WO2019144765A1 - 芳香杂环取代烯烃化合物、其制备方法、药物组合物和应用 - Google Patents

芳香杂环取代烯烃化合物、其制备方法、药物组合物和应用 Download PDF

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WO2019144765A1
WO2019144765A1 PCT/CN2018/124667 CN2018124667W WO2019144765A1 WO 2019144765 A1 WO2019144765 A1 WO 2019144765A1 CN 2018124667 W CN2018124667 W CN 2018124667W WO 2019144765 A1 WO2019144765 A1 WO 2019144765A1
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substituted
group
unsubstituted
alkyl
hydrogen
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French (fr)
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许祖盛
楼杨通
陈丽
曾坤
孙庆瑞
雷小莉
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上海璎黎药业有限公司
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Priority to US16/964,551 priority Critical patent/US11447490B2/en
Publication of WO2019144765A1 publication Critical patent/WO2019144765A1/zh

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Definitions

  • the present invention relates to an aromatic heterocyclic substituted olefin compound, a process for the preparation thereof, a pharmaceutical composition and use.
  • TGF- ⁇ Transforming growth factor- ⁇
  • TGF- ⁇ is a multifunctional cytokine that is involved in the regulation of cell proliferation, differentiation and regulation through cell surface complex receptor signaling pathways in an autocrine, paracrine and endocrine manner. Apoptosis.
  • TGF- ⁇ belongs to the transforming growth factor ⁇ superfamily, and various related proteins such as activins, inhibins, bone morphogenetic proteins, and Mullerian-inhibiting substances. TGF- ⁇ superfamily, TGF- ⁇ s).
  • TGF- ⁇ has three major cellular receptors: type I, type II, and type III receptors.
  • Type I and type II receptors are transmembrane serine/threonine kinases, which transmit information at the same time.
  • Type III receptors do not transmit information.
  • the function is mainly to transfer TGF- ⁇ to type II receptors.
  • Ligands are provided to indirectly affect signal transduction.
  • the TGF- ⁇ signaling pathway is mainly the TGF- ⁇ -Smad signaling pathway.
  • the Smad protein family is an intracellular signal transduction protein discovered in recent years. It is known that there are 8 Smad protein molecules in human body. After activation of TGF- ⁇ in the form of inactive protein complex, TGF- ⁇ is on the cell surface with type II receptor (TGF ⁇ R II) and type I receptor (TGF ⁇ R I, also known as activin-like kinase 5).
  • the type II receptor phosphorylates and activates the type I receptor, and then the type I receptor phosphorylates its linked Smad protein molecule (Smad2/3) and releases it into the cytosol,
  • Smad4 protein forming complex is transferred into the nucleus and binds to different transcription factors and transcriptional coactivators or transcriptional co-inhibitors to regulate the transcription of the TGF- ⁇ target gene and produce biological effects.
  • the TGF- ⁇ -Smad signaling pathway plays an important role in the regulation of cell proliferation, differentiation, apoptosis, adhesion, migration, extracellular matrix synthesis, wound repair, and immune function (Nature 2003, 425, 577).
  • TGF- ⁇ signaling is associated with many diseases, such as cancer, renal fibrosis, liver fibrosis, pulmonary fibrosis, viral infection, chronic nephritis, acute nephritis, diabetic nephropathy, osteoporosis, arthritis, Wound healing, ulceration, corneal trauma, heart valve stenosis, congestive cardiac necrosis, neurological impairment, Alzheimer's syndrome, peritoneal or subcutaneous adhesions, atherosclerosis, and tumor metastasis; and in the TGF- ⁇ signaling pathway
  • TGF ⁇ R I ALK5
  • TGF- ⁇ signal can treat and prevent various ALK5-mediated diseases (Nat Rev Drug Discov. 2012 October, 11(10): 790-811; Pharmacology & Therapeutics 147 (2015) 22-31).
  • the inventors have discovered through research that a class of aromatic heterocyclic substituted olefin compounds can be used as ALK5 inhibitors for the treatment and/or prevention of various diseases mediated by ALK5.
  • the present invention provides an aromatic heterocyclic substituted olefin compound, a process for its preparation, a pharmaceutical composition and use.
  • the aromatic heterocyclic substituted olefin compound of the present invention is a novel ALK5 inhibitor for the treatment and/or prevention of various ALK5 mediated diseases.
  • the present invention provides an aromatic heterocyclic substituted olefin compound of the formula I or a pharmaceutically acceptable salt thereof:
  • R 3, R 31, R 32 , R 33, R 3a, R 3a1, R 3b, R 3b1, R 3c, R 3c1, R 3c2, R 3d, R 3d1, R 3d2, R 3e, R 3e1, R 3f And R 3f1 , R 3f2 , R 3g and R 3g1 are each independently hydrogen, halogen, cyano, nitro, -NR a3 R a4 , -OR a5 , -SR a6 , -C(O)OR a7 , -C (O)NR a8 R a9 , -COR a10 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or Unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 2-8 heterocycloalkyl, substitute
  • R 3 R 31, R 32 , R 33, R 3a, R 3a1, R 3b, R 3b1, R 3c, R 3c1, R 3c2, R 3d, R 3d1, R 3d2, R 3e, R 3e1, R 3f And a substituted C 1-6 alkyl group, R 3f1 , R 3f2 , R 3g , R 3g1 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 and R a10 , and R 3, R 31, R 32 , R 33, R 3a, R 3a1, R 3b, R 3b1, R 3c, R 3c1, R 3c2, R 3d, R 3d1, R 3d2, R 3e, R 3e1, R In the 3f , R 3f1 , R 3f2 , R 3g , R 3g1 , the substituted C 2-8 alkenyl group, the substituted C 2-8 al
  • R 4 is hydrogen, cyano, C 1-6 alkyl, C 3-10 cycloalkyl, C 2-8 heterocycloalkyl, -C(O)OR a19 or C 1-6 substituted by -OR a20
  • An alkyl group; R a19 and R a20 are each independently a C 1-6 alkyl group;
  • R 5 , R 51 , R 5a , R 5a1 , R 5a2 , R 5b , R 5b1 , R 5c , R 5c1 , R 5c2 , R 5d , R 5d1 , R 5d2 , R 5e , R 5e1 and R 5e2 are each independently Is hydrogen, helium or halogen;
  • R 6 , R 6a , R 6b , R 6c , R 6d and R 6e are each independently hydrogen, deuterium, halogen, sulfonic acid group, substituted or unsubstituted C 1-6 alkyl group, substituted or unsubstituted C 2 -8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 2-8 heterocycloalkyl, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted C 2-10 heteroaryl, cyano, -OR 61 , -SR 62 , -NR a63 R a64 , -C(O)R 65 , -C(O)OR 66 , -OC(O)R 67 , -OC(O)OR 68 , -C(O)NR a69 R
  • R 61, R 62, R a64 , R 65, R 66, R 67, R 68, R a610, R 611, R 612, R 613, R 614, R a615, R a616, R a617, R a618, R 619 And R 620 , R 621 , R a622 , R a623 , R 624 , R 625 and R 626 are each independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-8 alkenyl , substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 2-8 heterocycloalkyl, substituted or unsubstituted C 6-20 aryl a substituted or unsubstituted C 2-10 heteroaryl group;
  • R a63 and R a69 are each independently hydrogen, hydroxy, C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 2-8 heterocycloalkyl, substituted or unsubstituted C 6-20 aryl, or substituted or not Substituted C 2-10 heteroaryl;
  • the substituents in the C 3-10 cycloalkyl group, the substituted C 2-8 heterocycloalkyl group, the substituted C 6-20 aryl group, the substituted C 2-10 heteroaryl group are each independently the following groups One or more of: hydrazine, halogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, C 2-8 heterocycloalkyl, C 6 -20 aryl, C 2-10 heteroaryl, cyano, -OR 71 , -SR 72 , -NR a73 R a74 , -C(O)R 75 , -C(O)OR 76 , -OC(O R 77
  • the substituent is one or more of the following groups: anthracene, halogen, cyano, C 1-6 alkyl,
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently hydrogen, deuterium or halogen;
  • R 1 and R 2 is hydrogen, deuterium, halogen, or a substituted or unsubstituted C 1-6 alkyl group, and the other is hydrogen, deuterium, halogen, cyano, sulfonic acid group, substituted or unsubstituted C 1 -6 alkyl, -C(O)OR 91 , -COR 92 , -S(O)R 95 , -S(O) 2 R 96 , -C(O)NR 97 R 98 , or a substituted or unsubstituted C 2-10 heteroaryl group; in R 1 and R 2
  • the substituted C 1-6 alkyl group and the substituent in the substituted C 2-10 heteroaryl group are each independently one or more of the following groups: anthracene, halogen, cyano, C 1- 6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OR 920 , -SR 921 , -C(
  • R 91 , R 92 , R 93 and R 94 are independently one or more of the following groups: hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3- 10 cycloalkyl, C 2-8 heterocycloalkyl, C 6-20 aryl or C 2-10 heteroaryl; R 95 and R 96 are independently hydrogen or C 1-6 alkyl;
  • R 97 and R 98 are independently hydroxy, hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or Unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 2-8 heterocycloalkyl, substituted or unsubstituted C 6-20 aryl, or substituted or unsubstituted C 2-10 heteroaryl ;
  • the substituents in the 2-8 heterocycloalkyl group, the substituted C 6-20 aryl group, and the substituted C 2-10 heteroaryl group are each independently one or more of the following groups: anthracene, halogen, cyano group , C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, C 2-8 heterocycloalkyl, C 6-20 aryl, C 2-10 Heteroaryl, -OR 101 , -SR 102 , -NR b103 R b104 , -C(O)R 105 , -C(O)OR 106 , -OC(O)R 107 , -OC(O)OR 108 , -C
  • R 1 and R 2 together with the carbon atom to which they are attached form a substituted or unsubstituted 4-8 membered carbocyclic ring containing a double bond, or a substituted or unsubstituted 4-8 membered heterocyclic ring, said 4-
  • the hetero atom in the 8-membered heterocyclic ring is selected from one or more of O, S and N, and the number of heteroatoms is 1, 2, 3 or 4;
  • the substituted 4-8 membered carbocyclic ring and the substituted 4-8 membered heterocyclic ring are each independently one or more of the following groups: anthracene, halogen, cyano, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OR 111 , -SR 112 , -C(O)OR 113 , -COR 114 , -C(O)NH 2 , C 3-10 cycloalkyl, C 2-8 heterocycloalkyl, C 6-20 aryl or C 2-10 heteroaryl;
  • R 111 , R 112 , R 113 and R 114 are each independently hydrogen or C 1-6 alkyl;
  • the substituted or unsubstituted C 2-8 heterocycloalkyl group or the hetero atom in the C 2-8 heterocycloalkyl group is selected from one of N, O and S. Or plural, the number of heteroatoms is 1, 2, 3 or 4; the substituted or unsubstituted C 2-10 heteroaryl or the hetero atom in the C 2-10 heteroaryl is selected from N, One or more of O and S, the number of heteroatoms is 1, 2, 3 or 4; when the number of heteroatoms is plural, the heteroatoms are the same or different;
  • R X and R Y together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group;
  • the hetero atom in the heterocyclic group is selected from N, N and O, N and S, or N, O and S; the number of heteroatoms is 1, 2, 3 or 4; the substituted 3-8 membered heterocyclic ring
  • the substituent in the group is one or more of the following groups: anthracene, halogen, cyano, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 2-8 alkenyl, C 2- 8 alkynyl, -OR a81 , -SR a82 , -C(O)OR a83 , -COR a84 , -C(O)NH 2 , C 3-10 cycloalkyl, C 2-8 heterocycloalkyl,
  • -NR X R Y for example: -NR a3 R a4, -NR a8 R a9, -NR a63 R a64, -NR a69 R a610, -NR a615 R a616, -NR a617 R a618, -NR a622 R a623 , -NR a73 R a74 , -NR a79 R a710 , -NR a715 R a716 , -NR a717 R a718 , -NR a722 R a723 , -NR b1 R b2 , -NR b3 R b4 , -NR b5 R b6 -NR b7 R b8 , -NR 93 R 94 , -NR 97 R 98 , -NR 924 R 925 , -NR b103 R b104 , -NR 93 R
  • C 1-6 alkyl group and the term C 1-6 alkyl group in the substituted or unsubstituted C 1-6 alkyl group are each independently preferably a C 1-4 alkyl group.
  • the C 1-4 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • C 2-8 alkenyl in the substituted or unsubstituted C 2-8 alkenyl group and the term C 2-8 alkenyl group are each independently preferably a C 2-4 alkenyl group.
  • the C 2-4 alkenyl group is preferably a vinyl group, a propenyl group, an allyl group,
  • C 2-8 alkynyl in the substituted or unsubstituted C 2-8 alkynyl group and the term C 2-8 alkynyl group are each independently preferably a C 2-4 alkynyl group.
  • the C 2-4 alkynyl group is preferably an ethynyl group, a propynyl group, a butynyl group or a 3-methylpropynyl group.
  • C 3-10 cycloalkyl in the substituted or unsubstituted C 3-10 cycloalkyl group and the term C 3-10 cycloalkyl are independently preferably cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl or bicyclic cycloalkyl such as bicyclo [3.1.1] heptyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] Octyl, bicyclo[3.2.2]nonanyl, bicyclo[3.3.1]decyl or bicyclo[4.2.1]decyl.
  • C 2-8 heterocycloalkyl in the substituted or unsubstituted C 2-8 heterocycloalkyl group and the term C 2-8 heterocycloalkyl are independently preferably azetidinyl, aza.
  • substituted or unsubstituted C 4-8 cycloalkenyl group is C 4-8 cycloalkenyl and C 4-8 cycloalkenyl term independently preferably cyclobutenyl, cyclopentenyl, cyclohexyl Alkenyl, cycloheptenyl, cyclooctenyl, norbornene or bicyclo[2.2.2]octenyl.
  • C 6-20 aryl group are independently preferably phenyl, naphthyl, anthryl, phenanthrenyl, azulenyl, Indoline-1-yl, indan-2-yl, indan-3-yl, indan-4-yl, 2,3-dihydroindol-4-yl, 2,3-di Hydroquinone-5-yl, 2,3-dihydroindole-6-yl, 2,3-dihydroindole-7-yl, indol-1-yl, indole-2-yl, indole-3- , ⁇ -4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-1-yl, 5,6,7,8-tetrahydrogen Naphthalen-1
  • the term substituted or unsubstituted C 2-10 heteroaryl C 2-10 aryl group and the term heteroaryl C 2-10 heteroaryl independently preferably furyl, imidazolyl, isoxazolyl, iso Thiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazole , triazinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzooxadiazolyl, benzothiazolyl, porphyrinyl, 5,6-dihydroquinolin-2-yl, 5,6-Dihydroquinolin-1-yl, furopyridinyl, oxazolyl, indolyl
  • one of R 1 and R 2 is hydrogen, or a substituted or unsubstituted C 1-6 alkyl group, and the other is hydrogen, cyano, sulfonate, substituted or unsubstituted C 1-6 alkyl, -C(O)OR 91 , -COR 92 , -S(O)R 95 , -S(O) 2 R 96 , -C(O)NR 97 R 98 , or substituted or unsubstituted C 2-10 heteroaryl; or R 1 and R 2 are attached to them
  • the carbon atoms together form a substituted or unsubstituted 4-8 membered carbocyclic ring containing a double bond, or a substituted or unsubstituted 4-8 membered heterocyclic ring; wherein R 91 , R 92 , R 93 , R 94 , R 95 , R 96 , R 97 and R 98 are as defined above
  • one of R 1 and R 2 is hydrogen and the other is hydrogen, cyano, substituted or unsubstituted C 1-6 alkyl, -C(O)OR 91 or -C ( O) NR 97 R 98 ; or R 1 and R 2 together with the carbon atom to which they are attached form a substituted or unsubstituted 4-8 membered carbocyclic ring containing a double bond; wherein R 91 is hydrogen or C 1-6 Alkyl; R 97 and R 98 are independently hydrogen, or substituted or unsubstituted C 1-6 alkyl; or R 97 and R 98 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-8 membered hetero a ring group; wherein, in R 1 or R 2 , the substituted C 1-6 alkyl group, the substituted 4-8 membered carbocyclic ring, and the substituted 4-8 membered heterocyclic ring are substitute
  • one of R 1 and R 2 is hydrogen and the other is hydrogen, C 1-6 alkyl, -C(O)OR 91 or -C(O)NR 97 R 98 ; R 1 and R 2 together with the carbon atom to which they are attached form a 4-8 membered carbocyclic ring containing a double bond; wherein R 91 , R 97 and R 98 are independently hydrogen or C 1-6 alkyl; R 97 and R 98 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic group; preferably, R 1 is hydrogen, R 2 is hydrogen, C 1-6 alkyl, -C(O)OR 91 or - C(O)NR 97 R 98 ; R 91 , R 97 and R 98 are independently hydrogen or C 1-6 alkyl.
  • R 1 and R 2 are simultaneously hydrogen
  • R 1 is hydrogen and R 2 is
  • R 1 and R 2 together with the C atom to which they are attached form a cyclohexene ring.
  • R 3 , R 31 , R 32 , R 33 , R 3a , R 3a1 , R 3b , R 3b1 , R 3c , R 3c1 , R 3c2 , R 3d , R 3d1 , R 3d2 , R 3e , R 3e1 , R 3f , R 3f1 , R 3f2 , R 3g and R 3g1 are each independently hydrogen, halogen, cyano, nitro, -NR a3 R a4 , -OR a5 , - SR a6 , -C(O)OR a7 , -C(O)NR a8 R a9 , -COR a10 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-8 heterocycloalkyl a substituted or unsubstituted C 6-20 aryl
  • R 3 , R 31 , R 32 , R 33 , R 3a , R 3a1 , R 3b , R 3b1 , R 3c , R 3c1 , R 3c2 , R 3d , R 3d1 , R 3d2 , R 3e , R 3e1 , R 3f , R 3f1 , R 3f2 , R 3g and R 3g1 are each independently hydrogen, halogen, —OR a5 , or a substituted or unsubstituted C 1-6 alkyl group; R a5 is C 1-6 alkyl; the substituent in the substituted C 1-6 alkyl group is one or more of the following groups: hydrazine or halogen.
  • R 3 , R 31 , R 32 , R 33 , R 3a , R 3a1 , R 3b , R 3b1 , R 3c , R 3c1 , R 3c2 , R 3d , R 3d1 , R 3d2 , R 3e , R 3e1 , R 3f , R 3f1 , R 3f2 , R 3g and R 3g1 are each independently hydrogen, halogen, trifluoromethyl, difluoromethyl, methyl, deuterated methyl Or methoxy.
  • one or two positions in ring A are not hydrogen.
  • R 3 and R 33 are independently preferably hydrogen, halogen, -OR a5 , or substituted or unsubstituted C 1-6 alkyl, but are not simultaneously hydrogen;
  • R 3b is hydrogen, halogen, -OR a5 , or substituted Or unsubstituted C 1-6 alkyl;
  • R a5 is as defined above; the substituents in the substituted C 1-6 alkyl are as defined above;
  • R 31 , R 32 and R 3b1 is hydrogen.
  • R 4 is hydrogen, C 1-6 alkyl or C 3-10 cycloalkyl.
  • R 5 , R 51 , R 5a , R 5a1 , R 5a2 , R 5b , R 5b1 , R 5c , R 5c1 , R 5c2 , R 5d , R 5d1 , R 5d2 , R 5e R 5e1 and R 5e2 are hydrogen.
  • R 6 , R 6a , R 6b , R 6c , R 6d and R 6e are each independently hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-8 heterocycloalkyl, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted C 2-10 heteroaryl, cyano, -OR 61 , -SR 62 , -NR a63 R A64 , -C(O)R 65 , -C(O)OR 66 , -OC(O)R 67 , -OC(O)OR 68 , -C(O)NR a69 R a610 , -N(R 611 ) C (O) R 612, S (O) R 613, -S (O) 2 R 614, -S (O) 2 NR a615 R a616, -
  • R 6 , R 6a , R 6b , R 6c , R 6d and R 6e are each independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 alkyl, substituted Or unsubstituted C 2-8 heterocycloalkyl, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted C 2-10 heteroaryl, cyano, -OR 61 , -SR 62 ,- C(O)R 65 , -C(O)OR 66 or -C(O)NR a69 R a610 ; R 61 , R 62 , R 65 , R 66 , R a69 and R a610 are as defined above;
  • the substituents in the substituted C 1-6 alkyl group, substituted C 2-8 heterocycloalkyl group, substituted C 6-20 aryl group or substituted C 2-10 heteroaryl group are the same as defined above
  • R 6 , R 6a , R 6b , R 6c , R 6d and R 6e are each independently cyano, -C(O)OR 66 or -C(O)NR a69
  • R a610 R 66 is preferably C 1-6 alkyl
  • R a69 and R a 610 are each independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or -OR 627
  • the substituents in the substituted C 1-6 alkyl group or the substituted C 3-10 cycloalkyl group are as defined above;
  • R 627 is as defined above.
  • R 6 , R 6a , R 6b , R 6c , R 6d and R 6e are each independently cyano, -C(O)OR 66 or -C(O)NR a69 R a610 ;
  • R 66 is C 1-6 alkyl;
  • R a69 and R a 610 are each independently hydrogen, substituted or unsubstituted C 1-6 alkyl, C 3-10 cycloalkyl or -OR 627 ;
  • the substituent in the substituted C 1-6 alkyl group is preferably a C 2-8 heterocycloalkyl group (for example R 627 is preferably a C 2-8 heterocycloalkyl group (for example) ).
  • R 6 , R 6a , R 6b , R 6c , R 6d and R 6e are independently -C(O)NR a69 R a610 ; R a69 and R a610 are as defined above. Said.
  • R 5 , R 51 , R 5a , R 5a1 , R 5a2 , R 5b , R 5b1 , R 5c , R 5c1 , R 5c2 , R 5d , R 5d1 , R 5d2 , R 5e And R 5e1 , R 5e2 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are hydrogen.
  • R 5a , R 5a1 , R 5a2 , R 5c , R 5c1 , R 5c2 , R 5d , R 5d1 , R 5d2 , R 8 , R 10 and R 11 are preferably hydrogen; and R 6a , R 6c and R 6d are each Independently cyano, C 2-10 heteroaryl, -C(O)OR 66 or -C(O)NR a69 R a610 ; wherein the C 2-10 heteroaryl, R 66 , R a69
  • the definitions of R a610 are the same as described above.
  • R 1 and R 2 is hydrogen, or a substituted or unsubstituted C 1-6 alkyl group, and the other is hydrogen, cyano, sulfonic acid group, substituted or unsubstituted C 1-6 alkyl group, -C ( O) OR 91 , -COR 92 , -S(O)R 95 , -S(O) 2 R 96 , -C(O)NR 97 R 98 , or substituted or unsubstituted C 2-10 heteroaryl; or R 1 and R 2 are attached to them
  • the carbon atoms together form a substituted or unsubstituted 4-8 membered carbocyclic ring containing a double bond, or a substituted or unsubstituted 4-8 membered heterocyclic ring; wherein R 91 , R 92 , R 93 , R 94 , R 95 , R 96 , R 97 and R 98 are as defined above; the substituted C
  • R 3 , R 31 , R 32 , R 33 , R 3a , R 3a1 , R 3b , R 3b1 , R 3c , R 3c1 , R 3c2 , R 3d , R 3d1 , R 3d2 , R 3e , R 3e1 , R 3f , R 3f1 , R 3f2 , R 3g and R 3g1 are each independently hydrogen, halogen, cyano, nitro, -NR a3 R a4 , -OR a5 , -SR a6 , -C(O)OR A7 , -C(O)NR a8 R a9 , -COR a10 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-8 heterocycloalkyl, substituted or unsubstituted C 6- a 20 aryl group, or a substituted or un
  • R 4 is hydrogen, C 1-6 alkyl or C 3-10 cycloalkyl
  • R 5 , R 51 , R 5a , R 5a1 , R 5a2 , R 5b , R 5b1 , R 5c , R 5c1 , R 5c2 , R 5d , R 5d1 , R 5d2 , R 5e , R 5e1 and R 5e2 are hydrogen;
  • R 6 , R 6a , R 6b , R 6c , R 6d and R 6e are each independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-8 Heterocycloalkyl, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted C 2-10 heteroaryl, cyano, -OR 61 , -SR 62 , -C(O)R 65 ,- C(O)OR 66 or -C(O)NR a69 R a610 ; R 61 , R 62 , R 65 , R 66 , R a69 and R a610 are as defined above; the substituted C 1-
  • the definitions of the substituents in the 6 alkyl group, the substituted C 2-8 heterocycloalkyl group, the substituted C 6-20 aryl group or the substituted C 2-10 heteroaryl group are the
  • R 1 and R 2 is hydrogen and the other is hydrogen, cyano, substituted or unsubstituted C 1-6 alkyl, -C(O)OR 91 or -C(O)NR 97 R 98 ; or R 1 and R 2 together with the carbon atom to which they are attached form a substituted or unsubstituted 4-8 membered carbocyclic ring containing a double bond; wherein R 91 is hydrogen or C 1-6 alkyl; R 97 and R 98 are independently Is hydrogen or a substituted or unsubstituted C 1-6 alkyl group; or R 97 and R 98 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic group; wherein R 1 or R In 2 , the substituents of the substituted C 1-6 alkyl group, the substituted 4-8 membered carbocyclic ring, and the substituted 4-8 membered heterocyclic ring are as defined above;
  • R 3 , R 31 , R 32 , R 33 , R 3a , R 3a1 , R 3b , R 3b1 , R 3c , R 3c1 , R 3c2 , R 3d , R 3d1 , R 3d2 , R 3e , R 3e1 , R 3f , R 3f1 , R 3f2 , R 3g and R 3g1 are each independently hydrogen, halogen, -OR a5 , or substituted or unsubstituted C 1-6 alkyl; R a5 is C 1-6 alkyl The substituent in the substituted C 1-6 alkyl group is one or more of the following groups: hydrazine or halogen;
  • R 4 is hydrogen, C 1-6 alkyl or C 3-10 cycloalkyl
  • R 5 , R 51 , R 5a , R 5a1 , R 5a2 , R 5b , R 5b1 , R 5c , R 5c1 , R 5c2 , R 5d , R 5d1 , R 5d2 , R 5e , R 5e1 and R 5e2 are hydrogen;
  • R 6 , R 6a , R 6b , R 6c , R 6d and R 6e are each independently cyano, -C(O)OR 66 or -C(O)NR a69 R a610 ; wherein R 66 is C 1 -6 alkyl; R a69 and R a 610 are each independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or -OR 627 ; The definition of the substituent in the C 1-6 alkyl group or the substituted C 3-10 cycloalkyl group is the same as previously described; R 627 is as defined above.
