazole- 1-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one( Compound 1)
- Example 2 4-(2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(2-oxo-2-(1,4, 6,7-Tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)-1H-pyrazole-3-carbonitrile (Compound 2)
- the fourth step 4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(2-oxo-2-(1,4, 6,7-Tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)-1H-pyrazole-3-carbonitrile (Compound 2)
- Example 3 4-(2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-N-methyl-1-(2-oxo-2- (1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)-1H-pyrazole-3-carboxamide (Compound 3)
- the fifth step 2-(4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-3-(methylcarbamoyl)-1H- Pyrazol-1-yl)acetic acid (3h)
- the sixth step 4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-N-methyl-1-(2-oxo-2- (1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)-1H-pyrazole-3-carboxamide (Compound 3)
- Dissolve compound 4a (500mg, 1.96mmol) in 10mL DMF, add HATU (1.11g, 2.94mmol), DIPEA (758mg, 5.88mmol), stir at room temperature, then add hydrazine hydrate (0.25mL), and react at room temperature overnight. After the reaction is complete, it is directly used in the next step.
- the fifth step (1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazole-2 -Yl)cyclopropyl)(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (Compound 4)
- the sixth step 2-(5-(6-((2,3-dihydro-1H-inden-2-yl)amino)pyridazin-3-yl)-1,3,4-oxadiazole-2 -Yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one (compound 5)
- Step 6 Ethyl 3-oxo-3-(2-(2-((1-phenylpyrrolidin-3-yl)amino)pyrimidine-5-carbonyl)hydrazino)propionate (6g)
- the eighth step 2-(5-(2-((1-phenylpyrrolidin-3-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetic acid ( 6i)
- the ninth step 2-(5-(2-((1-phenylpyrrolidin-3-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-1 -(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one (Compound 6)
- the starting material 7a (20g, 68.2mmol) was dissolved in 200mL of methanol, and then di-tert-butyl dicarbonate (16.4g, 75.1mmol) and triethylamine (20.7g, 204.6mmol) were added and stirred at room temperature overnight , Check that the reaction is complete, spin off most of the solvent, add 300 mL of saturated sodium bicarbonate solution, and then extract three times with 300 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate and spin dry to obtain a white solid 7b( 21g, yield 71.2%).
- LC-MS(ESI): m/z 313.2[M+H] + .
- the seventh step 3-(2-(2-((5-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)hydrazino)-3-oxy Ethyl Propionate (7h)
- the ninth step 2-(5-(2-((5-cyclopropyl-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Oxadiazol-2-yl)acetic acid (7j)
- Example 8 2-((5-(5-(2-(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)- (Yl)-2-oxoethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-5-carbonitrile ( Compound 8)
- the seventh step 3-(2-(2-((5-cyano-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)hydrazino)-3-oxo Ethyl propionate (8h)
- the ninth step 2-(5-(2-((5-cyano-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxa Diazol-2-yl)acetic acid (8j)
- the starting material 8b (10g, 32.1mmol) was dissolved in 400mL of anhydrous tetrahydrofuran, then n-butyllithium (2.5M, 32mL, 80.1mmol) was added at minus 78°C, and the reaction mixture was kept at the same temperature After stirring for 30 minutes, DMF (12.5 mL, 160.5 mmol) was added at minus 78 degrees, the mixture was slowly returned to room temperature, and then stirred for another 15 minutes. After the reaction was completed, saturated ammonium chloride solution was added, and then extracted three times with ethyl acetate.
- the seventh step 2-(5-(2-((5-(difluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3 ,4-oxadiazol-2-yl)ethyl acetate (9h)
- Step 8 2-(5-(2-((5-(Difluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3 ,4-oxadiazol-2-yl)acetic acid (9i)
- Step 9 2-(5-(2-((5-(Difluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3 ,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl ) Ethan-1-one (Compound 9)
- the compound 10g (0.12g, 0.35mmol), tetramethylurea chloride hexafluorophosphate (0.12g, 0.42mmol), N-methylimidazole (0.04g, 0.52mmol) of N, N- Intermediate 1i (0.11g, 0.61mmol), N,N-diisopropylethylamine (0.13g, 1mmol) were slowly added to the dimethylformamide (10mL) solution in sequence, and the mixture was placed under nitrogen at room temperature. Stir under protection for 3h. After the reaction was completed, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL ⁇ 2).
