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CN-122011029-A - Ternary condensed ring compound and application thereof in medicine

CN122011029ACN 122011029 ACN122011029 ACN 122011029ACN-122011029-A

Abstract

The invention provides a ternary condensed ring compound with a structure shown in a formula (I) or pharmaceutically acceptable salts, isotopic derivatives and solvates thereof, or stereoisomers, geometric isomers and tautomers thereof, or prodrug molecules and metabolites thereof, and pharmaceutical compositions and applications thereof. The compound disclosed by the invention can be used for effectively inhibiting STAT6 phosphorylation, can be used for preparing medicines for preventing and treating inflammatory diseases, and can be used for preparing antitumor medicines.

Inventors

  • ZHANG FENGMIN
  • LEI CHONG
  • YAN PENG
  • YUAN MENG

Assignees

  • 杭州百新生物医药科技有限公司

Dates

Publication Date
20260512
Application Date
20251106
Priority Date
20241108

Claims (11)

  1. 1. A ternary fused ring compound having a structure represented by formula (I) or a pharmaceutically acceptable salt, isotopic derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof: Wherein, the Is a single bond or a double bond; Is 9 membered aromatic heterocycle; X 1 is selected from CR 5 or N, X 2 is selected from C (R 5 ) f or N (R 5 ) g ;X 3 、X 4 、X 5 are each independently selected from C or N; X 7 is selected from C 5 ) h or N (R 5 ) i ;X 6 is selected from CR 11 、N(R 11 ) j , S, O or Se; f. h is independently selected from 1 or 2;g, i, j is independently selected from 0 or 1; p is selected from 1 or 2;s is selected from 0,1,2, 3, 4 or 5; n is selected from 0,1, 2, 3; R 1 、R 6 are each independently selected from R g 、CR 1a R 2a P(O)OR 1b OR 2b 、CR 1a R 2a P(O)OR 1b NHR 2b 、 CR 1a R 2a P(O)(OR 1b )(NH(AA)C(O)OR 1c )、CR 1a R 2a P(O)(NHR 2c )(NH(AA)C(O)OR 1c )、CR 1a R 2a P(O)(NH(AA)C(O)OR 1c )(NH(AA)C(O)OR 1c )、P(O)OR 1b OR 2b 、 P (O) (OR 1b )(NH(AA)C(O)OR 1c )、P(O)(NHR 2c )(NH(AA)C(O)OR 1c ) OR P(O)(NH(AA)C(O)OR 1c )(NH(AA)C(O)OR 1c ); R 1a 、R 2a is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 hydroxyalkyl, or R 1a and R 2a form, with the atom to which they are attached, a C 3 -C 6 cycloalkyl or a 3-6 membered heterocyclyl; Each R 1b 、R 2b is independently selected from -R 1aa 、-R 1aa -OC(O)-R 1ab 、-R 1aa -C(O)O-R 1ab 、-R 1aa -OC(O)O-R 1ab 、-R 1aa -O-R 1ab 、-R 1aa -SC(O)O-R 1ab 、-R 1aa -SC(O)-R 1ab 、-R 1aa -S-R 1ab 、-R 1aa -O-R 1ab 、-R 1aa -S-R 1ab -S-R 1ac 、-R 1aa -S-R 1ab -O-R 1ac 、-R 1aa -OC(O)NH-R 1ab 、-R 1aa -OC(O)NR 1ab R 1ac 、-R 1aa -OC(O)-R 1ab -O-R 1ac 、-R 1aa -OC(O)O-R 1ab -O-R 1ac 、-R 1aa -SC(O)O-R 1ab -O-R 1ac 、-R 1aa -SC(O)-R 1ab -O-R 1ac or-R 1aa -OC(O)-(NH(AA)C(O)OR 1c ); R 1aa 、R 1ab 、R 1ac is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, C 1-20 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 5-to 7-membered heterocyclyl, C 6-12 aryl, 5-to 12-membered heteroaryl, -C 1-20 alkylene C 2-6 alkynyl, -C 1-20 Alkylene C 3-12 cycloalkyl, -C 1-20 alkylene C 6-12 aryl or C 1-20 alkylene C 2-10 heteroaryl, said C 1-20 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-to 7-membered heterocyclyl, C 6-12 aryl, 5-to 12-membered heteroaryl, C 1-20 alkylene C 2-6 alkynyl, C 1-20 Alkylene C 3-12 cycloalkyl, C 1-20 Alkylene C 6-12 aryl OR C 1-20 alkylene C 2-10 heteroaryl, optionally further substituted with one OR more R h 、-Si(R h ) 3 OR C (O) OR h ; Each R 1c 、R 2c is independently selected from hydrogen, deuterium, or C 1-6 alkyl, 5-7 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-4 alkylene C 6-12 aryl, or C 1-4 alkylene C 2-10 heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy; AA is selected from the group consisting of residues of natural or unnatural amino acids in either the alpha or beta configuration; each R 2 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, or C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylthio, C 1-6 alkylthio, C 1-6 alkylamino, or 4-10 membered heterocyclyl, optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy; Or two R 2 and the atoms to which they are attached are cyclized