  • R 1 and R 2 is hydrogen and the other is hydrogen, C 1-6 alkyl, -C(O)OR 91 or -C(O)NR 97 R 98 ; or R 1 and R 2 are attached thereto
  • R 3c1 , R 3c2 , R 3d , R 3d1 , R 3d2 , R 3e , R 3e1 , R 3f , R 3f1 , R 3f2 , R 3g and R 3g1 are each independently hydrogen, halogen, trifluoromethyl, difluoro. Methyl, methyl, deuterated methyl or methoxy; 1 or 2 positions in ring A are not hydrogen;
  • R 4 is hydrogen, C 1-6 alkyl or C 3-10 cycloalkyl
  • R 5 , R 51 , R 5a , R 5a1 , R 5a2 , R 5b , R 5b1 , R 5c , R 5c1 , R 5c2 , R 5d , R 5d1 , R 5d2 , R 5e , R 5e1 and R 5e2 are hydrogen;
  • R 6 , R 6a , R 6b , R 6c , R 6d and R 6e are each independently cyano, -C(O)OR 66 or -C(O)NR a69 R a610 ; wherein R 66 is C 1 -6 alkyl; R a69 and R a610 are each independently hydrogen, substituted or unsubstituted C 1-6 alkyl, C 3-10 cycloalkyl or —OR 627 ; substituted C 1-6 alkane
  • the substituent in the group is a C 2-8 heterocycloalkyl group (for example R 627 is a C 2-8 heterocycloalkyl group (for example) ).
  • R 1 is hydrogen
  • R 2 is hydrogen, C 1-6 alkyl, -C(O)OR 91 or -C(O)NR 97 R 98
  • R 91 , R 97 and R 98 are independently hydrogen or C 1 -6 alkyl
  • Ring A is wherein R 3 and R 33 are independently hydrogen, halogen, -OR a5 , or substituted or unsubstituted C 1-6 alkyl, but are not simultaneously hydrogen; R 3b is hydrogen, halogen, -OR a5 , or substituted Or unsubstituted C 1-6 alkyl; R a5 is as defined above; the substituents in the substituted C 1-6 alkyl are as defined above; R 31 , R 32 and R 3b1 is hydrogen;
  • R 5a , R 5a1 , R 5a2 , R 5c , R 5c1 , R 5c2 , R 5d , R 5d1 , R 5d2 , R 8 , R 10 and R 11 are hydrogen; and R 6a , R 6c and R 6d are each independently Is a cyano group, a C 2-10 heteroaryl group, -C(O)OR 66 or -C(O)NR a69 R a610 ; wherein the C 2-10 heteroaryl group, R 66 , R a69 and The definition of R a610 is the same as previously described.
  • R 1 and R 2 are simultaneously hydrogen
  • R 1 is hydrogen and R 2 is
  • R 1 and R 2 together with the C atom to which they are attached form a cyclohexene ring
  • R 1 or R 2 is -C(O)NR 917 R 918
  • R 6 , R 6a , R 6b , R 6c , R 6d or R 6e is -C(O)
  • NR a69 R a610 , -C(O)NR 917 R 918 and -C(O)NR a69 R a610 are not simultaneously -C(O)NH 2 ; or -C(O)NR a69 R a610 is -C( O) NH 2 , -C(O)NR 917 R 918 is not -C(O)NHCH 3 .
  • R 1 or R 2 is -C(O)OR 98
  • R 6 , R 6a , R 6b , R 6c , R 6d or R 6e is -C(O)NR a69
  • R a 610 , -C(O)NR a69 R a610 is -C(O)NH 2
  • -C(O)OR 98 is not -COOH.
  • R 1 or R 2 is -C(O)NR 97 R 98
  • R 6 , R 6a , R 6b , R 6c , R 6d or R 6e is -CN
  • - C(O)NR 97 R 98 is not
  • the aromatic heterocyclic-substituted olefin compound represented by the above formula I is preferably one of the following compounds:
  • the invention also provides a preparation method of the aromatic heterocyclic substituted olefin compound represented by the formula I, which is prepared by the following method 1 or method 2:
  • the first method comprises the steps of: subjecting the compound II-A and the compound II-2 to a coupling reaction as shown below;
  • One of X and Y is halogen, such as Cl, Br or I; the other is an organotin reagent such as tri-n-butyltin reagent, or an organoboron reagent such as boric acid or pinacol boron ester; one of ring C1 and ring C2 is ring A And the other is ring B; R d and R c are each R 1 and the other is R 2 ; when ring C1 is ring A, R d is R 1 ; R 1 , R 2 , ring A and ring B are defined Same as previously stated;
  • Method two includes the following steps:
  • One of ring C1 and ring C2 is ring A and the other is ring B; one of R d and R c is R 1 and the other is R 2 ; when ring C1 is ring A, R d is R 1 ; R 1 , R 2 , ring A and ring B are as defined above; EWG 2 is an electron withdrawing group such as cyano, ester, carboxyl, alkylcarbonyl, sulfonate, aminosulfonyl, alkylaminoformyl , -S(O)R 613 , -S(O) 2 R 614 or Etc ; R 613 and R 614 are defined as described above.
  • R 1 and R 2 are hydrogen, which can be produced by the following method, which comprises the steps of: hydrogenating the compound I-1 under the action of a palladium reagent. Solution can be;
  • ring C1 and ring C2 is ring A and the other is ring B; wherein ring A and ring B are as defined above.
  • Scheme 1 includes the following steps: coupling of compound I-5 with trimethylsilyl (TMS) acetylene to give compound I-4, compound I-4 removing TMS protecting group to give compound I-3, compound I-3 and compound I-2 is subjected to a coupling reaction to obtain a compound I-1, which is hydrogenolyzed by a passivated palladium reagent to obtain the aromatic heterocyclic substituted olefin compound of the above formula I.
  • TMS trimethylsilyl
  • R 1 and R 2 are hydrogen, and X 1 and X 2 are independently Cl, Br or I.
  • ring C1 and ring C2 is ring A and the other is ring B; the definitions of ring A and ring B are the same as previously described;
  • Scheme 2 includes the following steps: Compound II-3 and bromomethyltriphenylphosphonium bromide are reacted by a base to form compound II-1 by a wittig reaction, and compound II-1 is further catalyzed by palladium reagent with compound II-2. The coupling reaction gives the aromatic heterocyclic substituted olefin compound of the above formula I.
  • R 2 is H
  • Y is an organotin reagent such as tri-n-butyltin reagent, or an organoboron reagent such as boric acid or pinacol boron ester
  • one of ring C1 and ring C2 is ring A and the other is ring B
  • d is R 1 or R 2
  • R 1 , ring A and ring B are as defined above.
  • Scheme 3 includes the following steps: compound III-4 and compound III-5 are reacted by a base to form compound III-2 by condensation reaction, and compound III-2 is further reacted with compound III-3 by palladium reagent to obtain a compound by coupling reaction.
  • III-1 Compound III-1, by further conversion, the aromatic heterocyclic substituted olefin compound of the above formula I is obtained.
  • one of X and Y is halogen, such as Cl, Br or I; the other is an organotin reagent such as tri-n-butyltin reagent, or an organic boron reagent such as boric acid or pinacol boron ester; one of ring C1 and ring C2 is Ring A, the other is ring B; R d and R c are each R 1 and the other is R 2 ; when ring C1 is ring A, R d is R 1 ; R 1 , R 2 , ring A and ring B
  • R d and R c are each R 1 and the other is R 2 ; when ring C1 is ring A, R d is R 1 ; R 1 , R 2 , ring A and ring B
  • EWG1 and EWG2 are independently electron withdrawing groups such as cyano, ester, carboxyl, alkylcarbonyl, sulfonate, aminosulfonyl, alkylaminoformyl, -S(O)R 613 , -S(O ) 2 R 614 or Wait.
  • Y is an organotin reagent such as tri-n-butyltin reagent or an organic boron reagent such as boric acid or pinacol boron ester.
  • the definitions of R 613 and R 614 are the same as previously described.
  • Scheme 4 includes the following steps: Compound IV-4 is synthesized by a coupling reaction with Compound IV-3 under the catalysis of a palladium reagent to synthesize Compound IV-1, and Compound IV-1 is further reacted with Compound IV-2 to obtain a compound.
  • the aromatic heterocyclic ring represented by Formula I is substituted for an olefin compound.
  • X 3 and X 4 are independently Cl, Br or I.
  • Y 1 and Y 2 are independently an organotin reagent such as a tri-n-butyltin reagent, or an organoboron reagent such as boric acid or pinacol boron ester.
  • organotin reagent such as a tri-n-butyltin reagent, or an organoboron reagent such as boric acid or pinacol boron ester.
  • One of ring C1 and ring C2 is ring A and the other is ring B; one of R d and R c is R 1 and the other is R 2 ; when ring C1 is ring A, R d is R 1 ; R 1 ,
  • R 2 , ring A and ring B are the same as previously described.
  • the conditions and steps employed in the chemical reactions involved in the various reaction routes described in the present invention can be carried out by referring to the conditions and procedures of such reactions conventional in the art, and can be referred to the literature: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3 rd ED., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994) L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent versions.
  • the entire text of the above references is hereby incorporated by reference.
  • the compound obtained by the above method can be further modified by the peripheral method to obtain another target compound of the present invention by referring to the method of the above-mentioned literature.
  • the invention also provides any of the following intermediate compounds:
  • the at least one aromatic heterocyclic-substituted olefin compound or a pharmaceutically acceptable salt thereof prepared by the above method can be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable conditions.
  • the conditions and steps of the purification methods such as column chromatography, high performance liquid chromatography and crystallization can be selected according to the conditions and procedures conventional in the art.
  • Compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures.
  • a single enantiomer or diastereomer, such as an optically active structure can be obtained by asymmetric synthesis or by resolution of a racemic mixture or mixture of diastereomers.
  • it can be isolated by conventional methods, for example, using a resolving agent; it can also be separated by chromatography. For example, a chiral high performance liquid chromatography (HPLC) column.
  • HPLC high performance liquid chromatography
  • the compounds described herein exist in various tautomers, and the term "compound” includes all tautomeric forms of the compound.
  • the compounds herein also include their different crystalline forms, including polycrystals and clathrates.
  • salt also encompasses all optical isomers, racemates, and other mixtures, tautomers, and crystalline forms.
  • the present invention also provides the aromatic heterocyclic substituted olefin compound of the above formula I or a pharmaceutically acceptable salt thereof for use in the preparation of an ALK5 inhibitor or in the preparation of a medicament for the treatment and/or prevention of an ALK5 mediated disease.
  • the "ALK5-mediated disease” includes, but is not limited to, cancer, organ fibrosis, viral infection, chronic nephritis, acute nephritis, diabetic nephropathy, osteoporosis, arthritis, wound healing, ulceration, corneal trauma, heart One or more of valvular stenosis, congestive cardiac necrosis, neurological impairment, Alzheimer's syndrome, peritoneal or subcutaneous adhesions, atherosclerosis, and tumor metastasis, preferably cancer and/or organ fibrosis.
  • the cancer includes, but is not limited to, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectum Cancer, liver cancer, colon cancer, esophageal cancer, gastric cancer, pancreatic cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.
  • the organ fibrosis includes, but is not limited to, renal fibrosis, liver fibrosis, and pulmonary fibrosis.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically and/or therapeutically effective amount of one or more of the aromatic heterocyclic substituted olefin compound of the above formula I and a pharmaceutically acceptable salt thereof. And a pharmaceutically acceptable carrier.
  • the "prophylactically and/or therapeutically effective dose” means (i) the amount of the compound of the present invention which prevents and/or treats a specific disease or condition described herein, and (ii) weakens, improves or eliminates the present invention.
  • the invention relates to the amount of a compound of the invention for one or more symptoms of a particular disease or condition, or (iii) the invention for preventing or delaying the onset of one or more symptoms of a particular disease or condition described herein.
  • the dosage for treating a human patient may range from 0.0001 mg/kg to 50 mg/kg, most typically from 0.001 mg/kg to 10 mg/kg body weight, such as from 0.01 mg/kg to 1 mg/kg. Such a dose can be administered, for example, 1-5 times a day.
  • the pharmaceutical composition can be formulated into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc., depending on the purpose of the treatment.
  • dosage unit dosage forms such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc.
  • any excipient known and widely used in the art can be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, dextrose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agents such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenation Oil; adsorption promoters such as quatern
  • any excipient known and widely used in the art may be used, for example, a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol, etc.; disintegrating agents such as agar and kelp powder.
  • a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.
  • disintegrating agents such as agar and kelp powder.
  • any excipient known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .
  • the solution or suspension may be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin, etc.) to prepare an isotonic injection with blood.
  • Any of the commonly used carriers in the art can also be used in the preparation of the injection.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan can be added.
  • the administration method of the pharmaceutical composition is not particularly limited.
  • Formulations of various dosage forms can be selected depending on the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; injections can be administered alone or in combination with injectable solutions (eg, glucose solutions and amino acid solutions); suppositories are given Drug to the rectum.
  • injectable solutions eg, glucose solutions and amino acid solutions
  • suppositories are given Drug to the rectum.
  • C 1 -6 alkoxycarbonyloxy and -OC(O)C 1 -6 alkyl represent the same function; likewise, arylalkyl, arylalkyl-, and -alkylaryl represent the same The function.
  • alkyl as used in the present invention means a branched and straight-chain saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, Isobutyl, pentyl, hexyl and various isomers thereof.
  • the definitions are the same except for the defined scope.
  • alkyl When an “alkyl” group is used as a linking group between two other classes, it may also be straight or branched, and examples include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CHC(CH 3 )-, -CH 2 CH 2 (CH 2 CH 3 )CH 2 -.
  • cycloalkyl refers to a monocyclic or bicyclic cycloalkyl group.
  • Monocyclic cycloalkyl groups are cyclic hydrocarbyl groups containing from 3 to 10 carbon atoms which may be saturated or unsaturated, but not aromatic. In certain embodiments, the cycloalkyl group is fully saturated.
  • Bicyclic cycloalkyl is a bridged monocyclic cycloalkyl or fused bicyclic cycloalkyl.
  • the bridged monocyclic cycloalkyl group contains a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic cycloalkyl ring are joined by an alkylene bridge between one to three additional carbon atoms (ie, - (CH 2 ) w - form of a bridging group, wherein w is 1, 2 or 3).
  • the fused bicyclic cycloalkyl group includes a monocyclic cycloalkyl ring fused to a phenyl group, a monocyclic cycloalkyl group, a monocyclic cycloalkenyl group, a monocyclic heterocyclic group or a monocyclic heteroaryl group.
  • a cycloalkyl group can be optionally substituted with one or two groups which are independent oxo or thio groups.
  • cycloalkenyl in the present invention means a monocyclic or bicyclic cycloalkenyl group.
  • Monocyclic cycloalkenyl groups are cyclic hydrocarbyl groups containing from 3 to 8 carbon atoms which are unsaturated (i.e., contain at least one cyclic carbon-carbon double bond) but are not aromatic.
  • the bicyclic cycloalkenyl ring is a bridged monocyclic ring or a fused bicyclic ring.
  • a bridged monocyclic ring contains a monocyclic cycloalkenyl ring in which two non-adjacent carbon atoms of a monocyclic ring are joined by an alkylene bridge between one to three additional carbon atoms (ie, -(CH 2 ) w a form of bridging group, wherein w is 1, 2 or 3).
  • the fused bicyclic cycloalkenyl ring system comprises a monocyclic cycloalkenyl ring fused to a phenyl group, a monocyclic cycloalkyl group, a monocyclic cycloalkenyl group, a monocyclic heterocyclic group or a monocyclic heteroaryl group.
  • a bridged or fused bicyclic cycloalkenyl group is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring.
  • the cycloalkenyl group may be optionally substituted with one or two groups which are independent oxo or thio groups.
  • alkoxy refers to a cyclic or acyclic alkyl group having the number of carbon atoms attached through an oxygen bridge.
  • alkoxy includes the definition of the above alkyl and cycloalkyl.
  • alkylthio refers to a cyclic or acyclic alkyl group having the number of carbon atoms attached through a sulfur bridge.
  • alkylthio embraces the definition of the above alkyl and cycloalkyl.
  • alkenyl means a straight-chain, branched or cyclic non-aromatic hydrocarbon group containing a specified number of carbon atoms and at least one carbon-carbon double bond. Preferably there is one carbon-carbon double bond and up to four non-aromatic carbon-carbon double bonds may be present.
  • C 2-8 alkenyl refers to an alkenyl group having 2-8 carbon atoms.
  • the linear, branched or cyclic moiety of the alkenyl group may contain a double bond and, if indicated to be a substituted alkenyl group, may be substituted.
  • alkynyl means a straight-chain, branched or cyclic hydrocarbon group containing a specified number of carbon atoms and at least one carbon-carbon triple bond. There may be up to three carbon-carbon triple bonds.
  • C 2-8 alkynyl refers to an alkynyl group having 2-8 carbon atoms.
  • C 2-6 alkynyl means an alkynyl group having 2 to 6 carbon atoms.
  • aryl means a bicyclic system containing at least one benzene ring or only carbon atoms in a monocyclic aryl or aromatic bicyclic system.
  • the bicyclic aryl group may be a phenyl group fused to a monocyclic cycloalkyl group, a monocyclic cycloalkenyl group or a monocyclic heterocyclic ring.
  • the bicyclic aryl group is attached to the parent molecule through any carbon atom contained in the phenyl moiety of the bicyclic system or any carbon atom bearing a naphthyl or an anthracenyl group.
  • the fused monocyclic cycloalkyl or monocyclic heterocyclyl moiety of the bicyclic aryl group can be optionally substituted with one or two oxo and/or thio groups.
  • the bicyclic aryl is fused to a 5- or 6-membered monocyclic cycloalkyl, 5- or 6-membered monocyclic cycloalkenyl or 5- or 6-membered monocyclic heterocyclyl (i) A naphthyl group or (ii) a phenyl ring wherein the fused cycloalkyl, cycloalkenyl and heterocyclic group may be optionally substituted by one or two groups which are independent oxo or thio groups.
  • cyano refers to a -CN group.
  • carboxy refers to a -COOH group.
  • sulfonic acid group means a -SOOOH group.
  • halogen means fluorine, chlorine, bromine or iodine.
  • heteroaryl refers to a monocyclic heteroaryl or bicyclic system containing at least one heteroaryl ring.
  • the monocyclic heteroaryl group can be a 5- or 6-membered ring.
  • a 5-membered ring consists of two double bonds and one, two, three or four nitrogen atoms and one oxygen or sulfur atom.
  • a 6-membered ring consists of three double bonds and one, two, three or four nitrogen atoms.
  • the 5- or 6-membered heteroaryl is attached to the parent molecule through any carbon or nitrogen atom contained within the heteroaryl.
  • the bicyclic heteroaryl group consists of a monocyclic heteroaryl group fused to a phenyl group, a monocyclic cycloalkyl group, a monocyclic cycloalkenyl group, a monocyclic heterocyclic group or a monocyclic heteroaryl group.
  • the cycloalkyl or heterocyclyl moiety of the fused bicyclic heteroaryl group can be optionally substituted with one or two groups which are independent oxo or thio groups.
  • the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl or heterocyclyl ring
  • the bicyclic heteroaryl is attached to the parent molecule through any carbon or nitrogen atom contained in the monocyclic heteroaryl portion of the bicyclic system. on.
  • the bicyclic heteroaryl is a monocyclic heteroaryl fused to a phenyl ring or a monocyclic heteroaryl
  • the bicyclic heteroaryl is attached to the parent molecule through any carbon or nitrogen atom in the bicyclic ring system.
  • the fused bicyclic heteroaryl is fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic ring.
  • a 5- or 6-membered monocyclic heteroaryl ring of a heterocyclic group or a 5- or 6-membered monocyclic heteroaryl group, wherein the fused cycloalkyl, cycloalkenyl and heterocyclic group may be optionally used as an independent oxo group. Substituted by one or two groups of a thiol group.
  • heterocyclic group or "heterocyclic ring” means a monocyclic heterocyclic ring or a bicyclic heterocyclic ring.
  • the monocyclic heterocyclic ring is a 3, 4, 5, 6 or 7 membered ring containing at least one hetero atom selected from the group consisting of O, N and S, wherein the ring is saturated or unsaturated, but not aromatic.
  • the monocyclic heterocycle is attached to the parent molecule through any carbon or nitrogen atom contained within the monocyclic heterocycle.
  • the bicyclic heterocyclic ring is a monocyclic heterocyclic ring fused to a phenyl group, a monocyclic cycloalkyl group, a monocyclic cycloalkenyl group, a monocyclic heterocyclic group or a monocyclic heteroaryl group.
  • the bicyclic heterocycle is attached to the parent molecule through any carbon or nitrogen atom contained within the monocyclic heterocyclic moiety of the bicyclic system.
  • the bicyclic heterocyclic group is fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclic group.
  • a 5- or 6-membered monocyclic heterocyclyl ring of a 5- or 6-membered monocyclic heteroaryl group characterized in that the bicyclic heterocyclic group may be optionally used as one or two groups of an independent oxo or thio group. Replaced by the regiment.
  • hydroxyl means an -OH group.
  • nitro refers to a -NO 2 group.
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt or solvate with an acid or a base.
  • pharmaceutically acceptable salts include, but are not limited to, salts formed with inorganic acids such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, and the like.
  • Salt also includes salts with organic acids, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, sulfonate, Tosylate, 2-hydroxyethyl sulfonate, benzoate, salicylate, stearate and alkanoate such as acetate, HOOC-(CH 2 ) n -COOH wherein n is a salt of 0-4, and the like.
  • pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.
  • the "solvate” such as “hydrate” is formed by the interaction of a solvent and a compound.
  • the term “compound” shall include solvates of the compounds (including hydrates of the compounds).
  • “salts” also include solvates of salts (such as hydrates of salts). Suitable solvates are pharmaceutically acceptable, such as hydrates, which include monohydrates and hemihydrates.
  • the reagents and starting materials used in the present invention are commercially available.
  • the room temperature refers to an ambient temperature of 10 ° C to 35 ° C.
  • the aromatic heterocyclic substituted olefin compound of the present invention is an ALK5 inhibitor which can be used for the preparation of cancer, renal fibrosis, liver fibrosis, pulmonary fibrosis, viral infection, chronic nephritis, acute nephritis. , diabetic nephropathy, osteoporosis, arthritis, wound healing, ulcers, corneal trauma, heart valve stenosis, congestive heart necrosis, neurological impairment, Alzheimer's syndrome, peritoneal or subcutaneous adhesions, atherosclerosis and tumors A drug that transfers diseases such as growth.
  • the reagents and starting materials (except intermediates) used in the present invention are commercially available.
  • the room temperature referred to in the present invention refers to an ambient temperature of from 10 ° C to 35 ° C. Overnight means 8-15 hours.
  • the reflux is the solvent reflux temperature at normal pressure.
  • the prepared compound was judged to be in the cis configuration (Z) or the trans configuration (E) by the coupling constant of hydrogen on the carbon-carbon double bond in the nuclear magnetic data.
  • the coupling constant between two H's on the double bond of the E-configuration compound is significantly greater than the coupling constant between the two H's on the double bond of the corresponding Z-type compound.
  • the obtained E-type compound is exemplified by Comparative Compounds 23 and 24, and the coupling constant of the two hydrogens on the carbon-carbon double bond is about 16.
  • the corresponding Z-type compound obtained, that is, the compound 1, 3, has a coupling constant of about 12.5 for the two hydrogens on the carbon-carbon double bond.
  • Pd-CaCO 3 (10 mg) was added to a solution of the compound 1-a (38 mg, 0.14 mmol) in ethyl acetate (8 mL) at room temperature, and the mixture was evaporated, and the mixture was washed with H 2 and the mixture was stirred at room temperature 2 hour.
  • Compound 4-c was synthesized according to the method of WO 2015/157093.
  • 1x kinase buffer 40 mM Tris (pH 7.5), 20 mM MgCl 2 , 0.10% BSA, 1 mM DTT.
  • the final concentration of the compound was 10 ⁇ M, and the concentration was 100-fold, that is, 1 mM.