- Example 12 1-(6,7-Dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)-yl)-2-(5-(2 -((2,3-Dihydro-1H-inden-2-yl)amino)-4-methoxypyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)ethanone ( Compound 12)
- Ethyl 2-chloro-4-methoxypyrimidine-5-carboxylate (12a) (2.2g, 10mmol), 2-aminoindan (1B) (1.33g, 10mmol) and N,N-diisopropyl Ethylethylamine (2.6 g, 20 mmol) was dissolved in ethanol (20 mL) and stirred at 90°C for 2 hours. After the completion of the reaction, the mixture was cooled to room temperature, and the obtained solid was filtered, washed with ethanol (20 mL), and dried to obtain the title compound (12c) as a beige solid (1.4 g, 45%).
- LC-MS (ESI): m/z 314.1 [M+H] + .
- the fifth step 2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)-4-methoxypyrimidin-5-yl)-1,3,4- Oxadiazol-2-yl)acetic acid (12h)
- Example 13 2-((2,3-Dihydro-1H-inden-2-yl)amino)-5-(5-(2-oxo-2-(1,4,6,7-tetrahydro -5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)nicotinonitrile (compound 13)
- the seventh step 2-(5-(5-cyano-6-((2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4-oxa Diazole-2-tert-Butyl Acetate (13j)
- the eighth step 2-(5-(5-cyano-6-((2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4-oxa Diazol-2-yl)acetic acid (13k)
- the ninth step 2-((2,3-dihydro-1H-inden-2-yl)amino)-5-(5-(2-oxo-2-(1,4,6,7-tetrahydro -5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)nicotinonitrile (compound 13)
- the third step (1-(2-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)hydrazine-1-carbonyl)cyclopropyl)carbamic acid Tert-Butyl ester (14d)
- the fifth step 5-(5-(1-aminocyclopropyl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl) )Pyrimidine-2-amine (14f)
- Dissolve compound 14f (400mg, 1.19mmol) in 5ml of DMF, add triethylamine (721mg, 7.14mmol) and CDI (193mg, 1.19mmol), stir at room temperature for 1h, and then add 4, 5, 6, 7-tetraethylamine (721mg, 7.14mmol) and CDI (193mg, 1.19mmol).
- Example 15 (1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazole-2 -Yl)cyclopropyl)(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone (Compound 15)
- the first step (1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazole-2 -Yl)cyclopropyl)(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)methanone (Compound 15)
- Example 17 2-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazole-2- Yl)-2,2-difluoro-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl -1-one (Compound 17)
- Example 18 (1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazole-2 -Yl)cyclopropyl)(4-(methylsulfonyl)piperazin-1-yl)methanone (Compound 18)
- the first step (1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazole-2 -Yl)cyclopropyl)(4-(methylsulfonyl)piperazin-1-yl)methanone (Compound 18)
- Example 20 1-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazole-2- Yl)cyclobutyl)(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (Compound 20)
- the seventh step 1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazole-2- Yl)cyclobutyl)(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (Compound 20)
- the sixth step 2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)oxazol-4-yl)-1,3,4-oxadiazole-2 -Yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethan-1-one (compound twenty one)
- the third step 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-2-methyloxazole-4-carbonitrile (22d)
- Diisopropylamine (127mg, 1.26mmol) was added to dry tetrahydrofuran (3mL), n-butyllithium (0.5mL, 1.26mmol, 2.5M) was added under nitrogen protection and ice bath, and stirred for half an hour. Then lower the temperature to -78°C, then add 22d (200mg, 0.63mmol) dissolved in tetrahydrofuran, continue stirring for half an hour, add dimethyl carbonate (114mg, 1.26mmol), stir for half an hour, raise to room temperature and stir half an hour. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate (80 mL).
