WO2018068759A1 - 五元杂芳环并桥环类衍生物、其制备方法及其在医药上的应用 - Google Patents
五元杂芳环并桥环类衍生物、其制备方法及其在医药上的应用 Download PDFInfo
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- WO2018068759A1 WO2018068759A1 PCT/CN2017/106052 CN2017106052W WO2018068759A1 WO 2018068759 A1 WO2018068759 A1 WO 2018068759A1 CN 2017106052 W CN2017106052 W CN 2017106052W WO 2018068759 A1 WO2018068759 A1 WO 2018068759A1
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- 0 C1CC*CC1 Chemical compound C1CC*CC1 0.000 description 8
- CKODZYQFISAILP-UHFFFAOYSA-N Cc1cccc(-c2c(-c3ccnc4c3cc(C3OC3N)cc4)[n](C3CC4CC3)c4n2)n1 Chemical compound Cc1cccc(-c2c(-c3ccnc4c3cc(C3OC3N)cc4)[n](C3CC4CC3)c4n2)n1 CKODZYQFISAILP-UHFFFAOYSA-N 0.000 description 2
- NXDCVJJDDFFEON-UHFFFAOYSA-N Cc1cccc(-c2n[n](C3CCC4CC3)c4c2-c2ccnc(-c(cc3)ccc3S(C)(=O)=O)c2)n1 Chemical compound Cc1cccc(-c2n[n](C3CCC4CC3)c4c2-c2ccnc(-c(cc3)ccc3S(C)(=O)=O)c2)n1 NXDCVJJDDFFEON-UHFFFAOYSA-N 0.000 description 2
- WXDFWGNBHNFNIF-UHFFFAOYSA-N Cc1cccc(-c2n[n](C3CCC4CC3)c4c2-c2ccnc(cc3)c2cc3C(N)=O)n1 Chemical compound Cc1cccc(-c2n[n](C3CCC4CC3)c4c2-c2ccnc(cc3)c2cc3C(N)=O)n1 WXDFWGNBHNFNIF-UHFFFAOYSA-N 0.000 description 2
- PCMMSLVJMKQWMQ-UHFFFAOYSA-N Brc1cc(Br)ncc1 Chemical compound Brc1cc(Br)ncc1 PCMMSLVJMKQWMQ-UHFFFAOYSA-N 0.000 description 1
- JVNDDGMPUUGWIX-UHFFFAOYSA-N C=NN1C(C2)CCCC2C1 Chemical compound C=NN1C(C2)CCCC2C1 JVNDDGMPUUGWIX-UHFFFAOYSA-N 0.000 description 1
- LTLZCPNHZNKBPF-UHFFFAOYSA-N CC(C)(C)OC(NNC(CC1)CCC1C(O)=O)=O Chemical compound CC(C)(C)OC(NNC(CC1)CCC1C(O)=O)=O LTLZCPNHZNKBPF-UHFFFAOYSA-N 0.000 description 1
- GGMMSCQAFIMDFR-UHFFFAOYSA-N CC(C)(C)OC(NNC(CC1)CCC1C(OC)=O)=O Chemical compound CC(C)(C)OC(NNC(CC1)CCC1C(OC)=O)=O GGMMSCQAFIMDFR-UHFFFAOYSA-N 0.000 description 1
- XJGLUHVKZFPGAN-UHFFFAOYSA-N CC(C)(C)OC(Nc1cc(-c2c(-c3nc(C)ccc3)nc3[n]2C2CC3CC2)ccn1)=O Chemical compound CC(C)(C)OC(Nc1cc(-c2c(-c3nc(C)ccc3)nc3[n]2C2CC3CC2)ccn1)=O XJGLUHVKZFPGAN-UHFFFAOYSA-N 0.000 description 1
- HKVFIMDCPKKUBN-UHFFFAOYSA-N CC(C)(C)OC(c(cc1)cc2c1nccc2-c1c(-c2nc(C)ccc2)nc2[n]1C1CC2CC1)=O Chemical compound CC(C)(C)OC(c(cc1)cc2c1nccc2-c1c(-c2nc(C)ccc2)nc2[n]1C1CC2CC1)=O HKVFIMDCPKKUBN-UHFFFAOYSA-N 0.000 description 1
- HOPDZEUIMRCYRS-UHFFFAOYSA-N CC1(C)OB(C2=CC(c3c[n](C)nc3)=NCC2)OC1(C)C Chemical compound CC1(C)OB(C2=CC(c3c[n](C)nc3)=NCC2)OC1(C)C HOPDZEUIMRCYRS-UHFFFAOYSA-N 0.000 description 1
- NRFTUWFLJKDFGM-UHFFFAOYSA-N CC1(C)OB(c2ccnc(-c(cc3)ccc3S(C)(=O)=O)c2)OC1(C)C Chemical compound CC1(C)OB(c2ccnc(-c(cc3)ccc3S(C)(=O)=O)c2)OC1(C)C NRFTUWFLJKDFGM-UHFFFAOYSA-N 0.000 description 1
- UCFSYHMCKWNKAH-UHFFFAOYSA-N CC1(C)OBOC1(C)C Chemical compound CC1(C)OBOC1(C)C UCFSYHMCKWNKAH-UHFFFAOYSA-N 0.000 description 1
- PFWJWDPDQYUGNE-JZJYNLBNSA-N CCOC(C/C(/c1cccc(C)n1)=N/N1C(CC2)CCC2C1)=O Chemical compound CCOC(C/C(/c1cccc(C)n1)=N/N1C(CC2)CCC2C1)=O PFWJWDPDQYUGNE-JZJYNLBNSA-N 0.000 description 1
- AFZCUUFXTFXYJV-UHFFFAOYSA-N CCOC(CC(c1nc(C)ccc1)=O)=O Chemical compound CCOC(CC(c1nc(C)ccc1)=O)=O AFZCUUFXTFXYJV-UHFFFAOYSA-N 0.000 description 1
- ZMDPWQNDJIRNLD-UHFFFAOYSA-N CCc1cccc(-c2n[n](C3CCC4CC3)c4c2C(O)=O)n1 Chemical compound CCc1cccc(-c2n[n](C3CCC4CC3)c4c2C(O)=O)n1 ZMDPWQNDJIRNLD-UHFFFAOYSA-N 0.000 description 1
- ROQUVZNXGSWDIG-UHFFFAOYSA-N CNN1C(CC2)CCC2C1 Chemical compound CNN1C(CC2)CCC2C1 ROQUVZNXGSWDIG-UHFFFAOYSA-N 0.000 description 1
- BLYKGTCYDJZLFB-UHFFFAOYSA-N COC(C(CC1)CCC1=O)=O Chemical compound COC(C(CC1)CCC1=O)=O BLYKGTCYDJZLFB-UHFFFAOYSA-N 0.000 description 1
- KBZHKMIEZMDMTO-UHFFFAOYSA-N C[n]1ncc(-c2cc(Br)ccn2)c1 Chemical compound C[n]1ncc(-c2cc(Br)ccn2)c1 KBZHKMIEZMDMTO-UHFFFAOYSA-N 0.000 description 1
- UQFQONCQIQEYPJ-UHFFFAOYSA-N C[n]1nccc1 Chemical compound C[n]1nccc1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
- BPRNIBFKCRFPOU-UHFFFAOYSA-N Cc1cccc(-c2c(-c3ccnc(-c4c[n](C)nc4)c3)[n](C3CC4CC3)c4n2)n1 Chemical compound Cc1cccc(-c2c(-c3ccnc(-c4c[n](C)nc4)c3)[n](C3CC4CC3)c4n2)n1 BPRNIBFKCRFPOU-UHFFFAOYSA-N 0.000 description 1
- RYSOTQGQTLXDEE-IKGGRYGDSA-N Cc1cccc(-c2c(-c3ccnc(NC[C@@H](CO)O)c3)[n]([C@@H]3C[C@H]4CC3)c4n2)n1 Chemical compound Cc1cccc(-c2c(-c3ccnc(NC[C@@H](CO)O)c3)[n]([C@@H]3C[C@H]4CC3)c4n2)n1 RYSOTQGQTLXDEE-IKGGRYGDSA-N 0.000 description 1
- ZNBWRFZEQGSDIJ-UHFFFAOYSA-N Cc1cccc(-c2c(-c3ccnc4c3cc(C3OC3O)cc4)[n](C3CC4CC3)c4n2)n1 Chemical compound Cc1cccc(-c2c(-c3ccnc4c3cc(C3OC3O)cc4)[n](C3CC4CC3)c4n2)n1 ZNBWRFZEQGSDIJ-UHFFFAOYSA-N 0.000 description 1
- MZKYEAYGQJHLMI-UHFFFAOYSA-N Cc1cccc(-c2n[n](C3CCC4CC3)c4c2-c2ccnc(cc3)c2cc3C#N)n1 Chemical compound Cc1cccc(-c2n[n](C3CCC4CC3)c4c2-c2ccnc(cc3)c2cc3C#N)n1 MZKYEAYGQJHLMI-UHFFFAOYSA-N 0.000 description 1
- KRFSUGPZCQQFPS-UHFFFAOYSA-N Cc1cccc(C(Cc(c2c3)ccnc2ccc3C#N)=O)n1 Chemical compound Cc1cccc(C(Cc(c2c3)ccnc2ccc3C#N)=O)n1 KRFSUGPZCQQFPS-UHFFFAOYSA-N 0.000 description 1
