WO2023134752A1 - 用于微管蛋白-src双靶点抑制剂的二芳基类化合物 - Google Patents

用于微管蛋白-src双靶点抑制剂的二芳基类化合物 Download PDF

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WO2023134752A1
WO2023134752A1 PCT/CN2023/072143 CN2023072143W WO2023134752A1 WO 2023134752 A1 WO2023134752 A1 WO 2023134752A1 CN 2023072143 W CN2023072143 W CN 2023072143W WO 2023134752 A1 WO2023134752 A1 WO 2023134752A1
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ring
alkyl
heterocyclic group
membered
group
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PCT/CN2023/072143
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English (en)
French (fr)
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张学军
臧杨
杨辉
雷四军
魏文军
吴智强
刘礼飞
张辛
李莉娥
杨俊�
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武汉人福创新药物研发中心有限公司
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Priority to IL314266A priority Critical patent/IL314266A/en
Priority to KR1020247024856A priority patent/KR20240128707A/ko
Priority to AU2023206724A priority patent/AU2023206724A1/en
Publication of WO2023134752A1 publication Critical patent/WO2023134752A1/zh

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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Definitions

  • the invention relates to a diaryl compound used as a tubulin-SRC dual-target inhibitor.
  • Microtubules are an important part of the cytoskeleton in eukaryotic cells and play an important role in maintaining cell shape, signal transmission, organelle transport, cell movement, cell division and mitosis and other cellular functions (Jordan M A et al. Nature Reviews Cancer, 2004, 4(4):253-265.).
  • Microtubules are composed of two types of tubulin subunits, ⁇ -tubulin and ⁇ -tubulin, which form tubulin heterodimers and are microtubule The basic unit of assembly.
  • Microtubule-targeting agents can destroy the dynamic stability and structure of microtubules, interfere with the formation of mitotic spindle, induce cell cycle arrest in G2/M phase, and promote cell apoptosis (Shuai W et al. Journal of Medicinal Chemistry, 2021, 64(12).).
  • Microtubules are involved in many important cellular processes and have become one of the most important drug targets for the treatment of hyperproliferative diseases.
  • dual-target inhibitors can overcome drug resistance and improve therapeutic effects, and have become research hotspots, such as: tubulin-SRC dual-target inhibitors, tubulin-receptor tyrosine Kinase (receptor tyrosine kinases inhibitor, RTK) dual-target inhibitor, tubulin-histone deacetylase (histone deacetylases inhibitor, HDAC) dual-target inhibitors, etc.
  • tubulin-SRC dual-target inhibitors tubulin-receptor tyrosine Kinase (receptor tyrosine kinases inhibitor, RTK) dual-target inhibitor
  • tubulin-histone deacetylase histone deacetylases inhibitor, HDAC
  • Actinic keratosis a skin disorder associated with prolonged exposure to UV light
  • AK Actinic keratosis
  • SCC cutaneous squamous cell carcinoma
  • the tubulin-SRC dual-target inhibitor Tirbanibulin has a significant clinical effect in the local treatment of AK (NCT03285477), and has been approved by the FDA for marketing, which indicates that the development of new tubulin-SRC dual-target inhibitors with better efficacy locally Treatment of AK may be a potential direction.
  • the object of the present invention is to provide a kind of diaryl compound for tubulin-SRC dual target inhibitor and its preparation method and application, said diaryl compound has formula I as described in the present invention structure.
  • the diaryl compound can be used as a dual-target inhibitor of tubulin and Src kinase, or can be used as a single inhibitor of tubulin or Src kinase.
  • W is selected from: -O-, -S-, -NH-, -N(C 1 -C 6 alkyl)-;
  • L is C 1 -C 6 alkylene
  • V is absent or selected from: -O-, -S-, -NH-, -N(C 1 -C 6 alkyl)-;
  • V is selected from: -O-, -S-, -NH-, -N(C 1 -C 6 alkyl)-, Q is ring C that is unsubstituted or substituted by m R 3 ;
  • the ring A is a 6-15 membered heterocyclic group; and when the ring A is a 6-membered heterocyclic group, the ring A is
  • the ring B is a 6-12 membered heterocyclic group containing a sulfone group
  • the ring C is a 4-15 membered heterocyclic group or a 6-12 membered heterocyclic group containing a sulfone group;
  • R 1 , R 2 , and R 3 are each independently hydrogen or selected from: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OC 1 -C 6 alkyl, -COO-C 1 -C 6 alkyl, -CO-C 1 -C 6 alkyl, -C(O)NR 11 R 12 , -COO-3-6 membered cycloalkane Group, -CO-3-6 membered cycloalkyl group, -S(O) 2 -C 1 -C 6 alkyl group, -S(O) 2 -3-6 membered cycloalkyl group, -C(O)-C 1 -C 6 alkyl-NR 11 R 12 ;
  • R 11 and R 12 are each independently hydrogen or C 1 -C 6 alkyl; or R 11 and R 12 form a 4-6 membered ring together with the N atom they are connected to;
  • R 1 , R 2 , R 3 are optionally substituted by one or more substituents selected from the following: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, 3-6 membered cycloalkyl ; When there are multiple substituents, the substituents are the same or different;
  • n 1, 2 or 3; when there are multiple R 1s , the R 1s are the same or different;
  • p is 1, 2 or 3; when R 2 is multiple, said R 2 are the same or different;
  • n 1, 2 or 3; when there are multiple R 3 s, the R 3 are the same or different;
  • R 3 is also hydrogen
  • R 1 and R 2 are selected from: cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C(O)NR 11 R 12 .
  • W is selected from: -O-, -S-, -NH-, -N(C 1 -C 6 alkyl)-;
  • L is C 1 -C 6 alkylene
  • V is absent or selected from: -O-, -S-, -NH-, -N(C 1 -C 6 alkyl)-;
  • V is selected from: -O-, -S-, -NH-, -N(C 1 -C 6 alkyl)-, Q is ring C that is unsubstituted or substituted by m R 3 ;
  • the ring A is a 6-15 membered heterocyclic group; and when the ring A is a 6-membered heterocyclic group, the ring A is
  • the ring B is a 6-12 membered heterocyclic group containing a sulfone group
  • the ring C is a 4-15 membered heterocyclic group or a 6-12 membered heterocyclic group containing a sulfone group;
  • R 1 , R 2 , and R 3 are each independently hydrogen or selected from: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OC 1 -C 6 alkyl, -COO-C 1 -C 6 alkyl, -CO-C 1 -C 6 alkyl, -C(O)NR 11 R 12, -COO-3-6 membered cycloalkane Group, -CO-3-6 membered cycloalkyl group, -S(O) 2 -C 1 -C 6 alkyl group, -S(O) 2 -3-6 membered cycloalkyl group, -C(O)-C 1 -C 6 alkyl-NR 11 R 12 ;
  • R 11 and R 12 are each independently hydrogen or C 1 -C 6 alkyl; or R 11 and R 12 form a 4-6 membered ring together with the N atom they are connected to;
  • R 1 , R 2 , R 3 are optionally substituted by one or more substituents selected from the following: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, 3-6 membered cycloalkyl ; When there are multiple substituents, the substituents are the same or different;
  • n 1, 2 or 3; when there are multiple R 1s , the R 1s are the same or different;
  • p is 1, 2 or 3; when R 2 is multiple, said R 2 are the same or different;
  • n 1, 2 or 3; when there are multiple R 3 s, the R 3 are the same or different;
  • V is selected from: -O-, -S-, -NH-, -N(C 1 -C 6 alkyl)-;
  • Q is a 6-12-membered sulfone-containing heterocyclic group that is unsubstituted or substituted by m R 3 ;
  • R 1 is selected from: hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OC 1 -C 6 alkyl, -COO -C 1 -C 6 alkyl, -CO-C 1 -C 6 alkyl, -C(O)NR 11 R 12, -COO-3-6-membered cycloalkyl, -CO-3-6-membered cycloalkane radical, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -3-6 membered cycloalkyl, -C(O)-C 1 -C 6 alkyl-NR 11 R 12 or, R 1 is halogen, and ring A, ring B or ring C is a parallel ring, a bridged ring or a spiro ring.
  • V is selected from: -O-, -S-, -NH-, -N(C 1 -C 6 alkyl)-.
  • V is selected from -NH-.
  • Q is a 6-12 membered sulfone-containing heterocyclic group that is unsubstituted or substituted by m R 3 .
  • Q is an unsubstituted 6-12 membered heterocyclic group containing a sulfone group.
  • R 1 is selected from: hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OC 1 -C 6 alkane -COO-C 1 -C 6 alkyl, -CO-C 1 -C 6 alkyl, -C(O)NR 11 R 12, -COO-3-6 membered cycloalkyl, -CO-3- 6-membered cycloalkyl, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -3-6-membered cycloalkyl, -C(O)-C 1 -C 6 alkyl- NR 11 R 12 .
  • R 1 is selected from: cyano, C 1 -C 6 alkyl and C 2 -C 6 alkynyl.
  • R 1 is halogen
  • ring A, ring B or ring C is a parallel ring, a bridged ring or a spiro ring.
  • diaryl compound shown in formula I is
  • n 1 or 2;
  • R 3 is selected from: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OC 1 -C 6 alkyl, -COO- C 1 -C 6 alkyl, -CO-C 1 -C 6 alkyl, -C(O)NR 11 R 12 ;
  • R 1 is selected from: cyano, C 2 -C 6 alkenyl, C 2 -C 6 Alkynyl, -C(O)NR 11 R 12 .
  • the diaryl compound shown in formula I is m is 1; R 3 is C 1 -C 6 alkyl.
  • the diaryl compound shown in formula I is m is 1; R 3 is C 1 -C 6 alkyl; R 1 is selected from: cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C(O)NR 11 R 12 .
  • condition is that when Q is ring A, R 1 and R 2 are not hydrogen at the same time;
  • R 3 is not hydrogen, or at least one of R 1 and R 2 is selected from: cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C(O)NR 11 R 12 .
  • W is selected from -O-.
  • L is C 1 -C 6 alkylene.
  • V is absent or selected from: -NH-;
  • V is selected from: -NH-, Q is ring C that is unsubstituted or substituted by m R 3 ;
  • the ring A is a 6-15 membered heterocyclic group; and when the ring A is a 6-membered heterocyclic group, the ring A is
  • the ring B is a 6-12 membered heterocyclic group containing a sulfone group
  • the ring C is a 4-15 membered heterocyclic group or a 6-12 membered heterocyclic group containing a sulfone group;
  • n 1, 2 or 3; when there are multiple R 3 s, the R 3 are the same or different;
  • R 3 is C 1 -C 6 alkyl or -CO-C 1 -C 6 alkyl; R 3 is optionally substituted by one or more 3-6 membered cycloalkyl groups; when there are multiple substituents, all The above substituents are the same or different.
  • n 1, 2 or 3; when R 1 is multiple, the R 1 is the same or not same;
  • R 1 is hydrogen, halogen, cyano, unsubstituted C 1 -C 6 alkyl or unsubstituted C 2 -C 6 alkynyl.
  • n 1;
  • R 1 is hydrogen, halogen, cyano, unsubstituted C 1 -C 6 alkyl or unsubstituted C 2 -C 6 alkynyl.
  • p is 1, 2 or 3; when there are multiple R 2 , the R 2 are the same or different;
  • R 2 is hydrogen or halogen.
  • the diaryl compound shown in formula I satisfies 1, 2 or 3 of the following conditions:
  • V is selected from -NH-;
  • Q is a 6-12-membered sulfone-containing heterocyclic group that is unsubstituted or substituted by m R 3 ;
  • R 1 is cyano, unsubstituted C 1 -C 6 alkyl or unsubstituted C 2 -C 6 alkynyl; or, R 1 is halogen, ring A, ring B or ring C is a parallel ring, Bridged ring or spiro ring.
  • W is selected from -O-;
  • L is C 1 -C 6 alkylene
  • V is absent or selected from: -NH-;
  • V is selected from: -NH-, Q is ring C that is unsubstituted or substituted by m R 3 ;
  • the ring A is a 6-15 membered heterocyclic group; and when the ring A is a 6-membered heterocyclic group, the ring A is
  • the ring B is a 6-12 membered heterocyclic group containing a sulfone group
  • the ring C is a 4-15 membered heterocyclic group or a 6-12 membered heterocyclic group containing a sulfone group;
  • n 1, 2 or 3; when there are multiple R 1s , the R 1s are the same or different;
  • R 1 is hydrogen, halogen, cyano, unsubstituted C 1 -C 6 alkyl or unsubstituted C 2 -C 6 alkynyl;
  • p is 1, 2 or 3; when R 2 is multiple, said R 2 are the same or different;
  • R 2 is hydrogen or halogen
  • n 1, 2 or 3; when there are multiple R 3 s, the R 3 are the same or different;
  • R 3 is C 1 -C 6 alkyl or -CO-C 1 -C 6 alkyl; R 3 is optionally substituted by one or more 3-6 membered cycloalkyl groups; when there are multiple substituents, all The above substituents are the same or different;
  • V is selected from -NH-;
  • Q is a 6-12-membered sulfone-containing heterocyclic group that is unsubstituted or substituted by m R 3 ;
  • R 1 is cyano, unsubstituted C 1 -C 6 alkyl or unsubstituted C 2 -C 6 alkynyl; or, R 1 is halogen, ring A, ring B or ring C is a parallel ring, Bridged ring or spiro ring.
  • W is selected from -O-;
  • L is C 1 -C 6 alkylene
  • V is absent or selected from: -NH-;
  • V is selected from: -NH-, Q is ring C that is unsubstituted or substituted by m R 3 ;
  • the ring A is a 6-15 membered heterocyclic group; and when the ring A is a 6-membered heterocyclic group, the ring A is
  • the ring B is a 6-12 membered heterocyclic group containing a sulfone group
  • the ring C is a 4-15 membered heterocyclic group or a 6-12 membered heterocyclic group containing a sulfone group;
  • n 1;
  • R 1 is hydrogen, halogen, cyano, unsubstituted C 1 -C 6 alkyl or unsubstituted C 2 -C 6 alkynyl;
  • p 1;
  • R is hydrogen
  • n 1, 2 or 3; when there are multiple R 3 s, the R 3 are the same or different;
  • R 3 is C 1 -C 6 alkyl or -CO-C 1 -C 6 alkyl; R 3 is optionally replaced by one or more 3-6 membered cycloalkane substituent; when there are multiple substituents, the substituents are the same or different;
  • V is selected from -NH-;
  • Q is a 6-12-membered sulfone-containing heterocyclic group that is unsubstituted or substituted by m R 3 ;
  • R 1 is cyano, unsubstituted C 1 -C 6 alkyl or unsubstituted C 2 -C 6 alkynyl; or, R 1 is halogen, ring A, ring B or ring C is a parallel ring, Bridged ring or spiro ring.
  • L is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -; preferably, L is -CH 2 CH 2 -.
  • the 6-15 membered heterocyclic group is a 6-8 membered heterocyclic group.
  • the 6-15 membered heterocyclic group is a monocyclic ring, a parallel ring, a bridged ring or a spiro ring.
  • the 6-15 membered heterocyclic group is a saturated ring.
  • the heteroatoms in the 6-15 membered heterocyclic group are N and/or O.
  • the heteroatoms in the 6-15 membered heterocyclic group are N and O.
  • the 6-15 membered heterocyclic group is connected to V through an N atom.
  • the ring A is (For example ),
  • the 4-15 membered heterocyclylheterocyclyl is a 6-8 membered heterocyclyl.
  • the 4-15 membered heterocyclic group is a monocyclic ring, a parallel ring, a bridged ring or a spiro ring.
  • the 4-15 membered heterocyclic group is a saturated ring.
  • the heteroatoms in the 4-15 membered heterocyclic group are N and/or O.
  • the heteroatoms in the 4-15 membered heterocyclic group are N and O.
  • the 4-15 membered heterocyclic group is connected to V through an N atom.
  • the 4-15 membered heterocyclic group is (For example ),
  • the 6-12-membered sulfone-containing heterocyclic group is a 6-8-membered sulfone-containing heterocyclic group.
  • the 6-12 membered heterocyclic group containing a sulfone group is a monocyclic ring, a double ring, a bridged ring or a spiro ring.
  • the 6-12 membered heterocyclic group containing a sulfone group is a monocyclic ring or a spiro ring.
  • the 6-12 membered heterocyclic group containing a sulfone group is a saturated ring.
  • the 6-12 membered heterocyclic group containing a sulfone group is connected to V through an N atom.
  • the 6-12 membered heterocyclic group containing a sulfone group is
  • the 6-12-membered sulfone-containing heterocyclic group is a 6-8-membered sulfone-containing heterocyclic group.
  • the 6-12 membered heterocyclic group containing a sulfone group is a monocyclic ring, a double ring, a bridged ring or a spiro ring.
  • the 6-12 membered heterocyclic group containing a sulfone group is a monocyclic ring or a spiro ring.
  • the 6-12 membered heterocyclic group containing a sulfone group is a saturated ring.
  • the 6-12 membered heterocyclic group containing a sulfone group is connected to V through an N atom.
  • the 6-12 membered heterocyclic group containing a sulfone group is
  • said halogen is fluorine or chlorine.
  • said C 1 -C 6 alkyl group is methyl or ethyl.
  • said C 2 -C 6 alkynyl is ethynyl or propynyl.
  • said halogen is fluorine or chlorine.
  • said C 1 -C 6 alkyl group is methyl or ethyl.
  • the C 1 -C 6 alkyl in the "-CO-C 1 -C 6 alkyl" is methyl or ethyl.
  • the 4-6 membered ring formed by R 11 and R 12 together with the N atoms they are connected to can be a 4-6 membered N-containing heterocycloalkyl group or a 5-6 membered heteroaryl group.
  • W is selected from: -O-, -S-, -NH-; preferably, W is -O-.
  • L is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -; preferably, L is -CH 2 CH 2 -.
  • V is absent or -NH-.
  • the ring A is a 7-15 membered monocyclic, parallel, bridged or spiro heterocyclic group
  • the ring A contains 1, 2 or 3 heteroatoms selected from N, O or S; when there are multiple heteroatoms, the heteroatoms are the same or different; preferably, the ring A Contains 1 N atom and 1 O atom.
  • the ring A has the structure Wherein, Z represents C or N; preferably, Z is N; preferably, the ring A also contains 1 O atom; preferably, for
  • the ring B is a 6-12-membered sulfone-containing monocyclic ring, a ring, a spiro ring, and a bridged heterocyclic ring; preferably, the ring B is a 6-8-membered sulfone-containing Monocyclic heterocyclic group; preferably, ring B is a 7-12 membered heterocyclic group containing a sulfone group, a spiro ring, or a bridged ring.
  • Ring B is Among them, K represents C or N.
  • the diaryl compound, its tautomer, stereoisomer, solvate (such as hydrate), pharmaceutically acceptable salt or prodrug has formula Ia, Structure shown in Ib or Ic:
  • K represents C or N
  • Ring A, Ring B, m, n, p, R 1 , R 2 , R 3 are as described in the first aspect of the present invention.
  • the ring A is a 7-10 membered monocyclic heterocyclic group or a 7-12 membered ring, bridged ring, or spirocyclic heterocyclic group.
  • the ring A is selected from:
  • R 1 and R 2 are each independently hydrogen or selected from: halogen, hydroxyl, amino, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl; the C 1 -C 6 alkyl is optionally substituted by one or more halogens; R is selected from: halogen, hydroxyl, amino, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl; said C 1 -C 6 alkane The group is optionally substituted by one or more halogens; and R 1 and R 2 are not hydrogen at the same time;
  • each of R 1 , R 2 , and R 3 is independently selected from: halogen, C 1 -C 6 alkyl; said C 1 -C 6 alkyl is optionally substituted by one or more halogens;
  • R 1 , R 2 , R 3 are each independently selected from: fluorine, methyl, ethyl, propyl; said methyl, ethyl, propyl are optionally substituted by one or more halogens;
  • the halogen is F.
  • ring B is a 6-12 membered monocyclic, double ring, spiro ring, bridged ring heterocyclic group; preferably, ring B is a 6-8 membered monocyclic heterocyclic group; preferably, Ring B is a 7-12 membered heterocyclic ring, a spiro ring, or a bridged ring heterocyclic group.
  • the ring B is selected from:
  • each of R 1 , R 2 , and R 3 is independently hydrogen or selected from: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -C(O)NR 11 R 12 ;
  • R 11 and R 12 are each independently hydrogen or C 1 -C 6 alkyl;
  • the C 1 -C 6 alkyl is optionally substituted by one or more halogens
  • each of R 1 , R 2 , and R 3 is independently selected from: halogen, C 1 -C 6 alkyl; said C 1 -C 6 alkyl is optionally substituted by one or more halogens;
  • R 1 , R 2 , R 3 are each independently selected from: fluorine, methyl, ethyl, propyl; the C 1 -C 6 alkyl is optionally substituted by one or more fluorine; relatively
  • the halogen is F.
  • n 1
  • R is hydrogen or is selected from: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl;
  • R 1 is hydrogen or selected from: halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl;
  • R 1 is hydrogen or selected from: fluorine, chlorine, cyano, methyl, -C ⁇ C-CH 3 .
  • R2 is hydrogen
  • R3 is hydrogen
  • the diaryl compound, its tautomer, stereoisomer, solvate (such as hydrate), pharmaceutically acceptable salt or prodrug has the structure Id