- the fifth step 2-(4-cyano-5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)oxazol-2-yl)acetic acid (22f)
- the sixth step 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-2-(2-oxo-2-(1,4, 6,7-Tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl)oxazole-4-carbonitrile (Compound 22)
- the first step 3-(2-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonyl)hydrazino)-2-fluoro-3-oxopropane Ethyl acid (23b)
- the fourth step 2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazole-2- Yl)-2-fluoro-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)ethyl-1- Ketone (Compound 23)
- the first step 2-(hydroxyimino)-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (24b)
- the third step 2-(5-(2-((5-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3 ,4-oxadiazol-2-yl)ethyl acetate (24d)
- Example 25 1-(6,7-Dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)-yl)-2-(5-(2 -((5,6-Dihydro-4H-cyclopenta[b]thiophen-5-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)ethanone ( Compound 25)
- the seventh step 2-(5-(2-((5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)amino)pyrimidin-5-yl)-1,3,4- Oxadiazol-2-yl)acetic acid (25h)
- the ninth step 2-(5-(2-((5,6-dihydro-4H-cyclopenta[c]thiophen-5-yl)amino)pyrimidin-5-yl)-1,3,4- Oxadiazol-2-yl)acetic acid (26j)
- Example 27 2-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazole-2- Yl)-2-fluoro-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)prop-1- Ketone (Compound 27)
- the fourth step 2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazole-2- Base)-2-fluoropropionic acid (27e)
- the ninth step 2-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazole-2- Yl)-2-fluoro-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)prop-1- Ketone (Compound 27)
- Example 28 2-(5-(2-((5-(furan-3-yl)-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1, 3,4-oxadiazol-2-yl)-1-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine-5- Yl)ethan-1-one (Compound 28)
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Abstract
Description
Claims (32)