- FAYBYWFQMRWTED-UHFFFAOYSA-N Cc1nc(-c2n[n](C3CCC4CC3)c4c2Br)ccc1 Chemical compound Cc1nc(-c2n[n](C3CCC4CC3)c4c2Br)ccc1 FAYBYWFQMRWTED-UHFFFAOYSA-N 0.000 description 1
- IGWPJSQVBRPANZ-MJGOQNOKSA-N NC(c(cc1)ccc1-c1cc(-c2c(-c(nc3)ccc3F)nc3[n]2[C@@H]2C[C@H]3CC2)ccn1)=O Chemical compound NC(c(cc1)ccc1-c1cc(-c2c(-c(nc3)ccc3F)nc3[n]2[C@@H]2C[C@H]3CC2)ccn1)=O IGWPJSQVBRPANZ-MJGOQNOKSA-N 0.000 description 1
- DMZNSRNZWNDXSI-UHFFFAOYSA-N NN(C1CC2CC1)C2=O Chemical compound NN(C1CC2CC1)C2=O DMZNSRNZWNDXSI-UHFFFAOYSA-N 0.000 description 1
- JATKRPGDXDPAOX-UHFFFAOYSA-N NN1C(CC2)CCC2C1 Chemical compound NN1C(CC2)CCC2C1 JATKRPGDXDPAOX-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the invention belongs to the field of medicine and relates to a novel five-membered heteroaryl ring-bridged ring-like derivative, a preparation method thereof and a pharmaceutical composition containing the same and as a therapeutic agent, particularly as an inhibitor of TGF- ⁇ . Uses and uses in the manufacture of a medicament for the treatment, prevention or reduction of cancer mediated by TGF-[beta] overexpression.
- TGF- ⁇ Transforming growth factor
- BMPs Bone morphogenetic proteins
- GDFs Differentiation factors
- MIS Müllerian-inhibiting substances
- TGF- ⁇ has three subtypes of TGF- ⁇ 1, TGF- ⁇ 2 and TGF- ⁇ 3, which are involved in the regulation of cell proliferation and differentiation, wound healing, extracellular matrix production and immunosuppression. See, eg, Massague, J. Ann. Rev, Cell. Biol. 6: 594-641 (1990); Roberts, ABPeptide Growth Factor and Their receptors, 95: 419-472 Berlin: Springer-Verlag (1990); Roberts, AB and Sporn MBGrowth Factor 8: 1-9 (1993); and Alexandrow, MG, Moses, HL Cancer Res. 55: 1452-1457 (1995). Three subtypes of TGF- ⁇ are present in most cells along with their receptors.
- Each TGF- ⁇ isoform is synthesized as a precursor protein that is cleaved intracellularly into a C-terminal region (latency related peptide, LAP) and an N-terminal portion, termed mature or active TGF. - ⁇ .
- LAP latency related peptide
- LAP is typically linked to mature TGF- ⁇ in a non-covalent manner.
- the LAP-TGF- ⁇ complex does not bind to the TGF- ⁇ receptor and is not biologically active.
- TGF-[beta] is typically released (and is active) from the complex by a variety of mechanisms including, for example, interaction with thrombospondin-1 or plasmin.
- TGF- ⁇ 1 transduces signals through two highly conserved single transmembrane serine/threonine kinases, namely type I (ALK5) and type II TGF- ⁇ receptors.
- type II receptor hyperphosphorylates the serine/threonine residue in the ALK5GS region, causing activation of ALK5 by creating a binding site for the Smad protein.
- Activated ALK5 in turn phosphorylates the Smad2 and Smad3 proteins at the C-terminal SSXS-motif, causing them to dissociate from the receptor and form a heteromeric complex with Smad4.
- the Smad complex is readily located in the nucleus and assembles with specific DNA-binding cofactors and co-regulators, ultimately activating the transcription of extracellular matrix components and matrix-degrading protease inhibitors.
- TGF- ⁇ signaling pathway The extreme activity of the TGF- ⁇ signaling pathway is responsible for many human diseases such as excessive deposition of extracellular matrices, abnormally high levels of inflammatory responses, fibrotic disorders, and progressive cancer.
- tumor cells and intratumoral stromal cells In the advanced stages of various cancers, tumor cells and intratumoral stromal cells generally overexpress TGF- ⁇ . This causes stimulation of angiogenesis and cell movement, inhibition of the immune system, and increased interaction of tumor cells with extracellular matrices (e.g., Hojo, M. et al, Nature 397: 530-534 (1999)). Therefore, tumor cells become more aggressive and metastasize to distant organs. For example, Maehara, Y. et al., J. Clin. Oncol. 17: 607-614 (1999); Picon, A. et al., Cancer Epidemiol. Biomarkers Prev. 7: 497-504 (1998)).
- TGF- ⁇ TGF- ⁇
- Thy-1 rat model of proliferative glomerulonephritis rabbit anti-GBM glomerulonephritis and bureau
- a 5/6 nephrectomized rat model of focal segmental glomerulosclerosis has recently been reviewed (eg, Bitzer, M. et al., Kidney Blood Press. Res. 21:1-12 (1998)).
- Neutralizing antibodies to TGF- ⁇ improve glomerular histology in the Thy-1 nephritis model (e.g., Border, W. A. et al, Nature 346: 371-374 (1990)).
- TGF- ⁇ 1 and its receptor are overexpressed in damaged vascular and fibroproliferative vascular injury, causing excessive production of extracellular matrix (eg, Saltis, J. et al., Clin. Exp. Pharmacol. Physiol. 23: 193). -200 (1996); McCaffrey, TA et al, J. Clin. Invest. 96: 2667-2675 (1995)).