  • 100 ⁇ L of 100-fold compound was added to the second well of the 384-well plate, and 60 ⁇ L of 100% DMSO was added to the other wells.
  • 30 ⁇ L of the compound was taken from the second well and added to the third well, and then serially diluted 3 times, and a total of 10 concentrations were diluted.
  • 50 nL of the compound was transferred to the reaction plate by echo.
  • Kinase reaction The kinase was added to 1X kinase buffer to form a 2-fold enzyme solution. The final concentration of the kinase solution was ALK 5: 25 nM.
  • the polypeptide TGFbR1 purchased from Signal Chem, catalog number T36-58
  • ATP were added to 1X kinase buffer to form a 2-fold substrate solution. The final concentration of the substrate solution was 0.1 mg/mL of polypeptide TGFbR1 and 7 ⁇ M of ATP.
  • To a 384-well reaction plate 50 nL of 100% DMSO dissolved compound) was added 2.5 ⁇ L of 2-fold enzyme solution, and the negative control well was added with 1X kinase buffer.
  • ADP-Glo reagent purchased from Promege, catalog number v9102 was equilibrated to room temperature. The reaction was stopped by transferring 5 ⁇ L of ADP-Glo reagent into a 384-well plate reaction well.
  • SB431542 (CAS No.: 301836-41-9) is a known ALK5 inhibitor, and its structure is as follows:

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Abstract

本发明提供一种芳香杂环取代烯烃化合物、其制备方法、药物组合物和应用。本发明的芳香杂环取代烯烃化合物是一种新型ALK5抑制剂，用于治疗和/或预防各种ALK5介导的疾病。

Description

芳香杂环取代烯烃化合物、其制备方法、药物组合物和应用
本申请要求申请日为2018年1月24日的中国专利申请CN201810069892.9的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种芳香杂环取代烯烃化合物、其制备方法、药物组合物和应用。
背景技术
转化生长因子-β(transforming growth factorβ,TGF-β)是一种多功能细胞因子，以自分泌、旁分泌和内分泌的方式通过细胞表面复杂的受体信号传导途径参与调节细胞的增殖，分化和凋亡。TGF-β与活化素(activins)、抑制素(inhibins)、骨形态发生蛋白(bone morphogenetic proteins)和谬氏抑制物质(Mullerian-inhibiting substance)等多种相关蛋白同属于转化生长因子β超家族(TGF-βsuperfamily，TGF-βs)。
TGF-β有3个主要的细胞受体：I型、II型和III型受体。I型和II型受体是跨膜丝氨酸/苏氨酸激酶，二者同时传导信息，III型受体不传递信息，功能主要是将TGF-β传递给II型受体，通过为受体II提供配体而间接地影响信号传导。
TGF-β的信号传导通路主要是TGF-β-Smad信号通路，Smad蛋白家族是近年来发现的细胞内信号转导蛋白，已知人体内有8种Smad蛋白分子。无活性的蛋白复合物形式的TGF-β经过激活后，TGF-β在细胞表面与II型受体(TGFβR II)和I型受体(TGFβR I，又称ALK5(activin-like kinase 5))形成一个双二聚体受体复合物，II型受体磷酸化并激活I型受体，接着I型受体磷酸化其连接的Smad蛋白分子(Smad2/3)并释放到胞浆中，与Smad4蛋白形成复合体转移到细胞核内，结合不同的转录因子和转录共激活剂或转录共抑制剂，来调节TGF-β靶基因的转录，产生生物效应。TGF-β-Smad信号通路对细胞的增殖、分化、凋亡、附着、迁移，对细胞外基质的合成、创伤的修复、免疫功能等都有重要的调节作用(Nature 2003,425,577)。研究表明，异常的TGF-β信号和许多种疾病相关，比如癌症、肾纤维化、肝纤维化、肺纤维化、病毒感染、慢性肾炎、急性肾炎、糖尿病肾病、骨质疏松症、关节炎、伤口愈合、溃疡、角膜创伤、心脏瓣膜狭窄、充血性心脏坏死、神经功能损伤、阿尔兹海默综合征、腹膜或皮下粘连、动脉硬化症和肿瘤转移生长等；而TGF-β信号通路中的重要节点TGFβR I(ALK5)是治疗这些疾病的理想靶点，通过抑制ALK5对其下游信号Smad2或Smad3的磷酸化，阻断或部分阻断TGF-β 信号向细胞内的传播，从而纠正异常的TGF-β信号，可以治疗和预防各种ALK5介导的疾病(Nat Rev Drug Discov.2012October,11(10):790-811；Pharmacology&Therapeutics147(2015)22-31)。
现有技术已公开了一些作为ALK5抑制剂的化合物，例如：WO2012002680，WO2009022171，WO2009133070，WO2004048383，WO2004013135，WO2002094833等。
发明人通过研究，发现了一类芳香杂环取代烯烃化合物，可作为ALK5抑制剂，具有治疗和/或预防由ALK5介导的多种疾病的用途。
发明内容
本发明提供一种芳香杂环取代烯烃化合物、其制备方法、药物组合物和应用。本发明的芳香杂环取代烯烃化合物是一种新型ALK5抑制剂，用于治疗和/或预防各种ALK5介导的疾病。
本发明提供了一种如通式I所示的芳香杂环取代烯烃化合物或其药学上可接受的盐：
Figure PCTCN2018124667-appb-000001
其中，环A与环B位于双键的同侧；
Figure PCTCN2018124667-appb-000002
为
Figure PCTCN2018124667-appb-000003
Figure PCTCN2018124667-appb-000004
R 3、R 31、R 32、R 33、R 3a、R 3a1、R 3b、R 3b1、R 3c、R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、R 3e1、R 3f、R 3f1、R 3f2、R 3g和R 3g1各自独立地为氢、卤素、氰基、硝基、-NR a3R a4、-OR a5、-SR a6、-C(O)OR a7、-C(O)NR a8R a9、-COR a10、取代或未取代的C 1-6烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 3-10环烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 4-8环烯基、取代或未取代的C 6-20芳基、或取代或未取代的C 2-10杂芳基；其中，R a3、R a4、R a5、R a6、R a7、R a8、R a9和R a10各自独立地为氢、取代或未取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；R a3和R a8还可独立地为羟基或C 1-6烷氧基；
R 3、R 31、R 32、R 33、R 3a、R 3a1、R 3b、R 3b1、R 3c、R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、 R 3e1、R 3f、R 3f1、R 3f2、R 3g、R 3g1、R a3、R a4、R a5、R a6、R a7、R a8、R a9和R a10中，所述的取代的C 1-6烷基、以及R 3、R 31、R 32、R 33、R 3a、R 3a1、R 3b、R 3b1、R 3c、R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、R 3e1、R 3f、R 3f1、R 3f2、R 3g、R 3g1中，所述的取代的C 2-8烯基、取代的C 2-8炔基、取代的C 3-10环烷基、取代的C 2-8杂环烷基、取代的C 4-8环烯基、取代的C 6-20芳基、取代的C 2-10杂芳基中的取代基各自独立地为下列基团中的一个或多个：氘、卤素、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、-OR a15、-SR a16、-C(O)OR a17、-COR a18、-C(O)NH 2、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；R a15、R a16、R a17和R a18各自独立地为氢或C 1-6烷基；当取代基为多个时，所述的取代基相同或不同；
R 4为氢、氰基、C 1-6烷基、C 3-10环烷基、C 2-8杂环烷基、-C(O)OR a19或被-OR a20取代的C 1-6烷基；R a19和R a20各自独立地为C 1-6烷基；
Figure PCTCN2018124667-appb-000005
为
Figure PCTCN2018124667-appb-000006
Figure PCTCN2018124667-appb-000007
R 5、R 51、R 5a、R 5a1、R 5a2、R 5b、R 5b1、R 5c、R 5c1、R 5c2、R 5d、R 5d1、R 5d2、R 5e、R 5e1和R 5e2各自独立地为氢、氘或卤素；
R 6、R 6a、R 6b、R 6c、R 6d和R 6e各自独立地为氢、氘、卤素、磺酸基、取代或未取代的C 1-6烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 3-10环烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、取代或未取代的C 2-10杂芳基、氰基、-OR 61、-SR 62、-NR a63R a64、-C(O)R 65、-C(O)OR 66、-OC(O)R 67、-OC(O)OR 68、-C(O)NR a69R a610、-N(R 611)C(O)R 612、-S(O)R 613、-S(O) 2R 614、-S(O) 2NR a615R a616、-OC(O)NR a617R a618、-N(R 619)C(O)OR 620、-N(R 621)C(O)NR a622R a623、-N(R 624)S(O) 2R 625或-OP(O)(OR 626) 2；
R 61、R 62、R a64、R 65、R 66、R 67、R 68、R a610、R 611、R 612、R 613、R 614、R a615、R a616、R a617、R a618、R 619、R 620、R 621、R a622、R a623、R 624、R 625和R 626各自独立地为氢、取代或未取代的C 1-6烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 3-10环烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、或取代或未取代的C 2-10杂芳基；
R a63和R a69各自独立地为氢、羟基、C 1-6烷氧基、取代或未取代的C 1-6烷基、取代或 未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 3-10环烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、或取代或未取代的C 2-10杂芳基；
R 6、R 6a、R 6b、R 6c、R 6d和R 6e中，所述的取代的C 1-6烷基、取代的C 2-8烯基、取代的C 2-8炔基、取代的C 3-10环烷基、取代的C 2-8杂环烷基、取代的C 6-20芳基、取代的C 2-10杂芳基中的取代基各自独立地为下列基团中的一个或多个：氘、卤素、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基、C 2-10杂芳基、氰基、-OR 71、-SR 72、-NR a73R a74、-C(O)R 75、-C(O)OR 76、-OC(O)R 77、-OC(O)OR 78、-C(O)NR a79R a710、-N(R 711)C(O)R 712、S(O)R 713、-S(O) 2R 714、-S(O) 2NR a715R a716、-OC(O)NR a717R a718、-N(R 719)C(O)OR 720、-N(R 721)C(O)NR a722R a723、-N(R 724)S(O) 2R 725或-OP(O)(OR 726) 2；当取代基为多个时，所述的取代基相同或不同；R 71、R 72、R a73、R a74、R 75、R 76、R 77、R 78、R a79、R a710、R 711、R 712、R 713、R 714、R a715、R a716、R a717、R a718、R 719、R 720、R 721、R a722、R a723、R 724、R 725和R 726各自独立地为氘、C 1-6烷基、卤素取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；
R 61、R 62、R a63、R a64、R 65、R 66、R 67、R 68、R a69、R a610、R 611、R 612、R 613、R 614、R a615、R a616、R a617、R a618、R 619、R 620、R 621、R a622、R a623、R 624、R 625和R 626中，所述的取代的C 1-6烷基、取代的C 2-8烯基、取代的C 2-8炔基、取代的C 3-10环烷基、取代的C 2-8杂环烷基、取代的C 6-20芳基或取代的C 2-10杂芳基中的取代基为下列基团中的一个或多个：氘、卤素、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基、C 2-10杂芳基、-OR c、-SR c1、-NR b1R b2、-C(O)R c2、-C(O)OR c3、-OC(O)R c4、-OC(O)OR c5、-C(O)NR b3R b4、-N(R c6)C(O)OR c7、S(O)R c8、-S(O) 2R c9、-S(O) 2NR b5R b6、-N(R c10)C(O)R c11、-N(R c12)C(O)NR b7R b8或-N(R c13)S(O) 2R c14；R c、R c1、R b1、R b2、R c2、R c3、R c4、R c5、R b3、R b4、R c6、R c7、R c8、R c9、R b5、R b6、R c10、R c11、R c12、R b7、R b8、R c13和R c14各自独立地为氢、羟基、C 1-6烷基、卤素取代的C 1-6烷基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；
R 7、R 8、R 9、R 10、R 11、R 12、R 13各自独立地为氢、氘或卤素；
R 1和R 2其中一个为氢、氘、卤素、或取代或未取代的C 1-6烷基，另一个为氢、氘、卤素、氰基、磺酸基、取代或未取代的C 1-6烷基、-C(O)OR 91、-COR 92、
Figure PCTCN2018124667-appb-000008
-S(O)R 95、-S(O) 2R 96、-C(O)NR 97R 98、或取代或未取代的C 2-10杂芳基；R 1和R 2中，所述的取代的C 1-6烷基和所述的取代的C 2-10杂芳基中的取代基各自独立地为下列基团中的一个或多个：氘、卤素、氰基、C 1-6烷基、C 2-8烯基、C 2-8炔基、-OR 920、-SR 921、-C(O)OR 922、-COR 923、 -C(O)NH 2、-NR 924R 925、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；R 920、R 921、R 922、R 923、R 924和R 925各自独立地为氢或C 1-6烷基；
R 91、R 92、R 93和R 94独立地为下列基团中的一个或多个：氢、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；R 95和R 96独立地为氢或C 1-6烷基；
R 97和R 98独立地为羟基、氢、取代或未取代的C 1-6烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 3-10环烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、或取代或未取代的C 2-10杂芳基；
R 97和R 98中，所述的取代的C 1-6烷基、取代的C 2-8烯基、取代的C 2-8炔基、取代的C 3-10环烷基、取代的C 2-8杂环烷基、取代的C 6-20芳基、取代的C 2-10杂芳基中的取代基各自独立地为下列基团中的一个或多个：氘、卤素、氰基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基、C 2-10杂芳基、-OR 101、-SR 102、-NR b103R b104、-C(O)R 105、-C(O)OR 106、-OC(O)R 107、-OC(O)OR 108、-C(O)NR b109R b1010、-N(R 1011)C(O)OR 1012、S(O)R 1013、-S(O) 2R 1014、-S(O) 2NR b1015R b1016、-N(R 1017)C(O)OR 1018、-OC(O)NR b1019R b1020、或-N(R 1021)S(O) 2R 1022；当取代基为多个时，所述的取代基相同或不同；R 101、R 102、R b103、R b104、R 105、R 106、R 107、R 108、R b109、R b1010、R 1011、R 1012、R 1013、R 1014、R b1015、R b1016、R 1017、R 1018、R b1019、R b1020、R 1021和R 1022各自独立地为氢、羟基、C 1-6烷基、卤素取代的C 1-6烷基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；
或者R 1和R 2与它们相连的碳原子一起形成含有一个双键的取代或未取代的4-8元的碳环、或取代或未取代的4-8元杂环，所述的4-8元杂环中的杂原子选自O、S和N中的一个或多个，杂原子数为1、2、3或4；
所述的取代的4-8元的碳环和所述的取代的4-8元杂环中的取代基各自独立地为下列基团中的一个或多个：氘、卤素、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、-OR 111、-SR 112、-C(O)OR 113、-COR 114、-C(O)NH 2、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；R 111、R 112、R 113和R 114各自独立地为氢或C 1-6烷基；
上述各字母和基团中，所述的取代或未取代的C 2-8杂环烷基或所述的C 2-8杂环烷基中的杂原子选自N、O和S中的一个或多个，杂原子数为1、2、3或4；所述的取代或未取代的C 2-10杂芳基或所述的C 2-10杂芳基中的杂原子选自N、O和S中的一个或多个，杂原子数为1、2、3或4；当杂原子为多个时，所述的杂原子相同或不同；
或者上述各基团或取代基中，当存在NR XR Y时，R X和R Y与它们相连的氮原子一起形成取代或未取代的3-8元杂环基；所述的3-8元杂环基中的杂原子选自N、N和O、N 和S、或N、O和S；杂原子数为1、2、3或4；所述的取代的3-8元杂环基中的取代基为下列基团中的一个或多个：氘、卤素、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、-OR a81、-SR a82、-C(O)OR a83、-COR a84、-C(O)NH 2、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；R a81、R a82、R a83和R a84各自独立地为氢或C 1-6烷基。
在本发明一优选实施方案中，当
Figure PCTCN2018124667-appb-000009
为
Figure PCTCN2018124667-appb-000010
时，
Figure PCTCN2018124667-appb-000011
不为
Figure PCTCN2018124667-appb-000012
本发明中，-NR XR Y例如：-NR a3R a4、-NR a8R a9、-NR a63R a64、-NR a69R a610、-NR a615R a616、-NR a617R a618、-NR a622R a623、-NR a73R a74、-NR a79R a710、-NR a715R a716、-NR a717R a718、-NR a722R a723、-NR b1R b2、-NR b3R b4、-NR b5R b6、-NR b7R b8、-NR 93R 94、-NR 97R 98、-NR 924R 925、-NR b103R b104、-NR b109R b1010、-NR b1015R b1016或-NR b1019R b1020。
本发明中，术语取代或未取代的C 1-6烷基中的C 1-6烷基和术语C 1-6烷基独立地优选C 1-4烷基。所述的C 1-4烷基优选甲基、乙基、正丙基、异丙基、正丁基、异丁基、或叔丁基。
本发明中，术语取代或未取代的C 2-8烯基中的C 2-8烯基和术语C 2-8烯基独立地优选C 2-4烯基。所述的C 2-4烯基优选乙烯基、丙烯基、烯丙基、
Figure PCTCN2018124667-appb-000013
本发明中，术语取代或未取代的C 2-8炔基中的C 2-8炔基和术语C 2-8炔基独立地优选C 2-4炔基。所述的C 2-4炔基优选乙炔基、丙炔基、丁炔基或3-甲基丙炔基。
本发明中，术语取代或未取代的C 3-10环烷基中的C 3-10环烷基和术语C 3-10环烷基独立地优选环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基或双环环烷基例如双环[3.1.1]庚烷基、双环[2.2.1]庚烷基、双环[2.2.2]辛烷基、双环[3.2.2]壬烷基、双环[3.3.1]壬烷基或双环[4.2.1]壬烷基。
本发明中，术语取代或未取代的C 2-8杂环烷基中的C 2-8杂环烷基和术语C 2-8杂环烷基独立地优选氮杂环丁烷基、氮杂环庚烷基、氮丙啶、二氮杂环庚烷基、1,3-二噁烷基、1,3-二氧戊环基、1,3-二硫戊环基、1,3-二噻烷基、咪唑啉基、咪唑烷基、异噻唑烷基、异噻唑基、异噁唑啉基、吗啉基、噁二唑啉基、噁二唑烷基、噁唑啉基、噁唑烷基、哌嗪基、哌啶基、吡喃基、吡唑啉基、吡唑烷基、吡咯啉基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻二唑啉基、噻二唑烷基、噻唑啉基、噻唑烷基、硫代吗啉基、1,1-二氧硫代吗啉基、噻喃基、三噻烷基、2,3-二氢苯并呋喃-2-基、2,3-二氢苯并呋喃-3-基、二氢吲哚-1-基、二氢吲哚-2-基、二氢吲哚-3-基、2,3-二氢苯并噻吩-2-基、十氢喹啉基、十氢异喹啉基、八氢-1H-吲哚基或八氢苯并呋喃基。
本发明中，术语取代或未取代的C 4-8环烯基中的C 4-8环烯基和术语C 4-8环烯基独立地优选环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基、降冰片烯基或双环[2.2.2]辛烯基。
本发明中，术语取代或未取代的C 6-20芳基中的C 6-20芳基或术语C 6-20芳基独立地优选苯基、萘基、蒽基、菲基、薁基、二氢茚-1-基、二氢茚-2-基、二氢茚-3-基、二氢茚-4-基、2,3-二氢吲哚-4-基、2,3-二氢吲哚-5-基、2,3-二氢吲哚-6-基、2,3-二氢吲哚-7-基、茚-1-基、茚-2-基、茚-3-基、茚-4-基、二氢萘-2-基、二氢萘-3-基、二氢萘-4-基、二氢萘-1-基、5,6,7,8-四氢化萘-1-基、5,6,7,8-四氢化萘-2-基、2,3-二氢苯并呋喃-4-基、2,3-二氢苯并呋喃-5-基、2,3-二氢苯并呋喃-6-基、2,3-二氢苯并呋喃-7-基、苯并[d][1,3]间二氧杂环戊烯-4-基、苯并[d][1,3]间二氧杂环戊烯-5-基、2H-苯并呋喃-2-酮-5-基、2H-苯并呋喃-2-酮-6-基、2H-苯并呋喃-2-酮-7-基、2H-苯并呋喃-2-酮-8-基、异吲哚啉-1,3-二酮-4-基、异吲哚啉-1,3-二酮-5-基、茚-1-酮-4-基、茚-1-酮-5-基、茚-1-酮-6-基、茚-1-酮-7-基、2,3-二氢苯并[b][1,4]二噁烷-5-基、2,3-二氢苯并[b][1,4]二噁烷-6-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-5-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-6-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-7-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-8-基、苯并[d]杂氧嗪-2(3H)-酮-5-基、苯并[d]杂氧嗪-2(3H)-酮-6-基、苯并[d]杂氧嗪-2(3H)-酮-7-基、苯并[d]杂氧嗪-2(3H)-酮-8-基、喹唑啉-4(3H)-酮-5-基、喹唑啉-4(3H)-酮-6-基、喹唑啉-4(3H)-酮-7-基、喹唑啉-4(3H)-酮-8-基、喹噁啉-2(1H)-酮-5-基、喹噁啉-2(1H)-酮-6-基、喹噁啉-2(1H)-酮-7-基、喹噁啉-2(1H)-酮-8-基、苯并[d]噻唑-2(3H)-酮-4-基、苯并[d]噻唑-2(3)-酮-5-基、苯并[d]噻唑-2(3H)-酮-6-基或苯并[d]噻唑-2(3H)-酮-7-基。
本发明中，术语取代或未取代的C 2-10杂芳基中的C 2-10杂芳基和术语C 2-10杂芳基独立地优选呋喃基、咪唑基、异噁唑基、异噻唑基、噁二唑基、噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、噻二唑基、噻唑基、噻吩基、三唑基、三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噁二唑基、苯并噻唑基、噌啉基、5,6-二氢喹啉-2-基、5,6-二氢喹啉-1-基、呋喃并吡啶基、吲唑基、吲哚基、异喹啉基、萘啶基、嘌呤基、喹啉基、5,6,7,8-四氢喹啉-2-基、5,6,7,8-四氢喹啉-3-基、5,6,7,8-四氢喹啉-4-基、5,6,7,8-四氢异喹啉-1-基、噻吩并吡啶基、4,5,6,7-四氢并[c][1,2,5]噁二唑基或6,7-二氢并[c][1,2,5]噁二唑-4(5H)酮基。
在本发明一优选实施方案中，R 1和R 2其中一个为氢、或取代或未取代的C 1-6烷基，另一个为氢、氰基、磺酸基、取代或未取代的C 1-6烷基、-C(O)OR 91、-COR 92、
Figure PCTCN2018124667-appb-000014