- 一种式(I)所示的含氮杂环化合物,其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,L 1为键、-(CR 1R 2) a-(NR 7) b-W-(CR 3R 4) c-(NR 8) d-(CR 5R 6) e-或-C(O)-(CR 3R 4) c-C=CR 7-;W为-C(=X)-或含有1-3个选自N、O或S杂原子的3-6元亚杂环基;X为O、S或NR x,其中R x为H或氰基;每个R 1至R 6独立地选自H、卤素、C 1-4烷基或C 3-6环烷基;每个R 7和R 8独立地选自H、C 1-4烷基或C 3-6环烷基;作为选择,同碳原子上的R 1和R 2、R 3和R 4、或R 5和R 6与其连接的碳原子一起形成3-6元碳环,所述碳环任选地被1-4个选自卤素或C 1-4烷基的取代基取代;a、c和e独立地选自0-5的整数,b和d独立地为0或1;Ra'和Ra”独立地为H或C 1-4烷基;n为1-2的整数;X 1和X 2独立地为N或CR A1,且不同时为CR A1,X 3为S、O或NR A1;X 4、X 5和X 6独立地为N、NR A1、S、O或CR A1,且不同时为CR A1;每个R A1独立地为H、氰基、-R A、卤素、-C 1-4烷基R A、-NHC(O)R A、-C(O)R A、-C 1-4烷基-O-C 1-4烷基、-NHR A、-C(O)NHR A或-OR A;R A为C 1-4烷基、C 3-6环烷基、C 3-6环烷基氧基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基或含有1-3个选自N、O或S杂原子的3-6元杂环基,所述烷基、环烷基、环烷基氧基、烷氧基、卤代烷基、卤代烷氧基和杂环基任选进一步地被1-6个选自C 3-6环烷基、C 1-4烷基、卤素、-S(O) 2C 1-4烷基、-OC 1-4烷基或氰基的基团取代;Y 1为O、S或NR B3;Cy具有结构: 其中, 表示单键或双键,Z 1为C或N,环E为含有1-3个选自N、O或S杂原子的5元杂环,环D为含有0-3个选自N、O或S杂原子的6元环;所述5元杂环和6元环独立任选地被1-3个R B2取代;每个R B1和R B2独立地选自H、氧代、OH、卤素、氰基、C 1-4烷基、卤代C 1-4烷基、C 1- 4烷基氧基或C 3-6环烷基;R B3选自H、C 1-4烷基或C 3-6环烷基;作为选择,A上的基团R A1和B上的基团R B1与其连接的原子一起形成含有1-3个选自N、S、O杂原子的6-10元杂环;f为0-3的整数;L 2为-O-、-NR 9-、-C(O)NR 9-、-NR 9C(O)NR 9-、-(CR 10R 11) g-、-NR 9-(CR 10R 11) g-或键,其中g为1-3的整数;R 9为H或C 1-4烷基;每个R 10和R 11独立地为H、卤素、C 1-4烷基或C 3-6环烷基;作为选择,同碳原子上的R 10和R 11与其连接的碳原子形成3-6元碳环;Z 2和Z 3各自独立地为CR M或N,Z 4为O、S或NR M1;每个R M独立地为H、C 1-4烷基、C 1-4烷氧基烷基、氰基、C 3-6环烷基、C 3-6环烷基氧基、-SRm'、-S(O) 2Rm'、-C(O)NRmRm'、-NRmC(O)Rm'、C 2-6烯基、C 2-6炔基、-NR M1,含有1-3个选自N、O或S杂原子的3-6元杂环基或卤素,所述烷基、烯基、炔基和环烷基各自任选地被1-3个选自卤素、氰基、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基的基团取代,所述杂环基任选地被1-3个选自卤素、氧代或C 1-4烷基的基团取代;作为选择,M 2中相邻环碳原子上的两个R M与它们连接的碳原子一起形成含有0-3选自N、O或S杂原子的3-6元碳环或3-6元杂环基;Rm为H、C 1-4烷基或卤代C 1-4烷基;Rm'为C 1-4烷基或卤代C 1-4烷基;R M1为H、C 1-4烷基、C 3-6环烷基、C 1-4卤代烷基或C 1-4烷氧基烷基;R M2为卤代C 1-4烷氧基;每个R 12独立地为H、卤素、C 1-4烷基、C 3-6环烷基或卤代C 1-4烷基;h为0-3的整数;i为0、1或2;当M 1为 L 1为-C(O)-CH 2-,A为 B为 L 2为-NH-,M 2为 时,A至少有一个取代基R A1选自氰基、卤素、C 3-4环烷基氧基、环丙基甲基氧基、C 1-4卤代烷氧基、环丙基甲基、-C 1-4烷基-O-C 1-4烷基、-NHC(O)R A、-C(O)NHR A、-C(O)-C 3-6环烷基、
- 根据权利要求1所述的含氮杂环化合物,其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,其中:a、c和e独立地选自0-3的整数,b和d独立地为0或1;W为-C(=X)-或含有1-2个选自N、O杂原子的5元亚杂环基,其中X为O、S或NR x,R x为氰基;每个R 1至R 6独立地选自H、卤素、C 1-4烷基,R 7和R 8独立地选自H或C 1-4烷基;作为选择,同碳原子上的R 3和R 4、或R 5和R 6与其连接的碳原子一起形成3-4元碳环,所述碳环任选地被1-2个选自卤素或C 1-2烷基的取代基取代;R A为C 1-4烷基、C 3-4环烷基或含有1-2个选自N、O杂原子的4-6元杂环基,所述烷基和杂环基各自任选进一步地被1-5个选自C 3-4环烷基、C 1-4烷基、卤素、-S(O) 2C 1-2烷基、-OC 1-2烷基或氰基的基团取代。