- TGF- ⁇ 2 levels are elevated in most eyes with aqueous glaucoma with juvenile glaucoma and almost half in eyes with primary open angle glaucoma (POAG) (eg, Picht, G. et al., Graefes Arch. Clin) .Exp. Ophthalmol. 239: 199-207 (2001)). Both TGF- ⁇ 1 and TGF- ⁇ 2 subtypes have been reported to increase the extracellular matrix production of cultured human Tenon's capsule fibroblasts from patients with pseudo-exfoliative glaucoma and POAG (eg, Kottler, UB et al., Exp. Eye Res. 80: 121-134 (2005)).
- POAG primary open angle glaucoma
- Modulators (e.g., antagonists) of the disclosed TGF-[beta] family member receptors include WO2004111046, WO2012000595, WO2012002680, WO2013009140, WO2016106266.
- the present invention provides a novel structure of a TGF- ⁇ receptor kinase inhibitor, and has found that a compound of such a structure has good activity and exhibits excellent TGF- ⁇ receptor inhibitory action.
- the object of the present invention is to provide a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or In the form of a mixture or a pharmaceutically acceptable salt thereof,
- G 1 and G 2 are N or C, and when G 1 is N, G 2 is C; when G 1 is C, G 2 is N;
- Ring A is an aryl or heteroaryl group
- Ring B is selected from the group consisting of an aryl group, a heteroaryl group, and a heterocyclic group;
- R 1 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a heterocyclic group;
- R 2 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
- R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, an amino group, a cyano group, and a nitro group;
- R 4 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclic group are mentioned.
- an aryl group and a heteroaryl group are each independently selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero Substituting one or more substituents in the aryl group;
- R 5 and R 6 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, and the heteroaryl group
- the cyclo, aryl and heteroaryl are each independently selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl , one of heteroaryl, -NR 8 R 9 , -C(O)R 7 , -C(O)OR 7 , -S(O) m NR 8 R 9 and -S(O) m R 7 or Substituted by a plurality of substituents;
- R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
- R 8 and R 9 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
- n 0, 1 or 2;
- s 0, 1 or 2;
- r is 1 or 2;
- p 0, 1 or 2;
- q 0, 1 or 2;
- n 0, 1 or 2;
- x 0, 1, 2, 3 or 4.
- the compound of the formula (I) is a compound of the formula (II):
- Rings B, G 1 , G 2 , R 1 , R 2 , s and r are as defined in the formula (I).
- the compound of the formula (I) is a compound of the formula (II-1):
- Rings B, G 1 , G 2 , R 1 , R 2 , s, n and r are as defined in claim 1.
- the compound of the formula (I), wherein the ring B is selected from the group consisting of:
- the compound of the formula (I) is a compound of the formula (III) or (IV):
- Rings B, R 1 , R 2 , s and r are as defined in the general formula (I).
- the compound of the formula (I) is a compound of the formula (V) or (VI):
- Rings B, G 1 , G 2 , R 1 , R 2 and s are as defined in the formula (I).
- the compound represented by the formula (V) is a compound represented by the formula (V-1) or (V-2):
- Rings B, R 1 , R 2 and s are as defined in the formula (I).
- the compound of the formula (VI) is a compound of the formula (VI-1) or (VI-2):
- Rings B, R 1 , R 2 and s are as defined in the formula (I).
- the compounds of the present invention include all conformational isomers thereof, such as cis and trans isomers; and all optical isomers and stereoisomers thereof, and mixtures thereof.
- the compounds of the invention have asymmetric centers and therefore different enantiomers and diastereomers.
- the invention relates to the use of the compounds of the invention, and to all pharmaceutical compositions and methods of treatment which may be employed and contained therein.
- the invention relates to the use of all such isomers and mixtures thereof.
- Typical compounds of the invention include, but are not limited to:
- a tautomer a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof.
- Another aspect of the invention relates to a compound of the formula (I-B):
- X is a halogen
- Rings A, G 1 , G 2 , R 1 , R 3 , r, p, n and q are as defined in the formula (I).
- a compound of the formula (I-B) which is a compound of the formula (I-Bb):
- G 1 , G 2 , R 1 and r are as defined in the formula (I).
- a compound of the formula (I-B) which is a compound of the formula (I-Bc):
- G 1 , G 2 , R 1 , n and r are as defined in claim 1.
- a compound of the formula (I-Bb) which is a compound of the formula (I-Bb-1) or (I-Bb-2):
- R 1 and r are as defined in the formula (I).
- the compound represented by the formula (I-B) includes, but is not limited to:
- Another aspect of the invention relates to a process for the preparation of a compound of formula (I), which process comprises:
- the compound of the formula (I-A) and the compound of the formula (I-B) are subjected to a Suzuki reaction in the presence of a catalyst under basic conditions to give a compound of the formula (I).
- G is selected from halogen
- X is a halogen, preferably chlorine or bromine
- Ring A, Ring B, G 1 , G 2 , R 1 to R 3 , r, p, n, s and q are as defined in the general formula (I).
- Another aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesogen, a racemate thereof, Enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.
- the present invention also relates to a process for the preparation of the above composition, which comprises the compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non- The enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is admixed with one or more pharmaceutically acceptable carriers, diluents or excipients.
- the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting the signaling pathway of TGF- ⁇ and/or activin, in particular human TGF- ⁇ and/or activin.
- the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the preparation of a medicament for the treatment, prevention or reduction of metastasis of tumor cells, particularly human tumor cells.
- the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the preparation of a medicament for the treatment, prevention or reduction of cancer mediated by TGF- ⁇ overexpression, in particular by inhibiting the human TGF- ⁇ signaling pathway Use in the treatment, prevention or reduction of a medicament for cancer mediated by TGF- ⁇ overexpression.
- the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the preparation of a medicament for the treatment, prevention or alleviation (especially human) selected from the group consisting of vascular injury, glomerulonephritis, diabetic nephropathy , lupus nephritis, hypertension-induced nephropathy, renal interstitial fibrosis, renal fibrosis caused by drug exposure complications, HIV-associated nephropathy, graft nephropathy, liver fibrosis of various causes, return Hepatic dysfunction due to infection, alcohol-induced hepatitis, cystic fibrosis, interstitial lung disease, acute lung injury, adult respiratory distress syndrome, myelodysplastic syndrome, idiopathic pulmonary fibrosis, chronic obstruction
- the invention further relates to a method of treating, preventing or reducing human tumor cell metastasis comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, a mesogen thereof, A racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
- the invention further relates to a method of treating, preventing or reducing cancer mediated by TGF- ⁇ overexpression, in particular by treating, preventing or reducing cancer mediated by TGF- ⁇ overexpression by inhibiting the TGF- ⁇ signaling pathway
- a method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer A composition, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
- the invention further relates to a method of treating, preventing or ameliorating (particularly human) a disease selected from the group consisting of vascular injury, glomerulonephritis, diabetic nephropathy, lupus nephritis, hypertension-induced nephropathy, kidney Interstitial fibrosis, renal fibrosis caused by drug exposure complications, HIV-associated nephropathy, graft nephropathy, liver fibrosis of various causes, liver dysfunction attributable to infection, alcohol-induced hepatitis , cystic fibrosis, interstitial lung disease, acute lung injury, adult respiratory distress syndrome, myelodysplastic syndrome, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, lung disease caused by infectious or toxic factors, Post-infarction cardiac fibrosis, congestive heart failure, dilated cardiomyopathy, myocarditis, intimal thickening, vascular stenosis, vascular remodeling caused by hypertension,
- a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable drug thereof Use salt or drugs containing it combination.
- the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which is used as a medicament.
- the invention further relates to a compound of the formula (I) or a tautomer thereof, a mesogen thereof, A racemic form, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a TGF-beta receptor kinase inhibitor.
- the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for use in the treatment, prevention or reduction of metastasis of tumor cells, particularly human tumor cells.