to form a C 3 -C 6 cycloalkyl, C 6-12 aryl, or a 3-6 membered heterocyclyl, which C 3 -C 6 cycloalkyl, C 6-12 aryl, or 3-6 membered heterocyclyl may be optionally further substituted with one or more substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 haloalkyl; Each R 2A 、R 2B is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, or C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylthio, C 1-6 alkylthio, C 1-6 alkylamino, or 4-10 membered heterocyclyl, optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy; Or R 2A and R 2B together with the atoms to which they are attached form a C 7 -C 10 cycloalkyl or 7-10 membered heterocyclyl, which C 7 -C 10 cycloalkyl or 7-10 membered heterocyclyl may be optionally substituted with one or more groups selected from R 3 or R 4 ; Or R 2 and R 2A together with the atoms to which they are attached are cyclized to form C 3 -C 6 cycloalkyl, C 6-12 aryl, or 3-6 membered heterocyclyl, which C 3 -C 6 cycloalkyl, C 6-12 aryl, or 3-6 membered heterocyclyl may be optionally further substituted with one or more substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 haloalkyl; Each R 3 、R 4 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, or C 1-6 alkyl optionally substituted with one or more R Y , C 1-6 alkoxy, C 1-6 alkyl-NH (CO) (CO) -, C 1-6 alkyl (CO) -, C 1-6 alkyl (CO) (CO) -, C 6-12 aryl (CO) -, and, c 6-12 aryl (CO) (CO) -, C 6-12 aryl-NH (CO) (CO) -, 5-12 membered heteroaryl (CO) (CO) -, 5-12 membered heteroaryl-NH (CO) (CO) -, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylthio, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -C 1-6 alkylene C 6-12 aryl, or C 1-6 alkylene-C 2-10 heteroaryl; or R 3 and R 4 together with the atoms to which they are attached form a C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl, which C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl may be optionally substituted by one or more R Y1 or R Y2 ; R Y1 、R Y2 is each independently selected from deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy; Each R 5 is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, or two R 5 groups and the atoms to which they are attached are cyclized to form a C 3 -C 6 cycloalkyl group or a 3-6 membered heterocyclyl group, which C 3 -C 6 cycloalkyl group or 3-6 membered heterocyclyl group may be optionally further substituted with one or more substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 haloalkyl; R 7 、R 8 is each independently selected from hydrogen, deuterium, or C 1-6 alkyl, 5-12 membered heterocyclyl, 5-12 membered cycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-4 alkylene C 6-12 aryl, or C 1-4 alkylene C 2-10 heteroaryl optionally substituted with one or more R Z ; Or R 7 and R 8 together with the atoms to which they are attached form a 4-14 membered heterocyclyl or a 5-12 membered heteroaryl, which 4-14 membered heterocyclyl or 5-12 membered heteroaryl may be optionally further substituted with one or more R Z ; R 11 is selected from hydrogen or deuterium; R Y is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, imino, or C 1-6 alkyl optionally substituted with one or more R Q , C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylthio, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl 、-NR a R b 、-OR a 、-C(O)R a 、-C(O)OR a 、-NHC(O)OR a 、-NR b C(O)OR a 、-NR b C(O)R a 、-NR a C(O)NR b R c 、-C(O)NR a R b 、-S(O)R c 、-S(O) 2 R c 、-S(O)＝NHR c 、-S(O)NR c R d , or-S (O) 2 NR c R d ; r Z is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, imino, or C 1-6 alkyl optionally substituted with one or more R Q , C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylthio, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl 、-NR a R b 、-OR a 、-C(O)R a 、-C(O)OR a 、-NHC(O)OR a 、-NR b C(O)OR a 、-NR b C(O)R a 、-NR a C(O)NR b R c 、-C(O)NR a R b 、-S(O)R c 、-S(O) 2 R c 、-S(O)＝NHR c 、-S(O)NR c R d , or-S (O) 2 NR c R d ; R Q is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, imino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylthio, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl 、-NR e R f 、-OR e 、-C(O)R e 、-C(O)OR