  • n is 1 or 2; preferably m is 1;
  • R 3 is hydrogen or is selected from: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OC 1 -C 6 alkyl, -COO-C 1 -C 6 alkyl, -CO-C 1 -C 6 alkyl, -C(O)NR 11 R 12 ;
  • R 1 is selected from: cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C (O) NR 11 R 12 ;
  • R 1 and R 3 are each independently selected from: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OC 1 -C 6 alkyl, -COO-C 1 -C 6 alkyl, -CO-C 1 -C 6 alkyl, -C(O)NR 11 R 12 ;
  • R 11 and R 12 are each independently hydrogen or C 1 -C 6 alkyl; or R 11 and R 12 form a 4-6 membered ring together with the N atom they are connected to;
  • the R 3 is optionally substituted by one or more substituents selected from the following: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different.
  • R 3 is hydrogen or selected from: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OC 1 -C 6 alkyl, -COO-C 1 -C 6 alkyl, -CO-C 1 -C 6 alkyl, -C(O)NR 11 R 12 ;
  • R 1 is selected from: cyano, C 2 - C 3 alkenyl, C 2 -C 3 alkynyl, -C(O)NR 11 R 12 ;
  • R 1 and R 3 are each independently selected from: halogen, C 1 -C 6 alkyl; said C 1 -C 6 alkyl is optionally substituted by one or more substituents selected from the following: halogen, hydroxyl , amino, cyano, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • R is hydrogen or is selected from: halogen, methyl, ethyl, propyl; said methyl, ethyl, propyl are optionally substituted by one or more halogens;
  • R is selected from: Cyano, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl; more preferably, R 3 is hydrogen;
  • R 1 is selected from: cyano, C 2 -C 3 alkenyl, C 2 -C 3 alkyne base;
  • R 1 and R 3 are each independently selected from: halogen, methyl, ethyl, propyl; said methyl, ethyl, propyl are optionally substituted by one or more halogens; preferably Alternatively, the halogen is fluorine.
  • diaryl compounds having structure Ie or If
  • ring C, R 1 , R 2 , n, p are defined as described in the first aspect of the present invention.
  • R 3 is C 1 -C 6 alkyl, -CO-C 1 -C 6 alkyl, -C(O)NR 11 R 12 , 3-6 membered cycloalkyl, -COO-C 1 -C 6 alkyl , -COO-3-6 membered cycloalkyl, -CO-3-6 membered cycloalkyl, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2 -3-6 membered ring Alkyl, -C(O)-C 1 -C 6 alkyl-NR 11 R 12 ;
  • R 11 and R 12 are each independently hydrogen or C 1 -C 6 alkyl; or R 11 and R 12 form a 4-6 membered ring together with the N atom they are connected to;
  • the R 3 is optionally substituted by one or more substituents selected from the following: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, 3-6 membered cycloalkyl; when the substituent is poly When, the substituents are the same or different;
  • ring C is a 4-8 membered heterocyclic group; preferably, ring C is a 4-6 membered heterocyclic group; more preferably, ring C is a 4-membered ring;
  • R 3 is -CO-C 1 -C 6 alkyl
  • the R 3 is optionally substituted by one or more substituents selected from the following: halogen, 3-6 membered cycloalkyl;
  • R 3 is -CO-C 1 -C 3 alkyl-cyclopropyl, -CO-C 1 -C 3 alkyl-cyclobutyl.
  • R 1 is hydrogen or selected from: halogen, hydroxyl, amino, cyano, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl;
  • R 1 is hydrogen or selected from: halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl;
  • R 1 is hydrogen or selected from: fluorine, chlorine, cyano, methyl, -C ⁇ C-CH 3 .
  • the Diaryl compounds are any of the following compounds:
  • the Diaryl compounds are any of the following compounds:
  • X is halogen or substituent G
  • the substituent G is selected from: borate group, borate group, alkyl tin, trifluoromethanesulfonate group, methanesulfonate group, p-toluenesulfonate group;
  • said halogen is chlorine, bromine or iodine.
  • the compound B has the following structure
  • K represents C or N
  • Ring A, Ring B, m, n, p, R 1 , R 2 , R 3 are as defined in the first aspect;
  • X is halogen or substituent G
  • the substituent G is selected from: borate group, borate group, alkyl tin, trifluoromethanesulfonate group, methanesulfonate group, p-toluenesulfonate group;
  • said halogen is chlorine, bromine or iodine.
  • X is halogen or substituent G
  • the substituent G is selected from: borate group, borate group, alkyl tin, trifluoromethanesulfonate group, methanesulfonate group, p-toluenesulfonate group;
  • said halogen is chlorine, bromine or iodine.
  • the intermediate B has the following structure
  • K represents C or N
  • Ring A, Ring B, m, n, p, R 1 , R 2 , R 3 are as defined in the first aspect;
  • X is halogen or substituent G
  • the substituent G is selected from: borate group, borate group, alkyl tin, trifluoromethanesulfonate group, methanesulfonate group, p-toluenesulfonate group;
  • said halogen is chlorine, bromine or iodine.
  • the ring A is a 7-15 membered monocyclic, parallel, bridged or spiro heterocyclic group
  • the ring A is a 7-10 membered monocyclic heterocyclic group or a 7-12 membered ring, bridged ring or spirocyclic heterocyclic group;
  • the ring A contains 1 N atom and 1 O atom.
  • the borate ester group is selected from: bis-boronic acid pinacol ester, biscatechol borate, bis (3,3-dimethyl-2,4-pentanediol) Borate ester, triethanolamine borate, trimethyl borate, triisopropyl borate, triethyl borate, tributyl borate, neopentyl glycol diborate.
  • ring B is a 6-12 membered monocyclic, double ring, spiro ring, bridged ring heterocyclic group; preferably, ring B is a 6-8 membered monocyclic heterocyclic group; preferably, Ring B is a 7-12 membered heterocyclic ring, a spiro ring, or a bridged ring heterocyclic group.
  • the alkyl tin is butyl tin, isopropyl tin, or propyl tin.
  • R 1 , R 2 , and R 3 are each independently selected from: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OC 1 -C 6 alkyl, -COO-C 1 -C 6 alkyl, -CO-C 1 -C 6 alkyl, -C(O)NR 11 R 12 ;
  • R 11 and R 12 are each independently hydrogen or C 1 -C 6 alkyl; or R 11 and R 12 form a 4-6 membered ring together with the N atom they are connected to;
  • the R 3 is optionally substituted by one or more substituents selected from the following: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different.
  • R 3 is hydrogen or selected from: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OC 1 -C 6 alkyl, -COO-C 1 -C 6 alkyl, -CO-C 1 -C 6 alkyl, -C(O)NR 11 R 12 ;
  • R 1 is selected from: cyano, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, -C(O)NR 11 R 12 .
  • R is hydrogen or is selected from: halogen, methyl, ethyl, propyl; said methyl, ethyl, propyl are optionally substituted by one or more halogens; R is selected from: Cyano, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl;
  • R 1 , R 2 , and R 3 are each independently selected from: halogen, C 1 -C 6 alkyl; said C 1 -C 6 alkyl is optionally selected from one or more The following substituents are substituted: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • R 1 and R 3 are each independently selected from: halogen, methyl, ethyl, propyl; said methyl, ethyl, propyl are optionally substituted by one or more halogens; preferably Alternatively, the halogen is fluorine.
  • R 3 is C 1 -C 6 alkyl, -CO-C 1 -C 6 alkyl, -C(O)NR 11 R 12 , 3-6 membered cycloalkyl, -COO- C 1 -C 6 alkyl, -COO-3-6 membered cycloalkyl, -CO-3-6 membered cycloalkyl, -S(O) 2 -C 1 -C 6 alkyl, -S(O) 2-3-6 membered cycloalkyl, -C(O)-C 1 -C 6 alkyl-NR 11 R 12 ; wherein, R 11 and R 12 are each independently hydrogen or C 1 -C 6 alkyl; or R 11 and R 12 form a 4-6 membered ring together with the N atoms to which they are attached;
  • the R 3 is optionally substituted by one or more substituents selected from the following: halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, 3-6 membered cycloalkyl; when the substituent is poly When each, the substituents are the same or different.
  • ring C is a 4-8 membered heterocyclic group; preferably, ring C is a 4-6 membered heterocyclic group; more preferably,
  • R 3 is -CO-C 1 -C 6 alkyl;
  • said R 3 is optionally substituted by one or more substituents selected from the group consisting of: halogen, 3-6 membered cycloalkane base;
  • R 3 is -CO-C 1 -C 3 alkyl-cyclopropyl, -CO-C 1 -C 3 alkyl-cyclobutyl.
  • a method for preparing the diaryl compound as described in any one of the first aspect, its tautomers, stereoisomers, solvates (such as hydrates), pharmaceutically Acceptable salt or prodrug methods include:
  • R and p are as defined in the first aspect
  • Y is halogen or substituent G
  • the substituent G is selected from: borate group, borate group, alkyl tin, trifluoromethanesulfonate group, methanesulfonate group, p-toluenesulfonate group;
  • said halogen is chlorine, bromine or iodine
  • intermediate C has the structure
  • the borate ester group is selected from: bis-boronic acid pinacol ester, biscatechol borate, bis (3,3-dimethyl-2,4-pentanediol) Borate ester, triethanolamine borate, trimethyl borate, triisopropyl borate, triethyl borate, tributyl borate, neopentyl glycol diborate.
  • the alkyl tin is butyl tin, isopropyl tin, or propyl tin.
  • the reaction requires inert gas protection, and the inert gas includes but Not limited to: nitrogen, helium, neon, argon.
  • the reaction is performed under a palladium catalyst condition; preferably, the palladium catalyst is selected from:
  • each step reaction of the present invention is preferably carried out in an inert solvent
  • the inert solvent includes but not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethylmethylene Sulfone, tetrahydrofuran dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or combinations thereof things.
  • the palladium catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), palladium acetate , palladium chloride, bis(triphenylphosphine)palladium dichloride, palladium trifluoroacetate, palladium triphenylphosphineacetate, [1,1 ⁇ -bis(diphenylphosphino)ferrocene]palladium dichloride , bis(tri-orthophenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethanepalladium dichloride, or a combination thereof.
  • the borate group is selected from the group consisting of pinacol borate, bicatechol borate, bi(3,3-dimethyl-2,4-pentanediol)boronic acid Ester, triethanolamine borate, trimethyl borate, triisopropyl borate, triethyl borate, tributyl borate, neopentyl glycol diboronate.
  • a pharmaceutical composition including the diaryl compound as described in the first aspect, its tautomers, stereoisomers, solvates (such as hydrates), pharmaceutical acceptable salts or prodrugs.
  • a pharmaceutical composition comprising the diaryl compound described in the first aspect, its tautomer, stereoisomer, solvate (such as hydrate), pharmaceutically acceptable salt or prodrug , and a pharmaceutically acceptable carrier and/or other active drugs.
  • the diaryl compound as described in the first aspect its tautomer, stereoisomer, solvate (such as hydrate), pharmaceutically acceptable salt or pro
  • solvate such as hydrate
  • the use includes: inhibiting tubulin polymerization; and/or, preventing and/or treating diseases mediated by tubulin polymerization; and/or, preparing tubulin polymerization inhibitors, and/or preventing and/or treating diseases mediated by tubulin polymerization; /or a drug, a pharmaceutical composition or a preparation for treating a disease mediated by tubulin polymerization.
  • the use includes: inhibiting Src kinase; and/or, preventing and/or treating diseases mediated by Src kinase; and/or, preparing Src kinase inhibitors; and/or, preparing prevention and/or treatment and A medicament, pharmaceutical composition or formulation for a Src kinase mediated disease.
  • the drug is an external preparation.
  • the drug is a drug for transdermal administration.
  • the diseases related to tubulin polymerization and/or Src kinase include tumors and skin diseases.
  • the diaryl compound as described in the first aspect its tautomer, stereoisomer, solvate (such as hydrate), pharmaceutically acceptable salt or pro
  • solvate such as hydrate
  • pharmaceutically acceptable salt or pro The use of the medicine in the preparation of a medicine for treating tumors and/or skin diseases; or the use of the pharmaceutical composition as described in the fourth aspect in the preparation of medicines for treating tumors and/or skin diseases.
  • the drug is an external preparation.
  • the drug is a drug for transdermal administration.
  • the diaryl compound described in the first aspect of the present invention there is provided the diaryl compound described in the first aspect of the present invention, its tautomers, stereoisomers, solvates (such as hydrates), pharmaceutically acceptable salts or Use of at least one of the prodrugs or the pharmaceutical composition described in the fourth aspect of the present invention for treating or preventing tumors and/or skin diseases.
  • the tumors include: solid tumors, sarcomas, and hematological cancers;
  • the tumors include: breast cancer, ovarian cancer, prostate cancer, cervical cancer, testicular cancer, colon cancer, colorectal cancer, liver cancer, non-small cell lung cancer, squamous cell carcinoma (such as squamous cell carcinoma of the skin) ), small cell lung cancer, gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, bladder cancer, germ cell tumor, mastocytoma, mastocytosis, glioblastoma, neuroblastoma, astrocytoma melanoma, B-cell lymphoma, T-cell lymphoma, indolent lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid Leukemia, chronic lymphocytic leukemia, myeloma, and/or myelodysplastic syndrome.
  • squamous cell carcinoma such as squamous cell carcinoma of the
  • the skin diseases include: actinic keratosis, psoriasis, atopic dermatitis, psoriasis, vitiligo, roseola and/or systemic lupus erythematosus.
  • a method for inhibiting Src kinase, or preventing and/or treating Src kinase-related (or mediated) diseases comprising the steps of: administering to a subject in need as described in the first aspect of the present invention
  • the above compound, its tautomer, stereoisomer, solvate (such as hydrate), pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the fourth aspect of the present invention comprising the steps of: administering to a subject in need as described in the first aspect of the present invention.
  • a method for inhibiting tubulin, or preventing and/or treating tubulin-related (or mediated) diseases comprising the steps of: administering to a subject in need as described in the first aspect of the present invention
  • the compound as described in one aspect, its tautomer, stereoisomer, solvate (such as hydrate), pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition as described in the fourth aspect of the present invention comprising the steps of: administering to a subject in need as described in the first aspect of the present invention
  • reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein.
  • the techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left.
  • CH2O is equivalent to OCH2 .
  • halogen means fluorine, chlorine, bromine, iodine alone or as part of another substituent.
  • alkyl alone or as part of another substituent, means consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms, and is bonded to the molecule by a single bond. The rest are connected straight or branched hydrocarbon chain groups.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl.
  • the alkyl groups may also be isotopomers of naturally abundant alkyl groups that are rich in carbon and/or hydrogen isotopes (ie, deuterium or tritium).
  • alkenyl means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds.
  • alkynyl refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.
  • C 1 -C 6 alkyl alone or as part of another substituent is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3
  • alkylene by itself or as part of another substituent, means a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group.
  • alkylene groups include methylene (-CH 2 -), ethylene (including -CH 2 CH 2 - or -CH(CH 3 )-), isopropylidene (including including -CH(CH 3 )CH 2 - or -C(CH 3 ) 2 -) and the like.
  • cycloalkyl or “carbocyclyl” by themselves or as part of another substituent refer to a cyclic alkyl group.
  • mn-membered cycloalkyl or " Cm - Cncycloalkyl” is understood to mean a saturated, unsaturated or partially saturated carbocycle having m to n atoms.
  • 3-15 membered cycloalkyl or “C 3 -C 15 cycloalkyl” refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which May contain 1 to 4 rings.
  • "5-8 membered cycloalkyl” then contains 5-8 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as decahydronaphthalene rings.
  • Cycloalkyl groups may be substituted with one or more substituents.
  • a cycloalkyl group can be a cycloalkyl group fused to an aryl or heteroaryl group.
  • C 3 -C 6 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. For example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • m-n membered heterocyclic group is understood to mean saturated, unsaturated or partially saturated monocyclic, asymmetric rings (including bicyclic and tricyclic), having m to n atoms, A spiro ring or a bridged ring, preferably a saturated heterocyclic ring.
  • heterocyclyl should be understood to mean a saturated, unsaturated or partially saturated monocyclic, asymmetric (including bicyclic and tricyclic), spiro or bridged ring having 7 to 15 atoms, Preferred is a saturated heterocycle. wherein 1, 2, 3, 4 or 5 ring atoms are selected from N, O and S. It should be understood that when the total number of S atoms and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclyl is monocyclic, it must not be aromatic.
  • heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroindolyl, tetrahydropyranyl, dihydro -2H-pyranyl, tetrahydrofuranyl, tetrahydrofuryl Hydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5-dioxoimidazolidinyl.
  • merged ring refers to a cyclic hydrocarbon in which any two rings in the compound share two directly connected carbon atoms, and can be divided into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc. according to the number of rings.
  • Non-limiting examples include:
  • spirocycle refers to a polycyclic group that shares one carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings has a fully conjugated ⁇ -electron system. Preferably it is 6 to 12 yuan, more preferably 7 to 8 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocycloalkyl groups include:
  • spirocycloalkyls in which a single spirocycloalkyl shares a spiro atom with a heterocycloalkyl, non-limiting examples include:
  • bridged ring refers to a cyclic hydrocarbon in which any two rings in a compound share two carbon atoms that are not directly connected, and can be divided into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc.
  • Non-limiting examples include:
  • C 2 -C 6 alkenyl by itself or as part of another substituent is understood to mean a straight or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, preferably eg having 2 or 3 carbon atoms (ie, C 2 -C 3 alkenyl). It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
  • the alkenyl is example Such as vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-ene Base, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3- Alkenyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5 -alkenyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E )-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-eny
  • C 2 -C 6 alkynyl is understood to mean a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, preferably For example with 2 or 3 carbon atoms (" C2 - C3 alkynyl").
  • the alkynyl group is for example ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl , Pent-2-ynyl, Pent-3-ynyl, Pent-4-ynyl, Hex-1-ynyl, Hex-2-ynyl, Hex-3-ynyl, Hex-4-ynyl, Hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl , 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpentyl -4-ynyl, 2-methylpent-3-ynyl, 1-methylp