- the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for use in the treatment, prevention or reduction of cancer mediated by TGF- ⁇ overexpression, in particular by inhibiting the TGF- ⁇ signaling pathway for treatment, prevention or reduction Cancer mediated by overexpression of TGF- ⁇ .
- the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which is used for the treatment, prevention or alleviation (especially human) of a disease selected from the group consisting of vascular injury, glomerulonephritis, diabetic nephropathy, lupus Nephritis, hypertension-induced nephropathy, renal interstitial fibrosis, renal fibrosis caused by drug exposure complications, HIV-associated nephropathy, graft nephropathy, liver fibrosis of various causes, attributable to Infected liver dysfunction, alcohol-induced hepatitis, cystic fibrosis, interstitial lung disease, acute lung injury, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, by infectious or toxic
- the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
- Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain There are one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
- the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
- Oil suspensions can be formulated by suspending the active ingredient in vegetable oil.
- the oil suspension may contain a thickening agent.
- the above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an antioxidant.
- the dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents may also be added. These compositions are preserved by the addition of an antioxidant.
- compositions of the invention may also be in the form of an oil-in-water emulsion.
- the oil phase can be a vegetable oil.
- Suitable emulsifiers can be naturally occurring phospholipids.
- the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
- compositions of the invention may be in the form of a sterile injectable aqueous solution.
- the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
- compositions of the invention may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
- the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
- sterile fixed oils may conveniently be employed as a solvent or suspension medium.
- the compounds of the invention may be administered in the form of a suppository for rectal administration.
- These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
- the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, and the patient's behavior.
- the dosage, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt The type can be verified according to traditional treatment options.
- alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpent
- lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
- the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably independently selected from alkyl, alkenyl, alkynyl, Alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy , cycloalkylthio, heterocycloalkylthio, oxo, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -S(O) m R 7 , -NR 8 R 9 And one or more substituents in -C(O)NR 8 R 9 are substituted.
- cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 10 carbon atoms. One carbon atom, most preferably containing from 3 to 6 carbon atoms.
- Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
- a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
- spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
- spirocycloalkyl groups include:
- fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- fused cycloalkyl groups include:
- bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
- bridged cycloalkyl groups include:
- the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
- the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio , oxo, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -S(O) m R 7 , -NR 8 R 9 and -C(O)NR 8 R 9 Substituted by one or more substituents.
- heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
- a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are hetero atoms; more preferably, the cycloalkyl ring contains 3 to 10 ring atoms.
- Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1, 2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, High piperazinyl and the like.
- Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
- spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
- Non-limiting examples of spiroheterocyclyl groups include:
- fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
- the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- fused heterocyclic groups include:
- bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A ⁇ -electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. 7 to 10 yuan.
- bridge heterocyclic groups include:
- the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
- the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy.
- alkylthio alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, oxo, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -S(O) m R 7 , -NR 8 R 9 and - Substituting one or more substituents in C(O)NR 8 R 9 .
- aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups which are polycyclic rings having a conjugated ⁇ -electron system (ie, The ring group adjacent to a carbon atom is preferably 6 to 10 members such as a phenyl group and a naphthyl group.
- the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
- the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently optionally selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -S(O) m R 7 , -NR 8 R 9 and -C(O)NR 8 R Substituting one or more substituents in 9 .
- heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
- the heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, pyridyl Azolyl, tetrazolyl, and the like.
- the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:
- the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio group, alkylamino group, halogen, thiol, hydroxyl group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkyl sulfide Base, heterocycloalkylthio, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -S(O) m R 7 , -NR 8 R 9 and -C(O)NR 8 Substituted by one or more substituents in R 9 .
- alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
- alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
- the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio group, alkylamino group, halogen, thiol, hydroxy, amino, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -S(O) m R 7 , -NR 8 R 9 and -C(O) Substituted by one or more substituents in NR 8 R 9 .
- the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl
- hydroxy refers to an -OH group.
- halogen means fluoro, chloro, bromo or iodo.
- amino means -NH 2.
- cyano refers to -CN.
- nitro refers to -NO 2 .
- hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
- haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
- heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
- Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3
- the hydrogen atoms are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort.
- an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
- “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
- the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
- “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
- a method for preparing a medicinal salt comprising the steps of:
- the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, sodium t-butoxide or potassium t-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, carbonic acid Antimony, sodium hydroxide and lithium hydroxide;
- Catalysts include, but are not limited to, palladium on carbon, Raney nickel, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene] dichloride Palladium, 1,1'-bis(dibenzylphosphine) dichlorodipentadium iron palladium or tris(dibenzylideneacetone) dipalladium, preferably [1,1'-bis(diphenylphosphino)dilenole Iron] palladium dichloride;
- the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two.
- a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two.
- Oxy hexacyclohexane water, N,N-dimethylformamide and mixtures thereof;
- G is selected from halogen
- X is a halogen, preferably bromine
- Ring A, Ring B, G 1 , G 2 , R 1 to R 3 , r, p, n, s and q are as defined in the general formula (I).
- a method for preparing a medicinal salt comprising the steps of:
- the first step of the reaction is a compound of the formula (III-a) and (III-b), which is nucleophilically substituted under high temperature to obtain a compound of the formula (III-c);
- the second step of the reaction is a compound of formula (III-c) and ammonium acetate under acidic conditions, ring closure to obtain formula (III-d);
- the third step is a reaction of the compound of the formula (III-d) under acidic conditions, followed by halogenation to obtain a compound of the formula (III-e);
- the fourth step is a compound of the formula (III-e) and a compound of (III-f), which are subjected to Suzuki coupling under basic conditions to obtain a compound of the formula (III);
- Agents providing acidic conditions include, but are not limited to, pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably acetic acid;
- the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, sodium t-butoxide or potassium t-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, carbonic acid Antimony, sodium hydroxide and lithium hydroxide;
- Reagents providing a halogenation reaction include, but are not limited to, liquid bromine, hydrogen bromide, N-bromosuccinimide (NBS), PBr 3 , POBr 3 , pyridinium bromide hydrobromide (PHP), tetrabromo Cyclic ketone (TBCO), diethyl bromomalonate and tetrabutylammonium bromide, N-chlorosuccinimide, PCl 3 and POCl 3 ;
- Catalysts include, but are not limited to, palladium on carbon, Raney nickel, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene] dichloride Palladium, 1,1'-bis(dibenzylphosphine) dichlorodipentadium iron palladium or tris(dibenzylideneacetone) dipalladium, preferably [1,1'-bis(diphenylphosphino)dilenole Iron] palladium dichloride;
- the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two.
- a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two.
- Oxy hexacyclohexane water, N,N-dimethylformamide and mixtures thereof;
- X is a halogen, preferably bromine
- G is a leaving group selected from halogen
- Rings B, R 1 , R 2 , r and s are as defined in the formula (I).
- a method for preparing a medicinal salt comprising the steps of:
- the first step is a reaction of a compound of formula (IV-a) and formula (IV-b) under acidic conditions to give a compound of formula (IV-c), or formula (IV-a) and formula (IV-bb). a compound which reacts under acidic conditions to give a compound of formula (IV-cc);
- the third step is a reaction of the compound of the formula (IV-d) under acidic conditions, followed by halogenation to obtain a compound of the formula (IV-e);
- the fourth step is a compound of the formula (IV-e) and a compound of (IV-f), which are subjected to Suzuki coupling under basic conditions to obtain a compound of the formula (IV);
- Agents that provide acidic conditions include, but are not limited to, pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably acetic acid.
- the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, sodium t-butoxide or potassium t-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, carbonic acid Bismuth, sodium hydroxide and lithium hydroxide.