e 、-NHC(O)OR e 、-NHC(O)R e 、-NR e C(O)OR f 、-NR e C(O)R f 、-NR g C(O)NR e R f 、-C(O)NR e R f 、-S(O)R e 、-S(O) 2 R e 、-S(O)＝NHR e 、-S(O)NR e R f or-S (O) 2 NR e R f ; Each R 1-6 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, imino, or C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-4 alkylene C 6-12 aryl, or C 1-4 alkylene C 2-10 heteroaryl, which may be optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, C3836 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl, or benzyl; Provided that the compound of formula (I) is not any one or more compounds selected from the following compounds, or an isomer or mixture of isomers of any one of the compounds:
  2. 2. the compound of claim 1, or a pharmaceutically acceptable salt, isotopic derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein said compound has a structure represented by formula (IIA-a1)、(IIA-b1)、(IIA-c1)、(IIA-d1)、(IIA-e1)、(IIA-f1)、(IIA-a2)、(IIA-b2)、(IIA-c2)、(IIA-d2)、(IIA-e2)、(IIA-f2)(IIIA-a1)、(IIIA-b1)、(IIIA-c1)、(IVA-a1)、(IVA-b1)、(IVA-c1)、(VA-a1)、(VA-b1)、(VA-c1)、(VIA-a1)、(VIA-b1) or (VIA-c 1): Wherein, the Z is selected from S, O, -S (=O) -, -S (=O) 2 -,-S(＝O)＝NH,CHR 10 ,CR 9 R 10 or NR 10 ; Y is selected from CHR 9 ,CR 9 R 10 or NR 9 ; each R 2 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, or C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylthio, C 1-6 alkylthio, C 1-6 alkylamino, or 4-10 membered heterocyclyl, optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy; Or two R 2 and the atoms to which they are attached are cyclized to form a C 3 -C 6 cycloalkyl, C 6-12 aryl, or a 3-6 membered heterocyclyl, which C 3 -C 6 cycloalkyl, C 6-12 aryl, or 3-6 membered heterocyclyl may be optionally further substituted with one or more substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 haloalkyl; R 3 、R 4 is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, or C 1-6 alkyl optionally substituted with one or more R Y , C 1-6 alkoxy, C 1-6 alkyl-NH (CO) (CO) -, C 1-6 alkyl (CO) -, C 1-6 alkyl (CO) (CO) -, C 6-12 aryl (CO) -, and, c 6-12 aryl (CO) (CO) -, C 6-12 aryl-NH (CO) (CO) -, 5-12 membered heteroaryl (CO) (CO) -, 5-12 membered heteroaryl-NH (CO) (CO) -, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylthio, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-6 alkylene C 6-12 aryl or C 1-6 alkylene C 2-10 heteroaryl; or R 3 and R 4 together with the atoms to which they are attached form a C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl, which C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl may be optionally substituted by one or more R Y1 or R Y2 ; R 5 is each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl or C 1-6 haloalkyl, or two R 5 and the atoms to which they are attached are cyclized to form a C 3 -C 6 cycloalkyl or a 3-6 membered heterocyclyl, which C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl may be optionally further substituted with one or more substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl; R 9 、R 10 is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, or C 1-6 alkyl optionally substituted with one or more R Y , C 1-6 alkoxy, C 1-6 alkyl-NH (CO) (CO) -, C 1-6 alkyl (CO) -, C 1-6 alkyl (CO) (CO) -, C 6-12 aryl (CO) -, and, c 6-12 aryl (CO) (CO) -, C 6-12 aryl-NH (CO) (CO) -, 5-12 membered heteroaryl (CO) (CO) -, 5-12 membered heteroaryl-NH (CO) (CO) -, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylthio, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-6 alkylene C 6-12 aryl or C 1-6 alkylene C 2-10 heteroaryl; Or R 9 and R 10 together with the atoms to which they are attached form a C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl, which C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl may be optionally substituted by one or more R Y1 or R Y2 ; R Y1 、R Y2 is each independently selected from deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy; R Y is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, imino, or C 1-6 alkyl optionally substituted with one or more R Q , C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylthio, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl 、-NR a R b 、-OR a 、-C(O)R a 、-C(O)OR a 、-NHC(O)OR a 、-NR b C(O)OR a 、-NR b C(O)R a 、-NR a C(O)NR b R c 、-C(O)NR a R b 、-S(O)R c 、-S(O) 2 R c 、-S(O)＝NHR c 、-S(O)NR c R d , or-S (O) 2 NR c R d ; s、R 1 、R 6 、R 7 、R 8 、R Q 、R a 、R b 、R c 、R d Is defined as in claim 1.