-S(O)R 95、-S(O) 2R 96、-C(O)NR 97R 98、或取代或未取代的C 2-10杂芳基；或者R 1和R 2与它们相连的碳原子一起形成含有一个双键的取代或未取代的4-8元的碳环、或取代或未取代的4-8元杂环；其中，R 91、R 92、R 93、R 94、R 95、R 96、R 97和R 98的定义均同前所述；所述的取代的C 1-6烷基、所述的取代的C 2-10杂芳基、所述的取代的4-8元的碳环和所述的取代的4-8元杂环中取代基的定义均同前所述。
在本发明一优选实施方案中，R 1和R 2其中一个为氢，另一个为氢、氰基、取代或未取代的C 1-6烷基、-C(O)OR 91或-C(O)NR 97R 98；或者R 1和R 2与它们相连的碳原子一起形成含有一个双键的取代或未取代的4-8元的碳环；其中，R 91为氢或C 1-6烷基；R 97和R 98独立地为氢、或取代或未取代的C 1-6烷基；或者R 97和R 98与它们相连的氮原子一起形成取代或未取代的3-8元杂环基；其中，R 1或R 2中，所述的取代的C 1-6烷基、所述的取代的4-8元的碳环和所述的取代的4-8元杂环中取代基的定义均同前所述；R 97或R 98中，所述的取代的C 1-6烷基或所述的取代的3-8元杂环基中的取代基的定义同前所述。
在本发明一优选实施方案中，R 1和R 2其中一个为氢，另一个为氢、C 1-6烷基、-C(O)OR 91或-C(O)NR 97R 98；或者R 1和R 2与它们相连的碳原子一起形成含有一个双键的的4-8元的碳环；其中，R 91、R 97和R 98独立地为氢或C 1-6烷基；或者R 97和R 98与它们相连的氮原子一起形成3-8元杂环基；优选地，R 1为氢，R 2为氢、C 1-6烷基、-C(O)OR 91或-C(O)NR 97R 98；R 91、R 97和R 98独立地为氢或C 1-6烷基。
在发明一优选实施方案中，
R 1和R 2同时为氢；
或，R 1为氢，R 2为
Figure PCTCN2018124667-appb-000015
Figure PCTCN2018124667-appb-000016
或，R 1和R 2与它们所连接的C原子一起形成环己烯环。
在本发明一优选实施方案中，环A中，R 3、R 31、R 32、R 33、R 3a、R 3a1、R 3b、R 3b1、R 3c、R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、R 3e1、R 3f、R 3f1、R 3f2、R 3g和R 3g1各自独立地为氢、卤素、氰基、硝基、-NR a3R a4、-OR a5、-SR a6、-C(O)OR a7、-C(O)NR a8R a9、-COR a10、取代或未取代的C 1-6烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、或取代或未取代的C 2-10杂芳基；其中，R a3、R a4、R a5、R a6、R a7、R a8、R a9和R a10的定义均同前所述；所述的取代的C 1-6烷基、取代的C 2-8杂环烷基、取代的C 6-20芳基或取代的 C 2-10杂芳基中取代基的定义均同前所述。
在本发明一优选实施方案中，环A中，R 3、R 31、R 32、R 33、R 3a、R 3a1、R 3b、R 3b1、R 3c、R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、R 3e1、R 3f、R 3f1、R 3f2、R 3g和R 3g1各自独立地为氢、卤素、-OR a5、或取代或未取代的C 1-6烷基；R a5为C 1-6烷基；所述的取代的C 1-6烷基中的取代基为下列基团中的一个或多个：氘或卤素。
在本发明一优选实施方案中，环A中，R 3、R 31、R 32、R 33、R 3a、R 3a1、R 3b、R 3b1、R 3c、R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、R 3e1、R 3f、R 3f1、R 3f2、R 3g和R 3g1各自独立地为氢、卤素、三氟甲基、二氟甲基、甲基、氘代甲基或甲氧基。
在本发明一优选实施方式中，环A中有1或2个位置不为氢。
在本发明一优选实施方案中，环A优选
Figure PCTCN2018124667-appb-000017
其中，R 3和R 33独立地优选氢、卤素、-OR a5、或取代或未取代的C 1-6烷基，但不同时为氢；R 3b为氢、卤素、-OR a5、或取代或未取代的C 1-6烷基；R a5的定义均同前所述；所述的取代的C 1-6烷基中取代基的定义均同前所述；R 31、R 32和R 3b1为氢。
在本发明一优选实施方案中，
Figure PCTCN2018124667-appb-000018
优选
Figure PCTCN2018124667-appb-000019
Figure PCTCN2018124667-appb-000020
在本发明一优选实施方案中，R 4为氢、C 1-6烷基或C 3-10环烷基。
在本发明一优选实施方案中，R 5、R 51、R 5a、R 5a1、R 5a2、R 5b、R 5b1、R 5c、R 5c1、R 5c2、R 5d、R 5d1、R 5d2、R 5e、R 5e1和R 5e2为氢。
在本发明一优选实施方案中，R 6、R 6a、R 6b、R 6c、R 6d和R 6e各自独立地为氢、卤素、取代或未取代的C 1-6烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、取代或未取代的C 2-10杂芳基、氰基、-OR 61、-SR 62、-NR a63R a64、-C(O)R 65、-C(O)OR 66、-OC(O)R 67、-OC(O)OR 68、-C(O)NR a69R a610、-N(R 611)C(O)R 612、S(O)R 613、-S(O) 2R 614、-S(O) 2NR a615R a616、-OC(O)NR a617R a618、-N(R 619)C(O)OR 620、-N(R 621)C(O)NR a622R a623、-N(R 624)S(O) 2R 625或-OP(O)(OR 626) 2；R 61、R 62、R a63、R a64、R 65、R 66、R 67、R 68、R a69、R a610、R 611、R 612、R 613、R 614、R a615、R a616、R a617、R a618、R 619、R 620、R 621、R a622、R a623、R 624、R 625和R 626的定义均同前所述；所述的取代的C 1-6烷基、取代的C 2-8杂环烷基、取 代的C 6-20芳基或取代的C 2-10杂芳基中的取代基的定义均同前所述。
在本发明一优选实施方案中，R 6、R 6a、R 6b、R 6c、R 6d和R 6e各自独立地为氢、卤素、氰基、取代或未取代的C 1-6烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、取代或未取代的C 2-10杂芳基、氰基、-OR 61、-SR 62、-C(O)R 65、-C(O)OR 66或-C(O)NR a69R a610；R 61、R 62、R 65、R 66、R a69和R a610的定义均同前所述；所述的取代的C 1-6烷基、取代的C 2-8杂环烷基、取代的C 6-20芳基或取代的C 2-10杂芳基中的取代基的定义均同前所述。
在本发明一优选实施方案中，R 6、R 6a、R 6b、R 6c、R 6d和R 6e各自独立地为氰基、-C(O)OR 66或-C(O)NR a69R a610；R 66优选C 1-6烷基；R a69和R a610各自独立地为氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-10环烷基或-OR 627；所述的取代的C 1-6烷基或所述的取代的C 3-10环烷基中取代基的定义均同前所述；R 627的定义同前所述。
在本发明一优选实施方案中，R 6、R 6a、R 6b、R 6c、R 6d和R 6e各自独立地为氰基、-C(O)OR 66或-C(O)NR a69R a610；；R 66为C 1-6烷基；R a69和R a610各自独立地为氢、取代或未取代的C 1-6烷基、C 3-10环烷基或-OR 627；所述的取代的C 1-6烷基中取代基优选为C 2-8杂环烷基(例如
Figure PCTCN2018124667-appb-000021
)；R 627优选为C 2-8杂环烷基(例如
Figure PCTCN2018124667-appb-000022
)。
在本发明一优选实施方案中，R 6、R 6a、R 6b、R 6c、R 6d和R 6e独立地为-C(O)NR a69R a610；R a69和R a610的定义均同前所述。
在本发明一优选实施方案中，R 6、R 6a、R 6b、R 6c、R 6d和R 6e各自独立地为CN、-C(＝O)NH 2、-C(＝O)(OEt)、
Figure PCTCN2018124667-appb-000023
在本发明一优选实施方案中，R 5、R 51、R 5a、R 5a1、R 5a2、R 5b、R 5b1、R 5c、R 5c1、R 5c2、R 5d、R 5d1、R 5d2、R 5e、R 5e1、R 5e2、R 7、R 8、R 9、R 10、R 11、R 12和R 13为氢。
在本发明一优选实施方案中，
Figure PCTCN2018124667-appb-000024
优选
Figure PCTCN2018124667-appb-000025
Figure PCTCN2018124667-appb-000026
进一步优选
Figure PCTCN2018124667-appb-000027
其中，R 5a、R 5a1、R 5a2、R 5c、R 5c1、R 5c2、R 5d、R 5d1、R 5d2、R 8、R 10和R 11优选为氢；R 6a、R 6c和R 6d各自独立地为氰基、 C 2-10杂芳基、-C(O)OR 66或-C(O)NR a69R a610；其中，所述的C 2-10杂芳基、R 66、R a69和R a610的定义均同前所述。
在本发明一优选实施方案中，
Figure PCTCN2018124667-appb-000028
优选
Figure PCTCN2018124667-appb-000029
Figure PCTCN2018124667-appb-000030
在本发明一优选实施方案中，
R 1和R 2其中一个为氢、或取代或未取代的C 1-6烷基，另一个为氢、氰基、磺酸基、取代或未取代的C 1-6烷基、-C(O)OR 91、-COR 92、
Figure PCTCN2018124667-appb-000031
-S(O)R 95、-S(O) 2R 96、-C(O)NR 97R 98、或取代或未取代的C 2-10杂芳基；或者R 1和R 2与它们相连的碳原子一起形成含有一个双键的取代或未取代的4-8元的碳环、或取代或未取代的4-8元杂环；其中，R 91、R 92、R 93、R 94、R 95、R 96、R 97和R 98的定义均同前所述；所述的取代的C 1-6烷基、所述的取代的C 2-10杂芳基、所述的取代的4-8元的碳环和所述的取代的4-8元杂环中取代基的定义均同前所述；
环A中，R 3、R 31、R 32、R 33、R 3a、R 3a1、R 3b、R 3b1、R 3c、R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、R 3e1、R 3f、R 3f1、R 3f2、R 3g和R 3g1各自独立地为氢、卤素、氰基、硝基、-NR a3R a4、-OR a5、-SR a6、-C(O)OR a7、-C(O)NR a8R a9、-COR a10、取代或未取代的C 1-6烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、或取代或未取代的C 2-10杂芳基；其中，R a3、R a4、R a5、R a6、R a7、R a8、R a9和R a10的定义均同前所述；所述的取代的C 1-6烷基、取代的C 2-8杂环烷基、取代的C 6-20芳基或取代的C 2-10杂芳基中取代基的定义均同前所述；
R 4为氢、C 1-6烷基或C 3-10环烷基；
R 5、R 51、R 5a、R 5a1、R 5a2、R 5b、R 5b1、R 5c、R 5c1、R 5c2、R 5d、R 5d1、R 5d2、R 5e、R 5e1和R 5e2为氢；
和R 6、R 6a、R 6b、R 6c、R 6d和R 6e各自独立地为氢、卤素、氰基、取代或未取代的C 1-6烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、取代或未取代的C 2-10杂芳基、氰基、-OR 61、-SR 62、-C(O)R 65、-C(O)OR 66或-C(O)NR a69R a610；R 61、R 62、R 65、R 66、R a69和R a610的定义均同前所述；所述的取代的C 1-6烷基、取代的C 2-8杂环烷基、取代的C 6-20芳基或取代的C 2-10杂芳基中的取代基的定义均同前所述。
在本发明一优选实施方案中，
R 1和R 2其中一个为氢，另一个为氢、氰基、取代或未取代的C 1-6烷基、-C(O)OR 91或-C(O)NR 97R 98；或者R 1和R 2与它们相连的碳原子一起形成含有一个双键的取代或未取代的4-8元的碳环；其中，R 91为氢或C 1-6烷基；R 97和R 98独立地为氢、或取代或未取代的C 1-6烷基；或者R 97和R 98与它们相连的氮原子一起形成取代或未取代的3-8元杂环基；其中，R 1或R 2中，所述的取代的C 1-6烷基、所述的取代的4-8元的碳环和所述的取代的4-8元杂环中取代基的定义均同前所述；R 97或R 98中，所述的取代的C 1-6烷基或所述的取代的3-8元杂环基中的取代基的定义同前所述；
环A中，R 3、R 31、R 32、R 33、R 3a、R 3a1、R 3b、R 3b1、R 3c、R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、R 3e1、R 3f、R 3f1、R 3f2、R 3g和R 3g1各自独立地为氢、卤素、-OR a5、或取代或未取代的C 1-6烷基；R a5为C 1-6烷基；所述的取代的C 1-6烷基中的取代基为下列基团中的一个或多个：氘或卤素；
R 4为氢、C 1-6烷基或C 3-10环烷基；
R 5、R 51、R 5a、R 5a1、R 5a2、R 5b、R 5b1、R 5c、R 5c1、R 5c2、R 5d、R 5d1、R 5d2、R 5e、R 5e1和R 5e2为氢；
和R 6、R 6a、R 6b、R 6c、R 6d和R 6e各自独立地为氰基、-C(O)OR 66或-C(O)NR a69R a610；其中，R 66为C 1-6烷基；R a69和R a610各自独立地为氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-10环烷基或-OR 627；所述的取代的C 1-6烷基或所述的取代的C 3-10环烷基中取代基的定义均同前所述；R 627的定义同前所述。
在本发明一优选实施方案中，
R 1和R 2其中一个为氢，另一个为氢、C 1-6烷基、-C(O)OR 91或-C(O)NR 97R 98；或者R 1和R 2与它们相连的碳原子一起形成含有一个双键的的4-8元的碳环；其中，R 91、R 97和R 98独立地为氢或C 1-6烷基；或者R 97和R 98与它们相连的氮原子一起形成3-8元杂环基；
R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、R 3e1、R 3f、R 3f1、R 3f2、R 3g和R 3g1各自独立地为氢、卤素、三氟甲基、二氟甲基、甲基、氘代甲基或甲氧基；环A中有1或2个位置不 为氢；
R 4为氢、C 1-6烷基或C 3-10环烷基；
R 5、R 51、R 5a、R 5a1、R 5a2、R 5b、R 5b1、R 5c、R 5c1、R 5c2、R 5d、R 5d1、R 5d2、R 5e、R 5e1和R 5e2为氢；
和R 6、R 6a、R 6b、R 6c、R 6d和R 6e各自独立地为氰基、-C(O)OR 66或-C(O)NR a69R a610；其中，R 66为C 1-6烷基；R a69和R a610各自独立地为氢、取代或未取代的C 1-6烷基、C 3-10环烷基或-OR 627；所述的取代的C 1-6烷基中取代基为C 2-8杂环烷基(例如
Figure PCTCN2018124667-appb-000032
)；R 627为C 2-8杂环烷基(例如
Figure PCTCN2018124667-appb-000033
)。
在本发明一优选实施方案中，
R 1为氢，R 2为氢、C 1-6烷基、-C(O)OR 91或-C(O)NR 97R 98；R 91、R 97和R 98独立地为氢或C 1-6烷基；
环A为
Figure PCTCN2018124667-appb-000034
其中，R 3和R 33独立地为氢、卤素、-OR a5、或取代或未取代的C 1-6烷基，但不同时为氢；R 3b为氢、卤素、-OR a5、或取代或未取代的C 1-6烷基；R a5的定义均同前所述；所述的取代的C 1-6烷基中取代基的定义均同前所述；R 31、R 32和R 3b1为氢；
和
Figure PCTCN2018124667-appb-000035
为
Figure PCTCN2018124667-appb-000036
进一步优选
Figure PCTCN2018124667-appb-000037
Figure PCTCN2018124667-appb-000038
其中，R 5a、R 5a1、R 5a2、R 5c、R 5c1、R 5c2、R 5d、R 5d1、R 5d2、R 8、R 10和R 11为氢；R 6a、R 6c和R 6d各自独立地为氰基、C 2-10杂芳基、-C(O)OR 66或-C(O)NR a69R a610；其中，所述的C 2-10杂芳基、R 66、R a69和R a610的定义均同前所述。
在本发明一优选实施方案中，
R 1和R 2同时为氢；
或，R 1为氢，R 2为
Figure PCTCN2018124667-appb-000039
或，R 1和R 2与它们所连接的C原子一起形成环己烯环；
Figure PCTCN2018124667-appb-000040
为
Figure PCTCN2018124667-appb-000041
和
Figure PCTCN2018124667-appb-000042
为
Figure PCTCN2018124667-appb-000043
Figure PCTCN2018124667-appb-000044
在本发明一优选实施方案中，当R 1或R 2为-C(O)NR 917R 918时，R 6、R 6a、R 6b、R 6c、R 6d或R 6e为-C(O)NR a69R a610时，-C(O)NR 917R 918和-C(O)NR a69R a610不同时为-C(O)NH 2；或者-C(O)NR a69R a610为-C(O)NH 2，-C(O)NR 917R 918不为-C(O)NHCH 3。
在本发明一优选实施方案中，当R 1或R 2为-C(O)OR 98时，R 6、R 6a、R 6b、R 6c、R 6d或R 6e为-C(O)NR a69R a610时，-C(O)NR a69R a610为-C(O)NH 2，-C(O)OR 98不为-COOH。
在本发明一优选实施方案中，当R 1或R 2为-C(O)NR 97R 98时，R 6、R 6a、R 6b、R 6c、R 6d或R 6e为-CN时，-C(O)NR 97R 98不为
Figure PCTCN2018124667-appb-000045
本发明中，所述的通式I所示的芳香杂环取代烯烃化合物，其优选为下列任一化合物：
Figure PCTCN2018124667-appb-000046
Figure PCTCN2018124667-appb-000047
本发明还提供了一种所述的通式I所示的芳香杂环取代烯烃化合物的制备方法，其采用下列方法一或方法二制备：
方法一包括下列步骤：将化合物II-A和化合物II-2进行如下所示的偶联反应，即可；
Figure PCTCN2018124667-appb-000048
X和Y一个为卤素，例如Cl、Br或I；另一个为有机锡试剂如三正丁基锡试剂、或有机硼试剂如硼酸或频哪醇硼酯等；环C1和环C2其中一个为环A，另一个为环B；R d和R c一个为R 1，另一个为R 2；当环C1为环A时，R d为R 1；R 1、R 2、环A和环B的定义均同前所述；
方法二包括下列步骤：
Figure PCTCN2018124667-appb-000049
环C1和环C2其中一个为环A，另一个为环B；R d和R c一个为R 1，另一个为R 2；当环C1为环A时，R d为R 1；R 1、R 2、环A和环B的定义均同前所述；EWG 2为吸电子基团，如氰基、酯基、羧基、烷羰基、磺酸基、氨基磺酰基、烷基胺基甲酰基、-S(O)R 613、-S(O) 2R 614或
Figure PCTCN2018124667-appb-000050
等；R 613和R 614的定义均同前所述。
当通式I所示的芳香杂环取代烯烃化合物中，R 1和R 2为氢，其可采用下列方法制备，所述的方法包括下列步骤：将化合物I-1在钯试剂的作用下氢解即可；
Figure PCTCN2018124667-appb-000051
环C1和环C2其中一个为环A，另一个为环B；其中，环A和环B的定义均同前所述。
其中，部分化合物可以通过路线1的方法合成。路线1包括下列步骤：将化合物I-5 与三甲硅基(TMS)乙炔进行偶联反应得到化合物I-4，化合物I-4脱除TMS保护基得到化合物I-3，化合物I-3与化合物I-2进行偶联反应得到化合物I-1，化合物I-1在钝化的钯试剂作用下氢解得到所述的通式I所示的芳香杂环取代烯烃化合物。
路线1：
Figure PCTCN2018124667-appb-000052
其中，R 1和R 2为氢，X 1和X 2独立地为Cl、Br或I。环C1和环C2其中一个为环A，另一个为环B；环A和环B的定义均同前所述；
例如：
Figure PCTCN2018124667-appb-000053
另一些化合物可以通过路线2的方法合成。路线2包括下列步骤：化合物II-3与溴甲基三苯基溴化磷在碱的作用下通过wittig反应生成化合物II-1，化合物II-1再与化合物II-2在钯试剂催化下通过偶联反应获得所述的通式I所示的芳香杂环取代烯烃化合物。
路线2：
Figure PCTCN2018124667-appb-000054
其中，R 2为H，Y为有机锡试剂如三正丁基锡试剂、或有机硼试剂如硼酸或频哪醇硼酯等；环C1和环C2其中一个为环A，另一个为环B；R d为R 1或R 2；当环C1为环A时，R d为R 1；R 1、环A和环B的定义均同前所述。
例如：
Figure PCTCN2018124667-appb-000055
另一些化合物通过路线3的方法合成。路线3包括下列步骤：化合物III-4与化合物III-5在碱的作用下通过缩合反应生成化合物III-2，化合物III-2再与化合物III-3在钯试剂催化下通过偶联反应获得化合物III-1，化合物III-1通过进一步的转化得到所述的通式I所示的芳香杂环取代烯烃化合物。
路线3：
Figure PCTCN2018124667-appb-000056
其中，X和Y一个为卤素，例如Cl、Br或I；另一个为有机锡试剂如三正丁基锡试剂、或有机硼试剂如硼酸或频哪醇硼酯等；环C1和环C2其中一个为环A，另一个为环B；R d和R c一个为R 1，另一个为R 2；当环C1为环A时，R d为R 1；R 1、R 2、环A和环B的定义均同前所述。EWG1和EWG2独立地为吸电子基团，如氰基、酯基、羧基、烷羰基、磺酸基、氨基磺酰基、烷基胺基甲酰基、-S(O)R 613、-S(O) 2R 614或
Figure PCTCN2018124667-appb-000057
等。Y为有机锡试剂如三正丁基锡试剂、或有机硼试剂如硼酸或频哪醇硼酯等。R 613和R 614的定义均同前所述。
例如：
Figure PCTCN2018124667-appb-000058
还有一些化合物通过路线4的方法合成。路线4包括下列步骤：化合物IV-4在钯试剂催化下与化合物IV-3通过偶联反应合成化合物IV-1，化合物IV-1再进一步与化合物IV-2通过偶联反应得到化合物所述的通式I所示的芳香杂环取代烯烃化合物。
路线4：
Figure PCTCN2018124667-appb-000059
其中，X 3和X 4独立地为Cl、Br或I。Y 1和Y 2独立地为有机锡试剂如三正丁基锡试剂、或者有机硼试剂如硼酸或频哪醇硼酯等。环C1和环C2其中一个为环A，另一个为环B；R d和R c一个为R 1，另一个为R 2；当环C1为环A时，R d为R 1；R 1、R 2、环A和环B的定义均同前所述。
例如：
Figure PCTCN2018124667-appb-000060
本发明中所述各条反应路线中涉及的化学反应所采用的条件和步骤均可参照本领域常规的此类反应的条件和步骤进行，具体可参照文献：R.Larock,Comprehensive Organic Transformations,VCH Publishers(1989)；T.W.Greene and P.G.M.Wuts,Protective Groups in Organic Synthesis,3 rd ED.,John Wiley and Sons(1999)；L.Fieser and M.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis,John Wiley and Sons(1994)；L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis,John Wiley and Sons(1995)及其后续的版本。本申请在此引用上述文献全文。此外，上述方法所得的化合物还可以参照上述文献的相关方法，进一步通过对外周位置进行修饰而获得本发明的其它目标化合物。
本发明还提供了下列任一中间体化合物：
Figure PCTCN2018124667-appb-000061
Figure PCTCN2018124667-appb-000062
按照上述方法制备得到的至少一种芳香杂环取代烯烃化合物或其药学上可接受的盐可以通过柱层析、高效液相色谱、结晶或其它适当的条件进行纯化。所述柱层析、高效液相色谱和结晶等纯化方法的条件和步骤均可按照本领域常规的条件和步骤选择。
本文所述的化合物，包括但不限于，它们的光学异构体、外消旋体及其他混合物。在这些情况下，单一对映体或非对映体，例如具有光学活性的结构，可通过不对称合成或由外消旋混合物或非对映体混合物拆分得到。对于消旋混合物或非对映体混合物的拆分，可以用传统的方法分离，例如使用拆分试剂结晶；也可以用色谱法分离。例如手性高效液相色谱(HPLC)柱。本文所述化合物存在各种互变异构体，术语“化合物”包括该化合物的所有互变异构形式。这里化合物也包括其不同的晶体形式，包含多晶和包合物。同样，术语“盐”也包括了其所有光学异构体、消旋体，及其他混合物、互变异构体和晶体形式。
本发明还提供了所述的通式I所示的芳香杂环取代烯烃化合物或其药学上可接受的盐在制备ALK5抑制剂或者制备用于治疗和/或预防ALK5介导的疾病的药物中的应用。
所述的“ALK5介导的疾病”包括但不限于：癌症、器官纤维化、病毒感染、慢性肾炎、急性肾炎、糖尿病肾病、骨质疏松症、关节炎、伤口愈合、溃疡、角膜创伤、心脏瓣膜狭窄、充血性心脏坏死、神经功能损伤、阿尔兹海默综合征、腹膜或皮下粘连、动脉硬化症和肿瘤转移生长中的一种或多种，优选癌症和/或器官纤维化。所述的癌症包括但不限于结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、子宫颈癌、睾丸癌、肾癌、头或颈癌、骨癌、皮肤癌、直肠癌、肝癌、结肠癌、食道癌、胃癌、胰腺癌、甲状腺癌、膀胱癌、淋巴瘤、白血病和黑色素瘤。所述的器官纤维化包括但不限于 肾纤维化、肝纤维化和肺纤维化。
本发明还提供了一种药物组合物，其包含预防和/或治疗有效剂量的所述的通式I所示的芳香杂环取代烯烃化合物和其药学上可接受的盐中的一种或多种，以及药学上可接受的载体。
本发明中，所述的“预防和/或治疗有效剂量”表示(i)预防和/或治疗本申请所述的具体疾病或病症的本发明化合物的量，(ii)削弱、改善或消除本申请所述的具体疾病或病症的一种或多种症状的本发明化合物的量，或(iii)预防或延迟本申请所述的具体疾病或病症的一种或多种症状的发作的本发明化合物的量。治疗人类患者的剂量可为0.0001mg/kg-50mg/kg，最通常为0.001mg/kg-10mg/kg体重，例如0.01mg/kg-1mg/kg范围内。这样的剂量可给予例如每日1-5次。