- Reagents providing a halogenation reaction include, but are not limited to, liquid bromine, hydrogen bromide, N-bromosuccinimide (NBS), PBr 3 , POBr 3 , pyridinium bromide hydrobromide (PHP), tetrabromo Cyclic ketone (TBCO), diethyl bromomalonate and tetrabutylammonium bromide, N-chlorosuccinimide, PCl 3 and POCl 3 ;
- Catalysts include, but are not limited to, palladium on carbon, Raney nickel, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene] dichloride Palladium, 1,1'-bis(dibenzylphosphine) dichlorodipentadium iron palladium or tris(dibenzylideneacetone) dipalladium, preferably [1,1'-bis(diphenylphosphino)dilenole Iron] palladium dichloride.
- the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two. Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof.
- a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two.
- R 13 is selected from the group consisting of alkyl, cycloalkyl and heterocyclic, preferably alkyl, more preferably ethyl;
- X is a halogen, preferably bromine
- G is a leaving group selected from halogen
- Rings B, R 1 , R 2 , r and s are as defined in the formula (I).
- the preparation method comprises the following steps:
- the first step is a reaction of a compound of the formula (IV-aa) and the formula (IV-b) under acidic conditions to obtain a compound of the formula (IV-g);
- the second step of the reaction is a compound of formula (IV-g) under basic conditions, ring closure to obtain formula (IV);
- Agents that provide acidic conditions include, but are not limited to, pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably acetic acid.
- the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, sodium t-butoxide or potassium t-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, carbonic acid Bismuth, sodium hydroxide and lithium hydroxide.
- the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two. Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof.
- a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two.
- Rings B, R 1 , R 2 , r and s are as defined in the formula (I).
- the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
- NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
- NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), internal standard was four.
- DMSO-d 6 dimethyl sulfoxide
- CDCl 3 deuterated chloroform
- CD 3 OD deuterated methanol
- TMS Methyl silane
- the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
- ESI FINNIGAN LCQAd
- the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
- Chiral HPLC analysis assays were performed using LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.).
- Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
- the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
- the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
- the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
- the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
- An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
- the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
- the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
- the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
- the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
- the solution means an aqueous solution.
- reaction temperature is room temperature and is 20 ° C to 30 ° C.
- the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
- TLC thin layer chromatography
- the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloro Methane and acetone systems, D: petroleum ether and ethyl acetate systems, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
- Purification compounds using column chromatography eluent systems and thin layer chromatography developer systems include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone System, D: petroleum ether and ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.
- A dichloromethane and methanol systems
- B n-hexane and ethyl acetate systems
- C dichloromethane and acetone System
- D petroleum ether and ethyl acetate system
- the volume ratio of the solvent is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic
- 6-bromoquinoline-4-carbonitrile 1 g (550 mg, 2.36 mmol, prepared by the method disclosed in the patent application "WO2014022128”), boranoic acid pinacol ester (898.91 mg, 3.54 mmol), potassium acetate (926.41) Mg, 9.44 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (350.11 mg, 0.47 mmol) dissolved in 10 mL of 1,4-dioxane and warmed to The reaction was stirred at 90 ° C for 12 hours. The reaction mixture was cooled to room temperature, and then evaporated.
- 6-bromoquinoline-4-carboxylic acid 1j (3.5 g, 13.89 mmol) was dissolved in 50 mL of methanol, and thionyl chloride (1.65 g, 13.89 mmol) was added, and the mixture was heated to reflux and stirred for 12 hours. The reaction mixture was cooled to room temperature and then evaporated.
- the compound 1m (1.g, 2.44 mmol) was dissolved in 80 mL of a 7 M ammonia solution in methanol, and the mixture was warmed to 100 ° C, and the mixture was stirred and reacted for 12 hours. The reaction mixture was cooled to room temperature.
- the compound 4d (30 mg, 0.07 mmol) was dissolved in 10 mL of a 7 M ammonia solution in methanol, and the mixture was warmed to 110 ° C, and the mixture was stirred and reacted for 12 hours. The reaction mixture was cooled to room temperature.
- 2-Bromo-4-chloropyridine 14a (576 mg, 2.993 mmol), 4-aminobenzenesulfonamide 14b (515.42 mg, 2.99 mmol, prepared by the method disclosed in the patent application "CZ105175294"), 4,5-double Diphenylphosphine-9,9-dimethyloxaxime (173.19 mg, 0.299 mmol), cesium carbonate (1.462 g, 4.49 mmol) and palladium acetate (67.199 mg, 0.299 mmol) dissolved in 10 mL 1,4-di In the hexacyclohexane, the temperature was raised to 90 ° C and the reaction was stirred for 12 hours. The reaction mixture was cooled to room temperature, filtered, and then evaporated.
- the title compound 26 (10 mg) was obtained by substituting the starting material 4-aminocyclohexanol to ethylene glycol.
- Methyl 4-cyclohexanonecarboxylate 33a (2 g, 12.806 mmol), tert-butyl carbazate (1.86 g, 14.286 mmol) and sodium triacetoxyborohydride (5.4 g, 25.612 mmol) were dissolved in 30 mL of dichloro To the methane, 0.5 mL of acetic acid was added, and the reaction was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjjj (1.5 g, yield: 43%).
- the compound 33 g (1.3 g, 3.95 mmol) was dissolved in 20 mL of toluene, sodium ethoxide (537.14 mg, 7.89 mmol) was added, and the mixture was heated to 100 ° C and stirred for 12 hours. The reaction mixture was cooled to EtOAc. g), the product is directly subjected to the next reaction without purification.
- the crude compound 33h (1.1 g, 3.88 mmol) was dissolved in 15 mL of N,N-dimethylformamide, and N-bromosuccinimide (1.38 g, 7.76 mmol) was added, and the mixture was heated to 40 ° C to stir the reaction 12 hour. The reaction mixture was cooled to room temperature, and then evaporated.
- the crude compound 34c (70 mg, 0.179 mmol) was dissolved in 3 mL of dimethyl sulfoxide, and 0.3 mL of hydrogen peroxide solution (30%) and potassium carbonate (74 mg, 0.536 mmol) were added, and the reaction was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was evaporated. :27%).
- 2-Nitroso-2-azabicyclo[2.2.1]heptan-3-one 35a (15 g, 107 mmol, prepared by the method disclosed in the patent application "WO2010132509") was dissolved in 75 mL of acetic acid and cooled to At 0 ° C, zinc powder (10.2 g, 159 mmol) was added, and the temperature was slowly raised to room temperature, and the reaction was stirred until the reaction mixture was gray, and the reaction was stopped. The reaction mixture was filtered with EtOAcq.
- the compound 35c (2 g, 6.9 mmol) was dissolved in 50 mL of toluene, and sodium ethoxide (1.4 g, 20.9 mmol) was added thereto, and the mixture was heated to 100 ° C and stirred for 16 hours. The reaction mixture was cooled to room temperature, water was added, EtOAc (EtOAc m. g), the product is directly subjected to the next reaction without purification.
- the crude compound 35d (600 mg, 2.23 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and N-bromosuccinimide (422 mg, 2.45 mmol) was added, and the reaction was stirred at room temperature for 4 hours. The reaction mixture was stirred with EtOAc EtOAc EtOAc. The title compound 35e (610 mg, yield: 90.3%) was obtained.
- the compound 35 g (250. mg, 0.66 mmol) was dissolved in 3 mL of dimethyl sulfoxide, and 0.5 mL of a hydrogen peroxide solution (30%) and potassium carbonate (273 mg, 1.98 mmol) were added, and the reaction was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was evaporated. :37.6%).