- 根据权利要求1或2所述的含氮杂环化合物,其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,其中:L 1为-C(=O)-(NH) d-CR 3R 4-,其中d为0或1,R 3和R 4中至少有一个为卤素,或R 3和R 4及其连接的碳原子一起形成3-4元碳环;或者L 1为-C(=S)-CR 3R 4-,其中R 3和R 4独立地选自H、卤素或C 1-4烷基;或者L 1为-C(=N-CN)-CR 3R 4-,其中R 3和R 4独立地选自H、卤素或C 1-4烷基;或者L 1为-C(O)-CR 3R 4-C=CR 7-,其中R 3和R 4独立地选自H、卤素或C 1-4烷基,R 7为H或C 1-4烷基;或者L 1为-W-(CR 3R 4) c-,其中W为含有1-2个选自N、O杂原子的5元亚杂环基,c为0-3的整数。
- 根据权利要求1或2所述的含氮杂环化合物,其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,其中,L 2为-C(O)NR 9-、-NR 9C(O)NR 9-、-O-、或-CR 10R 11-,R 10和R 11中至少一个为卤素或C 1-4烷基,或R 10和R 11与其连接的碳原子形成3-4元碳环。
- 根据权利要求1或2所述的含氮杂环化合物,其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,其中:A为C 3-6亚环烷基、C 2-4亚炔基、 -RaC(O)NRa'-或 其中X 1为N或CR A1,X 3为S、O或NR A1,每个R A1独立地为H、氰基、-R A、卤素、-C 1-4烷基R A、-NHC(O)R A、-C(O)R A、-C 1-4烷基-O-C 1-4烷基、-NHR A、-C(O)NHR A或-OR A,Ra为 Ra'为H或C 1-4烷基;或者
- 根据权利要求1或2所述的含氮杂环化合物,其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,其中:B为 R B1和R B2中至少有一个选自OH、卤素、氰基、卤代C 1-4烷基、C 1- 4烷基氧基或C 3-6环烷基,或者A上的基团R A1和B上的基团R B1与其连接的原子一起形成含有1个O原子的6-8元杂环;或者
- 根据权利要求1或2所述的含氮杂环化合物,其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,所述化合物如(VI)所示:其中,L 1为-C(=O)-(CR 3R 4) c-(NR 8) d-、c为0-3的整数,d为0或1,R 3、R 4和R 8独立地选自H、C 1-3烷基或卤素,R 3和R 4与其连接的碳原子一起形成3-6元碳环,所述碳环任选地被1-4个选自卤素或C 1-4烷基的取代基取代;Cy具有结构: 其中, 表示单键或双键,Z 1为C或N,环E为含有1-3个选自N、O或S杂原子的5元杂环,环D为饱和或不饱和的含有0-3个选自N、O或S杂原子的6元环;所述5元杂环和6元环独立任选地被1-3个R B2取代;每个R B2独立地选自H、卤素、氰基、C 1-4烷基或卤代C 1-4烷基;L 2为-NH-或键。
- 根据权利要求1或2所述的含氮杂环化合物,其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,其中:当M 2为 时,h不为0,且至少有一个R M为卤代C 1-4烷基、氰基、C 3-6环烷基、C 2-6炔基或含有1-3个选自N、O或S杂原子的3-6元杂环基;所述烷基任选地被1-3个选自卤素或氰基的基团取代,所述杂环基任选地被1-3个选自卤素、氧代或C 1-4烷基的基团取代;或者,作为选择,M 2中相邻环碳原子上的两个R M与它们连接的碳原子一起形成含有0-3选自N、O或S杂原子的3-6元碳环或3-6元杂环基;
- 根据权利要求1所述的含氮杂环化合物,其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,其中,L 1为-(CR 1R 2) a-(NR 7) b-W-(CR 3R 4) c-(NR 8) d-(CR 5R 6) e-;W为-C(=X)-,X为O或S;a、b为0,c为1或2,d、e为0;每个R 3和R 4独立地选自H、卤素或C 1-4烷基,且不同时为H;L 2为-NR 9-,R 9为H;每个R 12独立地为H、卤素、C 1-4烷基、C 3-6环烷基或卤代C 1-4烷基;h为0、1或2;每个R M独立地为H或C 1-4烷基,所述烷基任选地被1-3个卤素取代。