  • protons can occupy two or more positions of the ring form of the heterocyclic ring system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms may be in equilibrium or sterically fixed in one form by appropriate substitution. For example:
  • the hydrogen of the nitrogen on the triazole can be on any of the three nitrogens, so the naming will be different, but these three forms actually represent a compound.
  • the compounds provided herein, including intermediates useful in the preparation of the compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof.
  • "Protected derivatives” are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also known as protecting groups).
  • Suitable protecting groups for the carboxyl moiety include benzyl, tert-butyl, etc., and isotopes, etc.
  • Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable hydroxy protecting groups include benzyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art.
  • salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • other salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of compounds of the invention.
  • amine salt refers to the product obtained by neutralizing an alkyl primary, secondary or tertiary amine with an acid.
  • the acid Included are inorganic or organic acids as described in this application.
  • stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
  • the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms.
  • the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule.
  • the prefixes D and L or (+) and (-) are symbols used to designate the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or D are dextrorotatory.
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species.
  • Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form predominates
  • the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • a "pharmaceutical composition” refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory agency as acceptable for human or livestock use , diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.
  • solvate means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bonded by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.
  • prodrug refers to a compound of the invention that can be converted to biological activity under physiological conditions or by solvolysis.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound.
  • Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • examples of categories of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flow and/or cohesiveness.
  • treatment and other similar synonyms include the following meanings:
  • the reaction temperature can be suitably selected due to solvent, starting material, reagent, etc., and the reaction The time can also be appropriately selected according to the reaction temperature, solvent, starting materials, reagents and the like.
  • the target compound can be separated and purified from the reaction system according to common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and other methods. Without affecting the next step reaction, the target compound can also directly enter the next step reaction without separation and purification.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention lies in that the inventors have unexpectedly developed a diaryl compound for tubulin-SRC dual-target inhibitors and its preparation method and use after extensive and in-depth research.
  • the diaryl compounds have the structure of formula I as described in the present invention.
  • the diaryl compound can be used as a dual-target inhibitor of tubulin and Src kinase, or can be used as a single inhibitor of tubulin or Src kinase.
  • the compound of the present invention can obviously inhibit the polymerization of tubulin monomer and inhibit cell proliferation. It has good pharmacokinetic properties of topical skin administration and good druggability. It can be used to prepare skin external preparations, and has the advantages of fast metabolism and few side effects.
  • Fig. 1 is the polymerization curve of compound to tubulin monomer in Test Example 1;
  • Figure 2 is a graph showing the results of compounds inhibiting the Src signaling pathway.
  • the synthetic route is as follows:
  • the first step the preparation of 2-(5-bromopyridin-2-yl)acetonitrile
  • reaction solution was poured into saturated ammonium chloride solution/ethyl acetate (300mL/300mL), separated, and the aqueous phase was extracted with ethyl acetate (200mL ⁇ 3), and the organic phase was combined.
  • the phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified on a thin-layer silica gel plate to obtain compound A1-2 (22.5 g, yield 67%).
  • the second step the preparation of 2-(5-bromopyridin-2-yl) methyl acetate
  • reaction solution was concentrated under reduced pressure to remove methanol, the residue was dissolved in dichloromethane (500mL), and the organic phase was sequentially dissolved in water (200mL), saturated sodium bicarbonate solution (200mL) and saturated brine (200mL) After washing, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified on a thin-layer silica gel plate to obtain compound A1-3 (31 g, yield 88%).
  • the third step the preparation of N-benzyl-2-(5-bromopyridin-2-yl)acetamide
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the first step the preparation of 1-bromo-4-(2-bromoethoxy)-2-fluorobenzene
  • the first step the synthesis of 1-bromo-4-(2-bromoethoxy)-2-methylbenzene
  • the second step 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)thio Preparation of Morpholine 1,1-dioxide
  • the third step the preparation of N-benzyl-2-(5-(4-(2-(1,1-dioxythiomorpholine)ethoxy)phenyl)pyridin-2-yl)acetamide
  • the second step the preparation of N-benzyl-2-(5-(2-fluoro-4-hydroxyphenyl)pyridin-2-yl)acetamide
  • the third step the preparation of N-benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridin-2-yl)acetamide
  • N-benzyl-2-(5-(2-fluoro-4-hydroxyphenyl)pyridin-2-yl)acetamide (0.14g, 0.416mmol), 1,2-dibromoethane (0.469g, 2.497mmol) and potassium carbonate (0.345g, 2.497mmol) were placed in acetonitrile (3mL), heated to 85°C and stirred for 12h. Add water (5 mL) to dilute, extract with ethyl acetate (5 mL ⁇ 3), separate the layers, and combine the organic phases.
  • N-benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridin-2-yl)acetamide (0.14g, 0.316 mmol)
  • 2-oxo-6-azaspiro[3.3]heptane 0.063g, 0.632mmol
  • potassium carbonate 0.131g, 0.947mmol
  • the second step the preparation of N-benzyl-2-(5-(4-hydroxy-2-methylphenyl)pyridin-2-yl)acetamide
  • the third step the preparation of N-benzyl-2-(5-(4-(2-bromoethoxy)-2-methylphenyl)pyridin-2-yl)acetamide
  • N-benzyl-2-(5-(2-methyl-4-hydroxyphenyl)pyridin-2-yl)acetamide (0.6g, 1.8mmol) and potassium carbonate (1.5g, 10.7mmol) were mixed at room temperature Added into anhydrous acetonitrile (15mL), heated to 80°C and stirred for 1h, then added 1,2-dibromoethane (2.01g, 10.7mmol), and continued to stir at 80°C for 10h.
  • N-benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridin-2-yl)acetamide (500.0mg, 1.14mmol) Dissolve in acetonitrile (5.0mL), then add potassium carbonate (786.4mg, 5.69mmol), add dropwise 2-oxa-6-azaspiro[3.3]heptane (124.1mg, 1.25mmol) and raise the temperature of the system Stir at 85°C for 16 hours.
  • the synthetic route is as follows:
  • the first step the preparation of N-benzyl-2-(5-(4-(2-bromoethoxy)phenyl)pyridin-2-yl)acetamide
  • N-benzyl-2-(5-(4-hydroxyphenyl)pyridin-2-yl)acetamide (0.5g, 1.56mmol), 1,2-dibromoethane (1.75g, 9.35mmol) and Potassium carbonate (1.29g, 9.35mmol) was placed in acetonitrile (6mL), and the reaction solution was heated to 85°C and stirred for 12h. Add water (10 mL) to dilute, extract with ethyl acetate (5 mL ⁇ 3), separate the layers, and combine the organic phases.
  • N-Benzyl-2-(5-(4-(2-bromoethoxy)phenyl)pyridin-2-yl)acetamide (0.1 g, 0.23 mmol) was added to DMF (2 mL) at room temperature, Triethylamine (91 mg, 0.9 mmol), potassium iodide (150 mg, 0.9 mmol) and crude 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide trifluoroacetate ( 120mg, 0.47mmol), then stirred at 60°C for 8h, after the completion of the reaction monitored by TLC, purified by preparative high performance liquid chromatography to obtain the compound N-benzyl-2-(5-(4-(2-(2,2 -Dioxo-2-thia-6-azaspiro[3.3]heptan-6-yl)ethoxy)phenyl)pyridin-2-yl)acetamide (68.1 mg, yield 59%).
  • the synthetic route is as follows:
  • the first step the preparation of N-benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridin-2-yl)acetamide
  • N-benzyl-2-(5-(2-fluoro-4-hydroxyphenyl)pyridin-2-yl)acetamide (0.6g, 1.8mmol) and potassium carbonate (1.5g, 10.7mmol) were added at room temperature into anhydrous acetonitrile (15mL), heated to 80°C and stirred for 1h, then added 1,2-dibromoethane (2.01g, 10.7mmol), and continued to heat at 80°C Stirred under 10h, TLC detects that the reaction is completed and then cooled to room temperature, and the solvent is concentrated by rotary evaporation to obtain a crude product, which is separated and purified on a silica gel column to obtain the compound N-benzyl-2-(5-(4-(2-bromoethoxy)- 2-fluorophenyl)pyridin-2-yl)acetamide (0.55g, yield 69%).
  • N-benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridin-2-yl)acetamide (0.1 g, 0.23 mmol) was added to N at room temperature, N-dimethylformamide (2mL), then added triethylamine (91mg, 0.9mmol), potassium iodide (150mg, 0.9mmol) and (S)-3-methylmorpholine (34mg, 0.34mmol), then Stirring at 60°C for 8h, the reaction solution was purified by preparative high performance liquid chromatography to obtain compound (S)-N-benzyl-2-(5-(2-fluoro-4-(2-(3-methylmorpholino) )ethoxy)phenyl)pyridin-2-yl)acetamide (I-24A) (18.9mg, yield 18%).
  • N-Benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridin-2-yl)acetamide (0.1 g, 0.23 mmol) was added to DMF ( 2mL), then added triethylamine (91mg, 0.9mmol), potassium iodide (150mg, 0.9mmol) and (R)-3-methylmorpholine (34mg, 0.34mmol), then stirred at 60°C for 8h, TLC After the detection reaction was completed, the compound (R)-N-benzyl-2-(5-(2-fluoro-4-(2-(3- Methylmorpholino)ethoxy)phenyl)pyridin-2-yl)acetamide (I-24B) (19.9 mg, yield 19%).
  • the synthetic route is as follows:
  • the first step the preparation of (1-(2-cyclopropylacetyl) azetidin-3-yl) tert-butyl carbamate
  • reaction solution is diluted with dichloromethane (50mL) , washed with saturated sodium bicarbonate solution/brine (50mL/50mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified on a thin-layer silica gel plate to obtain compound (1-(2-cyclopropylacetyl yl) azetidin-3-yl) tert-butyl carbamate (0.6 g, yield 81%).
  • the second step the preparation of 1-(3-aminoazetidin-1-yl)-2-cyclopropylethane-1-one
  • Step 3 Preparation of 1-(3-((2-(4-bromophenoxy)ethyl)amino)azetidin-1-yl)-2-cyclopropylethane-1-one
  • the synthetic route is as follows:
  • the first step the preparation of 2-bromo-5-(2-morpholineethoxy)benzonitrile
  • the synthetic route is as follows:
  • the second step the preparation of N-benzyl-2-(5-(4-hydroxy-2,6-dimethylphenyl)pyridin-2-yl)acetamide
  • N-benzyl-2-(5-bromopyridin-2-yl)acetamide (0.45g, 1.5mmol), N-benzyl-2-(5-(4,4,5,5-tetra Crude methyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (0.55g, 2.2mmol), potassium fluoride (0.34g, 5.9mmol) and 1 , 1'-two (diphenylphosphino) ferrocene palladium dichloride (II) (108mg, 0.15mmol) joins in the reaction flask, replaces with nitrogen three times, then adds solvent dioxane (20mL), heats Stir at 85°C for 10h, TLC detects that the reaction is complete, cool to room temperature, concentrate and evaporate the solvent to obtain a crude product, and purify N-benzyl-2-(5-(4-hydroxy-2,6- Dimethylphenyl)pyridin-2-yl)acet
  • the third step the preparation of N-benzyl-2-(5-(4-(2-bromoethoxy)-2,6-dimethylphenyl)pyridin-2-yl)acetamide
  • N-benzyl-2-(5-(4-hydroxy-2,6-dimethylphenyl)pyridin-2-yl)acetamide (0.2g, 0.58mmol) and potassium carbonate (0.48g, 3.46mmol) were added to anhydrous acetonitrile (15mL), heated to 85°C and stirred for 1h, then added 1,2-dibromoethane (0.65g, 3.46mmol), and continued Heating and stirring at 85°C for 10 h, TLC detection of the completion of the reaction, cooling to room temperature, concentrating and rotary evaporating off the solvent to obtain a crude product, which was separated and purified with a silica gel column to obtain the compound N-benzyl-2-(5-(4-(2-bromoethyl Oxy)-2,6-dimethylphenyl)pyridin-2-yl)acetamide (0.2g, yield 76%).
  • N-benzyl-2-(5-(4-(2-bromoethoxy)-2,6-dimethylphenyl)pyridin-2-yl)acetamide (0.2g, 0.47mmol) at room temperature Added to N,N-dimethylformamide (2 mL), then added triethylamine (191 mg, 1.81 mmol), potassium iodide (312 mg, 1.81 mmol) and (3aR, 6aS)-hexahydro-1H-furan [3 ,4-c]pyrrole (53mg, 0.47mmol), then stirred at 60°C for 8h, after the completion of the TLC detection reaction, the compound N-benzyl-2-(5-(2,6-dimethyl -4-(2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy)phenyl)pyridin-2-yl)acetamide (59.5mg
  • the synthetic route is as follows:
  • the first step the preparation of 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
  • the second step the preparation of N-benzyl-2-(5-(2-chloro-4-hydroxyphenyl)pyridin-2-yl)acetamide
  • N-benzyl-2-(5-(2-chloro-4-hydroxyphenyl)pyridin-2-yl)acetamide (0.55g, 1.56mmol), 1,2-dibromoethane (1.75g, 9.35mmol) and potassium carbonate (1.29g, 9.35mmol) were placed in acetonitrile (6mL), and the reaction solution was heated to 85°C and stirred for 12h. Add water (5mL) to dilute, and dilute with ethyl acetate (5mL ⁇ 3) extraction, liquid separation, and merging of the organic phases.
  • N-benzyl-2-(5-(4-(2-bromoethoxy)-2-chlorophenyl)pyridin-2-yl)acetamide (0.2g, 0.435mmol), (3aR,6aS) - Hexahydro-1H-furo[3,4-c]pyrrole (0.054g, 0.479mmol) and potassium carbonate (0.180g, 1.30mmol) were dissolved in acetonitrile (3mL) and heated to 85°C and stirred for 12h. Add water (5 mL) to dilute, extract with ethyl acetate (5 mL ⁇ 3), separate the layers, and combine the organic phases.
  • the synthetic route is as follows:
  • the first step the preparation of 2-(5-bromopyridin-2-yl)-N-(2-fluorobenzyl)acetamide
  • the second step the preparation of 2-(5-(2-fluoro-4-hydroxyphenyl)pyridin-2-yl)-N-(2-fluorobenzyl)acetamide
  • the third step the preparation of 2-(5-(4-(2-bromoethoxy)-2-phenyl)pyridin-2-yl)-N-(2-fluorobenzyl)acetamide
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the second step the preparation of 2-(5-(4-(2-bromoethoxy)-2-methylphenyl)pyridin-2-yl)-N-(2-fluorobenzyl)acetamide
  • N-(2-fluorobenzyl)-2-(5-(4-hydroxy-2-methylphenyl)pyridin-2-yl)acetamide (0.8g, 2.3mmol) and potassium carbonate (1.89 g, 13.7mmol) into anhydrous acetonitrile (15mL), heated to 80°C and stirred for 1h, then added 1,2-dibromoethane (2.55g, 13.7mmol), and the reaction solution was stirred at 80°C for 10h.
  • the synthetic route is as follows:
  • the second step the preparation of 2-(5-(2-chloro-4-hydroxyphenyl)pyridin-2-yl)-N-(2-fluorobenzyl)acetamide
  • the third step the preparation of 2-(5-(4-(2-bromoethoxy)-2-chlorophenyl)pyridin-2-yl)-N-(2-fluorobenzyl)acetamide (A6)
  • the fourth step 2-(5-(2-chloro-4-(2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy )Phenyl)pyridin-2-yl)-N-(2-fluorobenzyl)acetamide preparation
  • control compound I (trade name Tirbanibulin) in the test example of the present invention is a dual-action Src kinase and tubulin polymerization inhibitor, which has been approved by the FDA and the European Union for local treatment of face or scalp actinic keratosis treat.
  • the preparation of reference compound I refers to the patent WO 2008/002676A2, and the structure of reference compound I is as follows:
  • the Tubulin Polymerization Assay Kit (cytoskeleton, Cat.#BK011P) was used to carry out the compound inhibition of tubulin monomer polymerization test.
  • the proliferation assay of human skin squamous cell carcinoma cell A-431 (ATCC, CRL-1555) and actinic keratosis patient-derived cells HT 297.T was used to detect the inhibitory effect of small molecule compounds on cell proliferation.
  • A-431 cells and HT 297.T cells were cultured in DMEM medium containing 10% fetal bovine serum at 37°C in a 5% CO 2 incubator.
  • the logarithmic phase cells were inoculated into 96-well cell culture plates at 1000 cells/well, 100 ⁇ L per well, and cultured overnight at 37°C in a 5% CO 2 incubator.
  • Add 100 ⁇ L of gradient diluted 2 ⁇ test compound solution to each well DMSO was used as a positive control, and 10 ⁇ M staurosporine (Aladdin, S102392) was set as a negative control group, and the culture plate after adding the compound was continued at 37°C , and incubate for 4 days in a 5% CO 2 incubator.
  • Inhibition% (signal of positive control group - signal of test well) / (signal of positive control group - signal of negative control group) * 100
  • Table 2 test compound inhibits the activity of A-431 cell proliferation
  • Table 3 Test compound inhibits the proliferation activity of HT 297.T cells
  • phosphate buffered saline PBS
  • FeSSIF solution at pH 6.5
  • FaSSGF solution at pH 1.6.
  • PBS phosphate buffered saline
  • the incubated solution was centrifuged at 12,000 rpm for 10 minutes to remove undissolved particles, and the supernatant was transferred to a new centrifuge tube. After appropriate dilution of the supernatant, the acetonitrile solution containing the internal standard was added, and the standard song prepared with the same matrix was used for quantification.
  • thermodynamic solubility test results are shown in Table 4, and the results show that, compared with the reference compound I, the compound of the present invention has greater thermodynamic solubility under neutral conditions and has better druggability.
  • mice Mouse pharmacokinetics test, using 3 male ICR mice, 20-25g, fasted overnight, administered by tail vein injection (1mg/kg or 5mg/kg), before administration and 15, 30min after administration And 1, 2, 4, 8, 24h blood collection. Another 3 mice were taken orally or gavaged (5 mg/kg), and blood was collected before administration, 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, plasma was collected and stored at -80°C.
  • mice pharmacokinetic test results are shown in Table 5, Table 6 and Table 7. The results show that compared with the reference compound I, the compound of the present invention has fast metabolism in mice, low potential systemic toxicity, and good druggability.
  • the stability test of human liver microsomes was detected by incubating the compound with human liver microsomes in vitro. Firstly, the compound to be tested was prepared as a 10 mM stock solution in DMSO solvent, and then the compound was diluted to 0.5 mM with acetonitrile. Use PBS to dilute human liver microsomes (Corning) into a microsome/buffer solution, and use this solution to dilute 0.5mM compounds to become a working solution. The compound concentration was 1.5 ⁇ M and the concentration in human liver microsomes was 0.75 mg/ml.
  • Test Example 6 Compounds Inhibit Src Signaling Pathway
  • Western Blot method was used to detect the p-SRC inhibition of the compound on A-431 skin cancer cells (ATCC, CRL-1555) to evaluate the inhibitory effect of the compound on the SRC signaling pathway.
  • A-431 cells were cultured in DMEM medium containing 10% fetal bovine serum and placed in a 37°C, 5% CO 2 incubator for growth. 500,000 cells/well were seeded in a 12-well cell culture plate and cultured overnight in a 37°C, 5% CO 2 incubator. The next day, the culture medium was replaced, and different concentrations of compounds were added for treatment. DMSO was used as a control, and the culture plate after adding the compound was placed in a 37° C., 5% CO 2 incubator to continue culturing for 24 hours.
  • test results are shown in Figure 2.
  • the results show that the compound of the present invention can significantly inhibit the phosphorylation of SRC at 80nM, and compared with the control compound I, it has better p-SRC inhibitory activity and can block the downstream signaling pathway of SRC.