- the compound 9a (4.5 g, 20.64 mmol) was dissolved in 50 mL of N,N-dimethylformamide, and the crude compound 1b-1 (5.19 g, 41.28 mmol) was added, and the reaction was stirred at 50 ° C for 18 hours under an argon atmosphere. The reaction mixture was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal
- the compound 39d-1 (60 mg, 0.14 mmol) was dissolved in 3 mL of a 7 M ammonia solution in methanol, and the mixture was heated to 50 ° C under a sealed condition and stirred for 3 hours. The reaction mixture was cooled to EtOAc.
- Example 12 Using the synthetic route of Example 12, the starting compound 12a was replaced by 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-1H-pyrazole 43a (prepared by the method disclosed in the patent application "WO20140005183") to give the title compound 43d (100 mg).
- the compound 44b (80 mg, 0.210 mmol) was dissolved in 10 mL of methanol, and then 10% palladium carbon (16 mg, 0.470 mmol) was added, and the mixture was replaced with hydrogen three times, and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was filtered and evaporated to dryness crystals crystals
- Test Example 1 Determination of the inhibitory effect of the compound of the present invention on TGF ⁇ RI kinase activity
- the inhibitory effect of the compound of the present invention on the activity of TGF ⁇ RI kinase ALK5 was determined by the following experimental method:
- Enzyme activity assay using TGF ⁇ RI kinase assay kit (V4093, Promega), 2 ⁇ l of lysis buffer (40 mM Tris pH 7.5, 20 mM MgCl 2 , 0.1 mg/ml BSA) was added to 384-well plates (4514, Corning).
- the enzyme solution (the final concentration of the enzyme in the reaction system is 2 ng / ⁇ L), 1 ⁇ l of a 3-fold gradient dilution of the compound dissolved in 5% DMSO, 2 ⁇ l of a mixture of ATP and TGF ⁇ RI substrate polypeptide (ATP final concentration of 50 ⁇ M, substrate final The concentration was 0.2 ⁇ g/ ⁇ L), and after reacting at 27 ° C for 2.5 hours, 5 ⁇ l of the ADP-Glo solution in the kit was added to each well, and the mixture was allowed to stand at 27 ° C for 40 minutes, and 10 ⁇ l of the kinase detection reagent was further added to each well, and the mixture was allowed to stand at 27 ° C for 30 minutes. Chemiluminescent signal values were measured using a Victor 3 (PerkinElmer) multi-plate reader. IC 50 values of inhibitory activity of the compound is calculated using Graphpad prism software corresponding to each concentration of compound according to the signal value.
- the compounds of the examples of the present invention have a significant inhibitory effect on the activity of TGF ⁇ RI kinase ALK5.
- Test Example 2 Determination of the inhibitory effect of the compound of the present invention on VEGFR2 kinase activity
- VEGFR2 kinase activity in vitro was tested by the following method.
- Enzyme activity detection Kinase Assay Kit-Tyrosine 1Peptide (PV3190, Invitrogen) kit 5 ⁇ l of reaction buffer (50 mM HEPES pH 7.5, 10 mM MgCl 2 , 1 mM EGTA, 0.05% BRIJ-35) was sequentially added to a 384-well plate (4513, Corning).
- the compounds of the present invention showed no significant inhibitory effect on VEGFR2 kinase activity, indicating that the compounds of the examples of the present invention selectively inhibited TGF ⁇ RI kinase.
- Test Example 3 Determination of the inhibitory effect of the compound of the present invention on p38 ⁇ kinase activity
- Enzyme activity assay using the p38 ⁇ kinase assay kit (V9591, Promega) was sequentially added to a 384-well plate (4514, Corning).
- Enzyme solution (final concentration of the enzyme in the reaction system is 0.5 ng / ⁇ L), 1 ⁇ l of a 3-fold gradient dilution of the compound in 5% DMSO, 2 ⁇ l of a mixture of ATP and p38 substrate polypeptide (ATP final concentration of 50 ⁇ M, substrate The final concentration was 0.2 ⁇ g/ ⁇ L), and after reacting at 27 ° C for 2.5 hours, 5 ⁇ l of the ADP-Glo solution in the kit was added to each well, and the mixture was allowed to stand at 27 ° C for 40 minutes, and 10 ⁇ l of the kinase detection reagent was further added to each well, and the mixture was allowed to stand at 27 ° C for 30 minutes. Chemiluminescent signal values were measured using a Victor 3 (PerkinElmer) multi-plate reader. IC 50 values of inhibitory activity of the compound is calculated using Graphpad prism software corresponding to each concentration of compound according to the signal value.
- Example number IC 50 (nM) 1-1 618 2-1 1710 3-1 686 4 638 Compounds with retention time of 3.747 minutes in 6-1 and 6-2 515 12 454 Compounds with retention time of 6.631 minutes in 9-1 and 9-2 5798 Compounds corresponding to the retention time of 13.001 minutes in 9-1 and 9-2 2456 3-2 654 33 563 36 598 39-1 4734 40-1 1362 42-1 7782
- the compounds of the present invention showed no significant inhibitory effect on p38 ⁇ kinase activity, indicating that the compounds of the examples of the present invention selectively inhibited TGF ⁇ RI kinase.
- Test Example 4 Inhibition of proliferation of NIH3T3 cells by the compounds of the present invention
- the compounds of the present invention have significant inhibitory activity on the proliferation of NIH3T3 cells.
- Test Example 5 Determination of the inhibitory activity of the compound of the present invention on the Smad signaling pathway of TGF ⁇ RI
- HepG2 TCHu 72, Cell Culture Bank of the Chinese Academy of Sciences
- EPM medium 42360-099, Gibco
- FBS FBS
- the seeding density was 2.5 ⁇ 10 4 cells/ Wells
- cells were incubated overnight at 37 ° C, 5% CO 2 .
- the fresh EMEM containing 10% FBS
- transfect 0.1 ⁇ g of 3TP-lux plasmid 11767, Pu Ruting Biotechnology (Beijing) Co., Ltd.
- the cells will continue to culture at 37 ° C, 5% CO 2 . hour.
- EMEM medium containing 0.5% FBS 90 ⁇ l was replaced per well and starved for 6 hours.
- the compound was configured to a 20 mM stock solution, diluted to a 400x concentration with a 100% DMSO gradient, and diluted 40-fold with EMEM containing 0.5% FBS.
- ONE-Glo TM Luciferase Assay (E6110 , Promega), at room temperature in the dark for 10 minutes, using Victor3.0 (PerkinElmer) chemiluminescent signal read value.
- Compound IC 50 value calculated using Graphpad Prism software corresponding to each concentration of compound according to the signal value.
- the compounds of the present invention have significant inhibitory activities against the Smad signaling pathway of TGF ⁇ RI.
- Rats were used as test animals, and the compounds of Example 1-1, the compound of Example 1-2, the compound of Example 2-1, and the compound of Example 3-1 were administered intragastrically by the LC/MS/MS method.
- the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
- Example 39-1 The compound corresponding to the compound of Example 1-1, the compound of Example 1-2, the compound of Example 2-1, the compound of Example 3-1, the retention time of 6.631 minutes in Examples 9-1 and 9-2, and the compound of Example 33 The compound of Example 39-1.
- a certain amount of the drug was weighed, and 5% by volume of DMSO, 5% by volume of Tween 80, and 90% by volume of physiological saline were added to prepare a 0.2 mg/mL colorless clear liquid.
- the SD rats were intragastrically administered overnight after fasting, and the dose was 2.0 mg/kg, and the administration volume was 10.0 mL/kg.
- Rats were administered intragastrically with the compound of Example 1-1, the compound of Example 1-2, the compound of Example 2-1, the compound of Example 3-1, and the retention time of Example 9-1, 9-2 for 6.631 minutes.