  3. 3. The compound of claim 2, or a pharmaceutically acceptable salt, isotopic derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or prodrug molecule, metabolite thereof, wherein said compound has a structure represented by formula (IIA-1)、(IIA-2)、(IIA-3)、(IIA-4)、(IIA-5)、(IIA-6)、(IIA-7)、(IIA-8)、(IIA-9)、(IIA-10)、(IIA-11)、(IIA-12)、(IIA-13)、(IIA-14)、(IIA-15)、(IIA-16)、(IIA-17)、(IIA-18)、(IIIA-1)、(IIIA-2)、(IIIA-3)、(IIIA-4)、(IIIA-5)、(IIIA-6)、(IIIA-7)、(IIIA-8)、(IIIA-9)、(IVA-1)、(IVA-2)、(IVA-3)、(IVA-4)、(IVA-5)、(IVA-6)、(IVA-7)、(IVA-8)、(IVA-9)、(VA-1)、(VA-2)、(VA-3)、(VA-4)、(VA-5)、(VA-6)、(VA-7)、(VA-8)、(VA-9)、(VIA-1)、(VIA-2)、(VIA-3)、(VIA-4)、(VIA-5)、(VIA-6)、(VIA-7)、(VIA-8) or (VIA-9) below: Wherein ,s、R 1 、R 2 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R Y1 、R Y2 is defined as set forth in claim 2.
  4. 4. The compound of claim 3, or a pharmaceutically acceptable salt, isotopic derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or prodrug molecule, metabolite thereof, wherein each of R 9 and R 10 is independently selected from hydrogen, deuterium, C 1-6 alkyl optionally substituted with one or more R Y , C 1-6 alkyl-NH (CO) -, C 1-6 alkyl (CO) -, C 1-6 alkyl (CO) -, C 6-12 aryl (CO) -, C 6-12 aryl (CO) -, C 6-12 aryl-NH (CO) -, 5-12 membered heteroaryl-NH (CO) -, each of R Y is independently selected from hydrogen, deuterium, cyano, hydroxy, amino, mercapto, oxo, imino, or C 1-6 alkyl.
  5. 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer, or prodrug molecule, metabolite thereof, wherein R 2 is selected from hydrogen or hydroxy, wherein R 5 is each independently selected from hydrogen, halogen, or C 1-6 alkyl, or wherein two R 5 and the atoms to which they are attached are cyclized to form C 3 -C 6 cycloalkyl, and wherein the C 3 -C 6 cycloalkyl is optionally further substituted with one or more substituents selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 haloalkyl.
  6. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotopic derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein R 1 or R 6 are independently selected from the group consisting of
  7. 7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein said compound is Selected from:
  8. 8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotopic derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein said compound is selected from the group consisting of:
  9. 9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-8, or a pharmaceutically acceptable salt, isotopic derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof.
  10. 10. Use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, isotopic derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment of STAT6 mediated diseases or disorders and related diseases or disorders.
  11. 11. The method of claim 10, wherein the STAT 6-mediated disease or disorder and related disease or disorder is a tumor or type II inflammation-related disease selected from atopic dermatitis, bullous pemphigoid, prurigo nodularis, chronic idiopathic urticaria, eosinophilic esophagitis, food allergy, chronic rhinosinusitis with nasal polyp (CRSwNP), chronic rhinosinusitis without nasal polyp (CRSsNP), non-steroidal anti-inflammatory drug-aggravated respiratory disease (NSAID-ERD/AERD), allergic rhinitis, asthma, chronic Obstructive Pulmonary Disease (COPD), eosinophilic Granulomatosis Polyangiitis (EGPA) or allergic bronchopulmonary aspergillosis, the tumor being selected from lymphoma, isolated fibrotic tumor, colon cancer, esophageal cancer, breast cancer, cholangiocarcinoma, liver cancer, kidney cancer, gastric cancer, squamous cell carcinoma, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), acute B-lymphocytic leukemia, bladder cancer, pancreatic cancer, glioblastoma, osteosarcoma, ovarian cancer, skin cancer or ovarian cancer.