- 根据权利要求1所述的式(I)的含氮杂环化合物,其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,L 1为键或-(CR 1R 2) a-(NR 7) b-W-(CR 3R 4) c-(NR 8) d-(CR 5R 6) e-;W为-C(=X)-;X为O、S或NR x,R x为H或氰基;每个R 1至R 6独立地选自H、卤素、C 1-4烷基或C 3-6环烷基;每个R 7和R 8独立地选自H、C 1-4烷基或C 3-6环烷基;作为选择,同碳原子上的R 1和R 2、R 3和R 4、或R 5和R 6与其连接的碳原子一起形成3-6元碳环,所述碳环任选地被1-4个选自卤素或C 1-4烷基的取代基取代;a、c和e独立地选自0、1、2和3,b和d独立地为0或1;Ra'和Ra”独立地为H或C 1-4烷基;n为1或2;X 1和X 2独立地为N、NR A1或CR A1,且不同时为CR A1;X 4、X 5和X 6独立地为N、NR A1、S、O或CR A1,且不同时为CR A1;每个R A1独立地为H、氰基、-R A、卤素、-C 1-4烷基R A、-NHC(O)R A、-C(O)R A、-C 1-4烷基-O-C 1-4烷基、-NHR A、-C(O)NHR A、-OR A的取代基取代;R A为C 1-4烷基、C 3-6环烷基或含有1-3个选自N、O或S杂原子的3-6元杂环基,所述烷基、环烷基、杂环基任选进一步地被1-6个选自C 3-6环烷基、C 1-4烷基、卤素、-S(O) 2C 1-4烷基、-OC 1-4烷基或氰基的基团取代;每个R B1和R B2独立地选自H、OH、卤素、氰基、C 1-4烷基、卤代C 1-4烷基、C 1-4烷基氧基或C 3-6环烷基;L 2为-O-、-NR 9-、-(CR 10R 11) g-、-NR 9-(CR 10R 11) g-或键,g为1-3的整数;R 9为H或C 1-4烷基;每个R 10和R 11独立地为H、卤素、C 1-4烷基或C 3-6环烷基;作为选择,同碳原子上的R 10和R 11与其连接的碳原子形成3-6元碳环;Z 2、Z 3为CR M或N,Z 4为O、S或NR M1;每个R M独立地为H、C 1-4烷基、氰基、C 3-6环烷基、-SRm'、-S(O) 2Rm'、-C(O)NRmRm'、-NRmC(O)Rm'、C 2-6炔基、含有1-3个选自N、O或S杂原子的3-6元杂环基、或卤素;所述烷基、炔基、环烷基任选地被1-3个选自卤素、氰基、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基的基团取代,所述杂环基任选地被1-3个选自卤素、氧代、C 1-4烷基的基团取代;Rm为H、C 1-4烷基、卤代C 1-4烷基,Rm'为C 1-4烷基、卤代C 1-4烷基;作为选择,M 2中相邻环碳原子上的两个R M与它们连接的碳原子一起形成含有0-2选自N、O或S杂原子的3-6元碳环或3-6元杂环基;R M1为H、C 1-4烷基或C 3-6环烷基;R M2为卤代C 1-4烷氧基;每个R 12独立地为H、卤素、C 1-4烷基、C 3-6环烷基或卤代C 1-4烷基;h为0-3的整数;i为0、1或2;
- 根据权利要求19所述的含氮杂环化合物,其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,其中,L 1为键或-W-(CR 3R 4) c-;W为-C(=X)-;X为O或S;每个R 3和R 4独立地选自H、卤素或C 1-4烷基;作为选择,同碳原子上的R 3和R 4与其连接的碳原子一起形成3-6元碳环;c选自0、1和2;Ra'和Ra”为H或C 1-4烷基;n为1或2;X 1和X 2独立地为N、NR A1或CR A1,且不同时为CR A1;X 4、X 5和X 6独立地为N、NR A1、S、O或CR A1,且不同时为CR A1;每个R A1独立地为H;R B1和R B2均为H;L 2为-NR 9-或-NR 9-(CR 10R 11) g-,g为1-3的整数;R 9为H;每个R 10和R 11独立地为H;Z 2、Z 3为CR M,Z 4为O或S;每个R M独立地为H、C 1-4烷基、C 3-6环烷基、-SRm'、-S(O) 2Rm'、-C(O)NRmRm'、-NRmC(O)Rm'、C 2-6炔基、含有1-3个选自N、O或S杂原子的3-6元杂环基或卤素;所述烷基、炔基、环烷基任选地被1-3个选自卤素、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基的基团取代,所述杂环基任选地被1-3个选自卤素、氧代、C 1-4烷基的基团取代;Rm为H或C 1-4烷基,Rm'为C 1-4烷基;作为选择,M 2中相邻环碳原子上的两个R M与它们连接的碳原子一起形成含有0-2选自N、O或S杂原子的3-6元碳环或3-6元杂环基;R M2为卤代C 1-4烷氧基;h为0、1或2;i为0、1或2。
- 根据权利要求20所述的含氮杂环化合物,其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,h为1或2,R M为C 1-4烷基、C 3-6环烷基、-SRm'、-S(O) 2Rm'、-C(O)NRmRm'、-NRmC(O)Rm'、C 2-6炔基或含有1-3个选自N、O或S杂原子的3-6元杂环基,所述烷基任选地被1-3个选自卤 素、C 1-4烷氧基或卤代C 1-4烷氧基的基团取代,所述杂环基任选地被1-3个选自卤素、氧代、C 1-2烷基的基团取代;作为选择,M 2中相邻环碳原子上的两个R M与它们连接的碳原子一起形成含有0-2选自N、O或S杂原子的3-6元碳环或3-6元杂环基。