根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等，优选片剂、丸剂、颗粒剂和胶囊等。
为了使片剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石粉等；粘合剂，如阿拉伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋性剂，例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油等)，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体。例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇 和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。
本发明中，所述药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状，选择各种剂型的制剂给药。例如，片剂、丸剂、溶液、悬浮液、乳液、颗粒剂或胶囊口服给药；针剂可以单独给药，或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射；栓剂为给药到直肠。
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：
本发明术语前面和/或后面可以加单破折号，“-”，或双破折号，“＝”，表明被命名取代基及其母体部分之间键的键序；单破折号表示单键，双破折号表示双键或螺环取代基情况下的一对单键。在没有单破折号或双破折号时，可以认为在取代基及其母体部分之间形成单键；此外，取代基是被“从左到右”阅读，除非另有指示。例如，C 1- 6烷氧基羰基氧基和-OC(O)C 1- 6烷基表示相同的功能；同样，芳基烷基，芳基烷基-，和-烷基芳基表示相同的功能。
本发明术语“烷基”指包括1～6个碳原子的支链和直链的饱和脂族烃基，比如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基及它们的各种异构体。本发明中确定了碳数范围的“C x1-y1”烷基(x1和y1为整数)，如“C 1-6烷基”，除碳数范围与本段中“烷基”的碳数定义范围不同外，其余定义均相同。当“烷基”基团作为两个其它类之间的连接基团时，它也可以是直链或支链，例子包括但不限于-CH 2-，-CH 2CH 2-，-CH 2CH 2CHC(CH 3)-，-CH 2CH 2(CH 2CH 3)CH 2-。
本发明术语“环烷基”指单环或双环环烷基。单环环烷基是含3至10个碳原子的环烃基基团，这些基团可以饱和或不饱和，但不是芳族。在某些实施方式中，环烷基基团完全饱和。双环环烷基是桥接的单环环烷基或稠合的双环环烷基。桥接的单环环烷基中含有单环环烷基环，其中单环环烷基环的两个非相邻碳原子被一至三个额外碳原子之间的亚烷基桥连接(即，-(CH 2) w-形式的桥接基团，其中w是1、2或3)。稠合双环环烷基包含稠合到苯基、单环环烷基、单环环烯基、单环杂环基或单环杂芳基的单环环烷基环。桥连或稠合的双环环烷基，通过单环环烷基环内含有的任何碳原子连接到母体分子部分。环烷基可以任选地被作为独立氧代基或硫基的一个或两个基团取代。
本发明中术语“环烯基”指单环或双环环烯基。单环环烯基是含3至8个碳原子的环烃基基团，这些基团不饱和(即，含有至少一个环形碳-碳双键)但不是芳族。双环环烯基环是桥连的单环环或稠合的双环环。桥接的单环环中含有单环环烯基环，其中单环环的两个非相邻碳原子被一至三个额外碳原子之间的亚烷基桥连接(即，-(CH 2) w-形式的桥接基团，其中w是1、2或3)。稠合双环环烯基环系统包含稠合到苯基、单环环烷基、 单环环烯基、单环杂环基或单环杂芳基的单环环烯基环。桥连或稠合的双环环烯基，通过单环环烯基环内含有的任何碳原子连接到母体分子部分。环烯基基团可以任选地被作为独立氧代基或硫基的一个或两个基团取代。
本发明中，术语“烷氧基”指通过氧桥连接的具有所述碳原子数目的环状或者非环状烷基。由此，“烷氧基”包含以上烷基和环烷基的定义。
本发明中，术语“烷硫基”指通过硫桥连接的具有所述碳原子数目的环状或者非环状烷基。由此，“烷硫基”包含以上烷基和环烷基的定义。
本发明中，术语“烯基”指含有指定数目碳原子和至少一个碳碳双键的直链、支链或者环状非芳香烃基。优选存在一个碳碳双键，并且可以存在高达四个非芳香碳碳双键。由此，“C 2-8烯基”是指具有2-8个碳原子的烯基。烯基的直链、支链或者环部分可以含有双键，并且如果表明为取代烯基，那么可以被取代。
本发明中，术语“炔基”指含有指定数目碳原子和至少一个碳碳三键的直链、支链或者环状烃基。其中可以存在高达三个碳碳三键。由此，“C 2-8炔基”是指具有2-8个碳原子的炔基。“C 2-6炔基”是指具有2-6个碳原子的炔基。
本发明中，术语“芳基”是指单环芳基或芳族双环体系中含有至少一个苯环或只含有碳原子的双环体系。双环芳基可以是稠合到单环环烷基、单环环烯基或单环杂环的苯基。双环芳基通过双环体系的苯基部分所含的任何碳原子或带有萘基或薁基的任何碳原子附到母体分子上。双环芳基的稠合单环环烷基或单环杂环基部分可以任选地被一个或两个氧代基和/或硫基基团取代。在某些实施例中，双环芳基是稠合到5元或6元单环环烷基、5元或6元单环环烯基或5元或6元单环杂环基的(i)萘基或(ii)苯基环，其中稠合的环烷基、环烯基和杂环基可以任选地被作为独立氧代基或硫基的一个或两个基团取代。
本发明中，术语“氰基”指-CN基团。
本发明中，术语“羧基”指-COOH基团。
本发明中，术语“磺酸基”指-SOOOH基团。
本发明中，术语“卤素”指氟、氯、溴或碘。
本发明中，术语“杂芳基”指含有至少一个杂芳环的单环杂芳基或双环体系。单环杂芳基可以是一个5元或6元环。5元环由两个双键和一个、两个、三个或四个氮原子以及一个氧原子或硫原子组成。6元环由三个双键和一个、两个、三个或四个氮原子组成。5元或6元杂芳基通过杂芳基内含有的任意碳原子或氮原子连接到母体分子上。双环杂芳基由稠合到苯基、单环环烷基、单环环烯基、单环杂环基或单环杂芳基的单环杂芳基组成。稠合的双环杂芳基的环烷基或杂环基部分可以任选地被作为独立氧代基或硫基的一 个或两个基团取代。当双环杂芳基含有稠合的环烷基、环烯基或杂环基环时，则双环杂芳基通过双环体系的单环杂芳基部分含有的任何碳原子或氮原子连接到母体分子上。当双环杂芳基是稠合到苯环或单环杂芳基的单环杂芳基时，双环杂芳基通过双环体系内任何碳原子或氮原子连接到母体分子上。在某些实施例中，稠合双环杂芳基是稠合到苯基环、5元或6元单环环烷基、5元或6元单环环烯基、5元或6元单环杂环基或5元或6元单环杂芳基的5元或6元单环杂芳环，其中稠合的环烷基、环烯基和杂环基可以任选地被作为独立氧代基或硫基的一个或两个基团取代。
本发明中，术语“杂环基”或“杂环”指单环杂环或双环杂环。该单环杂环是3、4、5、6或7元环，含有至少一个选自O、N和S的杂原子，其中该环为饱和或不饱和，但不是芳族。单环杂环通过单环杂环内含有的任何碳原子或氮原子连接到母体分子上。双环杂环是稠合到苯基、单环环烷基、单环环烯基、单环杂环基或单环杂芳基的单环杂环。双环杂环通过双环体系的单环杂环部分内含有的任何碳原子或氮原子连接到母体分子上。在某些实施例中，双环杂环基是稠合到苯环、5元或6元单环环烷基、5元或6元单环环烯基、5元或6元单环杂环基或5元或6元单环杂芳基的5元或6元单环杂环基环，其特征在于双环杂环基可以任选地被作为独立氧代基或硫基的一个或两个基团取代。
本发明中，术语“羟基”指一个-OH基团。
本发明中，术语“硝基”指一个-NO 2基团。
关于任一基团包含一个或多个取代基，本领域一般技术人员均可理解，但不包括不切实际的高位阻、合成上不可行的和/或内在不稳定的取代基。
本发明中，所用的术语“药学上可接受的盐”指药学上可接受的与酸或与碱形成的盐和溶剂化物。这类药学上可接受的盐包括但不限于与无机酸形成的盐，如盐酸盐、磷酸盐、二磷酸盐、氢溴酸盐、硫酸盐、亚磺酸盐、硝酸盐、及其类似盐；也包括与有机酸形成的盐，如苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、醋酸盐、乳酸盐、磺酸盐、对甲苯磺酸盐、2-羟基乙基磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐和链烷酸盐如醋酸盐，HOOC-(CH 2) n-COOH其中n为0-4的盐，及其类似盐。类似地，药学上可接受的阳离子包括但不限于钠、钾、钙、铝、锂和铵。本领域的成熟技术人员可识别各种可能用来制备无毒的药学上可接受的盐的合成方法。
本发明中，所述的“溶剂化物”如“水合物”，是由溶剂和化合物互相作用形成。术语“化合物”，应该包括了化合物的溶剂化物(包括化合物的水合物)。同样，“盐”也包括了盐的溶剂化物(如盐的水合物)。合适的溶剂化物是药学上可接受的，例如水合物，它包括了单水合物和半水合物。
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。
本发明中，所述的室温指环境温度，为10℃-35℃。
本发明的积极进步效果在于：本发明的芳香杂环取代烯烃化合物是一种ALK5抑制剂，可用于制备治疗癌症、肾纤维化、肝纤维化、肺纤维化、病毒感染、慢性肾炎、急性肾炎、糖尿病肾病、骨质疏松症、关节炎、伤口愈合、溃疡、角膜创伤、心脏瓣膜狭窄、充血性心脏坏死、神经功能损伤、阿尔兹海默综合征、腹膜或皮下粘连、动脉硬化症和肿瘤转移生长等疾病的药物。
具体实施方式
本发明所用的试剂和原料(除了中间体)均为商业渠道获得。本发明中所述的室温指环境温度，为10℃-35℃。过夜是指8-15小时。回流是常压下溶剂回流温度。
以下为实施例中使用到的缩写列表：
DMF                  N,N-二甲基甲酰胺
HATU                 2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯
EDCI                 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐
HOBt                 1-羟基苯并三唑
DIPEA                二异丙基乙基胺
Pd(PPh 3) 4            四三苯基膦钯
Pd(dppf)Cl 2          [1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物
Pd(PPh 3) 2Cl 2         二氯二(三苯基磷)钯
LiHMDS               双-(三甲基硅基)胺基锂
TBAF                 四丁基氟化铵
TMS                  三甲硅基
下述实施例中，通过核磁数据中碳碳双键上氢的耦合常数来判断制备的化合物为顺式构型(Z)还是反式构型(E)。通常，E构型化合物双键上两个H之间的耦合常数明显大于相应的Z型化合物双键上的两个H之间的耦合常数。在本发明中，获得的E型化合物，以对比化合物23，24为例，碳碳双键上的两个氢的耦合常数为16左右。而获得的相应的Z型化合物，即化合物1，3，碳碳双键上的两个氢的耦合常数为12.5左右。
化合物1的合成路线
Figure PCTCN2018124667-appb-000063
化合物1-f的合成
往反应瓶中加入SM-1(2g,7.4mmol)，三甲硅基乙炔(0.73g,7.4mmol)，二(三苯基膦)二氯化钯(104mg，0.148mmol)，碘化亚铜(28mg，0.148mmol)和三乙胺(15mL)。反应混合物用N 2置换，于20℃反应2小时。反应结束后，浓缩除去有机溶剂，加入水(30mL)，用乙酸乙酯(30mL)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干，粗品经柱层析(PE:EA＝4:1)纯化得到化合物1-f(1.34g，63％)为黄色固体。LC-MS(ESI):m/z＝287.3[M+H]+.
化合物1-e的合成
往化合物1-f(1.24g，4.33mmol)的甲醇(20mL)和二氯甲烷(20mL)溶液中加入碳酸钾(1.8g，13mmol)，混合物在室温条件下搅拌2小时。浓缩除去有机溶剂，加入水(20mL)，用乙酸乙酯(30mL*2)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干，得到化合物1-e(435mg，50％)为黄色固体。LC-MS(ESI):m/z＝201.3[M+H] +.
化合物1-d的合成
往反应瓶中加入1-e(435mg，2.17mmol)，2-溴-6-甲基吡啶(374mg，2.17mmol)，二(三苯基膦)二氯化钯(152mg，0.217mmol)，碘化亚铜(41mg，0.217mmol)和三乙胺(15mL)。反应混合物用N 2置换，于20℃反应2小时。反应结束后，浓缩除去有机溶剂，加入水(30mL),用乙酸乙酯(30mL*2)萃取，有机相依次用水洗，饱和氯化 钠水溶液洗，无水硫酸钠干燥。过滤，旋干，粗品经柱层析(DCM:MeOH＝20:1)纯化得到化合物1-d(476mg，75％)为黄色固体。LC-MS(ESI):m/z＝292.0[M+H] +.
化合物1-c的合成
往反应瓶中加入化合物1-d(200mg，0.69mmol)，四氢呋喃(6mL)，甲醇(6mL)和水(3mL)，氢氧化锂一水合物(144mg，3.43mmol)。混合物在室温搅拌过夜后，加入稀盐酸将pH值调节为6-7，用乙酸乙酯(30mL*3)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干，得到粗品化合物1-c(101mg，53％)。LC-MS(ESI):m/z＝278.1[M+H] +.
化合物1-b的合成
在冰浴条件下往化合物1-c(101mg，0.36mmol)的二氯甲烷(6mL)溶液中慢慢加入草酰氯(3mL)，再加入一滴DMF，混合物在室温搅拌过夜后，浓缩即得到粗品化合物1-b(138mg)。
化合物1-a的合成
在冰浴条件下，往氨水(6mL)中慢慢加入化合物1-b(138mg，0.36mmol)的二氯甲烷(6mL)溶液，混合物在室温搅拌十分钟后。浓缩，粗品经Prep-TLC(展开剂DCM:MeOH＝10:1)纯化得到化合物1-a(45mg，45％)为白色固体。LC-MS(ESI):m/z＝277.1[M+H]+； 1H NMR(400MHz,MeOD):δ9.85(s,1H),8.35(s,1H),7.80(t,J＝7.8Hz,1H),7.76(dd,J＝9.3,0.9Hz,1H),7.68(dd,J＝9.3,1.7Hz,1H),7.53(d,J＝7.7Hz,1H),7.35(d,J＝7.7Hz,1H),2.58(s,3H).
化合物1的合成
在室温下往化合物1-a(38mg，0.14mmol)的乙酸乙酯(8mL)溶液中加入Pd-CaCO 3(10mg)，反应液抽真空，用H 2置换多次，混合物在室温下搅拌2小时。过滤，浓缩，粗品经Prep-HPLC纯化得到化合物1(10mg，26％)为白色固体。LC-MS(ESI):m/z＝279.1[M+H]+； 1H NMR(400MHz,MeOD):δ9.47-9.57(m,1H),8.25(s,1H),7.59(t,J＝7.8Hz,1H),7.52(dd,J＝9.2,0.8Hz,1H),7.33(dd,J＝8.8,2.0Hz,1H),7.16(d,J＝7.6Hz,1H),7.11(d,J＝7.6Hz,1H),6.87(d,J＝12.4Hz,1H),6.82(d,J＝12.4Hz,1H),2.50(s,3H).其中，6.87(d,J＝12.4Hz,1H),6.82(d,J＝12.4Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
化合物2的合成路线
Figure PCTCN2018124667-appb-000064
化合物2-a的合成
在冰浴条件下往化合物1-c(100mg，0.36mmol)的二氯甲烷(10mL)溶液中慢慢加入草酰氯(1mL)，再加入一滴DMF，混合物在室温搅拌1小时后，浓缩，加入二氯甲烷(10mL)。在冰浴条件下往SM-2(93.9mg，0.72mmol)的二氯甲烷(10mL)溶液中慢慢加入该溶液，混合物在室温搅拌过夜。次日，浓缩，粗品经Prep-TLC(DCM:MeOH＝10:1)纯化得到化合物2-a(60mg,43％)为白色固体，LC-MS(ESI):m/z＝390.1[M+H]+.
化合物2的合成
在室温下往化合物2-a(60mg，0.15mmol)的乙酸乙酯/甲醇(v/v＝2/1,5mL)溶液中加入喹啉(40mg，0.3mmol)和Pd-CaCO 3(20mg)，反应液抽真空，用H 2置换多次，混合物在室温下搅拌2小时。过滤，浓缩，粗品经Prep-HPLC纯化得到化合物2(20mg，33％)为白色固体。LC-MS(ESI):m/z＝392.2[M+H]+； 1H NMR(500MHz,MeOD)：δ9.52(s,1H),8.19(s,1H),7.60(t,J＝7.5Hz,1H),7.52(d,J＝9.5Hz,1H),7.33(dd,J＝9.5Hz,1.5Hz,1H),7.17(d,J＝8Hz,1H),7.12(d,J＝8Hz,1H),6.85(d,J＝12.5Hz,1H),6.83(d,J＝12.5Hz,1H),3.72-3.74(m,4H),3.54-3.58(m,2H),2.61-2.64(m,2H),2.55-2.60(m,4H),2.51(s,3H).其中，6.85(d,J＝12.5Hz,1H),6.83(d,J＝12.5Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
化合物3的合成路线
Figure PCTCN2018124667-appb-000065
化合物3-a的合成
往反应瓶中加入1-c(100mg，0.36mmol)，DMF(8mL)，甲胺四氢呋喃溶液(2.0M，0.36mL)，HATU(274mg，0.72mmol)，三乙胺(0.25mL，1.8mmol)。混合物在室温下反应4小时。反应结束后，加入水(100mL)，用乙酸乙酯(30mL*3)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干，粗品经柱层 析(DCM:MeOH＝20:1)纯化，得到化合物3-a(70mg，67％)为黄色固体。LC-MS(ESI):m/z＝291.1[M+H]+.
化合物3的合成
在室温下往化合物3-a(70mg，0.24mmol)的吡啶(10mL)溶液中加入Pd-CaCO 3(30mg)，反应液抽真空，用H 2置换多次，混合物在室温下搅拌过夜。过滤，浓缩，粗品经Prep-HPLC纯化得到化合物3(20mg,31％)为白色固体。LC-MS(ESI):m/z＝293.0[M+H]+； 1H NMR(500MHz,MeOD):δ9.51(s,1H),8.14(s,1H),7.59(t,J＝7.8Hz,1H),7.50(d,J＝9.3Hz,1H),7.31(dd,J＝9.3,1.7Hz,1H),7.17(d,J＝7.7Hz,1H),7.11(d,J＝7.8Hz,1H),6.86(d,J＝12.5Hz,1H),6.82(d,J＝12.5Hz,1H),2.92(s,3H),2.50(s,3H).其中，6.86(d,J＝12.5Hz,1H),6.82(d,J＝12.5Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
化合物4的合成路线
Figure PCTCN2018124667-appb-000066
化合物4-d的合成
将化合物溴甲基三苯基溴化磷(2.16g,4.95mmol)的四氢呋喃(10mL)溶液氮气保护下用干冰丙酮浴冷却至-78℃，向里慢慢加入叔丁醇钾(0.56g，4.95mmol)，得到的混合物于-78℃反应1小时，然后滴加6-甲基-2-吡啶甲醛(0.5g,4.95mmol)，加完后维持该低温搅拌5小时，慢慢升温至室温并搅拌过夜。次日，反应液用石油醚稀释，过滤，浓缩，粗品经柱层析纯化(石油醚/乙酸乙酯＝10：1)得化合物4-d(500mg，51％)。LC-MS(ESI):m/z＝197.9[M+H]+； 1H NMR(500MHz,DMSO-d 6):δ7.73-7.75(m,2H),7.26(d,J＝8Hz,1H),7.22(dd,J＝7.5Hz,2Hz,1H),6.90(d,J＝8Hz,1H),2.48(s,3H).
化合物4-c的合成
化合物4-c根据WO2015/157093方法合成。
化合物4-b的合成
往反应瓶中加入化合物4-c(0.3g，1.24mmol)，DCM(3mL)，THF(20mL)，HATU(943mg，2.48mmol)，混合物在室温下搅拌半小时后，加入环丙胺(0.13mL，1.88mmol)和DIPEA(1.08mL，6.2mmol)，混合物在室温搅拌4h。浓缩，加入水，用乙酸乙酯(30mL*2)萃取，有机相用无水硫酸钠干燥。过滤，旋干，粗品经柱层析(DCM:MeOH＝50:1)纯化得到粗品化合物4-b(350mg)为黄色油状物。LC-MS(ESI):m/z＝280.0[M+H]+.
化合物4-a的合成
往反应瓶中加入4-b(0.35g，1.24mmol)，双联频哪醇硼酸酯(381mg，1.5mmol)，Pd(dppf)Cl 2(92mg，0.125mmol)，醋酸钾(245mg，2.5mmol)，1,4-二氧六环(20mL)和甲苯(4mL)。反应混合物用N 2置换，于90℃反应过夜。反应结束后，浓缩除去有机溶剂，粗品经柱层析(DCM:MeOH＝20:1)纯化得到化合物4-a(0.3g，97％)为黑色固体。LC-MS(ESI):m/z＝246.1[M+H]+。
化合物4的合成
往反应瓶中加入4-a(300mg，1.22mmol)，4-d(241mg，1.22mmol)，Pd(dppf)Cl 2(89mg，0.122mmol)，碳酸钠(259mg，2.44mmol)1,4-二氧六环(15mL)和水(3mL)。反应混合物用N 2置换，于90℃反应过夜。反应结束后，浓缩除去有机溶剂，粗品经柱层析(DCM:MeOH＝20:1)和Prep-HPLC纯化得到化合物4(20mg，5％)。LC-MS(ESI):，m/z＝319.0[M+H]+； 1H NMR(500MHz,MeOD):δ9.51(s,1H),8.16(s,1H),7.56(t,J＝7.8Hz,1H),7.48(d,J＝9.3Hz,1H),7.29(dd,J＝9.3,1.6Hz,1H),7.14(d,J＝7.7Hz,1H),7.08(d,J＝7.7Hz,1H),6.83(d,J＝12.5Hz,1H),6.79(d,J＝12.5Hz,1H),2.82(m,1H),2.48(s,3H),0.84-0.80(m,2H),0.71-0.59(m,2H).其中，6.83(d,J＝12.5Hz,1H),6.79(d,J＝12.5Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
化合物5的合成路线
Figure PCTCN2018124667-appb-000067
化合物5-a的合成
往反应瓶中加入化合物1-c(0.55g，1.98mmol)，DMF(10mL)和THF(20mL)，HATU(1.5g，3.96mmol)，混合物在室温下搅拌半小时后，加入邻(四氢-2氢-吡喃-2- 基)羟基胺(0.23g，1.98mmol)和三乙胺(0.6g，5.94mmol)，混合物在室温搅拌过夜后，浓缩，加入水，用乙酸乙酯(30mL*3)萃取,有机相用无水硫酸钠干燥。过滤，旋干，粗品经Prep-TLC(DCM:MeOH＝20:1)纯化得到化合物5-a(200mg，27％)。LC-MS(ESI):m/z＝377.0[M+H]+.
化合物5的合成
在室温下往化合物5-a(38mg，0.10mmol)的吡啶(10mL)溶液中加入Pd-CaCO 3(100mg)，反应液抽真空，用H 2置换多次，混合物在室温下搅拌过夜.过滤，浓缩，粗品经Prep-HPLC纯化得到化合物5(5mg，13％)为白色固体。LC-MS(ESI):m/z＝379.0[M+H]+； 1H NMR(500MHz,MeOD):δ9.43(s,1H),8.18(s,1H),7.60(t,J＝7.8Hz,1H),7.55(d,J＝9.4Hz,1H),7.37(dd,J＝9.3,1.5Hz,1H),7.18(d,J＝7.7Hz,1H),7.13(d,J＝7.8Hz,1H),6.83(d,J＝12.5Hz,1H),6.79(d,J＝12.5Hz,1H),5.05(s,1H),4.14(t,J＝10.7Hz,1H),3.66(d,J＝11.6Hz,1H),2.87(s,1H),2.50(s,3H),2.01-1.69(m,5H).其中，6.83(d,J＝12.5Hz,1H),6.79(d,J＝12.5Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
化合物6的合成路线
Figure PCTCN2018124667-appb-000068
化合物6的合成
在冰浴条件下往化合物1(0.16g，0.57mmol)的THF(5mL)和DCM(5mL)溶液中加入吡啶(180mg，2.28mmol)和三氟醋酸酐(241mg，1.15mmol)，混合物在室温下搅拌2小时后。浓缩，溶于乙酸乙酯(30mL)中,分别用1M盐酸溶液和饱和碳酸氢钠溶液洗涤，有机相用无水硫酸钠干燥。过滤，旋干，粗品经柱层析(DCM:MeOH＝30:1)和Prep-HPLC纯化得到化合物6(30mg，20％)为白色固体。LC-MS(ESI):m/z＝261.1[M+H]+； 1H NMR(500MHz,MeOD):δ8.86(s,1H),8.26(s,1H),7.70–7.60(m,2H),7.47(dd,J＝9.4,1.6Hz,1H),7.22(d,J＝7.7Hz,1H),7.17(d,J＝7.7Hz,1H),6.90(d,J＝12.5Hz,1H),6.86(d,J＝12.5Hz,1H),2.54(s,3H).其中，6.90(d,J＝12.5Hz,1H),6.86(d,J＝12.5Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
化合物7的合成路线
Figure PCTCN2018124667-appb-000069
化合物7的合成
往反应瓶中加入化合物6(28mg，0.11mmol)，DMF(6mL)，叠氮基三甲基硅烷(25mg，0.22mmol)，氟化铵(12mg，0.33mmol)和混合物在70℃下搅拌4小时后，旋干，经Prep-HPLC纯化得到化合物7(3mg，9％)为白色固体。LC-MS(ESI):m/z304.0[M+H]+； 1H NMR(500MHz,MeOD):δ9.51(s,1H),8.12(s,1H),7.60(t,J＝7.8Hz,1H),7.51(d,J＝9.3Hz,1H),7.26(dd,J＝9.4,1.6Hz,1H),7.17(dd,J＝7.7,4.1Hz,2H),6.96(d,J＝12.5Hz,1H),6.85(d,J＝12.5Hz,1H),2.47(s,3H).其中，6.96(d,J＝12.5Hz,1H),6.85(d,J＝12.5Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
化合物8的合成路线
Figure PCTCN2018124667-appb-000070
化合物8-c的合成
将化合物SM-1(5.4g,20mmol)，三甲硅基乙炔(4g，40mmol)，PdCl 2(PPh 3) 2(1.4g，2mmol)和碘化亚铜(0.38g，2mmol)以及三乙胺(100mL)的混合物于氮气氛围下室温反应12小时。旋干有机相，柱层析(EA：PE＝1:5)纯化得到化合物8-c(2.86g，50％)为黄色固体。LC-MS(ESI):m/z＝287.0[M+H]+.
化合物8-b的合成
将8-c(2.86g，10mmol)加入THF(100mL)，加入TBAF溶液(1M，20mmol，20mL)，室温搅拌2小时。反应结束后，减压浓缩除去有机溶剂，加入水(1000mL)和DCM(500mL)，分液，旋干有机相，柱层析(EA：PE＝1:5然后1:3)纯化得到化合物8-c(1.6g，75％)为黄色固体。LC-MS(ESI):m/z＝215.1[M+H]+.