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Abstract

本发明公开了一种用于微管蛋白-SRC双靶点抑制剂的二芳基类化合物。本发明还提供了一种如式I所示二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药。所述二芳基类化合物可以作为微管蛋白和Src激酶双靶点抑制剂，也可以作为单独的微管蛋白或Src激酶抑制剂使用。本发明化合物能明显抑制微管蛋白单体的聚合、抑制细胞增殖。

Description

用于微管蛋白-SRC双靶点抑制剂的二芳基类化合物
本申请要求申请日为2022年1月14日的中国专利申请202210044016.7、申请日为2022年4月15日的中国专利申请202210399397.0、申请日为2022年9月19日的中国专利申请202211139978.7和申请日为2023年1月6日的中国专利申请202310020643.1的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种用于微管蛋白-SRC双靶点抑制剂的二芳基类化合物。
背景技术
微管是真核细胞中细胞骨架的重要组成部分，在维持细胞形态、信号传递、细胞器运输、细胞运动、细胞分裂和有丝分裂等多种细胞功能中发挥着重要作用(Jordan M A et al.Nature Reviews Cancer,2004,4(4):253-265.)。
微管由两种类型的微管蛋白亚基，即α-微管蛋白和β-微管蛋白组成，α-微管蛋白和β-微管蛋白形成微管蛋白异二聚体，是微管装配的基本单位。微管靶向剂(Microtubule-targeting agents，MTAs)能破坏微管的动力学稳定性和结构，干扰有丝分裂纺锤体的形成，诱导细胞周期阻滞于G2/M期，促使细胞凋亡(Shuai W et al.Journal of Medicinal Chemistry,2021,64(12).)。
微管参与很多重要的细胞过程，已成为治疗过度增殖性疾病最重要的药物靶点之一，美国FDA批准的几种微管靶向剂如长春花碱和紫杉烷类化合物被广泛用于治疗多实体肿瘤和血液系统恶性肿瘤，但微管靶向药物的耐药性和剂量限制性毒性限制了其临床疗效。双靶点抑制剂与单靶点药物相比克服了耐药性，可以改善治疗效果，已成为研究热点，如：微管蛋白-SRC双靶点抑制剂、微管蛋白-受体酪氨酸激酶(receptor tyrosine kinases inhibitor，RTK)双靶点抑制剂、微管蛋白-组蛋白去乙酰化酶(histone deacetylases inhibitor， HDAC)双靶点抑制剂等(Shuai W et al.Journal of Medicinal Chemistry,2021,64(12).)。
光化性角化病(Actinic keratosis，AK)是一种与长时间暴露在紫外线下有关的皮肤病，在美国AK是皮肤科医生第二常见的疾病，特征是突变的角质形成细胞不受控制的增殖，其被认为是一种癌前病变，如果不及时治疗，20％的病例可能会发展为皮肤鳞状细胞癌(SCC)。目前微管蛋白-SRC双靶点抑制剂Tirbanibulin临床上局部治疗AK效果显著(NCT03285477)，已被FDA批准上市，这表明开发新的具有更好效果的微管蛋白-SRC双靶点抑制剂局部治疗AK可能是一个有潜力的方向。
发明内容
本发明的目的是提供一种用于微管蛋白-SRC双靶点抑制剂的二芳基类化合物及其制备方法和用途，所述二芳基类化合物具有如本发明中所述的式I结构。所述二芳基类化合物可以作为微管蛋白和Src激酶双靶点抑制剂，也可以作为单独的微管蛋白或Src激酶抑制剂使用。
在本发明第一方面，提供了一种式I所示二芳基类化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药，具有结构：
其中，W选自：-O-、-S-、-NH-、-N(C1-C6烷基)-；
L为C1-C6亚烷基；
V为不存在或选自：-O-、-S-、-NH-、-N(C1-C6烷基)-；
当V不存在时，Q为未取代或被m个R3取代的环A、未取代或被m个R3取代的环B；
当V选自：-O-、-S-、-NH-、-N(C1-C6烷基)-时，Q为未取代或被m个R3取代的环C；
所述环A为6-15元杂环基；且当环A为6元杂环基时，所述环A为
所述环B为6-12元含砜基的杂环基；
所述环C为4-15元杂环基或6-12元含砜基的杂环基；
R1、R2、R3各自独立地为氢或选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12、-COO-3-6元环烷基、-CO-3-6元环烷基、-S(O)2-C1-C6烷基、-S(O)2-3-6元环烷基、-C(O)-C1-C6烷基-NR11R12；
其中，R11、R12各自独立地为氢或C1-C6烷基；或R11和R12与它们所连接的N原子一起形成4-6元环；
所述R1、R2、R3任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基、3-6元环烷基；当取代基为多个时，所述取代基相同或不同；
n为1、2或3；当R1为多个时，所述R1相同或不同；
p为1、2或3；当R2为多个时，所述R2相同或不同；
m为1、2或3；当R3为多个时，所述R3相同或不同；
条件是当Q为环A时，R1、R2不同时为氢；
当所述环A为时；R3也不为氢；
或当所述环A为时，R1和R2中至少一个选自：氰基、C2-C6烯基、C2-C6炔基、-C(O)NR11R12。
本发明中，所述的式I所示二芳基类化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药中某些取代基的定义可如下所述，未提及的取代基的定义均如本申请中任一方案所述(以下简称“在一优选实施例中”、“在一优选实施方式中”或“在一优选实施方案中”)：
其中，W选自：-O-、-S-、-NH-、-N(C1-C6烷基)-；
L为C1-C6亚烷基；
V为不存在或选自：-O-、-S-、-NH-、-N(C1-C6烷基)-；
当V不存在时，Q为未取代或被m个R3取代的环A、未取代或被m个R3取代的环B；
当V选自：-O-、-S-、-NH-、-N(C1-C6烷基)-时，Q为未取代或被m个R3取代的环C；
所述环A为6-15元杂环基；且当环A为6元杂环基时，所述环A为
所述环B为6-12元含砜基的杂环基；
所述环C为4-15元杂环基或6-12元含砜基的杂环基；
R1、R2、R3各自独立地为氢或选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12、-COO-3-6元环烷基、-CO-3-6元环烷基、-S(O)2-C1-C6烷基、-S(O)2-3-6元环烷基、-C(O)-C1-C6烷基-NR11R12；
其中，R11、R12各自独立地为氢或C1-C6烷基；或R11和R12与它们所连接的N原子一起形成4-6元环；
所述R1、R2、R3任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基、3-6元环烷基；当取代基为多个时，所述取代基相同或不同；
n为1、2或3；当R1为多个时，所述R1相同或不同；
p为1、2或3；当R2为多个时，所述R2相同或不同；
m为1、2或3；当R3为多个时，所述R3相同或不同；
式I所示二芳基类化合物满足以下条件中的1个、2个或3个：
(1)V选自：-O-、-S-、-NH-、-N(C1-C6烷基)-；
(2)Q为未取代或被m个R3取代的6-12元含砜基的杂环基；
(3)R1选自：羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12、-COO-3-6元环烷基、-CO-3-6元环烷基、-S(O)2-C1-C6烷基、-S(O)2-3-6元环烷基、-C(O)-C1-C6烷基-NR11R12；或者，R1为卤素，环A、环B或环C为并环、桥环或螺环。
在一优选实施例中，V选自：-O-、-S-、-NH-、-N(C1-C6烷基)-。
在一优选实施例中，V选自-NH-。
在一优选实施例中，Q为未取代或被m个R3取代的6-12元含砜基的杂环基。
在一优选实施例中，Q为未取代的6-12元含砜基的杂环基。
在一优选实施例中，R1选自：羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12、-COO-3-6元环烷基、-CO-3-6元环烷基、-S(O)2-C1-C6烷基、-S(O)2-3-6元环烷基、-C(O)-C1-C6烷基-NR11R12。
在一优选实施例中，R1选自：氰基、C1-C6烷基和C2-C6炔基。
在一优选实施例中，R1为卤素，环A、环B或环C为并环、桥环或螺环。
在一优选实施例中，式I所示二芳基类化合物为
m为1或2；
R3选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12；R1选自：氰基、C2-C6烯基、C2-C6炔基、-C(O)NR11R12。
在一优选实施例中，式I所示二芳基类化合物为 m为1；R3为C1-C6烷基。
在一优选实施例中，式I所示二芳基类化合物为m为1；R3为C1-C6烷基；R1选自：氰基、C2-C6烯基、C2-C6炔基、-C(O)NR11R12。
在一优选实施例中，条件是当Q为环A时，R1、R2不同时为氢；
且当所述环A为时，R3不为氢，或者R1和R2中至少一个选自：氰基、C2-C6烯基、C2-C6炔基、-C(O)NR11R12。
在一优选实施例中，W选自-O-。
在一优选实施例中，L为C1-C6亚烷基。
在一优选实施例中，V为不存在或选自：-NH-；
当V不存在时，Q为未取代或被m个R3取代的环A、未取代或被m个R3取代的环B；
当V选自：-NH-时，Q为未取代或被m个R3取代的环C；
所述环A为6-15元杂环基；且当环A为6元杂环基时，所述环A为
所述环B为6-12元含砜基的杂环基；
所述环C为4-15元杂环基或6-12元含砜基的杂环基；
m为1、2或3；当R3为多个时，所述R3相同或不同；
R3为C1-C6烷基或-CO-C1-C6烷基；R3任选地被一个或多个3-6元环烷基取代；当取代基为多个时，所述取代基相同或不同。
在一优选实施例中，n为1、2或3；当R1为多个时，所述R1相同或不 同；
R1为氢、卤素、氰基、未取代的C1-C6烷基或未取代的C2-C6炔基。
在一优选实施例中，n为1；
R1为氢、卤素、氰基、未取代的C1-C6烷基或未取代的C2-C6炔基。
在一优选实施例中，p为1、2或3；当R2为多个时，所述R2相同或不同；
R2为氢或卤素。
在一优选实施例中，p为1；R2为氢。
在一优选实施例中，式I所示二芳基类化合物满足以下条件中的1个、2个或3个：
(1)V选自-NH-；
(2)Q为未取代或被m个R3取代的6-12元含砜基的杂环基；
(3)R1为氰基、未取代的C1-C6烷基或未取代的C2-C6炔基；或者，R1为卤素，环A、环B或环C为并环、桥环或螺环。
在一优选实施例中，W选自-O-；
L为C1-C6亚烷基；
V为不存在或选自：-NH-；
当V不存在时，Q为未取代或被m个R3取代的环A、未取代或被m个R3取代的环B；
当V选自：-NH-时，Q为未取代或被m个R3取代的环C；
所述环A为6-15元杂环基；且当环A为6元杂环基时，所述环A为
所述环B为6-12元含砜基的杂环基；
所述环C为4-15元杂环基或6-12元含砜基的杂环基；
n为1、2或3；当R1为多个时，所述R1相同或不同；
R1为氢、卤素、氰基、未取代的C1-C6烷基或未取代的C2-C6炔基；
p为1、2或3；当R2为多个时，所述R2相同或不同；
R2为氢或卤素；
m为1、2或3；当R3为多个时，所述R3相同或不同；
R3为C1-C6烷基或-CO-C1-C6烷基；R3任选地被一个或多个3-6元环烷基取代；当取代基为多个时，所述取代基相同或不同；
式I所示二芳基类化合物满足以下条件中的1个、2个或3个：
(1)V选自-NH-；
(2)Q为未取代或被m个R3取代的6-12元含砜基的杂环基；
(3)R1为氰基、未取代的C1-C6烷基或未取代的C2-C6炔基；或者，R1为卤素，环A、环B或环C为并环、桥环或螺环。
在一优选实施例中，W选自-O-；
L为C1-C6亚烷基；
V为不存在或选自：-NH-；
当V不存在时，Q为未取代或被m个R3取代的环A、未取代或被m个R3取代的环B；
当V选自：-NH-时，Q为未取代或被m个R3取代的环C；
所述环A为6-15元杂环基；且当环A为6元杂环基时，所述环A为
所述环B为6-12元含砜基的杂环基；
所述环C为4-15元杂环基或6-12元含砜基的杂环基；
n为1；
R1为氢、卤素、氰基、未取代的C1-C6烷基或未取代的C2-C6炔基；
p为1；
R2为氢；
m为1、2或3；当R3为多个时，所述R3相同或不同；
R3为C1-C6烷基或-CO-C1-C6烷基；R3任选地被一个或多个3-6元环烷 基取代；当取代基为多个时，所述取代基相同或不同；
式I所示二芳基类化合物满足以下条件中的1个、2个或3个：
(1)V选自-NH-；
(2)Q为未取代或被m个R3取代的6-12元含砜基的杂环基；
(3)R1为氰基、未取代的C1-C6烷基或未取代的C2-C6炔基；或者，R1为卤素，环A、环B或环C为并环、桥环或螺环。
在一优选实施例中，L为-CH2-、-CH2CH2-、-CH2CH2CH2-；较佳地，L为-CH2CH2-。
在一优选实施例中，所述的环A里，所述的6-15元杂环基为6-8元杂环基。
在一优选实施例中，所述的环A里，所述的6-15元杂环基为单环、并环、桥环或螺环。
在一优选实施例中，所述的环A里，所述的6-15元杂环基为饱和环。
在一优选实施例中，所述的环A里，所述的6-15元杂环基中的杂原子为N和/或O。
在一优选实施例中，所述的环A里，所述的6-15元杂环基中的杂原子为N和O。
在一优选实施例中，所述的环A里，所述的6-15元杂环基通过N原子与V连接。
在一优选实施例中，所述环A为(例如)、
在一优选实施例中，所述的环C里，所述的4-15元杂环基杂环基为6-8元杂环基。
在一优选实施例中，所述的环C里，所述的4-15元杂环基为单环、并环、桥环或螺环。
在一优选实施例中，所述的环C里，所述的4-15元杂环基为饱和环。
在一优选实施例中，所述的环C里，所述的4-15元杂环基中的杂原子为N和/或O。
在一优选实施例中，所述的环C里，所述的4-15元杂环基中的杂原子为N和O。
在一优选实施例中，所述的环C里，所述的4-15元杂环基通过N原子与V连接。
在一优选实施例中，所述环C里，所述的4-15元杂环基为(例如)、
在一优选实施例中，所述的环B里，所述的6-12元含砜基的杂环基6-8元含砜基的杂环基。
在一优选实施例中，所述的环B里，所述的6-12元含砜基的杂环基为单环、并环、桥环或螺环。
在一优选实施例中，所述的环B里，所述的6-12元含砜基的杂环基为单环或螺环。
在一优选实施例中，所述的环B里，所述的6-12元含砜基的杂环基为饱和环。
在一优选实施例中，所述的环B里，所述的6-12元含砜基的杂环基中的杂为-S(＝O)2-和/或N。
在一优选实施例中，所述的环B里，所述的6-12元含砜基的杂环基中的杂为-S(＝O)2-和N。
在一优选实施例中，所述的环B里，所述的6-12元含砜基的杂环基通过N原子与V连接。
在一优选实施例中，所述环B里，所述的6-12元含砜基的杂环基为
在一优选实施例中，所述的环C里，所述的6-12元含砜基的杂环基6-8元含砜基的杂环基。
在一优选实施例中，所述的环C里，所述的6-12元含砜基的杂环基为单环、并环、桥环或螺环。
在一优选实施例中，所述的环C里，所述的6-12元含砜基的杂环基为单环或螺环。
在一优选实施例中，所述的环C里，所述的6-12元含砜基的杂环基为饱和环。
在一优选实施例中，所述的环C里，所述的6-12元含砜基的杂环基中的杂为-S(＝O)2-和/或N。
在一优选实施例中，所述的环C里，所述的6-12元含砜基的杂环基中的杂为-S(＝O)2-和N。
在一优选实施例中，所述的环C里，所述的6-12元含砜基的杂环基通过N原子与V连接。
在一优选实施例中，所述环C里，所述的6-12元含砜基的杂环基为
在一优选实施例中，所述R1里，所述的卤素为氟或氯。
在一优选实施例中，所述R1里，所述的C1-C6烷基为甲基或乙基。
在一优选实施例中，所述R1里，所述的C2-C6炔基为乙炔基或丙炔基。
在一优选实施例中，所述R2里，所述的卤素为氟或氯。
在一优选实施例中，所述R3里，所述的C1-C6烷基为甲基或乙基。
在一优选实施例中，所述R3里，所述的“-CO-C1-C6烷基”中的C1-C6烷基为甲基或乙基。
在一优选实施例中，R11和R12与它们所连接的N原子一起形成的4-6元环可以为4-6元含N杂环烷基或5-6元杂芳基。
在一优选实施例中，W选自：-O-、-S-、-NH-；较佳地，W为-O-。
在一优选实施例中，L为-CH2-、-CH2CH2-、-CH2CH2CH2-；较佳地，L为-CH2CH2-。
在一优选实施例中，V为不存在或-NH-。
在一优选实施例中所述环A为7-15元单环、并环、桥环或螺环的杂环基；
较佳地，所述环A含有1、2或3个选自N、O或S的杂原子；当杂原子为多个时，所述杂原子相同或不同；较佳地，所述环A含有1个N原子和1个O原子。
在一优选实施例中，所述环A具有结构其中，Z表示C或N；较佳地，Z为N；较佳地，所述环A还含有1个O原子；较佳地，为
在一优选实施例中，所述环B为6-12元含砜基的单环、并环、螺环、桥环杂环基；较佳地，环B为6-8元含砜基的单环杂环基；较佳地，环B为7-12元含砜基的并环、螺环、桥环杂环基。
在一优选实施例中，环B为其中，K表示C或N。
在一优选实施例中，所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药，具有式Ia、Ib或Ic所示结构：

其中，K表示C或N；
环A、环B、m、n、p、R1、R2、R3的定义如本发明第一方面中所述。
在一优选实施例中具有结构
在一优选实施例中，所述环A为7-10元单环杂环基或7-12元并环、桥环、螺环杂环基。
在一优选实施例中，所述环A选自：
较佳地，为
在一优选实施例中，R1、R2各自独立地为氢或选自：卤素、羟基、氨基、C1-C6烷基、-O-C1-C6烷基；所述C1-C6烷基任选地被一个或多个卤素取代；R3选自：卤素、羟基、氨基、C1-C6烷基、-O-C1-C6烷基；所述C1-C6烷基任选地被一个或多个卤素取代；且R1、R2不同时为氢；
较佳地，R1、R2、R3各自独立地选自：卤素、C1-C6烷基；所述C1-C6烷基任选地被一个或多个卤素取代；
更佳地，R1、R2、R3各自独立地选自：氟、甲基、乙基、丙基；所述甲基、乙基、丙基任选地被一个或多个卤素取代；
较佳地，所述卤素为F。
在一优选实施例中，环B为6-12元单环、并环、螺环、桥环杂环基；较佳地，环B为6-8元单环杂环基；较佳地，环B为7-12元并环、螺环、桥环杂环基。
在一优选实施例中，所述环B选自：
在一优选实施例中，R1、R2、R3各自独立地为氢或选自：卤素、羟基、氨基、氰基、C1-C6烷基、-O-C1-C6烷基、-C(O)NR11R12；R11、R12各自独立地为氢或C1-C6烷基；
所述C1-C6烷基任选地被一个或多个卤素取代；
较佳地，R1、R2、R3各自独立地选自：卤素、C1-C6烷基；所述C1-C6烷基任选地被一个或多个卤素取代；
更佳地，R1、R2、R3各自独立地选自：氟、甲基、乙基、丙基；所述C1-C6烷基任选地被一个或多个氟取代；较佳地，所述卤素为F。
在一优选实施例中，n为1。
在一优选实施例中，R1为氢或选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基；
较佳地，R1为氢或选自：卤素、氰基、C1-C6烷基、C2-C6炔基；
更佳地，R1为氢或选自：氟、氯、氰基、甲基、-C≡C-CH3。
在一优选实施例中，R2为氢。
在一优选实施例中，R3为氢。
在一优选实施例中，所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药，具有结构Id
其中，m为1或2；较佳地m为1；
R3为氢或选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12；R1选自：氰基、C2-C6烯基、C2-C6炔基、-C(O)NR11R12；
或者R1、R3各自独立地选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12；
其中，R11、R12各自独立地为氢或C1-C6烷基；或R11和R12与它们所连接的N原子一起形成4-6元环；
所述R3任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基；当取代基为多个时，所述取代基相同或不同。
在一优选实施例中，R3为氢或选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12；R1选自：氰基、C2-C3烯基、C2-C3炔基、-C(O)NR11R12；
或R1、R3各自独立地选自：卤素、C1-C6烷基；所述C1-C6烷基任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基；当取代基为多个时，所述取代基相同或不同；
较佳地，R3为氢或选自：卤素、甲基、乙基、丙基；所述甲基、乙基、丙基任选地被1个或多个卤素取代；R1选自：氰基、C2-C3烯基、C2-C3炔基；更佳地，R3为氢；R1选自：氰基、C2-C3烯基、C2-C3炔基；
较佳地，R1、R3各自独立地选自：卤素、甲基、乙基、丙基；所述甲基、乙基、丙基任选地被1个或多个卤素取代；较佳地，所述卤素为氟。
在一优选实施例中，所述的二芳基类化合物、其互变异构体、立体异构 体、溶剂化物(例如水合物)、药学上可接受的盐或前药，具有结构Ie或If
其中，环C、R1、R2、n、p的定义如本发明第一方面中所述；
R3为C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12、3-6元环烷基、-COO-C1-C6烷基、-COO-3-6元环烷基、-CO-3-6元环烷基、-S(O)2-C1-C6烷基、-S(O)2-3-6元环烷基、-C(O)-C1-C6烷基-NR11R12；
其中，R11、R12各自独立地为氢或C1-C6烷基；或R11和R12与它们所连接的N原子一起形成4-6元环；
所述R3任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基、3-6元环烷基；当取代基为多个时，所述取代基相同或不同；
较佳地，环C为4-8元杂环基；较佳地，环C为4-6元杂环基；更佳地，环C为4元环；
较佳地，R3为-CO-C1-C6烷基；
较佳地，所述R3任选地被一个或多个选自下列的取代基取代：卤素、3-6元环烷基；
更佳地，R3为-CO-C1-C3烷基-环丙基、-CO-C1-C3烷基-环丁基。
在一优选实施方式中，式I、Ia、Ib、Ic、Id、Ie或If所示二芳基类化合物中，R1为氢或选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基；
较佳地，R1为氢或选自：卤素、氰基、C1-C6烷基、C2-C6炔基；
更佳地，R1为氢或选自：氟、氯、氰基、甲基、-C≡C-CH3。
在一优选实施例中，所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药里，所述的二芳基类化合物为以下任一化合物：

在一优选实施例中，所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药里，所述的二芳基类化合物为以下任一化合物：

较佳地，为
较佳地，为
在本发明第二方面，提供了一种化合物B具有结构
其中，Q、L、W、R1、n的定义如第一方面所述；
X为卤素或者取代基G；
所述取代基G选自：硼酸酯基、硼酸基、烷基锡、三氟甲烷磺酸基、甲烷磺酸基、对甲苯磺酸基；
较佳地，所述卤素为氯、溴或碘。
在一优选实施例中，所述的化合物B具有下列结构

其中，K表示C或N；
环A、环B、m、n、p、R1、R2、R3的定义如第一方面中所述；
X为卤素或者取代基G；
在一优选实施例中，所述取代基G选自：硼酸酯基、硼酸基、烷基锡、三氟甲烷磺酸基、甲烷磺酸基、对甲苯磺酸基；
较佳地，所述卤素为氯、溴或碘。
在本发明第二方面，提供了一种中间体B具有结构
其中，Q、L、W、R1、n的定义如第一方面所述；
X为卤素或者取代基G；
所述取代基G选自：硼酸酯基、硼酸基、烷基锡、三氟甲烷磺酸基、甲烷磺酸基、对甲苯磺酸基；
较佳地，所述卤素为氯、溴或碘。
在一优选实施例中，所述的中间体B具有下列结构
其中，K表示C或N；
环A、环B、m、n、p、R1、R2、R3的定义如第一方面中所述；
X为卤素或者取代基G；
在一优选实施例中，所述取代基G选自：硼酸酯基、硼酸基、烷基锡、三氟甲烷磺酸基、甲烷磺酸基、对甲苯磺酸基；
较佳地，所述卤素为氯、溴或碘。
在一优选实施例中，所述环A为7-15元单环、并环、桥环或螺环的杂环基；
较佳地，所述环A为7-10元单环杂环基或7-12元并环、桥环或螺环杂环基；
较佳地，所述环A含有1个N原子和1个O原子。
在一优选实施例中，所述硼酸酯基选自：联硼酸频哪醇酯、联邻苯二酚硼酸酯、联(3,3-二甲基-2,4-戊二醇)硼酸酯、三乙醇胺硼酸酯、硼酸三甲酯、硼酸三异丙酯、硼酸三乙酯、硼酸三丁酯、联硼酸新戊二醇酯。
在一优选实施例中，环B为6-12元单环、并环、螺环、桥环杂环基；较佳地，环B为6-8元单环杂环基；较佳地，环B为7-12元并环、螺环、桥环杂环基。
在一优选实施例中，所述烷基锡为丁基锡、异丙基锡、丙基锡。
在一优选实施例中，R1、R2、R3各自独立地选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12；
其中，R11、R12各自独立地为氢或C1-C6烷基；或R11和R12与它们所连接的N原子一起形成4-6元环；
所述R3任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基；当取代基为多个时，所述取代基相同或不同。
在一优选实施例中，R3为氢或选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12；R1选自：氰基、C2-C6烯基、C2-C6炔基、-C(O)NR11R12。
较佳地，R3为氢或选自：卤素、甲基、乙基、丙基；所述甲基、乙基、丙基任选地被1个或多个卤素取代；R1选自：氰基、C2-C3烯基、C2-C3炔基；
在一优选实施例中，R1、R2、R3各自独立地选自：卤素、C1-C6烷基；所述C1-C6烷基任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基；当取代基为多个时，所述取代基相同或不同；
较佳地，R1、R3各自独立地选自：卤素、甲基、乙基、丙基；所述甲基、乙基、丙基任选地被1个或多个卤素取代；较佳地，所述卤素为氟。
在一优选实施例中，R3为C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12、3-6元环烷基、-COO-C1-C6烷基、-COO-3-6元环烷基、-CO-3-6元环烷基、-S(O)2-C1-C6烷基、-S(O)2-3-6元环烷基、-C(O)-C1-C6烷基-NR11R12；其中，R11、R12各自独立地为氢或C1-C6烷基；或R11和R12与它们所连接的N原子一起形成4-6元环；
所述R3任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基、3-6元环烷基；当取代基为多个时，所述取代基相同或不同。
较佳地，环C为4-8元杂环基；较佳地，环C为4-6元杂环基；更佳地，
较佳地，R3为-CO-C1-C6烷基；较佳地，所述R3任选地被一个或多个选自下列的取代基取代：卤素、3-6元环烷基；
更佳地，R3为-CO-C1-C3烷基-环丙基、-CO-C1-C3烷基-环丁基。
一种化合物，其为以下任一结构：