- the compound, the compound of Example 33 and the compound of Example 39-1 were collected from the orbital heparin in a heparinized test tube before administration and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours after administration.
- the plasma was separated by centrifugation at 3,500 rpm for 3 minutes at 4 ° C, stored at -20 ° C, and fed 2 hours after administration.
- the content of the test compound in the plasma of rats after different doses of the drug was measured: 25 ⁇ L of rat plasma at each time after administration, 50 ⁇ L of camptothecin (100 ng/mL), 175 ⁇ L of acetonitrile, vortex The mixture was spun for 5 minutes, centrifuged for 10 minutes (4000 rpm), and plasma samples were taken for 3.0 ⁇ L of the supernatant for LC/MS/MS analysis.
- the compound of the present invention has good pharmacological absorption and has obvious pharmacokinetic advantages.
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Abstract
本发明涉及五元杂芳环并桥环类衍生物、其制备方法及其在医药上的应用。具体而言,本发明涉及一种通式(I)所示的新的五元杂芳环并桥环类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂,特别是作为TGF-β抑制剂的用途和在制备治疗、预防或减少由TGF-β过度表达介导的癌症的药物中的用途,其中通式(I)的各取代基与说明书中的定义相同。
Description
本发明属于医药领域,涉及一种新的五元杂芳环并桥环类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂特别是作为TGF-β的抑制剂的用途和在制备治疗、预防或减少由TGF-β过度表达介导的癌症的药物中的用途。
转化生长因子TGF-β(Transforming Growth Factorβ)是二聚多肽生长因子超家族中的一员,其包括例如活化素、抑制素、骨形成蛋白(Bone morphogenetic proteins,BMPs)、生长和分化因子(Growth differentiation factors,GDFs)和繆勒氏管抑制物(Müllerian-inhibiting substance,MIS)。
TGF-β有TGF-β1、TGF-β2和TGF-β3三种亚型,它们参与细胞增殖与分化、伤口愈合、细胞外基质产生和免疫抑制的调控。参见如Massague,J.Ann.Rev,Cell.Biol.6:594-641(1990);Roberts,A.B.Peptide Growth Factor and Their receptors,95:419-472Berlin:Springer-Verlag(1990);Roberts,A.B.和Sporn M.B.Growth Factor 8:1-9(1993);以及Alexandrow,M.G.,Moses,H.L.Cancer Res.55:1452-1457(1995)。TGF-β的三种亚型与其受体一起存在于大多数的细胞中。每种TGF-β亚型被合成作为前体蛋白,该前体蛋白在细胞内裂解成C-端区域(潜伏相关肽latency associated peptide,LAP)和N-端部分,被称为成熟或活性TGF-β。从细胞中分泌前,LAP一般与成熟TGF-β以非共价的方式连接。LAP-TGF-β复合体不能与TGF-β受体结合且不具有生物学活性。TGF-β通常通过多种机制包括例如,与血小板反应蛋白-1或纤溶酶相互作用,从复合体中释放出来(并具有活性)。TGF-β1通过两种高保守性单跨膜丝氨酸/苏氨酸激酶转导信号,即I型(ALK5)和II型TGF-β受体。一旦配体诱发低聚化,II型受体过度磷酸化ALK5GS区中的丝氨酸/苏氨酸残基,通过创建Smad蛋白的结合位点引起ALK5的活化。活化的ALK5继而磷酸化C-末端SSXS-基序处的Smad2和Smad3蛋白,从而导致它们从受体中离解,并且与Smad4生成异质复合体(heteromeric complex)。Smad复合体易位于核,与特异性DNA-结合性辅因子和辅调控剂装配,最终活化细胞外基质组分和基质-降解性蛋白酶抑制剂的转录。
TGF-β信号通路的极度活跃是许多人类疾病(如细胞外基质的过量沉积、炎症应答的异常高水平、纤维变性病症以及进行性癌)的原因。在各种癌症的晚期,肿瘤细胞和肿瘤内基质细胞一般过度表达TGF-β。这引起血管生成与细胞运动的刺激、免疫***的抑制和肿瘤细胞与细胞外基质的相互作用增加(例如,Hojo,M.等人,Nature 397:530-534(1999))。所以,肿瘤细胞变得更有侵袭性,转移至远侧器官例如,Maehara,Y.等人,J.Clin.Oncol.17:607-614(1999);Picon,A.等人,Cancer
Epidemiol.Biomarkers Prev.7:497-504(1998))。
大量实验性动物研究证明了TGF-β的肾小球表达与纤维化之间的关联,包括增殖性肾小球性肾炎的Thy-1大鼠模型、兔抗-GBM肾小球性肾炎和局灶性节段性肾小球硬化的5/6肾切除大鼠模型,最近已有评述(例如,Bitzer,M.等,Kidney Blood Press.Res.21:1-12(1998))。TGF-β的中和抗体改进Thy-1肾炎模型中的肾小球组织学(如,Border,W.A.等人,Nature 346:371-374(1990))。
TGF-β1及其受体在受损血管和纤维增殖性血管损伤中被过度表达,引起细胞外基质的过度产生(例如,Saltis,J.等人,Clin.Exp.Pharmacol.Physiol.23:193-200(1996);McCaffrey,T.A.等人,J.Clin.Invest.96:2667-2675(1995))。
TGF-β2水平在大多数患有少年青光眼的眼房水肿瘤眼中和几乎一半患有原发性开放角度青光眼(POAG)的眼中都有增加(例如,Picht,G.等人,Graefes Arch.Clin.Exp.Ophthalmol.239:199-207(2001))。TGF-β1和TGF-β2亚型据报道都增加培养的来自假性剥脱性青光眼和POAG患者的人特农氏囊成纤维细胞的细胞外基质产生(例如,Kottler,U.B.等人,Exp.Eye Res.80:121-134(2005))。
因此希望开发出对TGF-β家族成员的抑制剂来预防和/或治疗包括这种信号通路的疾病。公开的TGF-β家族成员受体的调节剂(如拮抗剂)专利申请包括WO2004111046、WO2012000595、WO2012002680、WO2013009140、WO2016106266。
为了达到更好的治疗效果的目的,更好的满足市场需求,发明人希望能开发出新一代的高效低毒的TGF-β受体激酶抑制剂。本发明将提供一种新型结构的TGF-β受体激酶抑制剂,并发现此类结构的化合物具有良好的活性,并表现出优异的TGF-β受体抑制作用。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,
其中:
G1和G2为N或C,且当G1为N时,G2为C;当G1为C时,G2为N;
环A为芳基或杂芳基;
环B选自芳基、杂芳基和杂环基;
R1相同或不同,且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基;
R2相同或不同,且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、氧代基、-OR4、-C(O)R4、-C(O)OR4、-NHC(O)OR4、-O(CH2)xOR4、-NH(CH2)xOR4、-NR5R6、-O(CH2)xC(O)NR5R6、-NH(CH2)xNR5R6和-C(O)NR5R6,其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氢原子、烷基、烷氧基、卤素、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-S(O)mNR8R9、-NR8R9、和-C(O)NR8R9中的一个或多个取代基所取代;
R3相同或不同,且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氨基、氰基和硝基;