化合物8-a的合成
将8-b(1.1g，5.1mmol)，2-溴-6-甲氧基吡啶(1.1g，5.85mmol)，加入到三乙胺(20mL)加入碘化亚铜(0.1g，0.5mmol)和PdCl 2(PPh 3) 2(0.35g,0.5mmol)，室 温搅拌3小时。反应结束后，减压浓缩除去有机溶剂，加入水(100mL)和DCM(50mL)，柱层析(PE/EA＝5/1)得到化合物8-a(0.86g,5,2％)。LCMS(ESI):m/z＝322.0[M+H]+.
化合物8的合成
将化合物8-a(0.64g,2.0mmol)，Pd/CaCO 3(0.1g)和吡啶(10mL)在室温条件下混合，氢气置换后常温搅拌16小时，过滤，浓缩，柱层析(PE/EA＝5/1)得到固体8(0.36g，56％)。LC-MS(ESI):m/z＝324.1[M+H]+； 1H NMR(500MHz,CDCl 3)：δ9.31(s,1H),8.27(s,1H),7.59(d,J＝9.5Hz,1H),7.56(s,1H),7.43-7.53(m,2H),6.81(d,J＝6.0Hz,1H),6.71(d,J＝12.5Hz,1H),6.68(d,J＝12.5Hz,1H),6.60(d,J＝8.5Hz,1H),4.40(q,J＝7.0Hz,2H),3.53(s,3H),1.40(t,J＝7.0Hz,3H).其中，6.71(d,J＝12.5Hz,1H),6.68(d,J＝12.5Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
化合物9的合成路线
Figure PCTCN2018124667-appb-000071
化合物9-a的合成
往8(0.323g,1.0mmol)中分别加入到甲醇(2mL)和THF(8mL),加入氢氧化锂一水合物(0.42g，10mmol)水溶液,室温搅拌2小时。反应结束后，减压浓缩除去有机溶剂，加入水(50mL)和DCM(10mL)，分液，弃去有机层。将水层冷却至0℃,用盐酸(2M)中和至pH为6-7。过滤出棕色沉淀物，干燥得到化合物9-a(0.19g,64％)。LCMS(ESI):m/z＝296.0[M+H]+.
化合物9的合成
将9-a(0.15g,0.5mmol)的混合物溶于二氯甲烷(100mL)中。在冰浴下，向溶液中加入草酰氯(5mL)后慢慢将DMF(0.5mL)加入到反应液中。反应升至室温后继续反应6小时。反应液减压浓缩至干燥，后加入二氯甲烷(40mL)稀释。在冰浴下，将该溶液慢慢滴加到氨水(50mL)中，在0℃下反应10分钟，再升至室温搅拌2小时。浓缩除去二氯甲烷溶液，再将水(60mL)加入到水相稀释剧烈搅拌1小时。过滤，水洗，干燥得到化合物9(0.06g,41％)为白色固体。LC-MS(ESI):m/z＝295.0[M+H]+； 1H NMR(500MHz,MeOD):δ9.56(s,1H),8.27(s,1H),7.50-7.64(m,3H),6.90(d,J＝7.5Hz,1H),6.79(d,J＝12.5Hz,1H),6.74(d,J＝12.5Hz,1H),6.63(d,J＝8.5Hz,1H),3.45(s,3H).其 中，6.79(d,J＝12.5Hz,1H),6.74(d,J＝12.5Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
化合物10的合成路线
Figure PCTCN2018124667-appb-000072
化合物10-d的合成
将2,6-二溴吡啶(1g，4.22mmol)溶于四氢呋喃中(10mL)并冷却到-78℃，再将正丁基锂(2.5M，2.03mL,5.07mmol)慢慢加入其中。反应液在低温下反应半小时，将氘代碘甲烷(0.32mL,5.07mmol)加入反应液中，升温到常温再搅拌一小时。用水(10mL)淬灭，乙酸乙酯(10mL*3)萃取，合并有机相用无水硫酸钠干燥。过滤，浓缩得到化合物10-d(0.5g，67％)为棕色液体。LC-MS(ESI):m/z＝175.0[M+H]+.
化合物10-c的合成
往反应瓶中加入1-e(200mg,1mmol)，10-d(192mg,1.1mmol)，二(三苯基膦)二氯化钯(70mg,0.1mmol)，碘化亚铜(19mg，0.1mmol)和三乙胺(15mL)。反应混合物用N 2置换，于20℃反应2小时。反应结束后，浓缩除去有机溶剂，加入水(30mL),用乙酸乙酯(30mL*2)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干，粗品经柱层析(PE:EA＝1:1)纯化得到化合物10-c(60mg,20％)为黄色固体。LC-MS(ESI):m/z＝295.0[M+H]+.
化合物10-b的合成
往反应瓶中加入化合物10-c(60mg，0.2mmol)，四氢呋喃(6mL)，甲醇(6mL)和水(3mL)，氢氧化锂一水合物(34.2mg，0.8mmol)，混合物在室温搅拌过夜后，加入稀盐酸将pH值调节为6-7，用乙酸乙酯(30mL*3)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干即得到粗品化合物10-b(30mg,53％)。LC-MS(ESI):m/z＝281.1[M+H]+.
化合物10-a的合成
在冰浴条件下往化合物10-b(30mg，0.11mmol)的二氯甲烷(10mL)溶液中慢慢加入草酰氯(1mL)，再加入一滴DMF，混合物在室温搅拌1小时，浓缩即得到粗品。在冰浴条件下往氨水(5mL)中慢慢加入以上粗品的二氯甲烷(10mL)溶液，混合物在室温搅拌搅拌过夜，浓缩，粗品经Prep-TLC(DCM:MeOH＝10:1)纯化得到化合物10-a(15mg,50％)为白色固体。LC-MS(ESI):m/z＝280.2[M+H]+.
化合物10的合成
在室温下往化合物10-a(15mg，0.05mmol)的吡啶(10mL)溶液中加入Pd-CaCO 3(10mg)，反应液抽真空，用H 2置换多次，混合物在室温下搅拌过夜，过滤，浓缩，粗品经Prep-HPLC纯化得到化合物10(5mg，33％)为白色固体，LC-MS(ESI):m/z＝282.1[M+H]+； 1H NMR(500MHz,MeOD):δ9.54(s,1H),8.25(s,1H),7.60(t,J＝8.0Hz,1H),7.53(d,J＝9.0Hz,1H),7.35(d,J＝8.0Hz,1H),7.17(d,J＝7.5Hz,1H),7.12(d,J＝7.5Hz,1H),6.88(d,J＝12Hz,1H),6.83(d,J＝12Hz,1H).其中，6.88(d,J＝12Hz,1H),6.83(d,J＝12Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
化合物11的合成路线
Figure PCTCN2018124667-appb-000073
化合物11-f的合成
将SM-3(500mg，2.07mmol)溶于二氯甲烷(10mL)中。在冰浴下，向溶液中慢慢加入草酰氯(1mL)和一滴DMF。反应物升至室温反应60分钟。反应物减压浓缩，加入二氯甲烷(5mL)稀释。在冰浴下，将该溶液慢慢滴加到氨水(5mL)中，反应混合物在0℃下反应10分钟，再升至室温搅拌过夜。分液，水层用二氯甲烷萃取，合并有 机相分别用水和食盐水洗涤，无水硫酸钠干燥。浓缩得到化合物11-f(300mg,60％)为白色固体。LC-MS(ESI):m/z＝239.9[M+H]+.
化合物11-e的合成
将11-f(100mg,0.42mmol)溶于二氧六环(10mL)中。在冰浴下，向溶液中加入吡啶(0.34mL，4.2mmol)，搅拌5分钟后慢慢滴加三氟乙酸酐(0.29mL，2.08mmol)。反应物升至室温搅拌5小时。反应结束后，加入水淬灭，再减压浓缩除去有机溶剂。混合物溶于乙酸乙酯，分别经水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到化合物11-e(80mg,86％)为白色固体。LC-MS(ESI):m/z＝221.9[M+H]+.
化合物11-d的合成
往反应瓶中加入11-e(0.5g,2.25mmol)，三甲基硅基乙炔(0.24g,2.48mmol)，二(三苯基膦)二氯化钯(31.6mg，0.045mmol)，碘化亚铜(8.6mg,0.045mmol)和三乙胺(15mL)。反应混合物用N 2置换，于20℃反应2小时。反应结束后，浓缩除去有机溶剂，加入水(30mL)，用乙酸乙酯(30mL)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干，粗品经柱层析(PE:EA＝4:1)纯化得到化合物11-d(0.5g,92％)为黄色固体。LC-MS(ESI):m/z＝240.1[M+H]+.
化合物11-c的合成
往化合物11-d(0.5g，2.09mmol)的四氢呋喃(10mL)溶液中加入四丁基氟化铵的四氢呋喃溶液(1M，6.68mL,6.68mmol)，混合物在室温条件下搅拌2小时，浓缩除去有机溶剂，加入水(20mL)，用乙酸乙酯(30mL*2)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干。粗品经硅胶柱层析(PE:EA＝4:1)纯化得到化合物11-c(250mg，72％)为黄色固体。LC-MS(ESI):m/z＝168.1[M+H]+.
化合物11-b的合成
往反应瓶中加入11-c(250mg,1.50mmol)，2-溴-6-三氟甲基吡啶(371.8mg,1.65mmol)，二(三苯基膦)二氯化钯(21mg,0.03mmol)，碘化亚铜(5.7mg，0.03mmol)和三乙胺(15mL)。反应混合物用N 2置换，于20℃反应2小时。反应结束后，浓缩除去有机溶剂，加入水(30mL)，用乙酸乙酯(30mL*2)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干，粗品经柱层析(PE:EA＝3:1)纯化得到化合物11-b(100mg,21％)为黄色固体。LC-MS(ESI):m/z＝313.0[M+H]+.
化合物11-a的合成
往反应瓶中加入化合物11-b(60mg，0.19mmol)，碳酸钾(4mg，0.029mmol)，二甲亚砜(2mL)。冰浴下，滴加入H 2O 2(26.1mg，0.77mmol)，加毕混合物在室温搅 拌过夜。次日，过滤，滤饼用水洗涤，干燥得到化合物11-a(50mg，79％)为白色固体。LC-MS(ESI):m/z＝331.0[M+H]+.
化合物11的合成
在室温下往化合物11-a(50mg，0.15mmol)的吡啶(10mL)溶液中加入Pd-CaCO 3(20mg)，反应液抽真空，用H 2置换多次，混合物在室温下搅拌过夜，过滤，浓缩，粗品经Prep-HPLC纯化得到化合物11(20mg，40％)为白色固体。LC-MS(ESI):m/z＝333.1[M+H]+； 1H NMR(500MHz,MeOD)：δ9.52(s,1H),8.27(s,1H),7.93(t,J＝8.5Hz,1H),7.64(d,J＝7.5Hz,1H),7.50-7.57(m,3H),6.98(d,J＝12.5Hz,1H),6.90(d,J＝12.5Hz,1H).其中，6.98(d,J＝12.5Hz,1H),6.90(d,J＝12.5Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
化合物12的合成路线
Figure PCTCN2018124667-appb-000074
化合物12-c的合成
往反应瓶中加入1-e(400mg，2mmol)，2-溴-3-氟-6-甲基吡啶(417mg，2.2mmol)，二(三苯基膦)二氯化钯(140mg，0.2mmol)，碘化亚铜(38mg，0.2mmol)和三乙胺(15mL)。反应混合物用N 2置换，于20℃反应2小时。反应结束后，浓缩除去有机溶剂，加入水(30mL)，用乙酸乙酯(30mL*2)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干，粗品经柱层析(PE:EA＝1:1)纯化得到化合物12-c(400mg，65％)为黄色固体。LC-MS(ESI):m/z＝310.0[M+H]+.
化合物12-b的合成
往反应瓶中加入化合物12-c(400mg，1.29mmol)，四氢呋喃(6mL)，甲醇(6mL)和水(3mL)，氢氧化锂一水合物(217mg，5.17mmol),。混合物在室温搅拌过夜后，加入稀盐酸将pH值调节为6-7，用乙酸乙酯(30mL*3)萃取，有机相依次用水洗，饱和氯 化钠水溶液洗，无水硫酸钠干燥。过滤，旋干即得到粗品化合物12-b(300mg，78％)。LC-MS(ESI):m/z＝296.0[M+H]+.
化合物12-a的合成
在冰浴条件下往化合物12-b(100mg，0.34mmol)的二氯甲烷(10mL)溶液中慢慢加入草酰氯(1mL)，再加入一滴DMF，混合物在室温搅拌1小时，浓缩即得到粗品。在冰浴条件下往氨水(5mL)中慢慢加入以上粗品的二氯甲烷(10mL)溶液，混合物在室温搅拌搅拌过夜，浓缩，粗品经Prep-TLC(DCM:MeOH＝10:1)纯化得到化合物12-a(50mg,50％)为白色固体。LC-MS(ESI):m/z＝295.0[M+H]+.
化合物12的合成
在室温下往化合物12-a(50mg，0.17mmol)的吡啶(10mL)溶液中加入Pd-CaCO 3(20mg)，反应液抽真空，用H 2置换多次，混合物在室温下搅拌过夜，过滤，浓缩，粗品经Prep-HPLC纯化得到化合物12(17mg，40％)为白色固体，LC-MS(ESI):m/z＝297.0[M+H]+； 1H NMR(500MHz,MeOD):δ9.58(s,1H),8.25(s,1H),7.53(d,J＝9.5Hz,1H),7.46(t,J＝8.5Hz,1H),7.41(dd,J＝9,1.5Hz,1H),7.25(dd,J＝8.5,3.5Hz,1H),6.96(d,J＝12.5Hz,1H),6.82(dd,J＝12.5,2Hz,1H),2.43(s,3H).其中，6.96(d,J＝12.5Hz,1H),6.82(dd,J＝12.5,2Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
化合物13的合成路线
Figure PCTCN2018124667-appb-000075
化合物13-e的合成
往反应瓶中加入乙基5-溴吡唑并[1,5-A]吡啶-3-甲酸酯(2g，7.43mmol)，三甲硅基乙炔(0.8g，8.18mmol)，二(三苯基膦)二氯化钯(100mg，0.15mmol)，碘化亚铜(30mg，0.15mmol)和三乙胺(15mL)。反应混合物用N 2置换，于20℃反应2小时。反应结束后，浓缩除去有机溶剂，加入水(30mL)，用乙酸乙酯(30mL)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥，过滤，旋干，粗品经柱层析(PE:EA＝4:1)纯化得到化合物13-e(0.8g,38％)为黄色固体。LC-MS(ESI):m/z＝287.0[M+H]+。
化合物13-d的合成
往化合物13-e(0.8g,2.79mmol)的四氢呋喃(10mL)溶液中加入四丁基氟化铵的四氢呋喃溶液(1M，5.6mL,5.6mmol)，混合物在室温条件下搅拌2小时，浓缩除去有机溶剂，加入水(20mL)，用乙酸乙酯(30mL*2)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干。粗品经硅胶柱层析(PE:EA＝4:1)纯化得到化合物13-d(500mg,83％)为黄色固体。LC-MS(ESI):m/z＝215.3[M+H]+.
化合物13-c的合成
往反应瓶中加入13-d(500mg,2.33mmol)，2-溴-6-甲基吡啶(441.7mg,2.57mmol),二(三苯基膦)二氯化钯(32.8mg,0.047mmol)，碘化亚铜(9mg,0.047mmol)和三乙胺(15mL)。反应混合物用N 2置换，于20℃反应2小时。反应结束后，浓缩除去有机溶剂，加入水(30mL)，用乙酸乙酯(30mL*2)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥，过滤，旋干，粗品经柱层析(PE:EA＝3:1)纯化得到化合物13-c(400mg,56％)为黄色固体。LC-MS(ESI):m/z＝306.0[M+H]+.
化合物13-b的合成
往反应瓶中加入化合物13-c(400mg，1.31mmol)，四氢呋喃(6mL)，甲醇(6mL)和水(3mL)，氢氧化锂一水合物(220mg，5.24mmol)，混合物在室温搅拌过夜后，加入稀盐酸将pH值调节为6-7，用乙酸乙酯(30mL*3)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干即得到粗品化合物13-b(250mg,69％)。LC-MS(ESI):m/z＝278.0[M+H]+.
化合物13-a的合成
在冰浴条件下往化合物13-b(250mg，0.9mmol)的二氯甲烷(10mL)溶液中慢慢加入草酰氯(1mL)，再加入一滴DMF，混合物在室温搅拌1小时，浓缩即得到粗品。在冰浴条件下往氨水(5mL)中慢慢加入以上粗品的二氯甲烷(10mL)溶液，混合物在室温搅拌搅 拌过夜，浓缩，粗品经Prep-TLC(DCM:MeOH＝10:1)纯化得到化合物13-a(200mg，80％)为白色固体。LC-MS(ESI):m/z＝277.0[M+H]+.
化合物13的合成
在室温下往化合物13-a(40mg，0.15mmol)的吡啶(10mL)溶液中加入Pd-CaCO 3(20mg)，反应液抽真空，用H 2置换多次，混合物在室温下搅拌过夜，过滤，浓缩，粗品经Prep-HPLC纯化得到化合物13(20mg，49％)为白色固体。LC-MS(ESI):m/z＝279.0[M+H]+； 1H NMR(500MHz,MeOD):δ8.4-8.43(m,2H),8.18(s,1H),7.58(t,J＝7.5Hz,1H),7.17(d,J＝8Hz,1H),7.12(d,J＝8Hz,1H),6.90(d,J＝12.5Hz,1H),6.85(d,J＝12.5Hz,1H),6.81(dd,J＝7,2Hz,1H),2.51(s,3H).其中，6.90(d,J＝12.5Hz,1H),6.85(d,J＝12.5Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
化合物14的合成路线
Figure PCTCN2018124667-appb-000076
化合物14-d的合成
往反应瓶中加入化合物氰化锌(602mg,5.13mmol)，7-溴-2-氯喹喔啉(2.5g,10.27mmol)，四三苯基膦钯(1.2g，1.03mmol)和DMF(10mL)。反应液用N 2置换，在80℃下搅拌过夜。反应液用乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥。过滤，旋干。粗品经硅胶柱层析分离(PE:EA＝5:1)得到化合物14-d(2g，83％)为白色固体。LC-MS(ESI):m/z＝233.9[M+H]+.
化合物14-c的合成
往反应瓶中加入14-d(1g,4.27mmol)，三甲基硅基乙炔(0.46g，4.7mmol)，二(三苯基膦)二氯化钯(60mg,0.086mmol)，碘化亚铜(16mg,0.086mmol)和三乙胺(15mL)。反应混合物用N 2置换，于20℃反应2小时。反应结束后，浓缩除去有机溶剂，加入水(30mL)，用乙酸乙酯(30mL)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干，粗品经柱层析(PE:EA＝10:1)纯化得到化合物14-c(0.7g,65％)为黄色固体。LC-MS(ESI):m/z＝252.3[M+H]+.
化合物14-b的合成
往反应瓶中加入14-c(300mg,1.19mmol)，2-溴-6-三氟甲基吡啶(226mg,1.3mmol)，二(三苯基膦)二氯化钯(17mg,0.024mmol)，碘化亚铜(4.5mg,0.024mmol)和三乙胺(15mL)。用N 2置换，滴加入四丁基氟化铵的四氢呋喃溶液(1M，2.4mL,2.4mmol)。反应混合物于20℃反应2小时。反应结束后，浓缩除去有机溶剂，加入水(30mL)，用乙酸乙酯(30mL*2)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干，粗品经柱层析(PE:EA＝2:1)纯化得到化合物14-b(120mg,37％)为黄色固体。LC-MS(ESI):m/z＝271.0[M+H]+.
化合物14-a的合成
往反应瓶中加入化合物14-b(120mg，0.44mmol)，碳酸钾(9mg，0.067mmol),二甲亚砜(2mL)。冰浴下，滴加入H 2O 2(60mg，1.78mmol)，加毕混合物在室温搅拌过夜。次日，过滤，滤饼用水洗涤，干燥得到化合物14-a(100mg,78％)为白色固体。LC-MS(ESI):m/z＝289.0[M+H]+.
化合物14的合成
在室温下往化合物14-a(50mg，0.17mmol)的吡啶(10mL)溶液中加入Pd-CaCO 3(20mg)，反应液抽真空，用H 2置换多次，混合物在室温下搅拌过夜，过滤，浓缩，粗品经Prep-HPLC纯化得到化合物14(10mg，20％)为白色固体。LC-MS(ESI):m/z＝291.0[M+H]+； 1H NMR(500MHz,MeOD):δ9.45(s,1H),8.09(s,1H),8.00(d,J＝8.5Hz,1H),7.75(dd,J＝8.5 1.5Hz,1H),7.52(t,J＝7.5Hz,1H),7.16(d,J＝7.5Hz,1H),7.11(d,J＝12.5Hz,1H),7.05(d,J＝7.5Hz,1H),6.91(d,J＝12.5Hz,1H),2.49(s,3H).其中，7.11(d,J＝12.5Hz,1H)，6.91(d,J＝12.5Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
化合物15的合成路线
Figure PCTCN2018124667-appb-000077
化合物15-c的合成
往反应瓶中加入1-e(200mg,1mmol)，2-溴-4-甲基噻唑(196mg，1.1mmol),二(三苯基膦)二氯化钯(70mg，0.1mmol)，碘化亚铜(57mg，0.3mmol)和三乙胺(15mL)。反应混合物用N 2置换，于20℃反应2小时。反应结束后，浓缩除去有机溶剂，加入水(30mL)，用乙酸乙酯(30mL*2)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干，粗品经柱层析(PE:EA＝2:1)纯化得到化合物15-c(150mg,51％)为黄色固体。LC-MS(ESI):m/z＝298.0[M+H]+.
化合物15-b的合成
往反应瓶中加入化合物15-c(150mg，0.5mmol)，四氢呋喃(6mL)，甲醇(6mL)和水(3mL)，氢氧化锂一水合物(84.7mg，2mmol)。混合物在室温搅拌过夜后，加入稀盐酸将pH值调节为6-7，用乙酸乙酯(30mL*3)萃取，有机相依次用水洗，饱和氯化钠水溶液洗，无水硫酸钠干燥。过滤，旋干即得到粗品化合物15-b(100mg，70％)，LC-MS(ESI):m/z＝283.9[M+H]+.
化合物15-a的合成
在冰浴条件下往化合物15-b(100mg，0.35mmol)的二氯甲烷(10mL)溶液中慢慢加入草酰氯(1mL)，再加入一滴DMF，混合物在室温搅拌1小时，浓缩即得到粗品。在冰浴条件下往氨水(5mL)中慢慢加入以上粗品的二氯甲烷(10mL)溶液，混合物在室温搅拌搅拌过夜，浓缩，粗品经Prep-TLC(DCM:MeOH＝10:1)纯化得到化合物15-a(35mg，35％)为白色固体，LC-MS(ESI):m/z＝283.1[M+H]+.
化合物15的合成
在室温下往化合物15-a(35mg，0.124mmol)的吡啶(10mL)溶液中加入Pd-CaCO 3(20mg)，反应液抽真空，用H 2置换多次，混合物在室温下搅拌过夜，过滤，浓缩，粗品经Prep-HPLC纯化得到化合物15(20mg,56％)为白色固体。LC-MS(ESI):m/z＝285.0[M+H]+； 1H NMR(500MHz,MeOD):δ9.83(s,1H),8.29(s,1H),7.69(d,J＝9.5Hz,1H),7.56(dd,J＝9.5,1.5Hz,1H),7.03(s,1H),6.90-6.98(m,2H),2.40(s,3H).其中，6.90-6.98(m,2H)为碳碳双键上的氢的化合物位移。
化合物16的合成路线
Figure PCTCN2018124667-appb-000078
化合物16-e的合成
在冰浴条件下往五氯化磷(13.11g，63mmol)的氯仿(30mL)溶液中慢慢滴加环己酮(5.88g，60mmol)的氯仿(30mL)溶液。混合物慢慢升至室温，反应2小时后再在回流条件下反应2小时，然后倒入150g冰中，慢慢用碳酸氢钠固体中和，等到冰融化后，将有机相分离，用饱和碳酸氢钠水溶液洗涤，无水硫酸钠干燥。过滤，浓缩，然后溶于二氯甲烷(6mL)中，在-5℃下慢慢滴加液溴(6.24g，39mmol)，混合物在-5℃下搅拌5分钟，用10％硫代硫酸钠水溶液洗涤，无水硫酸钠干燥。浓缩，粗品经柱层析硅胶(石油醚为洗脱剂)纯化得到化合物16-e(10.1g，61％)为白色固体。
化合物16-d的合成
在回流状态下往氢氧化钾(4.1g，73.1mmol)的甲醇(40mL)溶液中慢慢加入化合物16-e(10.1g，36.5mmol)的甲醇(40mL)溶液。混合物在回流状态下反应3小时，然后降至室温，用6M盐酸溶液中和，有机相分离，水相用乙酸乙酯(40mL*3)萃取,有机相合并，用无水硫酸钠干燥。浓缩，粗品经柱层析硅胶(石油醚为洗脱剂)纯化得到化合物16-d(0.68g，7.7％)为白色固体。 1H NMR(500MHz,CDCl 3):δ2.61–2.51(m,4H),1.80–1.70(m,4H).