在本发明第三方面，提供了一种制备如第一方面中任一所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药的方法，包括：
将如第二方面中任一所述的中间体B与中间体C在碱性条件下反应得到所述二芳基类化合物
中间体C；
其中，R2和p的定义如第一方面中所述；
Y为卤素或者取代基G；
所述取代基G选自：硼酸酯基、硼酸基、烷基锡、三氟甲烷磺酸基、甲烷磺酸基、对甲苯磺酸基；
当中间体B中的X为卤素时，Y为G；
当中间体B中的X为G时，X为卤素；
较佳地，所述卤素为氯、溴或碘；
较佳地，中间体C具有结构
在一优选实施例中，所述硼酸酯基选自：联硼酸频哪醇酯、联邻苯二酚硼酸酯、联(3,3-二甲基-2,4-戊二醇)硼酸酯、三乙醇胺硼酸酯、硼酸三甲酯、硼酸三异丙酯、硼酸三乙酯、硼酸三丁酯、联硼酸新戊二醇酯。
在一优选实施例中，所述烷基锡为丁基锡、异丙基锡、丙基锡。
在一优选实施例中，所述反应需要惰性气体保护，所述惰性气体包括但 不限于：氮气、氦气、氖气、氩气。
在一优选实施例中，所述反应在钯催化剂条件下反应；较佳地，所述钯催化剂选自：
本发明各步反应优选地在惰性溶剂中进行，所述惰性溶剂包括但不限于：甲苯、苯、水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜、四氢呋喃二氯甲烷、三氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环，或其组合物。
优选地，所述钯催化剂选自下组：三(二亚苄基丙酮)二钯(Pd2(dba)3)、四(三苯基膦)钯(Pd(PPh3)4)、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1`-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯、1,2-二(二苯基膦基)乙烷二氯化钯，或其组合物。
优选地，所述硼酸酯基选自下组：联硼酸频哪醇酯、联邻苯二酚硼酸酯、联(3,3-二甲基-2,4-戊二醇)硼酸酯、三乙醇胺硼酸酯、硼酸三甲酯、硼酸三异丙酯、硼酸三乙酯、硼酸三丁酯、联硼酸新戊二醇酯。
在本发明第四方面，提供了一种药物组合物，包括如第一方面所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药。
提供了一种药物组合物，包括第一方面所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药，和药学上可接受的载体和/或其他活性药物。
在本发明第五方面，提供了如第一方面所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药的用途，或如第四方面所述的药物组合物的用途，所述用途包括：
1)抑制微管蛋白聚合和/或Src激酶；
2)预防和/或治疗与微管蛋白聚合和/或Src激酶相关的疾病；
3)制备微管蛋白聚合和/或Src激酶抑制剂；
4)制备预防和/或治疗与微管蛋白聚合和/或Src激酶相关的疾病的药物、药物组合物或制剂。
较佳地，所述用途包括：抑制微管蛋白聚合；和/或，预防和/或治疗微管蛋白聚合介导的疾病；和/或，制备微管蛋白聚合抑制剂，和/或预防和/或治疗与微管蛋白聚合介导的疾病的药物、药物组合物或制剂。
较佳地，所述用途包括：抑制Src激酶；和/或，预防和/或治疗Src激酶介导的疾病；和/或，制备Src激酶抑制剂；和/或，制备预防和/或治疗与Src激酶介导的疾病的药物、药物组合物或制剂。
较佳地，所述药物为外用制剂。
较佳地，所述药物为经皮给药的药物。
较佳地，所述微管蛋白聚合和/或Src激酶相关的疾病包括肿瘤、皮肤疾病。
在本发明第六方面，提供了如第一方面所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药在制备治疗肿瘤和/或皮肤疾病的药物中的用途；或如第四方面所述的药物组合物在制备治疗肿瘤和/或皮肤疾病的药物中的用途。
较佳地，所述药物为外用制剂。
较佳地，所述药物为经皮给药的药物。
在本发明第七方面，提供了本发明第一方面所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药中的至少一种或本发明第四方面所述的药物组合物用于治疗或者预防肿瘤和/或皮肤疾病的用途。
在一优选实施方式中，所述肿瘤包括：实体瘤、肉瘤、血液系统癌症；
较佳地，所述肿瘤包括：乳腺癌、卵巢癌、前列腺癌、子宫颈癌、睾丸癌、结肠癌、结肠直肠癌、肝癌、非小细胞肺癌、鳞状细胞癌(例如皮肤鳞状细胞癌)、小细胞肺癌、胃癌、胃肠道间质瘤、胰腺癌、膀胱癌、生殖细胞瘤、肥大细胞瘤、肥大细胞增多症、胶质母细胞瘤、神经母细胞瘤、星形细 胞瘤、黑色素瘤、B细胞淋巴瘤、T细胞淋巴瘤、缓慢进展淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性髓细胞性白血病、急性淋巴细胞性白血病、慢性髓细胞性白血病、慢性淋巴细胞性白血病、骨髓瘤和/或骨髓增生异常综合症。
在一优选实施方式中，所述皮肤疾病包括：光化性角化病、银屑病、异位性皮炎、牛皮癣、白癜风、玫瑰疹和/或系统性红斑狼疮。
在本发明第八方面，提供了一种抑制Src激酶，或预防和/或治疗Src激酶相关的(或介导的)疾病的方法，包括步骤：给需要的对象使用如本发明第一方面所述的化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药，或如本发明第四方面所述的药物组合物。
在本发明第九方面，提供了一种抑制微管蛋白，或预防和/或治疗与微管蛋白相关的(或介导的)疾病的方法，包括步骤：给需要的对象使用如本发明第一方面所述的化合物、其互变异构体、立体异构体、溶剂化物(例如水合物)、药学上可接受的盐或前药，或如本发明第四方面所述的药物组合物。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
术语和定义
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明 主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH2O等同于OCH2。如本文所用，表示基团的连接位点。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。 例如，“1～6的整数”应当理解为记载了1、2、3、4、5和6的每一个整数。
在本申请中，在单独或作为其他取代基一部分时，术语“卤素”是指氟、氯、溴、碘。
在单独或作为其他取代基一部分时，“砜基”是指基团。
如本文所用，在单独或作为其他取代基一部分时，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至6个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基，叔丁基，戊基，异戊基，新戊基和己基。烷基也可以是富含碳和/或氢的同位素(即氘或氚)的天然丰度烷基的同位素异构体。
如本文所用，术语“烯基”表示无支链或支链的单价烃链，其含有一个或多个碳-碳双键。
如本文所用，术语“炔基”是指无支链或支链的一价烃链，其含有一个或多个碳-碳三键。
在单独或作为其他取代基一部分时，术语“C1-C6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子(“C1-C3烷基”)，例如甲基、乙基、正丙基或异丙基。
在单独或作为其他取代基一部分时，术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。亚烷基基团的实例包括亚甲基(-CH2-)，亚乙基(包括-CH2CH2-或-CH(CH3)-)，亚异丙基(包 括-CH(CH3)CH2-或-C(CH3)2-)等等。
在单独或作为其他取代基一部分时，术语“环烷基”或“碳环基”是指一种环状烷基。术语“m-n元环烷基”或者“Cm-Cn环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的碳环。例如，“3-15元环烷基”或者“C3-C15环烷基”是指含有3至15，3至9，3至6或3至5个碳原子的环状烷基，它可能包含1至4个环。“5-8元环烷基”则含有5-8个碳原子。包括单环、二环、三环、螺环或桥环。未取代的环烷基的实例包括但不限于环丙基，环丁基，环戊基，环己基和金刚烷基，或者是双环烃基如十氢化萘环。环烷基可以被一个或多个取代基取代。在一些实施方案中，环烷基可以是与芳基或杂芳基稠合的环烷基。术语“C3-C6环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～6个碳原子，包括稠合或桥接的多环系统。例如环丙基、环丁基、环戊基、环己基。
在单独或作为其他取代基一部分时，“卤代烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw，其中v＝1至3，w＝1至(2v+1))。卤代烷基的实例包括，但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。
在单独或作为其他取代基一部分时，“m-n元杂环基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的单环、并环(包括二环和三环)、螺环或桥环，较佳地为饱和的杂环。
例如，“7-15元杂环基”应理解为表示具有7至15个原子的饱和、不饱和或部分饱和的单环、并环(包括二环和三环)、螺环或桥环，较佳地为饱和的杂环。其中1、2、3、4或5个环原子选自N、O和S。应该理解的是，当杂环基中S原子和O原子的总数超过1时，这些杂原子不彼此相邻。若所述杂环基为单环，则其一定不是芳族的。杂环基的实例包括但不限于哌啶基、N-乙酰基哌啶基、N-甲基哌啶基、N-甲酰基哌嗪基、N-甲磺酰基哌嗪基、高哌嗪基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、四氢异喹啉基、四氢喹啉基、二氢吲哚基、四氢吡喃基、二氢-2H-吡喃基、四氢呋喃基、四 氢噻喃基、四氢噻喃-1-氧化物、四氢噻喃-1,1-二氧化物、1H-吡啶-2-酮和2,5-二氧代咪唑烷基。“6-12元杂环基”是指具有6至12个原子的饱和、不饱和或部分饱和的单环、并环(包括二环和三环)、螺环或桥环。
术语“并环”是指化合物中的任意两个环共用两直接相连的碳原子的环烃，根据组成环的数目分为二环烃、三环烃、四环烃等。非限制性实例包括：
术语“螺环”指单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至12元，更优选为7至8元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：
术语“桥环”是指化合物中的任意两个环共用两不直接相连的碳原子的环烃,根据组成环的数目分为二环烃、三环烃、四环烃等。非限制性实例包括：
在单独或作为其他取代基一部分时，“C2-C6烯基”应理解为表示直连或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5或6个碳原子，较佳地例如具有2或3个碳原子(即，C2-C3烯基)。应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例 如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“C2-C6炔基”应理解为表示直连或支链的一价烃基，其包含一个或多个三键并且具有2、3、4、5或6个碳原子，较佳地例如具有2或3个碳原子(“C2-C3炔基”)。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基。特别地，所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。
本发明的实例中，质子可以占据杂环体系的两个或多个位置的环状形式，例如，1H-和3H-咪唑，1H-、2H-和4H-1，2，4-三唑，1H-和2H-异吲哚，以及1H-和2H-吡唑。互变异构形式可以通过适当的取代而处于平衡或空间上固定于一种形式。例如：
由于共振的原因，三氮唑上氮的氢可以在三个氮的任何一个上，所以命名会有所区别，但这三种形式表示的其实是一种化合物。
本文提供的化合物，包括可用于制备本文提供的化合物的中间体，其含有反应性官能团(例如但不限于羧基，羟基和氨基部分)，还包括其保护的衍生物。“受保护的衍生物”是其中一个或多个反应性位点被一个或多个保护基团(也称为保护基团)封闭的那些化合物。合适的羧基部分保护基包括苄基，叔丁基等，以及同位素等。合适的氨基和酰氨基保护基包括乙酰基，三氟乙酰基，叔丁氧基羰基，苄氧基羰基等。合适的羟基保护基包括苄基等。其他合适的保护基团是本领域普通技术人员所熟知的。
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。
在本申请中，术语“盐”或“药学上可接受的盐”，包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。
术语“胺盐”是指用酸中和烷基伯胺、仲胺或叔胺得到的产物。所述酸 包括本申请中所述的无机酸或有机酸。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。
依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。
当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。用楔形键和虚线键表示一个立体中心的绝对构型。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘(2H)，氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
各步骤的反应，反应温度可因溶剂、起始原料、试剂等适宜选择，反应 时间也可因反应温度、溶剂、起始原料、试剂等适宜选择。各步骤反应结束后，目标化合物可按常用方法自反应体系中进行分离、提纯等步骤，如过滤、萃取、重结晶、洗涤、硅胶柱层析等方法。在不影响下一步反应的情况下，目标化合物也可不经过分离、纯化直接进入下一步反应。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明人经过广泛而深入地研究，意外地开发了一种用于微管蛋白-SRC双靶点抑制剂的二芳基类化合物及其制备方法和用途，所述二芳基类化合物具有如本发明中所述的式I结构。所述二芳基类化合物可以作为微管蛋白和Src激酶双靶点抑制剂，也可以作为单独的微管蛋白或Src激酶抑制剂使用。本发明化合物能明显抑制微管蛋白单体的聚合、抑制细胞增殖。具有较好的皮肤局部给药的药代动力学性质，成药性良好。可用于制备皮肤外用制剂，具有代谢快，副作用小的优势。
附图说明
图1为测试例1中化合物对微管蛋白单体聚合曲线；
图2为化合物抑制Src信号通路的结果图。
具体实施方式
以下结合具体实施例，进一步说明本发明。需理解，以下的描述仅为本发明的最优选实施方式，而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上，下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件，本领域技术人员可以对本发明的技术方案作出非本质的改动，这样的改动应当被视为包括于本发明的保护范围之中的。
中间体A1：N-苄基-2-(5-溴吡啶-2-基)乙酰胺的制备
合成路线如下：
第一步：2-(5-溴吡啶-2-基)乙腈的制备
室温下将乙腈(19.6g，477mmol)加入到无水四氢呋喃中(500mL)，冷却到-78℃,缓慢滴加正丁基锂(170mL，426mmol)，反应液在-78℃下搅拌1h，然后滴加5-溴-2-氟吡啶(30g，170mmol)的四氢呋喃(100mL)，滴加完成后缓慢升温到室温，再继续搅拌2h。点板检测反应完成后，将反应液倒入饱和氯化铵溶液/乙酸乙酯(300mL/300mL)中，分液，水相再用乙酸乙酯(200mL×3)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物薄层硅胶板分离纯化得化合物A1-2(22.5g，产率67％)。
第二步：2-(5-溴吡啶-2-基)乙酸甲酯的制备
室温下将化合物A1-2(30g，152mmol)加入到无水甲醇(200mL)中，缓慢滴加浓硫酸(25mL，457mmol)，然后加热回流搅拌24h。点板监测反应完成后，将反应液减压浓缩除去甲醇，残留物用二氯甲烷(500mL)溶解，有机相依次用水(200mL)，饱和碳酸氢钠溶液(200mL)和饱和食盐水(200mL)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩，残留物薄层硅胶板分离纯化得化合物A1-3(31g，产率88％)。
第三步：N-苄基-2-(5-溴吡啶-2-基)乙酰胺的制备
室温下向化合物A1-3(28g，122mmol)中加入苄胺(39.1g，365mmol)，然后加热到125℃搅拌15h，点板检测反应完成后，将反应液冷却到室温，在搅拌状态下缓慢加入乙酸乙酯/石油醚(100mL/100mL)，析出的固体过滤，得化合物A1(黄色固体，28.5g，产率77％)。
1H NMR(400MHz,DMSO-d6):δ8.66–8.53(m,2H),7.97(dd,J＝8.3,2.5Hz,1H),7.38–7.19(m,6H),4.26(d,J＝5.9Hz,2H),3.66(s,2H).
LC-MS,M/Z(ESI):306.9[M+H]+。
中间体A2：N-苄基-2-(5-(三丁基甲锡烷基)吡啶-2-基)乙酰胺的制备
合成路线如下：
室温下将中间体A1(15g，49.2mmol)加入到1,4-二氧六环(300mL)中，然后加入氯化锂(6.2g，147mmol)，氮气保护下加入1,1,1,2,2,2-六丁基二锡烷(29.8mL，59.0mmol)和四(三苯基膦)钯(2.84g，2.46mmol)，然后加热到110℃搅拌15h。点板检测反应完成后，将反应液冷却到室温，减压浓缩掉溶剂，加入水(500mL)稀释，用乙酸乙酯(200mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用薄层硅胶板分离纯化(石油醚:乙酸乙酯(V/V)＝5:1)得中间体A2(10.5g，产率41.5％)。
1H NMR(400MHz,CDCl3):δ8.01(s,3H),7.71(dd,J＝7.5,1.6Hz,1H),7.31–7.26(m,2H),7.24–7.20(m,3H),4.47(d,J＝5.8Hz,2H),3.74(s,2H),1.56–1.47(m,5H),1.31(ddd,J＝22.6,14.9,7.3Hz,7H),1.08(dd,J＝9.5,6.8Hz,6H),0.87(t,J＝7.3Hz,9H).
LC-MS,M/Z(ESI):517.3[M+H]+。
实施例1 化合物I-1的制备
合成路线如下所示：
第一步：1-溴-4-(2-溴乙氧基)-2-氟苯的制备
将4-溴-3-氟苯酚(1g，5.24mmol)，1,2-二溴乙烷(5.90g，31.4mmol)和碳酸钾(4.41g，31.9mmol)溶于丙酮(30mL)中，升温至80℃反应18小时。反应液冷却至室温，过滤，滤液浓缩，残余物柱层析分离(石油醚:乙酸乙酯(V/V)＝30:1)得到1-溴-4-(2-溴乙氧基)-2-氟苯(1.3g，无色油状物，收率83％)。
第二步：(3aR,6aS)-5-(2-(4-溴-3-氟苯氧基)乙基)六氢-1H-呋喃[3,4-c]吡咯的制备
将1-溴-4-(2-溴乙氧基)-2-氟苯(1.3g，4.36mmol)溶于干燥的乙腈(30mL)中，加入(3aR,6aS)-六氢-1H-呋喃[3,4-c]吡咯盐酸盐(718mg，4.80mmol)和碳酸钾(1.809g，13.09mmol)，升温至80℃反应20小时。反应液冷却至室温，过滤，滤液浓缩，残余物用硅胶柱纯化(石油醚:乙酸乙酯(V/V)＝1:1)得到(3aR,6aS)-5-(2-(4-溴-3-氟苯氧基)乙基)六氢-1H-呋喃[3,4-c]吡咯(1.1g，黄色油状物，收率76％)。
LC-MS,M/Z(ESI)：330.0[M+H]+。
第三步：N-苄基-2-(5-(2-氟-4-(2-((3aR,6aS)-四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)乙氧基)苯基)吡啶-2-基)乙酰胺(I-1)的制备
将(3aR,6aS)-5-(2-(4-溴-3-氟苯氧基)乙基)六氢-1H-呋喃[3,4-c]吡咯(150mg，0.454mmol)溶于干燥的1,4-二氧六环(5mL)中，加入N-苄基-2-(5- (三丁基甲锡烷基)吡啶-2-基)乙酰胺(281mg，0.545mmol)和二(三苯基磷基)二氯化钯(31.9mg，0.045mmol)。氩气置换三次，氩气保护下升温至100℃反应4小时。反应液冷却至室温，加入水(50mL)稀释，二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，浓缩，残余物硅胶板分离(乙酸乙酯:甲醇(V/V)＝20:1，NH3·H2O)得到N-苄基-2-(5-(2-氟-4-(2-((3aR,6aS)-四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)乙氧基)苯基)吡啶-2-基)乙酰胺(I-1)(25mg，收率11.57％)。
1H NMR(400MHz,DMSO-d6)δ8.60(br，2H)，7.86(m，1H)，7.49～6.92(m，9H)，4.30(m，2H)，4.12(m，2H)，3.72(m，4H)，3.39(m，2H)，2.75～2.68(m，6H)，2.39(m，2H)。
LC-MS,M/Z(ESI)：476.2[M+H]+。
实施例2 化合物I-2的制备
合成路线如下所示
第一步：1-溴-4-(2-溴乙氧基)-2-甲基苯的合成
将4-溴-3-甲基苯酚(1g，5.37mmol)，1,2-二溴乙烷(5.99g，32.2mmol)和碳酸钾(4.45g，32.2mmol)溶于丙酮(30mL)中，升温至80℃回流反应18小时。冷却至室温，过滤，滤液浓缩，残余物柱层析分离(石油醚:乙酸乙酯(V/V)＝30:1)得到1-溴-4-(2-溴乙氧基)-2-甲基苯(1.3g，无色油状物，收率82.8％)
第二步：(3aR,6aS)-5-(2-(4-溴-3-甲基苯氧基)乙基)六氢-1H-呋喃[3,4-c]吡咯
将1-溴-4-(2-溴乙氧基)-2-甲基苯(1.3g，4.45mmol)溶于干燥的乙腈(30mL)中，加入(3aR,6aS)-六氢-1H-呋喃[3,4-c]吡咯盐酸盐(730mg，4.90mmol)和碳酸钾(1.844g，13.36mmol)，升温至80℃反应20小时。反应液冷却至室温，过滤，滤液浓缩，残余物用硅胶柱纯化(石油醚:乙酸乙酯(V/V)＝1:1)得到(3aR,6aS)-5-(2-(4-溴-3-甲基苯氧基)乙基)六氢-1H-呋喃[3,4-c]吡咯(1.0g，黄色油状物，收率69.1％)
LC-MS,M/Z(ESI)：326.0[M+H]+。
第三步：N-苄基-2-(5-(2-甲基-4-(2-((3aR,6aS)-四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)乙氧基)苯基)吡啶-2-基)乙酰胺(I-2)
将(3aR,6aS)-5-(2-(4-溴-3-甲基苯氧基)乙基)六氢-1H-呋喃[3,4-c]吡咯(150mg，0.460mmol)溶于干燥的1,4-二氧六环(5mL)中，加入N-苄基-2-(5-(三丁基甲锡烷基)吡啶-2-基)乙酰胺(355mg，0.690mmol)和二(三苯基磷基)二氯化钯(32.3mg，0.046mmol)。氩气置换三次，氩气保护下升温至100℃反应4小时。反应液冷却至室温，加入水(50mL)稀释，二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，浓缩，残余物硅胶板分离(乙酸乙酯:甲醇(V/V)＝20:1，NH3·H2O)得到N-苄基-2-(5-(2-甲基-4-(2-((3aR,6aS)-四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)乙氧基)苯基)吡啶-2-基)乙酰胺(I-2)(20mg，收率9.22％)。
1H NMR(400MHz,DMSO-d6)：δ8.62(t，1H)，8.41(d，1H)，7.70～6.83(m，10H)，4.30(d，2H)，4.07(t，2H)，3.78～3.62(m，4H)，3.39～3.37(m，2H)，2.75～2.61(m，6H)，2.39～2.37(m，2H)，2.21(s，3H)。
LC-MS,M/Z(ESI)：472.2[M+H]+。
实施例3 化合物I-3的制备
合成路线如下所示
第一步：4-(2-(4-溴苯氧基)乙基)硫代吗啉1,1-二氧化物的制备
室温下将1-溴-4-(2-溴乙氧基)苯(2.8g,10.0mmol)，K2CO3(4.14g,30mmol)和1,1-二氧化硫吗啉(1.5g,11.0mmol)加入到乙腈(30ml)中，氮气保护下，85℃搅拌12小时。待反应完全，加入水(100mL)稀释，用乙酸乙酯(30mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用薄层硅胶板分离纯化(石油醚:乙酸乙酯(V/V)＝2:3)得4-(2-(4-溴苯氧基)乙基)硫代吗啉1,1-二氧化物(2.5g,白色固体，产率75％)。
第二步：4-(2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯氧基)乙基)硫代吗啉1,1-二氧化物的制备
将化合物4-(2-(4-溴苯氧基)乙基)硫代吗啉1,1-二氧化物(2.0g,6.0mmol)，联硼酸频那醇酯(2.28g,9.0mmol)，醋酸钾(1.76g,18.0mmol)和1,1-双(二苯基膦)二茂铁二氯化钯(0.4g，0.6mmol)加入到1,4-二氧六环中(20mL)中，置换氮气，升温至85℃搅拌10小时。加入水(50mL)稀释，用乙酸乙酯(30mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用薄层硅胶板分离纯化(石油醚:乙酸乙酯(V/V)＝1:2)得4-(2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯氧基)乙基)硫代吗啉1,1-二氧化物(1.1g,白色固体，产率70％)。
第三步：N-苄基-2-(5-(4-(2-(1,1-二氧化硫代吗啉)乙氧基)苯基)吡啶-2-基)乙酰胺的制备
将4-(2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯氧基)乙基)硫代吗啉1,1-二氧化物(300mg,0.79mmol)，N-苄基-2-(5-溴吡啶-2-基)乙酰胺(287mg,0.95mmol)和四三苯基膦钯(80mg，0.071mmol)，碳酸钠(254mg,2.40mmol)加入到乙二醇二甲醚(3ml)和水(0.5ml)中，升温至100℃搅拌12小时。加入水(20mL)稀释，用乙酸乙酯(10mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用薄层硅胶板分离纯化(石油醚:乙酸乙酯(V/V)＝1:2)，然后用制备液相色谱纯化得产物N-苄基-2-(5-(4-(2-(1,1-二氧化硫代吗啉)乙氧基)苯基)吡啶-2-基)乙酰胺(I-3)(70mg,产率46.4％)。
1H NMR(400MHz,CDCl3)δ8.70(d,1H),7.81(dd,1H),7.59(s,1H),7.50(t,2H),7.35–7.30(m,2H),7.25(d,4H),6.99(d,2H),4.49(d,2H),4.14(t,2H),3.82(s,2H),3.22–3.14(m,4H),3.12–3.05(m,4H),3.02(t,2H).
LC-MS,M/Z(ESI):480.2[M+H]+。
实施例4 化合物I-4的制备
合成路线如下所示
第一步：3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚的制备
室温下将化合物4-溴-3-氟苯酚(5.0g,24.10mmol)，KOAc(9.99g,72.3mmol)，和联硼酸频那醇酯(12.24g,48.2mmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(II)(1.76g，2.41mmol)加入到二氧六环(80mL)中，氮气保护下85℃ 搅拌12h。待反应完全，加入水(100mL)稀释，用乙酸乙酯(50mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用薄层硅胶板分离纯化(石油醚:乙酸乙酯(V/V)＝2:3)得化合物3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚(3.8g,白色固体，产率60.1％)。
第二步：N-苄基-2-(5-(2-氟-4-羟基苯基)吡啶-2-基)乙酰胺的制备
将化合物3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚(2.1g,8.25mmol)，N-苄基-2-(5-溴吡啶-2-基)乙酰胺(2.77g,9.08mmol)，碳酸钾(3.42g,24.75mmol)和1,1-双(二苯基膦)二茂铁二氯化钯(0.065g，0.089mmol)加入到二氧六环中(30mL)中，置换氮气，升温至85℃搅拌10h。加入水(100mL)稀释，用乙酸乙酯(30mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:2)得化合物N-苄基-2-(5-(2-氟-4-羟基苯基)吡啶-2-基)乙酰胺(2.6g,白色固体，产率42.4％)。
LC-MS,M/Z(ESI):337.3[M+H]+。
第三步：N-苄基-2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)乙酰胺的制备
将N-苄基-2-(5-(2-氟-4-羟基苯基)吡啶-2-基)乙酰胺(0.14g,0.416mmol)，1,2-二溴乙烷(0.469g,2.497mmol)和碳酸钾(0.345g,2.497mmol)置于乙腈(3mL)中,升温至85℃搅拌12h。加入水(5mL)稀释，用乙酸乙酯(5mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用柱层析纯化(石油醚:乙酸乙酯(V/V)＝3:1)，得化合物N-苄基-2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)乙酰胺(0.14g,白色固体，产率76％)。
第四步：2-(5-(4-(2-(2-氧-6-氮杂螺环[3.3]庚烷-6-基)乙氧基)-2-氟苯基)吡啶-2-基)-N-苄基乙酰胺(I-4)的制备
将N-苄基-2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)乙酰胺(0.14g,0.316 mmol)，2-氧代-6-氮杂螺环[3.3]庚烷(0.063g,0.632mmol)和碳酸钾(0.131g,0.947mmol)置于乙腈(3mL)中，反应液升温至85℃搅拌12h。加入水(5mL)稀释，用乙酸乙酯(5mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用制备高效液相色谱分离纯化得化合物2-(5-(4-(2-(2-氧-6-氮杂螺环[3.3]庚烷-6-基)乙氧基)-2-氟苯基)吡啶-2-基)-N-苄基乙酰胺(I-4)(8.6mg,产率5.9％)。
1H NMR(400MHz,CDCl3)δ8.64(s,1H),7.80(d,1H),7.67(s,1H),7.33(dd,2H),7.30(d,1H),7.28(s,1H),7.24(dt,3H),6.75(m,2H),4.75(s,4H),4.47(t,2H),3.98(t,2H),3.82(s,2H),3.49(s,4H),2.80(t,2H).
LC-MS,M/Z(ESI):462.1[M+H]+。
实施例5 化合物I-5的制备
合成路线如下所示
第一步：3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚的制备
室温下将化合物4-溴-3-甲基苯酚(5g,26.7mmol)和联硼酸频那醇酯(10.2g,40.1mmol)加入到1,4-二氧六环(70mL)中,然后加入醋酸钾(6.56g,66.8mmol)，氮气保护下加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)(950mg,1.3mmol)，加热至95℃，搅拌6h。反应液冷却至室温，加入水(50mL)稀释，用乙酸乙酯(50mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用薄层硅胶板分离纯化(石油醚:乙酸乙酯(V/V)＝5:1)得化合物2-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基)丁-2-醇(6.1 g,产率97％)。
第二步：N-苄基-2-(5-(4-羟基-2-甲基苯基)吡啶-2-基)乙酰胺的制备
室温下将化合物3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚(1.15g,4.92mmol)和N-苄基-2-(5-溴吡啶-2-基)乙酰胺(1.0g,3.33mmol)加入到1,4-二氧六环/水(10mL/1mL)中，然后加入氟化钾(0.760g,13.1mmol)，氮气保护下加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)(117mg,0.16mmol)，加热到90℃搅拌10h。反应液冷却至室温，加入水(50mL)稀释，用乙酸乙酯(20mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物经柱层析硅胶纯化(CH2Cl2:MeOH(V/V)＝95:5)，得化合物N-苄基-2-(5-(4-(3-羟基-3-甲基丁氧基)苯基)吡啶-2-基)乙酰胺(850mg,产率78％)。
第三步：N-苄基-2-(5-(4-(2-溴乙氧基)-2-甲基苯基)吡啶-2-基)乙酰胺的制备
室温下将N-苄基-2-(5-(2-甲基-4-羟基苯基)吡啶-2-基)乙酰胺(0.6g,1.8mmol)和碳酸钾(1.5g,10.7mmol)加入到无水乙腈中(15mL)，加热到80℃搅拌1h，然后加入1,2-二溴乙烷(2.01g,10.7mmol)，继续在80℃下搅拌10h。反应液冷却到室温，浓缩除去溶剂得到粗品，用硅胶柱分离纯化(DCM:MeOH(V/V)＝95:5)得化合物N-苄基-2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)乙酰胺(0.55g,产率69％)。
第四步：2-(5-(4-(2-(2-氧杂-6-氮杂螺环[3.3]庚烷-6-基)乙氧基)-2-甲基苯基)吡啶-2-基)-N-苄基乙酰胺(I-5)的制备
在100.0mL单口瓶中将N-苄基-2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)乙酰胺(500.0mg，1.14mmol)溶于乙腈(5.0mL)中，随后加入碳酸钾(786.4mg,5.69mmol),滴加2-氧杂-6-氮杂螺环[3.3]庚烷(124.1mg,1.25mmol)后将体系升温至85℃搅拌16小时。反应完全后，过滤，母液旋干，残留物 用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝20:1至1:1)，得到2-(5-(4-(2-(2-氧杂-6-氮杂螺环[3.3]庚烷-6-基)乙氧基)-2-甲基苯基)吡啶-2-基)-N-苄基乙酰胺(340.0mg,产率65.3％)。
1H NMR(400MHz,DMSO-d6)δ8.64(t,1H),8.42(d,1H),7.70(dd,1H),7.39(d,1H),7.36–7.19(m,5H),7.14(d,1H),6.88(d,1H),6.83(dd,1H),4.60(s,4H),4.31(d,2H),3.93(t,2H),3.73(s,2H),3.35(s,4H),2.68(t,2H),2.22(s,3H).
LC-MS,M/Z(ESI):458.05[M+H]+。
下列化合物的制备参考本发明其他化合物的制备方法得到。