Description

Ternary condensed ring compound and application thereof in medicine Technical Field The invention belongs to the technical field of medicines, relates to a ternary condensed ring compound, a preparation method and application thereof in medicines, and in particular relates to a compound shown in a formula (I) or pharmaceutically acceptable salts, isotopic derivatives and solvates thereof, or stereoisomers, geometric isomers and tautomers thereof, or prodrug molecules and metabolites thereof, and application thereof in medicines. Background Transcription factors play an important role in eukaryotic gene expression by binding to specific DNA sites and regulating transcription of nearly every gene in the cell genome. It is estimated that 1600 or more transcription factors are present in the human genome, and nearly 20% have been associated with different disease phenotypes. A number of transcription factors have been identified as being associated with inflammatory and neoplastic diseases. STAT6 is an important factor in the Jak-STAT signaling pathway that links extracellular signals from various cytokines, hormones and growth factors to the nuclear transcription machinery. Four JAK (tyrosine kinase Janus kinase) proteins (JAK 1, JAK2, JAK3, TYK 2) and seven STAT members (STAT 1, STAT2, STAT3, STAT4, STAT5A, STAT B, STAT) have been identified in mammals. STAT proteins regulate the expression of numerous genes, including genes involved in cell survival, development, differentiation, migration, apoptosis, and immune responses. Whereas STAT6 is stimulated mainly by IL-4 and IL-13, it plays a very important role in helper T cell 2 (Th 2) -dominant type II inflammation. Thus, it is closely related to pathophysiology of various allergic diseases such as atopic dermatitis, bullous pemphigoid, prurigo nodularis and chronic idiopathic urticaria, eosinophilic esophagitis and food allergy, chronic rhinosinusitis with nasal polyp (CRSwNP), chronic rhinosinusitis without nasal polyp (CRSsNP), non-steroidal anti-inflammatory drug exacerbation respiratory disease (NSAID-ERD/AERD), allergic rhinitis, asthma, chronic Obstructive Pulmonary Disease (COPD), eosinophilic Granulomatous Polyangiitis (EGPA), allergic bronchopulmonary aspergillosis, and the like. The JAK-STAT6 transduction pathway can induce tumor-associated macrophages (TAMs) to polarize to an M2 type TAM, and has a certain effect on forming an immunosuppressive tumor microenvironment and promoting angiogenesis in tumors. In addition, STAT6 is also associated with tumor microenvironment regulation, and in addition, some forms of lymphomas, particularly the hodgkin's lymphoma group, primary mediastinal and primary central nervous system lymphomas, as well as some follicular and T cell lymphomas are associated with deregulation of STAT6 pathways. Therefore, STAT6 has wide application prospect in inflammation and tumor diseases. Because STAT6 is downstream of the JAK-STAT pathway, modulating STAT6 may be more safe than JAK inhibitors. At present, no STAT6 inhibitors are marketed, potentially providing a better therapeutic strategy for these diseases against STAT6 signaling pathways. Disclosure of Invention The technical problem to be solved by the invention is to provide a ternary condensed ring compound with a brand-new structure, which can be used as a STAT6 inhibitor for preparing medicines for treating STAT6 mediated diseases or symptoms and related diseases or symptoms. In one aspect, the invention provides a ternary fused ring compound shown in formula (I) or pharmaceutically acceptable salt, isotopic derivative and solvate thereof, or stereoisomer, geometric isomer and tautomer thereof, or prodrug molecule and metabolite thereof: Wherein, the Is a single bond or a double bond; Is 9 membered aromatic heterocycle; X 1 is selected from CR 5 or N, X 2 is selected from C (R 5)f or N (R 5)g;X3、X4、X5 are each independently selected from C or N; X 7 is selected from C 5)h or N (R 5)i;X6 is selected from CR 11、N(R11)j, S, O or Se; f. h is independently selected from 1 or 2;g, i, j is independently selected from 0 or 1; p is selected from 1 or 2;s is selected from 0,1,2, 3, 4 or 5; n is selected from 0,1, 2, 3; R 1、R6 are each independently selected from Rg、CR1aR2aP(O)OR1bOR2b、CR1aR2aP(O)OR1bNHR2b、CR1aR2aP(O)(OR1b)(NH(AA)C(O)OR1c)、CR1aR2aP(O)(NHR2c)(NH(AA)C(O)OR1c)、CR1aR2aP(O)(NH(AA)C(O)OR1c)(NH(AA)C(O)OR1c)、P(O)OR1bOR2b、 P (O) (OR 1b)(NH(AA)C(O)OR1c)、P(O)(NHR2c)(NH(AA)C(O)OR1c) OR P (O) (NH (AA) C (O) OR 1c)(NH(AA)C(O)OR1c); R 1a、R2a is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, mercapto, oxo, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 hydroxyalkyl, or R 1a and R 2a form, with the atom to which they are attached, a C 3-C6 cycloalkyl or a 3-6 membered heterocyclyl; Each R 1b、R2b is independently selected from -R1aa、-R1aa-OC(O)-R1ab、-R1aa-C(O)O-R1ab、-R1aa-OC(O)O-R1ab、-R1aa-O-R1ab、-R1aa-SC(O)O-R1ab、-R1aa-SC(O)-R1ab、-R1aa-S-R1ab、-R1aa-O-R