化合物16-c的合成
参考化合物4-a的方法合成。
化合物16-a的合成
往反应瓶中加入16-d(0.57g，2.38mmol)，16-c(0.44g，2.14mmol)，Pd(dppf)Cl 2(174mg，0.238mmol)，碳酸钠(504mg，4.76mmol)，1,4-二氧六环(20mL)和水(4mL)。反应混合物用N 2置换，于90℃反应过夜。反应结束后，浓缩除去有机溶剂，粗品经柱层析(DCM:MeOH＝30:1)纯化得到化合物16-a(420mg，55％)为黄色固体。LC-MS(ESI):m/z＝320.1[M+H]+.
化合物16-b的合成
根据文献(Organometallics,2017,vol.36,#8,1541–1549)方法制得。
化合物16的合成
往反应瓶中加入16-a(0.38g，1.19mmol)，16-b(2.27g，5.94mmol)，Pd(PPh 3) 4(137mg,0.119mmol)和甲苯(20mL)。反应混合物用N 2置换，于90℃反应过夜。反应结束后，浓缩除去有机溶剂，粗品经柱层析(DCM:MeOH＝20:1)和Prep-HPLC纯化得到化合物16(40mg，10％)为黄色固体。LC-MS(ESI):m/z＝333.3[M+H]+； 1H NMR(500MHz,MeOD):δ9.19(s,1H),8.17(s,1H),7.35-7.47(m,2H),7.22(dd,J＝9.5,2.0Hz,1H),6.99(d,J＝7.5Hz,1H),6.80(d,J＝8.0Hz,1H),2.58(m,4H),2.48(s,3H),1.94(m,4H).
化合物17a的合成路线
Figure PCTCN2018124667-appb-000079
化合物17a-c的合成
冰浴下，往氢氧化钠(20g，0.5mol)的水(60mL)溶液中缓慢滴加入溴(12.8mL,0.25mol)。反应液保持0℃下搅拌25分钟，再滴加入二乙基膦酰基乙酸叔丁酯(12.6mL，53.65mmol)。滴加结束后，反应液用二氯甲烷萃取(70mL*2)，有机相用水洗(50mL*1)，无水硫酸钠干燥。过滤，旋干得到产物17a-c(20g，91％)为无色油状物。 1H NMR(500MHz,CDCl 3):δ4.35-4.41(m,4H),1.54(s,9H),1.39(t,J＝6.5Hz,6H).
化合物17a-b的合成
冰浴下，往17a-c(10g，24.39mmol)的叔丁醇(50mL)溶液中缓慢滴加入二水氯化亚锡(5.39mL,23.90mmol)的水(50mL)溶液。白色的反应液保持0℃搅拌15分钟，用二氯甲烷萃取(50mL*3)，有机相用水洗(50mL*2)，无水硫酸钠干燥。过滤，旋干得到产物17a-b(7g，87％)为微黄色油状物。 1H NMR(500MHz,CDCl 3):δ4.25-4.30(m,5H),1.50(s,9H),1.38(t,J＝7.5Hz,6H).
化合物17a-a的合成
将17a-b(4.10g，12.38mmol)的四氢呋喃(50mL)溶液在氮气保护下冷却至-78℃，缓慢滴加入LiHMDS(1M inTHF，12.38mL，12.38mmol)超过10分钟，接着加入6-甲基-2-吡啶甲醛(1g，8.25mmol)。加毕，反应液在低温下搅拌30分钟，再升至室温反应1.5小时。用水(20mL)淬灭反应，乙酸乙酯萃取(50mL*3)，合并的有机相水洗(50mL*1),无水硫酸钠干燥。过滤，旋干。粗品经硅胶柱层析(PE:EA＝5:1)得到17a-a(2g，81％)为无色油状物。LC-MS(ESI):m/z＝242.1[M+H-tBu]+.
化合物17a的合成
将化合物17a-a(2g,6.71mmol)，16-c(10.06g,2.06mmol)，Pd(PPh 3) 4(0.78g,0.67mmol)，碳酸钠(1.42g,13.4mmol)，甲苯(10mL)，乙醇(5mL)和水(5mL)的混合物于氮气氛围下加热到80℃反应过夜。反应物冷至室温后浓缩，用水(10mL)和二氯甲烷(30mL)混合分层，水相用二氯甲烷萃取，合并有机层经水洗，饱和食盐水水洗，干燥过滤，浓缩。用硅胶柱层析初步分离(DCM:MeOH＝20:1)得到粗品。粗品加入乙酸乙酯(10mL)加热回流搅拌30分钟，冷却后过滤，取少量母液浓缩经高效液相制备分离得到17a为白色固体。LC-MS(ESI):m/z＝379.2[M+H]+； 1H NMR(500MHz,MeOD)δ:9.79(s,1H),8.32(s,1H),7.84(dd,J＝9.5,2Hz,1H),7.76(d,J＝9.5Hz,1H),7.73(t,J＝7.5Hz,1H),7.34(d,J＝8Hz,1H),7.22(d,J＝8Hz,1H),7.18(s,1H),2.57(s,3H),1.60(s,9H).
化合物17b的合成路线
Figure PCTCN2018124667-appb-000080
化合物17b的合成
冰浴下，往17a(1.5g,3.97mmol)的四氢呋喃(10mL)溶液中加入三乙胺(1.1mL，7.93mmol)和三氟乙酸酐(1.1mL，7.93mmol)。加毕，混合物升至室温搅拌2小时。反应结束后，加入冰水(10mL)，用乙酸乙酯萃取，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得到微黄色固体17b(1g，70％)。LC-MS(ESI):m/z＝361.3[M+H]+.
化合物17c的合成路线
Figure PCTCN2018124667-appb-000081
化合物17c的合成
往17b(1g，2.77mmol)的二氯甲烷(20mL)溶液中加入三氟乙酸(4mL)。所得反应液室温搅拌过夜。反应结束后，浓缩，在冰浴下用碳酸氢钠饱和溶液小心中和至pH约为6-7，搅拌半小时，过滤，滤饼用水洗，干燥得到化合物17c(0.6g，71％)为微黄色固体。LC-MS(ESI):m/z＝305.0[M+H] +； 1H NMR(500MHz,DMSO-d6):δ13.16(s,1H),9.60(s,1H),8.48(s,1H),7.89(s,1H),7.79(d,J＝8.5Hz,1H),7.59(t,J＝5Hz,1H),7.38(d,J＝7.5Hz,1H),7.12-7.16(m,2H),2.17(s,3H).
化合物18a的合成路线
Figure PCTCN2018124667-appb-000082
化合物18a的合成
往17c(100mg，0.33mmol)和氯化铵(1.3g，0.66mmol)的DMF(5mL)溶液中加入EDCI(75.6mg，0.39mmol)，HOBt(57.7mg，0.43mmol)和DIPEA(127.4mg，0.99mmol)。所得反应液室温搅拌过夜。反应结束后，加水稀释，分液，水相用二氯甲烷萃取，合并有机相用饱和食盐水洗涤，无水Na 2SO 4干燥。浓缩，粗品经Prep-TLC(DCM：MeOH＝20:1)纯化得到化合物18a(60mg，60％)为白色固体。LC-MS(ESI):m/z＝304.0[M+H]+.
化合物18的合成路线
Figure PCTCN2018124667-appb-000083
化合物18的合成
往反应瓶中加入化合物18a(60mg，0.2mmol)，碳酸钾(4mg，0.03mmol)，二甲亚砜(2mL)。冰浴下，滴加入H 2O 2(26.9mg，0.79mmol)，加毕，混合物在室温搅 拌过夜。次日，过滤，滤饼用水洗涤，干燥得到化合物18(35mg,55％)为白色固体。LC-MS(ESI):m/z＝322.0[M+H] +； 1H NMR(500MHz,MeOD):δ9.45(s,1H),8.30(s,1H),7.75(s,1H),7.71(d,J＝9Hz,1H),7.50(t,J＝8Hz,1H),7.35(dd,J＝9.0,1.5Hz,1H),7.11(d,J＝7.5Hz,1H),6.94(d,J＝8Hz,1H),2.37(s,3H).
化合物19a的合成路线
Figure PCTCN2018124667-appb-000084
化合物19a的合成
往17c(50mg，0.16mmol)和甲胺四氢呋喃溶液(2M，0.33mL，0.66mmol)的二氯甲烷(10mL)溶液中加入HATU(125mg，0.33mmol)和DIPEA(64mg，0.49mmol)。所得反应液室温搅拌过夜。反应结束后，加水稀释，分液，水相用二氯甲烷萃取，合并有机相用饱和食盐水洗涤，无水Na 2SO 4干燥，浓缩。粗品经Prep-TLC(DCM：Methanol＝20:1)纯化得到产物19a(30mg，58％)为白色固体。LC-MS(ESI):m/z＝318.2[M+H]+.
化合物19的合成路线
Figure PCTCN2018124667-appb-000085
化合物19的合成
往反应瓶中加入化合物19a(30mg，0.095mmol)，碳酸钾(2mg，0.014mmol),二甲亚砜(2mL)。冰浴下，滴加入H 2O 2(12.9mg，0.38mmol)。加毕，混合物在室温搅拌过夜。次日，过滤，滤饼用水洗涤，干燥，得到白色固体19(10mg,32％)为白色固体。LC-MS(ESI):m/z＝336.3[M+H]+； 1HNMR(500MHz,DMSO-d 6):δ9.31(s,1H),8.35(s,1H),7.95(bs,1H),7.73-7.78(m,1H),7.68(d,J＝9Hz,1H),7.57(s,1H),7.49(t,J＝8.5Hz,1H),7.35(bs,1H),7.18(dd,J＝9.5,2Hz,1H),7.05(d,J＝7.5Hz,1H),6.88(d,J＝7.5Hz,1H),2.67(d,J＝4Hz,3H),2.22(s,3H).
化合物20a的合成路线
Figure PCTCN2018124667-appb-000086
化合物20a的合成
往17c(50mg，0.16mmol)和二甲胺盐酸盐(329mg，0.66mmol)的二氯甲烷(10mL)溶液中加入HATU(125mg，0.33mmol)和DIPEA(212mg，1.6mmol)。所得反应液室温搅拌过夜。反应结束后，加水稀释，分液，水相用二氯甲烷萃取，合并有机相用饱和食盐水洗涤，无水Na 2SO 4干燥，浓缩，经Prep-TLC(DCM：Methanol＝20:1)纯化得到化合物20a(40mg，73％)为白色固体。LC-MS(ESI):m/z＝332.2[M+H]+.
化合物20的合成路线
Figure PCTCN2018124667-appb-000087
化合物20的合成
往反应瓶中加入化合物20a(40mg，0.12mmol)，碳酸钾(2.5mg，0.018mmol),二甲亚砜(2mL)。冰浴下，滴加入H 2O 2(16.4mg，0.48mmol)，加毕，混合物在室温搅拌过夜。次日，过滤，滤饼用水洗涤，干燥，得到20(25mg，59％)为白色固体，LC-MS(ESI):m/z＝350.0[M+H]+； 1H NMR(400MHz,DMSO-d 6):δ9.56(s,1H),8.33(s,1H),7.94(bs,1H),7.62(dd,J＝9.2,0.8Hz,1H),7.53(t,J＝7.6Hz,1H),7.35(bs,1H),7.26(dd,J＝9.2,1.6Hz,1H),7.08(d,J＝7.6Hz,1H),6.98(d,J＝7.6Hz,1H),6.78(s,1H),3.08(s,3H),2.94(s,3H),2.29(s,3H).
化合物21a的合成路线
Figure PCTCN2018124667-appb-000088
化合物21a的合成
往17c(50mg，0.16mmol)和哌啶(56mg，0.66mmol)的二氯甲烷(10mL)溶液中加入HATU(125mg，0.33mmol)和DIPEA(64mg，0.49mmol)。所得反应液室温搅拌过夜。反应结束后，加水稀释，分液，水相用二氯甲烷萃取，合并有机相用饱和食盐水洗涤，无水Na 2SO 4干燥，浓缩。粗品经Prep-TLC(DCM：Methanol＝20:1)纯化得到化合物21a(50mg，82％)为白色固体。LC-MS(ESI):m/z＝372.1[M+H]+.
化合物21的合成路线
Figure PCTCN2018124667-appb-000089
化合物21的合成
往反应瓶中加入化合物21a(50mg，0.13mmol)，碳酸钾(2.8mg，0.02mmol)，二甲亚砜(2mL)。冰浴下，滴加入H 2O 2(18.3mg，0.54mmol)。加毕，混合物在室温搅拌过夜。次日，过滤，滤饼用水洗涤，干燥得到化合物21(30mg,57％)为白色固体。LC-MS(ESI):m/z＝390.2[M+H]+； 1HNMR(500MHz,MeOD):δ9.61(s,1H),8.28(s,1H),7.60(d,J＝9.5Hz,1H),7.55(t,J＝7.5Hz,1H),7.34(dd,J＝10,2Hz,1H),7.16(d,J＝8Hz,1H),7.04(d,J＝8Hz,1H),6.89(s,1H),3.70(m,4H),2.46(s,3H),1.55-1.72(m,6H).
化合物22的合成路线
Figure PCTCN2018124667-appb-000090
化合物22-a的合成
往17c(300mg，0.99mmol)和甲醇(1.97g，3.94mmol)的二氯甲烷(10mL)溶液中加入HATU(949mg，1.97mmol)和DIPEA(637.1mg，4.93mmol)。所得反应液室温搅拌过夜。反应结束后，加水稀释，分液，水相用二氯甲烷萃取，合并有机相用饱和食盐水洗涤，无水Na 2SO 4干燥，浓缩。粗品经Prep-TLC(PE:EA＝1:1)纯化得到化合物22-a(250mg，80％)为白色固体。LC-MS(ESI):m/z＝319.0[M+H] +.
化合物22的合成
往反应瓶中加入化合物22-a(80mg，0.25mmol)，碳酸钾(5mg，0.038mmol)，二甲亚砜(2mL)。冰浴下，滴加入H 2O 2(34.2mg，1.0mmol)。加毕，混合物在室温搅 拌过夜。次日，过滤，滤饼用水洗涤，晾干得到白色固体22(40mg，47％)，LC-MS(ESI):m/z＝337.2[M+H] +； 1HNMR(500MHz,MeOD):δ:9.40(s,1H),8.30(s,1H),8.02(s,1H),7.67(d,J＝9Hz,1H),7.51(t,J＝8Hz,1H),7.37(dd,J＝9,1.5Hz,1H),7.13(d,J＝8.5Hz,1H),6.97(d,J＝8Hz,1H),3.88(s,3H),2.37(s,3H).
对比化合物23的合成路线
Figure PCTCN2018124667-appb-000091
化合物23-a的合成
往反应瓶中加入化合物2-溴-6-甲基吡啶(400mg，2.32mmol)，乙烯基硼酸频哪醇酯(430mg，2.79mmol)，Pd(dppf)Cl 2(85mg，0.116mmol)，Na 2CO 3(49mg，4.64mmol)，1,4-二氧六环(15mL)和水(3mL)。反应液用N 2置换，在90℃下搅拌过夜，加入水(30mL)，用乙酸乙酯(50mL)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，粗品经硅胶柱层析纯化(PE:EA＝10:1)得到化合物23-a(160mg，58％)为红色油状物。LC-MS(ESI):m/z＝120.2[M+H]+.
对比化合物23的合成
往反应瓶中加入化合物23-a(160mg，1.3mmol)，11-f(387mg，1.6mmol)，三邻甲苯基磷(79mg，0.26mmol)，醋酸钯(29mg，0.13mmol)，三乙胺(0.362mL，2.6mmol)和DMF(10mL)。反应液用N 2置换，在90℃下搅拌过夜，加入水(50mL)，用乙酸乙酯(30mL*2)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，粗品经Prep-HPLC化合物23(45mg，12％)为白色固体。LC-MS(ESI):m/z＝279.1[M+H]+； 1H NMR(500MHz,CDCl 3):δ9.63(s,1H),8.05(s,1H),7.75(dd,J＝9.5,1.5Hz,1H),7.70(d,J＝9.5Hz,1H),7.64(d,J＝16.5Hz,1H),7.58(t,J＝7.5Hz,1H),7.24(d,J＝8.0Hz,1H),7.20(d,J＝16.0Hz,1H),7.06(d,J＝8.0Hz,1H),5.67(brs,1H),2.60(s,3H).其中，7.64(d,J＝16.5Hz,1H)，7.20(d,J＝16.0Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
对比化合物24的合成路线
Figure PCTCN2018124667-appb-000092
化合物24-b的合成
往反应瓶中加入化合物23-a(300mg，2.52mmol)，SM-1(677mg，2.52mmol)，三邻甲苯基磷(153mg，0.5mmol)，醋酸钯(56mg，0.25mmol)，三乙胺(0.7mL，5mmol)和DMF(10mL)。反应液用N 2置换，在90℃下搅拌过夜，加入水(50mL)，用乙酸乙酯(30mL*2)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，粗品经硅胶柱层析得到化合物24-b(500mg，65％)为白色固体。LC-MS(ESI):m/z＝308.0[M+H] +.
化合物24-a的合成
将24-b(0.5g，1.63mmol)加入到甲醇(10mL)和THF(10mL)，加入氢氧化钠水溶液(4M，2mL)，室温搅拌过夜。反应结束后，减压浓缩除去有机溶剂，加入水(10mL)和DCM(50mL)，分液，弃去有机层。将水层冷却至0℃，用盐酸(2M)中和至pH为6-7。过滤出微黄色沉淀物，干燥得到化合物24-a(0.4g，88％)。LC-MS(ESI):m/z＝280.3[M+H] +； 1H NMR(400MHz,MeOD):δ9.76(s,1H),8.07(s,1H),7.85(d,J＝8.4Hz,1H),7.71(t,J＝7.6Hz,1H),7.61-7.65(m,2H),7.49(d,J＝8Hz,1H),7.28(d,J＝16.4Hz,1H),7.17(d,J＝7.6Hz,1H),2.57(s,3H).
对比化合物24的合成
将24-a(100mg，0.36mmol)溶于二氯甲烷(10mL)中。在冰浴下，向溶液中慢慢加入草酰氯(1mL)和一滴DMF。反应物升至室温反应60分钟。反应物减压浓缩，加入二氯甲烷(5mL)稀释。在冰浴下，将该溶液慢慢滴加到甲胺四氢呋喃溶液(2M，5mL)中，反应混合物在0℃下反应10分钟，再升至室温搅拌过夜。分液，水层用二氯甲烷萃取，合并有机相分别用水和食盐水洗涤，无水硫酸钠干燥，浓缩得到粗品。粗产品经高效液相制备色谱得到白色固体24(10mg，10％)。LC-MS(ESI):m/z＝293.3[M+H] +； 1H NMR(500MHz,MeOD):δ9.43(s,1H),8.06(s,1H),7.75(dd,J＝9.5,1.5Hz,1H),7.59(t,J＝7.5Hz,1H),7.54(d,J＝9.5Hz,1H),7.44(d,J＝16.0Hz,1H),7.34(d,J＝7.5Hz,1H),7.11(d,J＝16.5Hz,1H),7.06(d,J＝7.5Hz,1H),4.90(s,3H),2.91(s,3H).其中，7.44(d,J ＝16.0Hz,1H)，7.11(d,J＝16.5Hz,1H)为碳碳双键上的氢的化合物位移和耦合常数。
效果实施例1 ALK5酶活性抑制IC 50评价实验
1.配制1x的激酶缓冲液：40mM Tris(pH 7.5),20mM MgCl 2,0.10％BSA,1mM DTT。
2.化合物配制：化合物的检测终浓度为10μM，配置成100倍浓度，即1mM，在384孔板上第二个孔中加入100μL的100倍的化合物，其他孔加入60μL的100％DMSO。从第二孔中取30μL化合物加入第三孔中，依次往下做3倍稀释，共稀释10个浓度。用echo转移50nL化合物到反应板中。
3.激酶反应：将激酶加入1倍激酶缓冲液，形成2倍酶溶液。激酶溶液终浓度为ALK5:25nM。将多肽TGFbR1(购自Signal Chem公司，商品目录编号为T36-58)和ATP加入1倍激酶缓冲液，形成2倍底物溶液。底物溶液终浓度为多肽TGFbR1 0.1mg/mL，ATP 7μM。向384孔反应板中(已有50nL的100％DMSO溶解的化合物)加入2.5μL的2倍酶溶液，阴性对照孔加入1倍激酶缓冲液。室温下孵育10分钟。在384孔反应板中加入2.5μL的2倍底物溶液。将384孔板盖上盖子，于30℃下孵育1小时。将ADP-Glo试剂(购自Promege公司，商品目录编号为v9102)平衡到室温。转移5μL ADP-Glo试剂到384孔板反应孔中终止反应。
4.反应结果的检测：转移10μL激酶检测试剂到每个反应孔中，振荡1分钟，室温静置30分钟。在Synegy读取样品发光数值。
5.曲线拟合：从Synegy程序上复制发光读数的数据。将发光读数的值通过公式转换为抑制百分率(抑制百分率＝(max-sample RLU)/(max-min)*100，其中，“min”为不加酶进行反应的对照样荧光读数；“max”为加入DMSO作为对照的样品荧光读数)。将数据导入MS Excel并使用GraphPad Prism进行曲线拟合。计算IC 50值。
表1 本发明的化合物对ALK5活性的IC 50结果
Figure PCTCN2018124667-appb-000093
Figure PCTCN2018124667-appb-000094
其中，SB431542(CAS号：301836-41-9)是已知的ALK5抑制剂，其结构如下：
Figure PCTCN2018124667-appb-000095
由上述试验的结果可以确认，本发明的化合物对ALK5的活性具有明显的抑制作用。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (13)

  1. 一种通式I所示的芳香杂环取代烯烃化合物或其药学上可接受的盐：
    Figure PCTCN2018124667-appb-100001
    其中，环A与环B位于双键的同侧；
    Figure PCTCN2018124667-appb-100002
    为
    Figure PCTCN2018124667-appb-100003
    Figure PCTCN2018124667-appb-100004
    R 3、R 31、R 32、R 33、R 3a、R 3a1、R 3b、R 3b1、R 3c、R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、R 3e1、R 3f、R 3f1、R 3f2、R 3g和R 3g1各自独立地为氢、卤素、氰基、硝基、-NR a3R a4、-OR a5、-SR a6、-C(O)OR a7、-C(O)NR a8R a9、-COR a10、取代或未取代的C 1-6烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 3-10环烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 4-8环烯基、取代或未取代的C 6-20芳基、或取代或未取代的C 2-10杂芳基；其中，R a3、R a4、R a5、R a6、R a7、R a8、R a9和R a10各自独立地为氢、取代或未取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；R a3和R a8还可独立地为羟基或C 1-6烷氧基；
    R 3、R 31、R 32、R 33、R 3a、R 3a1、R 3b、R 3b1、R 3c、R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、R 3e1、R 3f、R 3f1、R 3f2、R 3g、R 3g1、R a3、R a4、R a5、R a6、R a7、R a8、R a9和R a10中，所述的取代的C 1-6烷基、以及R 3、R 31、R 32、R 33、R 3a、R 3a1、R 3b、R 3b1、R 3c、R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、R 3e1、R 3f、R 3f1、R 3f2、R 3g、R 3g1中，所述的取代的C 2-8烯基、取代的C 2-8炔基、取代的C 3-10环烷基、取代的C 2-8杂环烷基、取代的C 4-8环烯基、取代的C 6-20芳基、取代的C 2-10杂芳基中的取代基各自独立地为下列基团中的一个或多个：氘、卤素、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、-OR a15、-SR a16、-C(O)OR a17、-COR a18、-C(O)NH 2、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；R a15、R a16、R a17和R a18各自独立地为氢或C 1-6烷基；当取代基为多个时，所述的取代基相同或不同；
    R 4为氢、氰基、C 1-6烷基、C 3-10环烷基、C 2-8杂环烷基、-C(O)OR a19或被-OR a20取代的C 1-6烷基；R a19和R a20各自独立地为C 1-6烷基；
    Figure PCTCN2018124667-appb-100005
    为
    Figure PCTCN2018124667-appb-100006
    Figure PCTCN2018124667-appb-100007
    R 5、R 51、R 5a、R 5a1、R 5a2、R 5b、R 5b1、R 5c、R 5c1、R 5c2、R 5d、R 5d1、R 5d2、R 5e、R 5e1和R 5e2各自独立地为氢、氘或卤素；
    R 6、R 6a、R 6b、R 6c、R 6d和R 6e各自独立地为氢、氘、卤素、磺酸基、取代或未取代的C 1-6烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 3-10环烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、取代或未取代的C 2-10杂芳基、氰基、-OR 61、-SR 62、-NR a63R a64、-C(O)R 65、-C(O)OR 66、-OC(O)R 67、-OC(O)OR 68、-C(O)NR a69R a610、-N(R 611)C(O)R 612、-S(O)R 613、-S(O) 2R 614、-S(O) 2NR a615R a616、-OC(O)NR a617R a618、-N(R 619)C(O)OR 620、-N(R 621)C(O)NR a622R a623、-N(R 624)S(O) 2R 625或-OP(O)(OR 626) 2；
    R 61、R 62、R a64、R 65、R 66、R 67、R 68、R a610、R 611、R 612、R 613、R 614、R a615、R a616、R a617、R a618、R 619、R 620、R 621、R a622、R a623、R 624、R 625和R 626各自独立地为氢、取代或未取代的C 1-6烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 3-10环烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、或取代或未取代的C 2-10杂芳基；
    R a63和R a69各自独立地为氢、羟基、C 1-6烷氧基、取代或未取代的C 1-6烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 3-10环烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、或取代或未取代的C 2-10杂芳基；