实施例18化合物I-18的制备
合成路线如下所示：
第一步：N-苄基-2-(5-(4-(2-溴乙氧基)苯基)吡啶-2-基)乙酰胺的制备
将N-苄基-2-(5-(4-羟基苯基)吡啶-2-基)乙酰胺(0.5g,1.56mmol)，1,2-二溴乙烷(1.75g,9.35mmol)和碳酸钾(1.29g,9.35mmol)置于乙腈(6mL)中,反应液升温至85℃搅拌12h。加入水(10mL)稀释，用乙酸乙酯(5mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用柱层析纯化(石油醚:乙酸乙酯(V/V)＝3:1)，得化合物N-苄基-2-(5-(4-(2-溴乙氧基)苯基)吡啶-2-基)乙酰胺(0.4g,白色固体，产率60.0％)。
第二步：2-硫杂-6-氮杂螺[3.3]庚烷-2,2-二氧化物的制备
室温下将2-硫杂-6-氮杂螺[3.3]庚烷-6-羧酸叔丁酯2,2-二氧化物(0.2g,0.81mmol)加入到无水二氯甲烷中(2mL)，然后加入三氟乙酸(2mL)，在室温下搅拌2h，TLC监测反应完成后，浓缩溶剂得到粗品2-硫杂-6-氮杂螺[3.3]庚烷-2,2-二氧化物三氟乙酸盐(0.21g,产率100％)，粗品直接用于下一步。
第三步：N-苄基-2-(5-(4-(2-(2,2-二氧-2-硫杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)苯基)吡啶-2-基)乙酰胺(I-18)的制备
室温下将N-苄基-2-(5-(4-(2-溴乙氧基)苯基)吡啶-2-基)乙酰胺(0.1g,0.23mmol)加入到DMF(2mL)中，然后加入三乙胺(91mg,0.9mmol)、碘化钾(150mg,0.9mmol)和粗品2-硫杂-6-氮杂螺[3.3]庚烷-2,2-二氧化物三氟乙酸盐(120mg,0.47mmol)，然后在60℃下搅拌8h,TLC监测反应完成后,经制备高效液相色谱纯化，得到化合物N-苄基-2-(5-(4-(2-(2,2-二氧-2-硫杂-6-氮杂螺[3.3]庚烷-6-基)乙氧基)苯基)吡啶-2-基)乙酰胺(68.1mg,产率59％).
1H NMR(400MHz,DMSO-d6)δ8.74(d,1H),8.61(t,1H),7.96(dd,1H),7.64(d,2H),7.39(d,1H),7.34–7.20(m,5H),7.02(d,2H),4.37–4.25(m,6H),3.99(t,2H),3.70(s,2H),3.42(s,4H),2.77(t,2H).
LC-MS,M/Z(ESI):492.2[M+H]+。
实施例24化合物I-24A、I-24B的制备
合成路线如下所示：
第一步：N-苄基-2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)乙酰胺的制备
室温下将N-苄基-2-(5-(2-氟-4-羟基苯基)吡啶-2-基)乙酰胺(0.6g,1.8mmol)和碳酸钾(1.5g,10.7mmol)加入到无水乙腈中(15mL)，加热到80℃下搅拌1h，然后加入1,2-二溴乙烷(2.01g,10.7mmol)，继续加热在80℃ 下搅拌10h,TLC检测反应完成后冷却到室温，旋蒸浓缩掉溶剂得到粗品，用硅胶柱分离纯化得化合物N-苄基-2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)乙酰胺(0.55g,产率69％).
第二步：(S)-N-苄基-2-(5-(2-氟-4-(2-(3-甲基吗啉代)乙氧基)苯基)吡啶-2-基)乙酰胺的制备
室温下将N-苄基-2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)乙酰胺(0.1g,0.23mmol)加入到N,N-二甲基甲酰胺(2mL)中，然后加入三乙胺(91mg,0.9mmol)、碘化钾(150mg,0.9mmol)和(S)-3-甲基吗啉(34mg,0.34mmol)，然后在60℃下搅拌8h,反应液经制备高效液相色谱纯化得化合物(S)-N-苄基-2-(5-(2-氟-4-(2-(3-甲基吗啉代)乙氧基)苯基)吡啶-2-基)乙酰胺(I-24A)(18.9mg,产率18％).
1H NMR(400MHz,DMSO-d6)δ8.68–8.56(m,2H),7.86(d,1H),7.50(t,1H),7.43(d,1H),7.36–7.19(m,5H),7.03–6.88(m,2H),4.30(d,2H),4.13(t,2H),3.72(s,2H),3.70–3.64(m,1H),3.59(dd,1H),3.52–3.43(m,1H),3.06(ddd,2H),2.80(dt,1H),2.68–2.56(m,1H),2.47–2.34(m,2H),0.93(t,3H).
LC-MS,M/Z(ESI):464.3[M+H]+
第三步：(R)-N-苄基-2-(5-(2-氟-4-(2-(3-甲基吗啉代)乙氧基)苯基)吡啶-2-基)乙酰胺的制备
室温下将N-苄基-2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)乙酰胺(0.1g,0.23mmol)加入到DMF(2mL)中，然后加入三乙胺(91mg,0.9mmol)、碘化钾(150mg,0.9mmol)和(R)-3-甲基吗啉(34mg,0.34mmol)，然后在60℃下搅拌8h,TLC检测反应完成后,制备纯化得化合物(R)-N-苄基-2-(5-(2-氟-4-(2-(3- 甲基吗啉代)乙氧基)苯基)吡啶-2-基)乙酰胺(I-24B)(19.9mg,产率19％).
1H NMR(400MHz,DMSO-d6)δ8.63(dd,J＝11.8,5.6Hz,2H),7.86(d,J＝8.1Hz,1H),7.50(t,J＝9.0Hz,1H),7.43(d,J＝8.1Hz,1H),7.35–7.20(m,5H),6.99(dd,J＝12.9,2.2Hz,1H),6.92(dd,J＝8.6,2.1Hz,1H),4.30(d,J＝5.9Hz,2H),4.13(t,J＝5.9Hz,2H),3.73(s,2H),3.67(d,J＝11.1Hz,1H),3.59(dd,J＝11.0,2.9Hz,1H),3.47(td,J＝11.7,5.6Hz,1H),3.14–3.00(m,2H),2.80(d,J＝11.8Hz,1H),2.61(dt,J＝13.5,5.6Hz,1H),2.47–2.35(m,2H),0.94(d,J＝6.2Hz,3H)
LC-MS,M/Z(ESI):464.3[M+H]+。
实施例26化合物I-26的制备
合成路线如下所示：
第一步：(1-(2-环丙基乙酰基)氮杂环丁烷-3-基)氨基甲酸叔丁酯的制备
室温下将2-环丙基乙酸(0.35g,3.5mmol)加入到无水二氯甲烷中(15mL)，然后加入3-(((乙基亚氨基)亚甲基)氨基)-N,N-二甲基丙-1-胺盐酸盐(0.67g,3.5mmol)和1H-苯并[d][1,2,3]三唑-1-醇(0.54g,3.5mmol)，室温下搅拌10分钟，然后加入吖丁啶-3-基氨基甲酸叔丁酯(0.5g,2.9mmol)，室温下再继续搅拌5h,点板检测反应完成后，反应液用二氯甲烷(50mL)稀释，用饱和碳酸氢钠溶液/食盐水(50mL/50mL)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩，残留物薄层硅胶板分离纯化得化合物(1-(2-环丙基乙酰基)氮杂环丁烷-3-基)氨基甲酸叔丁酯(0.6g,产率81％).
第二步：1-(3-氨基氮杂环丁烷-1-基)-2-环丙基乙烷-1-酮的制备
室温下将(1-(2-环丙基乙酰基)氮杂环丁烷-3-基)氨基甲酸叔丁酯(0.6g,2.4mmol)加入到无水1,4-二氧六环(2mL)中，然后在搅拌下加入盐酸/1,4-二氧六环(4.7mL,4M),继续在室温下搅拌2h,点板检测反应完成后,浓缩旋蒸掉溶剂得到化合物1-(3-氨基氮杂环丁烷-1-基)-2-环丙基乙烷-1-酮盐酸盐(0.45g,产率100％).
第三步：1-(3-((2-(4-溴苯氧基)乙基)氨基)氮杂环丁烷-1-基)-2-环丙基乙烷-1-酮的制备
室温下将1-(3-氨基氮杂环丁烷-1-基)-2-环丙基乙烷-1-酮盐酸盐(0.45g,2.4mmol)加入到乙腈(5mL)中，然后加入碳酸钾(0.98g,7.2mmol)和1-溴-4-(2-溴乙氧基)苯(0.73g,2.6mmol)，然后在30℃下搅拌8h,点板检测反应完成后,浓缩旋蒸掉溶剂，残留物加乙酸乙酯(50mL)稀释，用水/食盐水(50mL/50mL)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩，残留物薄层硅胶柱分离纯化得化合物1-(3-((2-(4-溴苯氧基)乙基)氨基)氮杂环丁烷-1-基)-2-环丙基乙烷-1-酮(0.2g,产率24％).
第四步：N-苄基-2-(5-(4-(2-((1-(2-环丙基乙酰基)氮杂环丁烷-3-基)氨基)乙氧基)苯基)吡啶-2-基)乙酰胺(I-26)的制备
室温下将化合物1-(3-((2-(4-溴苯氧基)乙基)氨基)氮杂环丁烷-1-基)-2-环丙基乙烷-1-酮(60mg,0.17mmol)和N-苄基-2-(5-(三丁基甲锡烷基)吡啶-2-基)乙酰胺(110mg,0.21mmol)加入到甲苯(2mL)中，氮气保护下加入四(三苯基膦)钯(20mg,0.017mmol)，加热到100℃搅拌10h。冷却至室温，加入水(50mL)稀释，用乙酸乙酯(20mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物经碱性制备方法制备得化合物N-苄基-2-(5-(4-(3-羟基-3-甲基丁氧基)苯基)吡啶-2-基)乙酰胺(I-26)(10.7mg，产率 9.1％)。
1H NMR(400MHz,CDCl3)δ8.71(dd,J＝8.1,2.2Hz,1H),7.85–7.78(m,1H),7.62(s,1H),7.50(d,J＝8.7Hz,2H),7.32(dd,J＝14.5,7.3Hz,3H),7.24(d,J＝2.3Hz,2H),7.00(t,J＝9.2Hz,2H),4.49(d,J＝5.8Hz,2H),4.34–4.18(m,2H),4.11(t,J＝5.0Hz,2H),3.85(dd,J＝8.9,4.6Hz,1H),3.82(s,2H),3.80–3.71(m,2H),3.01(h,J＝9.3Hz,2H),2.04(t,J＝6.6Hz,2H),1.10–1.00(m,1H),0.60–0.51(m,2H),0.15(q,J＝4.8Hz,2H)。
LC-MS,M/Z(ESI):499.2[M+H]+。
实施例27化合物I-27的制备
合成路线如下所示：
第一步：2-溴-5-(2-吗啉乙氧基)苯腈的制备
将4-(2-氯乙基)吗啉(0.783g，4.21mmol)，2-溴-5-羟基苯腈(1g，5.05mmol)和碳酸钾(2.036g，14.73mmol)溶于乙腈(10mL)中，升温至80℃反应10小时。反应液冷却至室温，加氯化钠水溶液(100mL)和乙酸乙酯(100mL)，分液，有机相浓缩后采用柱层析分离(石油醚：乙酸乙酯(V/V)＝2:1)，得到化合物2-溴-5-(2-吗啉乙氧基)苯腈(1.21g，棕色固体，收率92％)。
第二步：N-苄基-2-(5-(2-氰基-4-(2-吗啉乙氧基)苯基)吡啶-2-基)乙酰胺
将2-溴-5-(2-吗啉乙氧基)苯腈(100mg,0.32mmol)，N-苄基-2-(5-(三丁基甲锡烷基)吡啶-2-基)乙酰胺(248mg,0.482mmol)，双三苯基膦二氯化钯(22.56mg,0.032mmol)溶于干燥的1,4-二氧六环中(15mL)，然后充氮气保护，升温至90℃反应10小时。反应液冷却至室温，过滤，滤液浓缩后，残余物用硅胶柱纯化(石油醚：乙酸乙酯(V/V)＝2:1)，得到N-苄基-2-(5-(2-氰基-4-(2-吗啉乙氧基)苯基)吡啶-2-基)乙酰胺(I-27)(5mg，收率3.41％)。
1H NMR(400MHz,DMSO-d6)δ8.66(dd,J＝14.2,3.9Hz,2H),7.93(dd,J＝8.0,2.3Hz,1H),7.58(d,J＝9.0Hz,2H),7.48(d,J＝8.0Hz,1H),7.40(dd,J＝8.7,2.6Hz,1H),7.34–7.26(m,4H),7.23(t,J＝7.0Hz,1H),4.31(d,J＝5.8Hz,2H),4.21(t,J＝5.6Hz,2H),3.76(s,2H),3.56(dd,J＝14.5,10.0Hz,4H),2.71(t,J＝5.6Hz,2H),2.50–2.45(m,4H).
LC-MS,M/Z(ESI)：457.2[M+H]+。
实施例28 化合物I-28的制备
化合物N-苄基-2-(5-(4-(2-吗啡啉代乙氧)-2-(丙-1-炔-1-基)苯基)吡啶-2-基)乙酰胺(I-28)的制备参考化合物I-27的制备方法得到。LC-MS,M/Z(ESI)：470.2[M+H]+。
实施例29 化合物I-29的制备
合成路线如下所示：
第一步：3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚的制备
室温下将4-溴-3,5-二甲基苯酚(2g,9.95mmol)，醋酸钾(2.93g,29.8mmol)、联硼酸频那醇酯(3.8g,14.9mmol)和1,1'-二(二苯膦基)二茂铁二氯化钯(II)(364mg,0.49mmol)加入到反应瓶中，以氮气置换三次，然后加入溶剂二氧六环(40mL)，加热在100℃下搅拌10h，TLC检测反应完成后冷却到室温，浓缩旋蒸掉溶剂，残留物加乙酸乙酯(100mL)溶解，用水(50mL)和饱和食盐水(50mL)洗涤，有机层用无水硫酸钠干燥，旋蒸得到N-苄基-2-(5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-基)乙酰胺粗品(2.4g,产率100％)，粗品直接用于下一步。
第二步：N-苄基-2-(5-(4-羟基-2,6-二甲基苯基)吡啶-2-基)乙酰胺的制备
室温下将N-苄基-2-(5-溴吡啶-2-基)乙酰胺(0.45g,1.5mmol)，N-苄基-2-(5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-基)乙酰胺粗品(0.55g,2.2mmol)、氟化钾(0.34g,5.9mmol)和1,1'-二(二苯膦基)二茂铁二氯化钯(II)(108mg,0.15mmol)加入到反应瓶中，以氮气置换三次，然后加入溶剂二氧六环(20mL)，加热在85℃下搅拌10h，TLC检测反应完成后冷却到室温，浓缩旋蒸掉溶剂得到粗品，经制备高效液相色谱纯化N-苄基-2-(5-(4-羟基-2,6-二甲基苯基)吡啶-2-基)乙酰胺(0.35g,产率68％)。
第三步：N-苄基-2-(5-(4-(2-溴乙氧基)-2,6-二甲基苯基)吡啶-2-基)乙酰胺的制备
室温下将N-苄基-2-(5-(4-羟基-2,6-二甲基苯基)吡啶-2-基)乙酰胺(0.2g, 0.58mmol)和碳酸钾(0.48g,3.46mmol)加入到无水乙腈中(15mL)，加热到85℃下搅拌1h，然后加入1,2-二溴乙烷(0.65g,3.46mmol)，继续加热在85℃下搅拌10h，TLC检测反应完成后冷却到室温，浓缩旋蒸掉溶剂得到粗品，用硅胶柱分离纯化得化合物N-苄基-2-(5-(4-(2-溴乙氧基)-2,6-二甲基苯基)吡啶-2-基)乙酰胺(0.2g,产率76％).
第四步：N-苄基-2-(5-(2,6-二甲基-4-(2-((3aR,6aS)-四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)乙氧基)苯基)吡啶-2-基)乙酰胺
室温下将N-苄基-2-(5-(4-(2-溴乙氧基)-2,6-二甲基苯基)吡啶-2-基)乙酰胺(0.2g,0.47mmol)加入到N,N-二甲基甲酰胺(2mL)中，然后加入三乙胺(191mg,1.81mmol)、碘化钾(312mg,1.81mmol)和(3aR,6aS)-六氢-1H-呋喃[3,4-c]吡咯(53mg,0.47mmol)，然后在60℃下搅拌8h,TLC检测反应完成后,通过制备纯化得化合物N-苄基-2-(5-(2,6-二甲基-4-(2-((3aR,6aS)-四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)乙氧基)苯基)吡啶-2-基)乙酰胺(59.5mg,产率26％).
1H NMR(400MHz,DMSO-d6)δ8.64(t,1H),8.25(d,1H),7.53(dd,1H),7.42(d,1H),7.34–7.19(m,4H),6.74(s,2H),4.32(d,2H),4.06(t,2H),3.77–3.66(m,4H),3.39(dd,2H),2.74(t,2H),2.71–2.66(m,2H),2.66–2.60(m,2H),2.40(dd,2H),1.95(s,6H)。
LC-MS,M/Z(ESI):486.2[M+H]+。
实施例30 化合物I-30的制备
合成路线如下所示：
第一步：3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚的制备
室温下将化合物4-溴-3-氯苯酚(5.0g,24.10mmol)，K2CO3(9.99g,72.3mmol)，和联硼酸频那醇酯(12.24g,48.2mmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(II)(1.76g，2.41mmol)加入到二氧六环(80mL)中，氮气保护下85℃搅拌12h。待反应完全，加入水(100mL)稀释，用乙酸乙酯(50mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用柱层析纯化(石油醚:乙酸乙酯(V/V)＝2:3)得化合物3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚(2.6g,白色固体，产率42.4％)。
第二步：N-苄基-2-(5-(2-氯-4-羟基苯基)吡啶-2-基)乙酰胺的制备
将化合物3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚(2.1g,8.25mmol)，N-苄基-2-(5-溴吡啶-2-基)乙酰胺(2.77g,9.08mmol)，碳酸钾(3.42g,24.75mmol)和1,1-双(二苯基膦)二茂铁二氯化钯(0.065g，0.089mmol)加入到二氧六环中(30mL)中，置换氮气，升温至85℃搅拌10h。加入水(100mL)稀释，用乙酸乙酯(30mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:2)得化合物N-苄基-2-(5-(2-氯-4-羟基苯基)吡啶-2-基)乙酰胺(2.6g,白色固体，产率42.4％)。
第三步：N-苄基-2-(5-(4-(2-溴乙氧基)-2-氯苯基)吡啶-2-基)乙酰胺
将N-苄基-2-(5-(2-氯-4-羟基苯基)吡啶-2-基)乙酰胺(0.55g,1.56mmol)，1,2-二溴乙烷(1.75g,9.35mmol)和碳酸钾(1.29g,9.35mmol)置于乙腈(6mL)中，反应液升温至85℃搅拌12h。加入水(5mL)稀释，用乙酸乙酯(5mL× 3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)，得化合物N-苄基-2-(5-(4-(2-溴乙氧基)-2-氯苯基)吡啶-2-基)乙酰胺(0.4g,白色固体，产率55.8％)。
第四步：N-苄基-2-(5-(2-氯-4-(2-((3aR,6aS)-四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)乙氧基)苯基))吡啶-2-基)乙酰胺(I-30)
将N-苄基-2-(5-(4-(2-溴乙氧基)-2-氯苯基)吡啶-2-基)乙酰胺(0.2g,0.435mmol)，(3aR,6aS)-六氢-1H-呋喃[3,4-c]吡咯(0.054g,0.479mmol)和碳酸钾(0.180g,1.30mmol)溶于乙腈(3mL)中升温至85℃搅拌12h。加入水(5mL)稀释，用乙酸乙酯(5mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用制备高效液相色谱纯化得化合物N-苄基-2-(5-(2-氯-4-(2-((3aR,6aS)-四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)乙氧基)苯基))吡啶-2-基)乙酰胺(I-30)(0.1g,产率46.7％)。
1H NMR(400MHz,CDCl3)δ8.56(d,1H),7.75(dd,1H),7.68(s,1H),7.28(ddt,6H),7.06(d,J＝2.5Hz,1H),6.91(dd,1H),4.50(d,2H),4.13(t,2H),3.83(s,2H),3.77(dd,2H),3.65–3.60(m,2H),2.89(t,2H),2.87–2.80(m,4H),2.41(dd,2H).
LC-MS,M/Z(ESI):492.3[M+H]+。
实施例31 化合物I-31的制备
合成路线如下所示：
第一步：2-(5-溴吡啶-2-基)-N-(2-氟苄基)乙酰胺的制备
将2-(5-溴吡啶-2-基)乙酸甲酯(30.0g,130.40mmol)、2-氟苄胺(48.96g，391.20mmol)置于圆底烧瓶中，升温至120℃搅拌12小时。反应液冷却至室温，加入石油醚/乙酸乙酯(V/V＝3:1,500mL)，室温打浆2小时，过滤收集滤饼，真空干燥后得到2-(5-溴吡啶-2-基)-N-(2-氟苄基)乙酰胺(35.2g,产率83.0％)。
LC-MS,M/Z(ESI):323.1[M+H]+。
第二步：2-(5-(2-氟-4-羟基苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺的制备
将3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)苯酚(5.5g,21.61mmol)，2-(5-溴吡啶-2-基)-N-(2-氟苄基)乙酰胺(6.98g,21.61mmol)和碳酸钾(8.96g,64.83mmol)以及[1,1'-双(二苯基膦)二茂铁]二氯化钯(1.96g，2.73mmol)溶于二氧六环(120mL)和水(3mL)中,升温至85℃搅拌12小时。加入水(200mL)稀释，用乙酸乙酯(200mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)，得到2-(5-(2-氟-4-羟基苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(4.0g,产率58.4％)。
LC-MS,M/Z(ESI):355.1[M+H]+。
第三步：2-(5-(4-(2-溴乙氧基)-2-苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺的制备
将2-(5-(2-氟-4-羟基苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(5.0g,13.48mmol)，1.2-二溴乙烷(15.20g,80.90mmol)和碳酸钾粉末(11.18g,80.90mmol)置于乙腈(50.0mL)中，反应液升温至85℃搅拌12h。加入水(100mL)稀释，用乙酸乙酯(50mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:1)，得到2-(5-(4-(2-溴乙氧基)-2-苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(3.0g,产率58.0％)。
LC-MS,M/Z(ESI):461.1[M+H]+。
第四步：(R)-2-(5-(2-氟-4-(2-(3-甲基吗啉代)乙氧基)苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(I-31)的制备
室温下将2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(0.6g,1.3mmol)加入到MeCN(20mL)中，然后依次加入K2CO3(540mg,3.9mmol)、碘化钾(26mg,0.13mmol)和(R)-3-甲基吗啉(170mg,1.7mmol)，反应液在80℃下搅拌8h。TLC监测原料消失后，将反应液浓缩,残留物用柱层析硅胶(DCM:MeOH(V/V)＝20:1)纯化，得化合物(R)-2-(5-(2-氟-4-(2-(3-甲基吗啉代)乙氧基)苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(I-31)(217.2mg,产率34.6％).
1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),7.84–7.69(m,2H),7.37–7.27(m,3H),7.25–7.20(m,1H),7.10–6.99(m,2H),6.83–6.70(m,2H),4.51(dd,2H),4.16–4.06(m,2H),3.85–3.78(m,3H),3.73–3.62(m,2H),3.27(dd,1H),3.20–3.11(m,1H),2.90–2.81(m,1H),2.80–2.70(m,1H),2.62–2.51(m,2H),1.04(d,3H)。
LC-MS,M/Z(ESI):482.1[M+H]+。
实施例32 化合物I-32的制备
合成路线如下所示：
将2-(5-(4-(2-溴乙氧基)-2-氟苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(2.0g,4.19mmol)，(S)-3-甲基吗啉(0.47g,4.19mmol)溶于乙腈(20.0mL)中，加入碳酸钾(1.74g,12.56mmol)，反应液升温至85℃搅拌12h。反应液冷至室温，加入水(100mL)稀释，用乙酸乙酯(50mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用柱层析硅胶纯化(石油醚:乙酸乙酯(V/V)＝1:1)，得(S)-2-(5-(2-氟-4-(2-(3-甲基吗啉代)乙氧基)苯基)吡啶- 2-基)-N-(2-氟苄基)乙酰胺(I-32)(200mg，产率10％)。
1H NMR(400MHz,CDCl3)δ8.67(s,1H),7.83–7.78(m,1H),7.77–7.70(m,1H),7.37–7.19(ddd,4H),7.10–6.99(m,2H),6.78(ddd,2H),4.53(d,2H),4.16–4.08(m,2H),3.86–3.75(m,3H),3.73–3.62(m,2H),3.27(dd,1H),3.16(dt,1H),2.85(dt,1H),2.75(dt,1H),2.61–2.50(m,2H),1.04(d,3H).
LC-MS,M/Z(ESI):482.5[M+H]+。
实施例33 化合物I-33的制备
合成路线如下所示：
第一步：N-(2-氟苄基)-2-(5-(4-羟基-2-甲基苯基)吡啶-2-基)乙酰胺
室温下将化合物3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯酚(1.15g,4.92mmol)和2-(5-溴吡啶-2-基)-N-(2-氟苄基)乙酰胺(1.0g,3.33mmol)加入到1,4-二氧六环/水(10mL/1mL)中，然后加入氟化钾(0.760g,13.1mmol)，氮气保护下加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)(117mg,0.16mmol)，反应液加热到90℃搅拌10h。反应液冷却至室温，加入水(50mL)稀释，用乙酸乙酯(20mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物经硅胶过柱(DCM:MeOH(V/V)＝95:5)方法纯化得化合物N-(2-氟苄基)-2-(5-(4-羟基-2-甲基苯基)吡啶-2-基)乙酰胺(840mg,产率76％)。
LC-MS,M/Z(ESI):351.4[M+H]+。
第二步：2-(5-(4-(2-溴乙氧基)-2-甲基苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺的制备
室温下将N-(2-氟苄基)-2-(5-(4-羟基-2-甲基苯基)吡啶-2-基)乙酰胺(0.8g,2.3mmol)和碳酸钾(1.89g,13.7mmol)加入到无水乙腈中(15mL)，加热至80℃搅拌1h，然后加入1,2-二溴乙烷(2.55g,13.7mmol)，反应液继续在80℃下搅拌10h。反应液冷却至室温，浓缩除去溶剂，粗品用硅胶柱(DCM:MeOH(V/V)＝20:1)分离纯化,得2-(5-(4-(2-溴乙氧基)-2-甲基苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(0.6g,产率69％).
第三步：N-(2-氟苄基)-2-(5-(2-甲基-4-(2-((3aR,6aS)-四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基))乙氧基)苯基)吡啶-2-基)乙酰胺的制备
室温下将2-(5-(4-(2-溴乙氧基)-2-甲基苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(0.6g,1.31mmol)加入到MeCN(20mL)中，然后加入K2CO3(543mg,3.94mmol)、碘化钾(33mg,0.2mmol)和(3aR,6aS)-六氢-1H-呋喃[3,4-c]吡咯盐酸盐(255mg,1.7mmol)，然后在80℃下搅拌8h。反应液减压浓缩，残留物用柱层析硅胶(DCM:MeOH(V/V)＝20:1)分离纯化，得到N-(2-氟苄基)-2-(5-(2-甲基-4-(2-((3aR,6aS)-四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基))乙氧基)苯基)吡啶-2-基)乙酰胺(I-33)(248.3mg,产率39％).
1H NMR(400MHz,DMSO-d6)δ8.63(t,1H),8.43–8.39(m,1H),7.69(m,1H),7.40–7.26(m,3H),7.20–7.08(m,3H),6.91(d,1H),6.85(m,1H),4.34(d,2H),4.07(t,2H),3.75–3.64(m,4H),3.38(m,2H),2.74(t,2H),2.70–2.60(m,4H),2.38(dd,2H),2.21(s,3H)
LC-MS,M/Z(ESI):490.4[M+H]+。
实施例34 化合物I-34的制备
合成路线如下所示：
第一步：3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)苯酚的制备
将4-溴-3-氯酚(6.0g,28.92mmol)，联硼酸频那醇酯(11.02g,43.38mmol)和醋酸钾(8.582g,86.77mmol)以及[1,1'-双(二苯基膦)二茂铁]二氯化钯(1.96g，2.73mmol)溶于二氧六环(120mL)和水(3mL)中，反应液升温至85℃搅拌12小时。加入水(200mL)稀释，用乙酸乙酯(200mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用柱层析硅胶分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)，得白色固体3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)苯酚(5.5g,产率74.0％)。
LC-MS,M/Z(ESI):255.1[M+H]+。
第二步：2-(5-(2-氯-4-羟基苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺的制备
将3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)苯酚(5.5g,21.61mmol)，2-(5-溴吡啶-2-基)-N-(2-氟苄基)乙酰胺(6.98g,21.61mmol)和碳酸钾(8.96g,64.83mmol)以及[1,1'-双(二苯基膦)二茂铁]二氯化钯(1.96g，2.73mmol)置于1,4-二氧六环(120mL)和水(3mL)中，反应液升温至85℃搅拌12小时。加入水(200mL)稀释，用乙酸乙酯(200mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用柱层析硅胶分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)，得白色固体2-(5-(2-氯-4-羟基苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(5.0g,产率62.4％)。
LC-MS,M/Z(ESI):371.1[M+H]+。
第三步：2-(5-(4-(2-溴乙氧基)-2-氯苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(A6)的制备
将2-(5-(2-氯-4-羟基苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(5.0g,13.48mmol)，1,2-二溴乙烷(15.20g,80.90mmol)和碳酸钾粉末(11.18g,80.90mmol)置于乙腈(50mL)中，反应液升温至85℃搅拌12h。加入水(100mL)稀释，用乙酸乙酯(50mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:1)，得2-(5-(4-(2-溴乙氧基)-2-氯苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(A6，4.0g,产率62.1％)。
LC-MS,M/Z(ESI):477.1[M+H]+。
第四步：2-(5-(2-氯-4-(2-((3aR,6aS)-四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)乙氧)苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺的制备
将2-(5-(4-(2-溴乙氧基)-2-氯苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(A6，2.0g,4.19mmol)，(3aR,6aS)--六氢-1H-呋喃[3,4-C]吡咯盐酸盐(0.63g,4.19mmol)和碳酸钾(1.74g,12.56mmol)溶于乙腈(20.0mL)中，反应液升温至85℃搅拌12h。加入水(100mL)稀释，用乙酸乙酯(50mL×3)萃取，分液，合并有机相。有机相用无水硫酸钠干燥，过滤，浓缩，残留物依次用层析柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:1)，制备高效液相色谱纯化，得到2-(5-(2-氯-4-(2-((3aR,6aS)-四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)乙氧)苯基)吡啶-2-基)-N-(2-氟苄基)乙酰胺(I-34，150mg,产率7％)。
1H NMR(400MHz,CDCl3)δ8.57(d,1H),7.80–7.69(m,2H),7.37–7.27(m,2H),7.25–7.19(m,2H),7.10–6.98(m,3H),6.91(dd,1H),4.54(d,2H),4.14(t,2H),3.82(s,2H),3.79–3.72(m,2H),3.64(dd,2H),2.97–2.83(m,6H),2.41(dd,2H).
本发明测试例中的对照化合物I(商品名Tirbanibulin)是一种双重作用的Src激酶和微管蛋白聚合抑制剂，已被FDA和欧盟获批用于面部或头皮光化性角化病的局部治疗。对照化合物I的制备参考专利WO 2008/002676A2，对照化合物I结构如下：
对照化合物I
测试例1：抑制微管蛋白单体聚合试验
采用Tubulin Polymerization Assay Kit(cytoskeleton，Cat.#BK011P)开展化合物抑制微管蛋白单体聚合试验。
试验前先将试剂盒配套的96孔板(Corning Costar，Cat.#3686)放置于酶标仪(MD，SpectraMax M5)中加热至37℃，维持10min，取出96孔板，加入5μL的12.5μM的化合物溶液或空白溶液，再将96孔板放入酶标仪37℃孵育1min，使化合物溶液升温至37℃，取出96孔板于每孔迅速加入按照供应商说明书配置的反应混合物50μL，1min内完成加样并避免产生气泡，然后立即将96孔板放入酶标仪，震荡5s，使用Kinetic mode在激发光360nm、发射光420nm条件下，37℃连续检测30min-60min，每30s检测一次，以检测时间为X轴，荧光信号值为Y轴得到微管蛋白单体聚合曲线。如图1和表1所示，聚合曲线的Vmax值越大和最大荧光信号值越高代表化合物抑制效率越低。
表1
化合物对微管蛋白聚合抑制试验结果如图1和表1所示，结果表明本发明化合物对应的聚合曲线的Vmax值和最大荧光信号值都明显更小，说明其 能明显抑制微管蛋白单体的聚合，与对照化合物I相比，抑制活性更优。
测试例2：化合物抑制细胞增殖试验
采用人皮肤鳞状细胞癌细胞A-431(ATCC，CRL-1555)和光化性角化病人来源的细胞HT 297.T(ATCC，CRL-7782)增殖试验检测小分子化合物对细胞增殖抑制作用。
A-431细胞和HT 297.T细胞培养于含10％胎牛血清的DMEM培养基中，于37℃，5％CO2培养箱中生长。将对数期细胞按照1000个细胞/孔，每孔100μL接种于96孔细胞培养板，置于37℃，5％CO2培养箱培养过夜。第二天每孔再加入100μL梯度稀释的2×待测化合物溶液，DMSO作为阳性对照，另设置10μM十字孢碱(阿拉丁，S102392)作为阴性对照组，加完化合物的培养板继续于37℃，5％CO2培养箱中孵育4天。孵育完成后使用luciferase assay system(Promega，G9243)并按照供应商提供的说明书在Envision 2104Multilabel Reader上测定荧光信号值。通过以下公式计算抑制率，然后以抑制剂的浓度Log值为X轴，抑制率为Y轴绘制曲线，用Graphpad 8.0计算得出IC50。
Inhibition％＝(阳性对照组信号-测试孔信号)/(阳性对照组信号-阴性对照组信号)*100
表2测试化合物对A-431细胞增殖活性抑制结果