- 根据权利要求20所述的含氮杂环化合物,其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,其中,c为1或2,同碳原子上的R 3和R 4与其连接的碳原子一起形成3-6元碳环。
- 根据权利要求1或2所述的含氮杂环化合物,其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,其中,L 1为-W-(CR 3R 4) c-或-W-(NR 8) d-(CR 5R 6) e-;W为-C(=X)-;X为O或S;每个R 3、R 4、R 5和R 6独立地选自H、卤素或C 1-4烷基;每个R 8独立地选自H、C 1-4烷基或C 3-6环烷基;作为选择,同碳原子上的R 3和R 4、或R 5和R 6与其连接的碳原子一起形成3-6元碳环;C和e选自0或1,d为1;X 1和X 2独立地为N或CR A1,且不同时为CR A1;R A1为氰基、C 1-4烷基、-R A或卤素;R A为C 3-6环烷基、C 3-6环烷基氧基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基,所述环烷基、环烷基氧基、烷氧基、卤代烷基、卤代烷氧基任选进一步地被1-3个选自C 1-4烷基、卤素、氰基的基团取代;R B1和R B2均为H;L 2为-NR 9-;R 9为H或C 1-4烷基;Z 2、Z 3为CR M或N,Z 4为O或S;每个R M独立地为H、C 1-4烷基、C 1-4烷氧基烷基、氰基、C 3-6环烷基、C 3-6环烷基氧基、C 2-6烯基、C 2-6炔基、-NR M1、或含有1-3个选自N、O或S杂原子的3-6元杂环基;所述烷基、烯基、炔基、环烷基任选地被1-3个选自卤素、氰基的基团取代,所述杂环基任选地被1-3个选自卤素或C 1-4烷基的基团取代;作为选择,M 2中相邻环碳原子上的两个R M与它们连接的碳原子一起形成含有0-3个选自N、O或S杂原子的3-6元碳环或3-6元杂环基;R M1为H、C 1-4烷基、C 3-6环烷基、C 1-4卤代烷基或C 1-4烷氧基烷基;每个R 12独立地为H、卤素或C 1-4烷基;h为0-3的整数;i为0、1或2。
- 一种药物组合物,其特征在于,含有药学有效量的权利要求1-27中任意一项所述的含氮杂环化合物,或其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,以及药学上可接受的辅料和/或载体。
- 权利要求1-27任意一项所述的含氮杂环化合物,或其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,或者权利要求28所述的组合物在制备治疗/预防自分泌运动因子介导的疾病的药物中的用途。
- 权利要求1-27任意一项所述的含氮杂环化合物,或其立体异构体、溶剂化物、氘代物、药学上可接受的盐或共晶,或者权利要求28所述的组合物在治疗或预防自分泌运动因子介导的疾病的中的用途。
- 根据权利要求29或30所述的用途,其中,所述自分泌运动因子介导的疾病选自心血管病症、癌症、代谢紊乱、肾脏病症、肝脏病症、炎症性病症、神经系统病症、呼吸系统病症、纤维化疾病、眼部病症、胆汁淤积和其他形式的慢性瘙痒症以及急性或慢性器官移植排斥。
- 根据权利要求31所述的用途,其中,所述炎症性病症选自关节炎、特应性皮炎、关节炎和哮喘。
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Cited By (3)
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CN114560854A (zh) * | 2022-02-11 | 2022-05-31 | 深圳湾实验室 | 芳香胺基嘧啶唑类化合物的合成方法 |
CN115232147A (zh) * | 2022-08-09 | 2022-10-25 | 南方科技大学 | 一种作为HIF-2α激动剂的杂环衍生物 |
CN115232147B (zh) * | 2022-08-09 | 2023-10-13 | 南方科技大学 | 一种作为HIF-2α激动剂的杂环衍生物 |
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US20230069174A1 (en) | 2023-03-02 |
JP2023505419A (ja) | 2023-02-09 |
TW202128682A (zh) | 2021-08-01 |
AU2020402940A1 (en) | 2022-06-02 |
EP4074711A1 (en) | 2022-10-19 |
CN114901658A (zh) | 2022-08-12 |
KR20220113731A (ko) | 2022-08-16 |
EP4074711A4 (en) | 2024-04-17 |
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