    R 6、R 6a、R 6b、R 6c、R 6d和R 6e中，所述的取代的C 1-6烷基、取代的C 2-8烯基、取代的C 2-8炔基、取代的C 3-10环烷基、取代的C 2-8杂环烷基、取代的C 6-20芳基、取代的C 2-10杂芳基中的取代基各自独立地为下列基团中的一个或多个：氘、卤素、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基、C 2-10杂芳基、氰基、-OR 71、-SR 72、-NR a73R a74、-C(O)R 75、-C(O)OR 76、-OC(O)R 77、-OC(O)OR 78、-C(O)NR a79R a710、-N(R 711)C(O)R 712、S(O)R 713、-S(O) 2R 714、-S(O) 2NR a715R a716、-OC(O)NR a717R a718、-N(R 719)C(O)OR 720、-N(R 721)C(O)NR a722R a723、-N(R 724)S(O) 2R 725或-OP(O)(OR 726) 2；当取代基为多个时，所述的取代基相同或不同；R 71、R 72、R a73、R a74、R 75、R 76、R 77、R 78、 R a79、R a710、R 711、R 712、R 713、R 714、R a715、R a716、R a717、R a718、R 719、R 720、R 721、R a722、R a723、R 724、R 725和R 726各自独立地为氘、C 1-6烷基、卤素取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；
    R 61、R 62、R a63、R a64、R 65、R 66、R 67、R 68、R a69、R a610、R 611、R 612、R 613、R 614、R a615、R a616、R a617、R a618、R 619、R 620、R 621、R a622、R a623、R 624、R 625和R 626中，所述的取代的C 1-6烷基、取代的C 2-8烯基、取代的C 2-8炔基、取代的C 3-10环烷基、取代的C 2-8杂环烷基、取代的C 6-20芳基或取代的C 2-10杂芳基中的取代基为下列基团中的一个或多个：氘、卤素、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基、C 2-10杂芳基、-OR c、-SR c1、-NR b1R b2、-C(O)R c2、-C(O)OR c3、-OC(O)R c4、-OC(O)OR c5、-C(O)NR b3R b4、-N(R c6)C(O)OR c7、S(O)R c8、-S(O) 2R c9、-S(O) 2NR b5R b6、-N(R c10)C(O)R c11、-N(R c12)C(O)NR b7R b8或-N(R c13)S(O) 2R c14；R c、R c1、R b1、R b2、R c2、R c3、R c4、R c5、R b3、R b4、R c6、R c7、R c8、R c9、R b5、R b6、R c10、R c11、R c12、R b7、R b8、R c13和R c14各自独立地为氢、羟基、C 1-6烷基、卤素取代的C 1-6烷基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；
    R 7、R 8、R 9、R 10、R 11、R 12、R 13各自独立地为氢、氘或卤素；
    R 1和R 2其中一个为氢、氘、卤素、或取代或未取代的C 1-6烷基，另一个为氢、氘、卤素、氰基、磺酸基、取代或未取代的C 1-6烷基、-C(O)OR 91、-COR 92、
    Figure PCTCN2018124667-appb-100008
    -S(O)R 95、-S(O) 2R 96、-C(O)NR 97R 98、或取代或未取代的C 2-10杂芳基；R 1和R 2中，所述的取代的C 1-6烷基和所述的取代的C 2-10杂芳基中的取代基各自独立地为下列基团中的一个或多个：氘、卤素、氰基、C 1-6烷基、C 2-8烯基、C 2-8炔基、-OR 920、-SR 921、-C(O)OR 922、-COR 923、-C(O)NH 2、-NR 924R 925、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；R 920、R 921、R 922、R 923、R 924和R 925各自独立地为氢或C 1-6烷基；
    R 91、R 92、R 93和R 94独立地为下列基团中的一个或多个：氢、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；R 95和R 96独立地为氢或C 1-6烷基；R 97和R 98独立地为羟基、氢、取代或未取代的C 1-6烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 3-10环烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、或取代或未取代的C 2-10杂芳基；
    R 97和R 98中，所述的取代的C 1-6烷基、取代的C 2-8烯基、取代的C 2-8炔基、取代的C 3-10环烷基、取代的C 2-8杂环烷基、取代的C 6-20芳基、取代的C 2-10杂芳基中的取代基各自独立地为下列基团中的一个或多个：氘、卤素、氰基、C 1-6烷基、C 2-8烯基、C 2-8炔基、 C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基、C 2-10杂芳基、-OR 101、-SR 102、-NR b103R b104、-C(O)R 105、-C(O)OR 106、-OC(O)R 107、-OC(O)OR 108、-C(O)NR b109R b1010、-N(R 1011)C(O)OR 1012、S(O)R 1013、-S(O) 2R 1014、-S(O) 2NR b1015R b1016、-N(R 1017)C(O)OR 1018、-OC(O)NR b1019R b1020、或-N(R 1021)S(O) 2R 1022；当取代基为多个时，所述的取代基相同或不同；R 101、R 102、R b103、R b104、R 105、R 106、R 107、R 108、R b109、R b1010、R 1011、R 1012、R 1013、R 1014、R b1015、R b1016、R 1017、R 1018、R b1019、R b1020、R 1021和R 1022各自独立地为氢、羟基、C 1-6烷基、卤素取代的C 1-6烷基、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；
    或者R 1和R 2与它们相连的碳原子一起形成含有一个双键的取代或未取代的4-8元的碳环、或取代或未取代的4-8元杂环，所述的4-8元杂环中的杂原子选自O、S和N中的一个或多个，杂原子数为1、2、3或4；
    所述的取代的4-8元的碳环和所述的取代的4-8元杂环中的取代基各自独立地为下列基团中的一个或多个：氘、卤素、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、-OR 111、-SR 112、-C(O)OR 113、-COR 114、-C(O)NH 2、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；R 111、R 112、R 113和R 114各自独立地为氢或C 1-6烷基；
    上述各字母和基团中，所述的取代或未取代的C 2-8杂环烷基或所述的C 2-8杂环烷基中的杂原子选自N、O和S中的一个或多个，杂原子数为1、2、3或4；所述的取代或未取代的C 2-10杂芳基或所述的C 2-10杂芳基中的杂原子选自N、O和S中的一个或多个，杂原子数为1、2、3或4；当杂原子为多个时，所述的杂原子相同或不同；
    或者上述各基团或取代基中，当存在NR XR Y时，R X和R Y与它们相连的氮原子一起形成取代或未取代的3-8元杂环基；所述的3-8元杂环基中的杂原子选自N、N和O、N和S、或N、O和S；杂原子数为1、2、3或4；所述的取代的3-8元杂环基中的取代基为下列基团中的一个或多个：氘、卤素、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 2-8烯基、C 2-8炔基、-OR a81、-SR a82、-C(O)OR a83、-COR a84、-C(O)NH 2、C 3-10环烷基、C 2-8杂环烷基、C 6-20芳基或C 2-10杂芳基；R a81、R a82、R a83和R a84各自独立地为氢或C 1-6烷基；NR XR Y为-NR a3R a4、-NR a8R a9、-NR a63R a64、-NR a69R a610、-NR a615R a616、-NR a617R a618、-NR a622R a623、-NR a73R a74、-NR a79R a710、-NR a715R a716、-NR a717R a718、-NR a722R a723、-NR b1R b2、-NR b3R b4、-NR b5R b6、-NR b7R b8、-NR 93R 94、-NR 97R 98、-NR 924R 925、-NR b103R b104、-NR b109R b1010、-NR b1015R b1016或-NR b1019R b1020。
  2. 如权利要求1所述的通式I所示的芳香杂环取代烯烃化合物或其药学上可接受的盐，其特征在于，
    所述的取代或未取代的C 1-6烷基中的C 1-6烷基和所述的C 1-6烷基独立地为C 1-4烷基； 所述的C 1-4烷基优选甲基、乙基、正丙基、异丙基、正丁基、异丁基、或叔丁基；
    和/或，所述的取代或未取代的C 2-8烯基中的C 2-8烯基和所述的C 2-8烯基独立地为C 2-4烯基；所述的C 2-4烯基优选乙烯基、丙烯基、烯丙基、
    Figure PCTCN2018124667-appb-100009
    和/或，所述的取代或未取代的C 2-8炔基中的C 2-8炔基和所述的C 2-8炔基独立地为C 2-4炔基；所述的C 2-4炔基优选乙炔基、丙炔基、丁炔基或3-甲基丙炔基；
    和/或，所述的取代或未取代的C 3-10环烷基中的C 3-10环烷基和所述的C 3-10环烷基独立地为环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基、双环[3.1.1]庚烷基、双环[2.2.1]庚烷基、双环[2.2.2]辛烷基、双环[3.2.2]壬烷基、双环[3.3.1]壬烷基或双环[4.2.1]壬烷基。
    和/或，所述的取代或未取代的C 2-8杂环烷基中的C 2-8杂环烷基和所述的C 2-8杂环烷基独立地为氮杂环丁烷基、氮杂环庚烷基、氮丙啶、二氮杂环庚烷基、1,3-二噁烷基、1,3-二氧戊环基、1,3-二硫戊环基、1,3-二噻烷基、咪唑啉基、咪唑烷基、异噻唑烷基、异噻唑基、异噁唑啉基、吗啉基、噁二唑啉基、噁二唑烷基、噁唑啉基、噁唑烷基、哌嗪基、哌啶基、吡喃基、吡唑啉基、吡唑烷基、吡咯啉基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻二唑啉基、噻二唑烷基、噻唑啉基、噻唑烷基、硫代吗啉基、1,1-二氧硫代吗啉基、噻喃基、三噻烷基、2,3-二氢苯并呋喃-2-基、2,3-二氢苯并呋喃-3-基、二氢吲哚-1-基、二氢吲哚-2-基、二氢吲哚-3-基、2,3-二氢苯并噻吩-2-基、十氢喹啉基、十氢异喹啉基、八氢-1H-吲哚基或八氢苯并呋喃基；
    和/或，所述的取代或未取代的C 4-8环烯基中的C 4-8环烯基和所述的C 4-8环烯基独立地为环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基、降冰片烯基或双环[2.2.2]辛烯基；
    和/或，所述的取代或未取代的C 6-20芳基中的C 6-20芳基或所述的C 6-20芳基独立地为苯基、萘基、蒽基、菲基、薁基、二氢茚-1-基、二氢茚-2-基、二氢茚-3-基、二氢茚-4-基、2,3-二氢吲哚-4-基、2,3-二氢吲哚-5-基、2,3-二氢吲哚-6-基、2,3-二氢吲哚-7-基、茚-1-基、茚-2-基、茚-3-基、茚-4-基、二氢萘-2-基、二氢萘-3-基、二氢萘-4-基、二氢萘-1-基、5,6,7,8-四氢化萘-1-基、5,6,7,8-四氢化萘-2-基、2,3-二氢苯并呋喃-4-基、2,3-二氢苯并呋喃-5-基、2,3-二氢苯并呋喃-6-基、2,3-二氢苯并呋喃-7-基、苯并[d][1,3]间二氧杂环戊烯-4-基、苯并[d][1,3]间二氧杂环戊烯-5-基、2H-苯并呋喃-2-酮-5-基、2H-苯并呋喃-2-酮-6-基、2H-苯并呋喃-2-酮-7-基、2H-苯并呋喃-2-酮-8-基、异吲哚啉-1,3-二酮-4-基、异吲哚啉-1,3-二酮-5-基、茚-1-酮-4-基、茚-1-酮-5-基、茚-1-酮-6-基、茚-1-酮-7-基、2,3-二氢 苯并[b][1,4]二噁烷-5-基、2,3-二氢苯并[b][1,4]二噁烷-6-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-5-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-6-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-7-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-8-基、苯并[d]杂氧嗪-2(3H)-酮-5-基、苯并[d]杂氧嗪-2(3H)-酮-6-基、苯并[d]杂氧嗪-2(3H)-酮-7-基、苯并[d]杂氧嗪-2(3H)-酮-8-基、喹唑啉-4(3H)-酮-5-基、喹唑啉-4(3H)-酮-6-基、喹唑啉-4(3H)-酮-7-基、喹唑啉-4(3H)-酮-8-基、喹噁啉-2(1H)-酮-5-基、喹噁啉-2(1H)-酮-6-基、喹噁啉-2(1H)-酮-7-基、喹噁啉-2(1H)-酮-8-基、苯并[d]噻唑-2(3H)-酮-4-基、苯并[d]噻唑-2(3)-酮-5-基、苯并[d]噻唑-2(3H)-酮-6-基或苯并[d]噻唑-2(3H)-酮-7-基；
    和/或，所述的取代或未取代的C 2-10杂芳基中的C 2-10杂芳基和所述的C 2-10杂芳基独立地为呋喃基、咪唑基、异噁唑基、异噻唑基、噁二唑基、噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、噻二唑基、噻唑基、噻吩基、三唑基、三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噁二唑基、苯并噻唑基、噌啉基、5,6-二氢喹啉-2-基、5,6-二氢喹啉-1-基、呋喃并吡啶基、吲唑基、吲哚基、异喹啉基、萘啶基、嘌呤基、喹啉基、5,6,7,8-四氢喹啉-2-基、5,6,7,8-四氢喹啉-3-基、5,6,7,8-四氢喹啉-4-基、5,6,7,8-四氢异喹啉-1-基、噻吩并吡啶基、4,5,6,7-四氢并[c][1,2,5]噁二唑基或6,7-二氢并[c][1,2,5]噁二唑-4(5H)酮基。
  3. 如权利要求1或2所述的通式I所示的芳香杂环取代烯烃化合物或其药学上可接受的盐，其特征在于，
    R 1和R 2其中一个为氢、或取代或未取代的C 1-6烷基，另一个为氢、氰基、磺酸基、取代或未取代的C 1-6烷基、-C(O)OR 91、-COR 92、
    Figure PCTCN2018124667-appb-100010
    -S(O)R 95、-S(O) 2R 96、-C(O)NR 97R 98、或取代或未取代的C 2-10杂芳基；或者R 1和R 2与它们相连的碳原子一起形成含有一个双键的取代或未取代的4-8元的碳环、或取代或未取代的4-8元杂环；其中，R 91、R 92、R 93、R 94、R 95、R 96、R 97和R 98的定义均同权利要求1所述；所述的取代的C 1-6烷基、所述的取代的C 2-10杂芳基、所述的取代的4-8元的碳环和所述的取代的4-8元杂环中取代基的定义均同权利要求1所述；
    和/或，R 3、R 31、R 32、R 33、R 3a、R 3a1、R 3b、R 3b1、R 3c、R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、R 3e1、R 3f、R 3f1、R 3f2、R 3g和R 3g1各自独立地为氢、卤素、氰基、硝基、-NR a3R a4、-OR a5、-SR a6、-C(O)OR a7、-C(O)NR a8R a9、-COR a10、取代或未取代的C 1-6烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、或取代或未取代的C 2-10杂芳基；其中，R a3、R a4、R a5、R a6、R a7、R a8、R a9和R a10的定义均同权利要求1所述；所述的取代 的C 1-6烷基、取代的C 2-8杂环烷基、取代的C 6-20芳基或取代的C 2-10杂芳基中取代基的定义均同权利要求1所述；
    和/或，R 4为氢、C 1-6烷基或C 3-10环烷基；
    和/或，R 5、R 51、R 5a、R 5a1、R 5a2、R 5b、R 5b1、R 5c、R 5c1、R 5c2、R 5d、R 5d1、R 5d2、R 5e、R 5e1、R 5e2、R 7、R 8、R 9、R 10、R 11、R 12和R 13为氢；
    和/或，R 6、R 6a、R 6b、R 6c、R 6d和R 6e各自独立地为氢、卤素、氰基、取代或未取代的C 1-6烷基、取代或未取代的C 2-8杂环烷基、取代或未取代的C 6-20芳基、取代或未取代的C 2-10杂芳基、氰基、-OR 61、-SR 62、-C(O)R 65、-C(O)OR 66或-C(O)NR a69R a610；R 61、R 62、R 65、R 66、R a69和R a610的定义均同权利要求1所述；所述的取代的C 1-6烷基、取代的C 2-8杂环烷基、取代的C 6-20芳基或取代的C 2-10杂芳基中的取代基的定义均同权利要求1所述。
  4. 如权利要求1-3中至少一项所述的通式I所示的芳香杂环取代烯烃化合物或其药学上可接受的盐，其特征在于，
    R 1和R 2其中一个为氢，另一个为氢、氰基、取代或未取代的C 1-6烷基、-C(O)OR 91或-C(O)NR 97R 98；或者R 1和R 2与它们相连的碳原子一起形成含有一个双键的取代或未取代的4-8元的碳环；其中，R 91为氢或C 1-6烷基；R 97和R 98独立地为氢、或取代或未取代的C 1-6烷基；或者R 97和R 98与它们相连的氮原子一起形成取代或未取代的3-8元杂环基；其中，R 1或R 2中，所述的取代的C 1-6烷基、所述的取代的4-8元的碳环和所述的取代的4-8元杂环中取代基的定义均同权利要求3所述；R 97或R 98中，所述的取代的C 1-6烷基或所述的取代的3-8元杂环基中的取代基的定义同权利要求3所述；
    和/或，R 3、R 31、R 32、R 33、R 3a、R 3a1、R 3b、R 3b1、R 3c、R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、R 3e1、R 3f、R 3f1、R 3f2、R 3g和R 3g1各自独立地为氢、卤素、-OR a5、或取代或未取代的C 1-6烷基；R a5为C 1-6烷基；所述的取代的C 1-6烷基中的取代基为下列基团中的一个或多个：氘或卤素；
    和/或，R 4为氢、C 1-6烷基或C 3-10环烷基；
    和/或，R 5、R 51、R 5a、R 5a1、R 5a2、R 5b、R 5b1、R 5c、R 5c1、R 5c2、R 5d、R 5d1、R 5d2、R 5e、R 5e1、R 5e2、R 7、R 8、R 9、R 10、R 11、R 12和R 13为氢；
    和/或，R 6、R 6a、R 6b、R 6c、R 6d和R 6e各自独立地为氰基、-C(O)OR 66或-C(O)NR a69R a610；其中，R 66为C 1-6烷基；R a69和R a610各自独立地为氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-10环烷基或-OR 627；所述的取代的C 1-6烷基或所述的取代的C 3-10环烷基中取代基的定义均同权利要求3所述；R 627的定义同权利要求3所述。
  5. 如权利要求1-4中至少一项所述的通式I所示的芳香杂环取代烯烃化合物或其药 学上可接受的盐，其特征在于，
    R 1和R 2其中一个为氢，另一个为氢、C 1-6烷基、-C(O)OR 91或-C(O)NR 97R 98；或者R 1和R 2与它们相连的碳原子一起形成含有一个双键的的4-8元的碳环；其中，R 91、R 97和R 98独立地为氢或C 1-6烷基；或者R 97和R 98与它们相连的氮原子一起形成3-8元杂环基；
    和/或，R 3、R 31、R 32、R 33、R 3a、R 3a1、R 3b、R 3b1、R 3c、R 3c1、R 3c2、R 3d、R 3d1、R 3d2、R 3e、R 3e1、R 3f、R 3f1、R 3f2、R 3g和R 3g1各自独立地为氢、卤素、三氟甲基、二氟甲基、甲基、氘代甲基或甲氧基；环A中有1或2个位置不为氢；和/或，R 4为氢、C 1-6烷基或C 3-10环烷基；
    和/或，R 5、R 51、R 5a、R 5a1、R 5a2、R 5b、R 5b1、R 5c、R 5c1、R 5c2、R 5d、R 5d1、R 5d2、R 5e、R 5e1、R 5e2、R 7、R 8、R 9、R 10、R 11、R 12和R 13为氢；
    和/或，R 6、R 6a、R 6b、R 6c、R 6d和R 6e各自独立地为氰基、-C(O)OR 66或-C(O)NR a69R a610；其中，R 66为C 1-6烷基；R a69和R a610各自独立地为氢、取代或未取代的C 1-6烷基、C 3-10环烷基或-OR 627；所述的取代的C 1-6烷基中取代基为C 2-8杂环烷基；R 627为C 2-8杂环烷基。
  6. 如权利要求1-5中至少一项所述的通式I所示的芳香杂环取代烯烃化合物或其药学上可接受的盐，其特征在于，
    R 1为氢，R 2为氢、C 1-6烷基、-C(O)OR 91或-C(O)NR 97R 98；R 91、R 97和R 98独立地为氢或C 1-6烷基；
    和/或，环A为
    Figure PCTCN2018124667-appb-100011
    其中，R 3和R 33独立地为氢、卤素、-OR a5、或取代或未取代的C 1-6烷基，但不同时为氢；R 3b为氢、卤素、-OR a5、或取代或未取代的C 1-6烷基；R a5的定义均同权利要求1所述；所述的取代的C 1-6烷基中取代基的定义均同权利要求1所述；R 31、R 32和R 3b1为氢；
    和/或，
    Figure PCTCN2018124667-appb-100012
    为
    Figure PCTCN2018124667-appb-100013
    进一步优选
    Figure PCTCN2018124667-appb-100014
    其中，R 5a、R 5a1、R 5a2、R 5c、R 5c1、R 5c2、R 5d、R 5d1、R 5d2、R 8、R 10和R 11为氢；R 6a、R 6c和R 6d各自独立地为氰基、C 2-10杂芳基、-C(O)OR 66或-C(O)NR a69R a610；其中，所述的C 2-10杂芳基、R 66、R a69和R a610的定义均同权利要求1所 述。
  7. 如权利要求1-6中至少一项所述的通式I所示的芳香杂环取代烯烃化合物或其药学上可接受的盐，其特征在于，
    R 1和R 2同时为氢；
    或，R 1为氢，R 2为
    Figure PCTCN2018124667-appb-100015
    R 1和R 2与它们所连接的C原子一起形成环己烯环；
    和/或，
    Figure PCTCN2018124667-appb-100016
    为
    Figure PCTCN2018124667-appb-100017
    和/或，
    Figure PCTCN2018124667-appb-100018
    为
    Figure PCTCN2018124667-appb-100019
    Figure PCTCN2018124667-appb-100020
  8. 如权利要求1-7中至少一项所述的通式I所示的芳香杂环取代烯烃化合物或其药学上可接受的盐，其特征在于，所述的通式I所示的芳香杂环取代烯烃化合物为下列任一化合物：
    Figure PCTCN2018124667-appb-100021
    Figure PCTCN2018124667-appb-100022
  9. 一种如权利要求1-8中至少一项所述的通式I所示的芳香杂环取代烯烃化合物的制备方法，其采用下列任一方法：
    方法一包括下列步骤：将化合物II-A和化合物II-2进行如下所示的偶联反应，即可；
    Figure PCTCN2018124667-appb-100023
    X和Y一个为卤素；另一个为有机锡试剂或有机硼试剂；环C1和环C2其中一个为环A，另一个为环B；R d和R c一个为R 1，另一个为R 2；当环C1为环A时，R d为R 1；R 1、R 2、环A和环B的定义均同权利要求1-8任一项所述；
    方法二包括下列步骤：将化合物III-1进行反应，制得通式I所示的化合物，其中化合物III-1中，EWG 2为能够转化为R 1或R 2的吸电子基团；
    Figure PCTCN2018124667-appb-100024
    环C1和环C2其中一个为环A，另一个为环B；R d和R c一个为R 1，另一个为R 2；当环C1为环A时，R d为R 1；R 1、R 2、环A和环B的定义均同权利要求1-8任一项所述；
    当通式I所示的芳香杂环取代烯烃化合物中，R 1和R 2为氢，其可采用下列方法三制备，所述的方法三包括下列步骤：将化合物I-1在钯试剂的作用下氢解即可；
    Figure PCTCN2018124667-appb-100025
    环C1和环C2其中一个为环A，另一个为环B；其中，环A和环B的定义均同权利要求1-8任一项所述。
  10. 一种用于制备如权利要求1-8中至少一项所述的通式I所示的芳香杂环取代烯烃化合物的中间体化合物，其为下列化合物中的任意一种：
    Figure PCTCN2018124667-appb-100026
  11. 一种如权利要求1-8中至少一项所述的通式I所示的芳香杂环取代烯烃化合物或其药学上可接受的盐在制备ALK5抑制剂或者制备用于治疗和/或预防ALK5介导的疾病的药物中的应用。
  12. 如权利要求11所述的应用，其特征在于，所述的ALK5介导的疾病为癌症、器官纤维化、病毒感染、慢性肾炎、急性肾炎、糖尿病肾病、骨质疏松症、关节炎、伤口愈合、溃疡、角膜创伤、心脏瓣膜狭窄、充血性心脏坏死、神经功能损伤、阿尔兹海默综合征、腹膜或皮下粘连、动脉硬化症和肿瘤转移生长中的一种或多种；所述的癌症优选为结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、子宫颈癌、睾丸癌、肾癌、头或颈癌、骨癌、皮肤癌、直肠癌、肝癌、结肠癌、食道癌、胃癌、胰腺癌、甲状腺癌、膀胱癌、淋巴瘤、白血病和黑色素瘤中的一种或多种；所述的器官纤维化优选 肾纤维化、肝纤维化和肺纤维化中的一种或多种。
  13. 一种药物组合物，其包含预防和/或治疗有效剂量的如权利要求1-8中至少一项所述的通式I所示的芳香杂环取代烯烃化合物和其药学上可接受的盐中的一种或多种，以及药学上可接受的载体。
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