表3测试化合物对HT 297.T细胞增殖活性抑制结果
化合物对细胞增殖抑制试验结果如表2和表3所示，结果表明，本发明中的化合物能明显抑制细胞增殖，尤其是对光化性角化病人来源的HT 297.T细胞抑制作用明显优于对照化合物I，说明本发明中的化合物对光化性角化病具有更好的治疗作用。
测试例3：热力学溶解度试验
配制pH 7.4的磷酸盐缓冲液(PBS)、pH 6.5的FeSSIF溶液、pH 1.6的FaSSGF溶液。精确称取化合物，加入配制好的pH 7.4的磷酸盐缓冲液、pH6.5的FeSSIF溶液和pH 1.6的FaSSGF溶液，配制成浓度为4mg/mL的溶液，以1000rpm的转速振摇1小时，然后室温孵育过夜。孵育后的溶液以12000rpm转速离心10分钟，去除未溶解的颗粒，上清液转移至新的离心管中。将上清液进行适当的稀释后，加入含内标的乙腈溶液，采用相同基质配制的标曲进行定量。
表4热力学溶解度试验结果

热力学溶解度试验结果如表4所示，结果表明，相比于对照化合物I，本发明化合物在中性条件下具有更大的热力学溶解度，成药性好。
测试例4：药代动力学试验
小鼠药代动力学试验，使用3只雄性ICR小鼠，20-25g，禁食过夜，尾静脉注射给药(1mg/kg或5mg/kg)，在给药前和给药后15、30min以及1、2、4、8、24h采血。另取3只小鼠，口服灌胃给药(5mg/kg)，在给药前和给药后15、30min以及1、2、4、8、24h采血。血液样品于6800g，2-8℃离心6min，收集血浆，于-80℃保存。取各时间点血浆，加入3-5倍量含内标的乙腈溶液混合，涡旋混合1分钟，13000转/min下于4℃离心10min，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。
表5小鼠药代动力学试验结果1
表6小鼠药代动力学试验结果2
表7小鼠药代动力学试验结果3
小鼠药代动力学试验结果如表5、表6和表7所示，结果表明与对照化合物I相比，本发明化合物小鼠体内代谢快，潜在全身毒性小，成药性良好。
测试例5：人肝微粒体稳定性试验
人肝微粒体稳定性试验采用化合物与人肝微粒体体外共孵育进行检测。首先将待测化合物在DMSO溶剂中配制成10mM的储备液，随后使用乙腈将化合物稀释至0.5mM。使用PBS稀释人肝微粒体(Corning)成微粒体/缓冲液溶液，并使用该溶液稀释0.5mM的化合物成为工作溶液，工作溶液中 化合物浓度为1.5μM，人肝微粒体浓度为0.75mg/ml。取深孔板，每孔加入30μL工作溶液，然后加入15μL预热好的6mM NADPH溶液启动反应，37℃孵育。在孵育的0、5、15、30、45分钟时，加入135μL乙腈至相应的孔中终止反应。在最后45分钟时间点用乙腈终止反应后，深孔板涡旋振动10分钟(600rpm/min)，然后离心15分钟。离心后取上清，1:1加入纯化水后进行LC-MS/MS检测，获得每个时间点化合物峰面积与内标峰面积比值，将5、15、30、45分钟时化合物的峰面积比值与0分钟时的峰面积比值进行比较，计算每个时间点化合物的剩余百分比，使用Graphpad 5软件计算T1/2。
表8人肝微粒体稳定性试验结果
人肝微粒体稳定性试验结果如表8所示，结果表明本发明化合物人肝微粒体代谢快，潜在全身毒性小，成药性良好。
测试例6：化合物抑制Src信号通路
采用Western Blot方法检测化合物对A-431皮肤癌细胞(ATCC，CRL-1555)的p-SRC抑制来评价化合物对SRC信号通路的抑制作用。
A-431细胞培养于含10％胎牛血清的DMEM培养基中，放置于37℃,5％CO2培养箱中生长。500000个细胞/孔接种于12孔细胞培养板，置于37℃,5％CO2培养箱培养过夜。第二天更换培养液，加不同浓度化合物处理， DMSO作为对照，加完化合物的培养板放置于37℃,5％CO2培养箱中继续培养24h。用PBS洗细胞1次，用RIPA裂解液(R0010，索莱宝)在低温下裂解细胞30分钟，之后将蛋白裂解液收集到离心管中，4℃下14000g离心10分钟，转移上清至新管。使用BCA蛋白浓度测定试剂盒(P0009，碧云天生物)进行检测并计算蛋白浓度。用5×蛋白上样缓冲液将各个样品的蛋白定量一致，100℃煮沸5min，进行western blot检测p-SRC水平，p-SRC抗体(Ab185617)购自Abcam公司，GAPDH抗体(60004-1-Ig)购买于proteintech公司。
试验结果如图2所示，结果表明本发明化合物在80nM时可显著抑制SRC的磷酸化，与对照化合物I相比，具有更优的p-SRC抑制活性，能阻断SRC下游信号通路。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (42)

  1. 式I所示二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，具有结构：
    其中，W选自：-O-、-S-、-NH-、-N(C1-C6烷基)-；
    L为C1-C6亚烷基；
    V为不存在或选自：-O-、-S-、-NH-、-N(C1-C6烷基)-；
    当V不存在时，Q为未取代或被m个R3取代的环A、未取代或被m个R3取代的环B；
    当V选自：-O-、-S-、-NH-、-N(C1-C6烷基)-时，Q为未取代或被m个R3取代的环C；
    所述环A为6-15元杂环基；且当环A为6元杂环基时，所述环A为
    所述环B为6-12元含砜基的杂环基；
    所述环C为4-15元杂环基或6-12元含砜基的杂环基；
    R1、R2、R3各自独立地为氢或选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12、-COO-3-6元环烷基、-CO-3-6元环烷基、-S(O)2-C1-C6烷基、-S(O)2-3-6元环烷基、-C(O)-C1-C6烷基-NR11R12；
    其中，R11、R12各自独立地为氢或C1-C6烷基；或R11和R12与它们所连接的N原子一起形成4-6元环；
    所述R1、R2、R3任选地被一个或多个选自下列的取代基取代：卤素、羟 基、氨基、氰基、C1-C6烷基、3-6元环烷基；当取代基为多个时，所述取代基相同或不同；
    n为1、2或3；当R1为多个时，所述R1相同或不同；
    p为1、2或3；当R2为多个时，所述R2相同或不同；
    m为1、2或3；当R3为多个时，所述R3相同或不同；
    条件是当Q为环A时，R1、R2不同时为氢；
    当所述环A为时，R1、R2、R3不同时为氢；
    或当所述环A为时，R1和R2中至少一个选自：氰基、C2-C6烯基、C2-C6炔基、-C(O)NR11R12。
  2. 如权利要求1所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，W选自：-O-、-S-、-NH-；
    较佳地，W为-O-。
  3. 如权利要求1所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，L为-CH2-、-CH2CH2-、-CH2CH2CH2-；
    较佳地，L为-CH2CH2-。
  4. 如权利要求1所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述环A为7-15元单环、并环、桥环或螺环的杂环基；
    较佳地，所述环A含有1、2或3个选自N、O或S的杂原子；
    当杂原子为多个时，所述杂原子相同或不同；
    较佳地，所述环A含有1个N原子和1个O原子。
  5. 如权利要求1所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述环A具有结构
    其中，Z表示C或N；较佳地，Z为N；
    较佳地，所述环A还含有1个O原子；
    较佳地，为
  6. 如权利要求1所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，环B为6-12元含砜基的单环、并环、螺环、桥环杂环基；
    较佳地，环B为6-8元含砜基的单环杂环基；
    较佳地，环B为7-12元含砜基的并环、螺环、桥环杂环基。
  7. 如权利要求1所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，环B为
    其中，K表示C或N。
  8. 如权利要求1所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，具有式Ia、Ib或Ic所示结构：

    其中，K表示C或N；
    环A、环B、m、n、p、R1、R2、R3的定义如权利要求1中所述。
  9. 如权利要求1或8所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，具有结构
  10. 如权利要求1或8所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述环A为7-10元单环杂环基或7-12元并环、桥环、螺环杂环基。
  11. 如权利要求1或8所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述环A选自：
    较佳地，为
  12. 如权利要求10所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，R1、R2各自独立地为氢或选自：卤素、羟基、氨基、C1-C6烷基、-O-C1-C6烷基；所述C1-C6烷基任选地被一个或多个卤素取代；
    R3选自：卤素、羟基、氨基、C1-C6烷基、-O-C1-C6烷基；所述C1-C6烷基任选地被一个或多个卤素取代；
    且R1、R2不同时为氢；
    较佳地，R1、R2、R3各自独立地选自：卤素、C1-C6烷基；所述C1-C6烷基任选地被一个或多个卤素取代；
    更佳地，R1、R2、R3各自独立地选自：氟、甲基、乙基、丙基；所述甲基、乙基、丙基任选地被一个或多个卤素取代；
    较佳地，所述卤素为F。
  13. 如权利要求1或8所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，环B为6-12元单环、并环、螺环、桥环杂环基；
    较佳地，环B为6-8元单环杂环基；
    较佳地，环B为7-12元并环、螺环、桥环杂环基。
  14. 如权利要求1或8所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述环B选自：
  15. 如权利要求13所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，R1、R2、R3各自独立地为氢或选自：卤素、羟基、氨基、氰基、C1-C6烷基、-O-C1-C6烷基、-C(O)NR11R12；
    R11、R12各自独立地为氢或C1-C6烷基；
    所述C1-C6烷基任选地被一个或多个卤素取代；
    较佳地，R1、R2、R3各自独立地选自：卤素、C1-C6烷基；所述C1-C6烷基任选地被一个或多个卤素取代；
    更佳地，R1、R2、R3各自独立地选自：氟、甲基、乙基、丙基；所述C1-C6烷基任选地被一个或多个氟取代；
    较佳地，所述卤素为F。
  16. 如权利要求1所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，具有结构Id
    其中，m为1或2；较佳地m为1；
    R3为氢或选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12；R1选自：氰基、C2-C6烯基、C2-C6炔基、-C(O)NR11R12；
    或者R1、R3各自独立地选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12；
    其中，R11、R12各自独立地为氢或C1-C6烷基；或R11和R12与它们所连接的N原子一起形成4-6元环；
    所述R3任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基；当取代基为多个时，所述取代基相同或不同。
  17. 如权利要求16所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，R3为氢或选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12；R1选自：氰基、C2-C3烯基、C2-C3炔基、-C(O)NR11R12；
    或R1、R3各自独立地选自：卤素、C1-C6烷基；所述C1-C6烷基任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基；当取代基为多个时，所述取代基相同或不同；
    较佳地，R3为氢或选自：卤素、甲基、乙基、丙基；所述甲基、乙基、丙基任选地被1个或多个卤素取代；R1选自：氰基、C2-C3烯基、C2-C3炔基；
    较佳地，R1、R3各自独立地选自：卤素、甲基、乙基、丙基；所述甲基、 乙基、丙基任选地被1个或多个卤素取代；
    较佳地，所述卤素为氟。
  18. 如权利要求1所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，具有结构Ie或If
    其中，环C、R1、R2、n、p的定义如权利要求1中所述；
    R3为C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12、-COO-C1-C6烷基、-COO-3-6元环烷基、-CO-3-6元环烷基、-S(O)2-C1-C6烷基、-S(O)2-3-6元环烷基、-C(O)-C1-C6烷基-NR11R12；
    其中，R11、R12各自独立地为氢或C1-C6烷基；或R11和R12与它们所连接的N原子一起形成4-6元环；
    所述R3任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基、3-6元环烷基；当取代基为多个时，所述取代基相同或不同；
    较佳地，环C为4-8元杂环基；较佳地，环C为4-6元杂环基；更佳地，环C为
    较佳地，R3为-CO-C1-C6烷基；
    较佳地，所述R3任选地被一个或多个选自下列的取代基取代：卤素、3-6元环烷基；
    更佳地，R3为-CO-C1-C3烷基-环丙基、-CO-C1-C3烷基-环丁基。
  19. 如权利要求1所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，W选自：-O-、-S-、-NH-、-N(C1-C6烷基)-；
    L为C1-C6亚烷基；
    V为不存在或选自：-O-、-S-、-NH-、-N(C1-C6烷基)-；
    当V不存在时，Q为未取代或被m个R3取代的环A、未取代或被m个R3取代的环B；
    当V选自：-O-、-S-、-NH-、-N(C1-C6烷基)-时，Q为未取代或被m个R3取代的环C；
    所述环A为6-15元杂环基；且当环A为6元杂环基时，所述环A为
    所述环B为6-12元含砜基的杂环基；
    所述环C为4-15元杂环基或6-12元含砜基的杂环基；
    R1、R2、R3各自独立地为氢或选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12、-COO-3-6元环烷基、-CO-3-6元环烷基、-S(O)2-C1-C6烷基、-S(O)2-3-6元环烷基、-C(O)-C1-C6烷基-NR11R12；
    其中，R11、R12各自独立地为氢或C1-C6烷基；或R11和R12与它们所连接的N原子一起形成4-6元环；
    所述R1、R2、R3任选地被一个或多个选自下列的取代基取代：卤素、羟基、氨基、氰基、C1-C6烷基、3-6元环烷基；当取代基为多个时，所述取代基相同或不同；
    n为1、2或3；当R1为多个时，所述R1相同或不同；
    p为1、2或3；当R2为多个时，所述R2相同或不同；
    m为1、2或3；当R3为多个时，所述R3相同或不同；
    式I所示二芳基类化合物满足以下条件中的1个、2个或3个：
    (1)V选自：-O-、-S-、-NH-、-N(C1-C6烷基)-；
    (2)Q为未取代或被m个R3取代的6-12元含砜基的杂环基；
    (3)R1选自：羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12、-COO-3-6元环烷基、-CO-3-6元环烷基、-S(O)2-C1-C6烷基、-S(O)2-3-6元环烷基、-C(O)-C1-C6烷基-NR11R12；或者，R1为卤素，环A、环B或环C为并环、桥环或螺环。
  20. 如权利要求1或19所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，其满足以下条件中的一个或多个：
    a)V选自：-O-、-S-、-NH-、-N(C1-C6烷基)-；
    b)Q为未取代或被m个R3取代的6-12元含砜基的杂环基；
    c)R1选自：羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12、-COO-3-6元环烷基、-CO-3-6元环烷基、-S(O)2-C1-C6烷基、-S(O)2-3-6元环烷基、-C(O)-C1-C6烷基-NR11R12。
  21. 如权利要求20所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，其满足以下条件中的一个或多个：
    d)V选自-NH-；
    e)Q为未取代的6-12元含砜基的杂环基；
    f)R1选自：氰基、C1-C6烷基和C2-C6炔基。
  22. 如权利要求1或19所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，其满足以下条件中的一个：
    g)R1为卤素，环A、环B或环C为并环、桥环或螺环；
    h)式I所示二芳基类化合物为m为1或2；R3选自：卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、-O-C1-C6烷基、-COO-C1-C6烷基、-CO-C1-C6烷基、-C(O)NR11R12；R1选自：氰基、C2-C6烯基、C2-C6炔基、-C(O)NR11R12；
    i)条件是当Q为环A时，R1、R2不同时为氢；且当所述环A为时，R3不为氢，或者R1和R2中至少一个选自：氰基、C2-C6烯基、C2-C6炔基、-C(O)NR11R12。
  23. 如权利要求1或19所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，其满足以下条件中的一个：
    j)W选自-O-；
    k)L为C1-C6亚烷基；
    l)V为不存在或选自：-NH-；当V不存在时，Q为未取代或被m个R3取代的环A、未取代或被m个R3取代的环B；当V选自：-NH-时，Q为未取代或被m个R3取代的环C；所述环A为6-15元杂环基；且当环A为6元杂环基时，所述环A为所述环B为6-12元含砜基的杂环基；所述环C为4-15元杂环基或6-12元含砜基的杂环基；m为1、2或3；当R3为多个时，所述R3相同或不同；R3为C1-C6烷基或-CO-C1-C6烷基；R3任选地被一个或多个3-6元环烷基取代；当取代基为多个时，所述取代基相同或不同；
    m)n为1、2或3；当R1为多个时，所述R1相同或不同；R1为氢、卤素、氰基、未取代的C1-C6烷基或未取代的C2-C6炔基；
    n)p为1、2或3；当R2为多个时，所述R2相同或不同；R2为氢或卤 素；
    o)式I所示二芳基类化合物满足以下条件中的1个、2个或3个：(1)V选自-NH-；(2)Q为未取代或被m个R3取代的6-12元含砜基的杂环基；(3)R1为氰基、未取代的C1-C6烷基或未取代的C2-C6炔基；或者，R1为卤素，环A、环B或环C为并环、桥环或螺环。
  24. 如权利要求1或19所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，其如下述任一方案所述：
    方案1：
    W选自-O-；
    L为C1-C6亚烷基；
    V为不存在或选自：-NH-；
    当V不存在时，Q为未取代或被m个R3取代的环A、未取代或被m个R3取代的环B；
    当V选自：-NH-时，Q为未取代或被m个R3取代的环C；
    所述环A为6-15元杂环基；且当环A为6元杂环基时，所述环A为
    所述环B为6-12元含砜基的杂环基；
    所述环C为4-15元杂环基或6-12元含砜基的杂环基；
    n为1、2或3；当R1为多个时，所述R1相同或不同；
    R1为氢、卤素、氰基、未取代的C1-C6烷基或未取代的C2-C6炔基；
    p为1、2或3；当R2为多个时，所述R2相同或不同；
    R2为氢或卤素；
    m为1、2或3；当R3为多个时，所述R3相同或不同；
    R3为C1-C6烷基或-CO-C1-C6烷基；R3任选地被一个或多个3-6元环烷基取代；当取代基为多个时，所述取代基相同或不同；
    式I所示二芳基类化合物满足以下条件中的1个、2个或3个：
    (1)V选自-NH-；
    (2)Q为未取代或被m个R3取代的6-12元含砜基的杂环基；
    (3)R1为氰基、未取代的C1-C6烷基或未取代的C2-C6炔基；或者，R1为卤素，环A、环B或环C为并环、桥环或螺环；
    方案2：
    W选自-O-；
    L为C1-C6亚烷基；
    V为不存在或选自：-NH-；
    当V不存在时，Q为未取代或被m个R3取代的环A、未取代或被m个R3取代的环B；
    当V选自：-NH-时，Q为未取代或被m个R3取代的环C；
    所述环A为6-15元杂环基；且当环A为6元杂环基时，所述环A为
    所述环B为6-12元含砜基的杂环基；
    所述环C为4-15元杂环基或6-12元含砜基的杂环基；
    n为1；
    R1为氢、卤素、氰基、未取代的C1-C6烷基或未取代的C2-C6炔基；
    p为1；
    R2为氢；
    m为1、2或3；当R3为多个时，所述R3相同或不同；
    R3为C1-C6烷基或-CO-C1-C6烷基；R3任选地被一个或多个3-6元环烷基取代；当取代基为多个时，所述取代基相同或不同；
    式I所示二芳基类化合物满足以下条件中的1个、2个或3个：
    (1)V选自-NH-；
    (2)Q为未取代或被m个R3取代的6-12元含砜基的杂环基；
    (3)R1为氰基、未取代的C1-C6烷基或未取代的C2-C6炔基；或者，R1为卤素，环A、环B或环C为并环、桥环或螺环。
  25. 如权利要求1或19所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，其如下述任一方案所述：
    p)L为-CH2-、-CH2CH2-、-CH2CH2CH2-；
    q)所述的环A里，所述的6-15元杂环基为6-8元杂环基；
    r)所述的环A里，所述的6-15元杂环基为单环、并环、桥环或螺环；
    s)所述的环A里，所述的6-15元杂环基为饱和环；
    t)所述的环A里，所述的6-15元杂环基中的杂原子为N和/或O；
    u)所述的环A里，所述的6-15元杂环基通过N原子与V连接；
    v)所述的环C里，所述的4-15元杂环基杂环基为6-8元杂环基；
    w)所述的环C里，所述的4-15元杂环基为单环、并环、桥环或螺环；
    x)所述的环C里，所述的4-15元杂环基为饱和环；
    y)所述的环C里，所述的4-15元杂环基中的杂原子为N和/或O；
    z)所述的环C里，所述的4-15元杂环基通过N原子与V连接；
    aa)所述的环B里，所述的6-12元含砜基的杂环基6-8元含砜基的杂环基；
    bb)所述的环B里，所述的6-12元含砜基的杂环基为单环、并环、桥环或螺环；
    cc)所述的环B里，所述的6-12元含砜基的杂环基为单环或螺环；
    dd)所述的环B里，所述的6-12元含砜基的杂环基为饱和环；
    ee)所述的环B里，所述的6-12元含砜基的杂环基中的杂为-S(＝O)2-和/或N；
    ff)所述的环B里，所述的6-12元含砜基的杂环基通过N原子与V连接；
    gg)所述的环C里，所述的6-12元含砜基的杂环基6-8元含砜基的杂环 基；
    hh)所述的环C里，所述的6-12元含砜基的杂环基为单环、并环、桥环或螺环；
    ii)所述的环C里，所述的6-12元含砜基的杂环基为饱和环；
    jj)所述的环C里，所述的6-12元含砜基的杂环基中的杂为-S(＝O)2-和/或N；
    kk)所述的环C里，所述的6-12元含砜基的杂环基通过N原子与V连接；
    ll)所述R1里，所述的卤素为氟或氯；
    mm)所述R1里，所述的C1-C6烷基为甲基或乙基；
    nn)所述R1里，所述的C2-C6炔基为乙炔基或丙炔基；
    oo)所述R2里，所述的卤素为氟或氯；
    pp)所述R3里，所述的C1-C6烷基为甲基或乙基；
    qq)所述R3里，所述的“-CO-C1-C6烷基”中的C1-C6烷基为甲基或乙基；
    rr)R11和R12与它们所连接的N原子一起形成的4-6元环为4-6元含N杂环烷基或5-6元杂芳基；
    ss)所述的溶剂化物为水合物。
  26. 如权利要求25所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，其如下述任一方案所述：
    tt)L为-CH2CH2-；
    uu)所述环A为(例如)、
    vv)所述环C里，所述的4-15元杂环基为(例如)、
    ww)所述环B里，所述的6-12元含砜基的杂环基为
    xx)所述环C里，所述的6-12元含砜基的杂环基为
  27. 如权利要求1或19所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述的二芳基类化合物为以下任一化合物：

  28. 如权利要求1或19所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述的二芳基类化合物为以下任一化合物：

  29. 一种化合物B具有结构
    其中，Q、L、W、R1、n的定义如权利要求1或19所述；
    X为卤素或者取代基G；
    所述取代基G选自：硼酸酯基、硼酸基、烷基锡、三氟甲烷磺酸基、甲烷磺酸基、对甲苯磺酸基；
    较佳地，所述卤素为氯、溴或碘；
    较佳地，所述的化合物B为用作中间体的化合物B。
  30. 如权利要求29所述的化合物B，其特征在于，具有下列结构

    其中，K表示C或N；
    环A、环B、m、n、p、R1、R2、R3的定义如权利要求1或19中所述；
    X为卤素或者取代基G；
    所述取代基G选自：硼酸酯基、硼酸基、烷基锡、三氟甲烷磺酸基、甲烷磺酸基、对甲苯磺酸基；
    较佳地，所述卤素为氯、溴或碘。
  31. 如权利要求29或30所述的化合物B，其特征在于，所述环A为7-15元单环、并环、桥环或螺环的杂环基；
    较佳地，所述环A为7-10元单环杂环基或7-12元并环、桥环或螺环杂环基；
    较佳地，所述环A含有1个N原子和1个O原子。
  32. 如权利要求29或30所述的化合物B，其特征在于，环B为6-12元单环、并环、螺环、桥环杂环基；
    较佳地，环B为6-8元单环杂环基；
    较佳地，环B为7-12元并环、螺环、桥环杂环基。
  33. 一种制备如权利要求1-28中任一所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药的方法，其特征在于，包括：
    将如权利要求29-32中任一所述的中间体B与中间体C在碱性条件下反应得到所述二芳基类化合物
    其中，R2和p的定义如权利要求1或19中所述；
    Y为卤素或者取代基G；
    所述取代基G选自：硼酸酯基、硼酸基、烷基锡、三氟甲烷磺酸基、甲烷磺酸基、对甲苯磺酸基；
    当中间体B中的X为卤素时，Y为G；
    当中间体B中的X为G时，X为卤素；
    较佳地，所述卤素为氯、溴或碘；
    较佳地，中间体C具有结构
  34. 一种药物组合物，包括如权利要求1-28中任一所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药。
  35. 一种药物组合物，包括如权利要求1-28中任一所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，和
    药学上可接受的载体和/或其他活性药物。
  36. 如权利要求1-28中任一所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药的用途，或如权利要求34所述的药物组合物的用途，或如权利要求35所述的药物组合物的用途，所述用途包括：
    1)抑制微管蛋白聚合和/或Src激酶；
    2)预防和/或治疗与微管蛋白聚合和/或Src激酶相关的疾病；
    3)制备微管蛋白聚合和/或Src激酶抑制剂；
    4)制备预防和/或治疗与微管蛋白聚合和/或Src激酶相关的疾病的药物、药物组合物或制剂；
    较佳地，所述与微管蛋白聚合和/或Src激酶相关的疾病包括肿瘤、皮肤疾病；
    较佳地，所述药物为外用制剂；
    较佳地，所述药物为经皮给药的药物。
  37. 如权利要求1-28中任一所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，或如权利要求34所述的药物组合物，或如权利要求35所述的药物组合物，在制备治疗肿瘤和/或皮肤疾病的药物中的用途；
    较佳地，所述药物为外用制剂；
    较佳地，所述药物为经皮给药的药物。
  38. 如权利要求37所述的用途，其特征在于，所述肿瘤包括：实体瘤、肉瘤、血液系统癌症；
    较佳地包括：乳腺癌、卵巢癌、前列腺癌、子宫颈癌、睾丸癌、结肠癌、结肠直肠癌、肝癌、非小细胞肺癌、鳞状细胞癌、小细胞肺癌、胃癌、胃肠道间质瘤、胰腺癌、膀胱癌、生殖细胞瘤、肥大细胞瘤、肥大细胞增多症、胶质母细胞瘤、神经母细胞瘤、星形细胞瘤、黑色素瘤、B细胞淋巴瘤、T细胞淋巴瘤、缓慢进展淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性髓细胞 性白血病、急性淋巴细胞性白血病、慢性髓细胞性白血病、慢性淋巴细胞性白血病、骨髓瘤和/或骨髓增生异常综合症。
  39. 如权利要求37所述的用途，其特征在于，所述皮肤疾病包括：光化性角化病、银屑病、异位性皮炎、牛皮癣、白癜风、玫瑰疹和/或系统性红斑狼疮。
  40. 如权利要求1-28中任一所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，或如权利要求34所述的药物组合物，或如权利要求35所述的药物组合物用于治疗或者预防肿瘤和/或皮肤疾病的用途。
  41. 一种抑制Src激酶，或预防和/或治疗Src激酶相关的疾病的方法，包括步骤：给需要的对象使用如权利要求1-28中任一所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，或如权利要求34所述的药物组合物，或如权利要求35所述的药物组合物。
  42. 一种抑制微管蛋白，或预防和/或治疗与微管蛋白相关的疾病的方法，包括步骤：给需要的对象使用如权利要求1-28中任一所述的二芳基类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，或如权利要求34所述的药物组合物，或如权利要求35所述的药物组合物。
PCT/CN2023/072143 2022-01-14 2023-01-13 用于微管蛋白-src双靶点抑制剂的二芳基类化合物 WO2023134752A1 (zh)

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