R4选自氢原子、烷基、卤代烷基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、烷氧基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代;
R5和R6各自独立地选自氢原子、烷基、卤代烷基、烷氧基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、烷氧基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-NR8R9、-C(O)R7、-C(O)OR7、-S(O)mNR8R9和-S(O)mR7中的一个或多个取代基所取代;
R7选自氢原子、烷基、卤代烷基、羟烷基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基;
R8和R9各自独立地选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基;
n为0、1或2;
s为0、1或2;
r为1或2;
p为0、1或2;
q为0、1或2;
m为0、1或2;且
x为0、1、2、3或4。
在本发明的一个优选的实施方案中,所述的通式(I)所示的化合物,其为通式(II)所示的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,
其中:
环B、G1、G2、R1、R2、s和r如通式(I)中所定义。
在本发明的一个优选的实施方案中,所述的通式(I)所示的化合物,其为通式(II-1)所示的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,
其中:
环B、G1、G2、R1、R2、s、n和r如权利要求1中所定义。
在本发明的一个优选的实施方案中,所述的通式(I)所示的化合物,其中R1为烷基或卤素,优选为甲基、乙基、氯原子、溴原子或氟原子。
在本发明的一个优选的实施方案中,所述的通式(I)所示的化合物,其中环B选自:
在本发明的一个优选的实施方案中,所述的通式(I)所示的化合物,其为通式(III)或(IV)所示的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,
其中:
环B、R1、R2、s和r如通式(I)中所定义。
在本发明的一个优选的实施方案中,所述的通式(I)所示的化合物,其为通式(V)或(VI)所示的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,
其中:
环B、G1、G2、R1、R2和s如通式(I)中所定义。
在本发明的一个优选的实施方案中,所述的通式(V)所示的化合物,其为通式(V-1)或(V-2)所示的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,
其中:
环B、R1、R2和s如通式(I)中所定义。
在本发明的一个优选的实施方案中,所述的通式(VI)所示的化合物,其为通式(VI-1)或(VI-2)所示的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,
其中:
环B、R1、R2和s如通式(I)中所定义。
本发明的化合物包括其所有构象异构体,例如顺式和反式异构体;以及其所有旋光异构体和立体异构体及其混合物。本发明的化合物具有不对称中心,因此存在不同的对映异构体与非对映异构体。本发明涉及本发明化合物的用途,和可以采用和含有它们的所有药物组合物和治疗方法。本发明涉及所有这类异构体及其混合物的用途。
本发明的典型化合物包括但不限于:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐。
本发明的另一方面涉及一种通式(I-B)所示的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其
混合物形式或其可药用的盐,
其中:
X为卤素;
环A、G1、G2、R1、R3、r、p、n和q如通式(I)中所定义。
在本发明的一个优选的实施方案中,一种通式(I-B)所示的化合物,其为通式(I-Bb)所示的化合物:
其中:
G1、G2、R1和r如通式(I)中所定义。
在本发明的一个优选的实施方案中,一种通式(I-B)所示的化合物,其为通式(I-Bc)所示的化合物:
其中:
G1、G2、R1、n和r如权利要求1中所定义。
在本发明的一个优选的实施方案中,一种通式(I-Bb)所示的化合物,其为通式(I-Bb-1)或(I-Bb-2)所示的化合物:
其中:
R1和r如通式(I)中所定义。
通式(I-B)所示的化合物包括,但不限于:
本发明的另一方面涉及一种制备通式(I)所示的化合物的方法,该方法包括:
通式(I-A)的化合物和通式(I-B)的化合物在碱性条件下,在催化剂存在下经Suzuki反应,得到通式(I)的化合物,
其中:
X为卤素,优选为氯或溴;
环A、环B、G1、G2、R1~R3、r、p、n、s和q如通式(I)中所定义。
本发明的另一方面涉及一种药物组合物,所述药物组合物含有治疗有效剂量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或可药用的盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。本发明还涉及一种制备上述组合物的方法,其包括将通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与一种或多种药学上可接受的载体、稀释剂或赋形剂相混合。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用盐、或包含其的药物组合物,在制备用于抑制TGF-β和/或活化素(特别是人类TGF-β和/或活化素)信号传导途径的药物中的用途。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物,在制备用于治疗、预防或减少肿瘤细胞(特别是人类肿瘤细胞)转移的药物中的用途。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物,在制备用于治疗、预防或减少由TGF-β过度表达介导的癌症的药物中的用途,特别是通过抑制人类TGF-β信号传导途径来治疗、预防或减少由TGF-β过度表达介导的癌症的药物中的用途。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物在制备用于治疗、预防或减轻(特别是人类的)选自下述疾病的药物中的用途:血管损伤、肾小球性肾炎、糖尿病性肾病、狼疮性肾炎、高血压-诱发的肾病、肾间质性纤维化、由药物暴露并发症所致肾纤维化、与HIV有关的肾病、移植物肾病、各种病因的肝纤维化、可归因于感染的肝功能障碍、酒精-诱发的肝炎、囊性纤维化病、间质性肺病、急性肺损伤、成人呼吸窘迫综合征、骨髓增生异常综合征、特发性肺纤维化、慢性阻塞性肺病、由感染性或毒性因子引起的肺病、梗塞后心纤维化、充血性心力衰竭、扩张型心肌病、心肌炎、内膜增厚、血管狭窄、高血压引起的血管重构、肺动脉高压、冠状动脉再狭窄、周围动脉再狭窄、颈动脉再狭窄、支架诱导的再狭窄、动脉粥样硬化、眼部瘢痕形成、角膜瘢痕形成、增生性玻璃体视网膜病变、青光眼、眼内压高、发生在由创伤或手术伤口所致伤口愈合期间的过度性或肥厚性真皮瘢痕或瘢痕疙瘩形成、腹膜与皮下粘连、硬皮病、纤维硬化、进行性***性硬化病、皮肌炎、多肌炎、关节炎、骨质疏松、溃疡、神经***功能减低、男性***功能障碍、佩罗尼氏病、杜普伊特伦氏挛缩、阿尔茨海默氏病、雷诺氏综合征、辐射-诱发的纤维化、血栓形成、肿瘤转移性生长、多发性骨髓瘤、黑素瘤、神经胶质瘤、胶质母细胞瘤、白血病、肉瘤、平滑肌瘤、间皮瘤、乳腺癌、***、肺癌、胃癌、直肠癌、结肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、***癌、骨癌、肾癌、卵巢癌、膀胱癌和肝癌。
本发明进一步涉及一种治疗、预防或减少人类肿瘤细胞转移的方法,其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物。
本发明进一步涉及一种治疗、预防或减少由TGF-β过度表达介导的癌症的方法,特别是通过抑制TGF-β信号传导途径来治疗、预防或减少由TGF-β过度表达介导的癌症的方法,其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物。
本发明进一步涉及一种治疗、预防或减轻(特别是人类的)选自下述疾病的方法:血管损伤、肾小球性肾炎、糖尿病性肾病、狼疮性肾炎、高血压-诱发的肾病、肾间质性纤维化、由药物暴露并发症所致肾纤维化、与HIV有关的肾病、移植物肾病、各种病因的肝纤维化、可归因于感染的肝功能障碍、酒精-诱发的肝炎、囊性纤维化病、间质性肺病、急性肺损伤、成人呼吸窘迫综合征、骨髓增生异常综合征、特发性肺纤维化、慢性阻塞性肺病、由感染性或毒性因子引起的肺病、梗塞后心纤维化、充血性心力衰竭、扩张型心肌病、心肌炎、内膜增厚、血管狭窄、高血压引起的血管重构、肺动脉高压、冠状动脉再狭窄、周围动脉再狭窄、颈动脉再狭窄、支架诱导的再狭窄、动脉粥样硬化、眼部瘢痕形成、角膜瘢痕形成、增生性玻璃体视网膜病变、青光眼、眼内压高、发生在由创伤或手术伤口所致伤口愈合期间的过度性或肥厚性真皮瘢痕或瘢痕疙瘩形成、腹膜与皮下粘连、硬皮病、纤维硬化、进行性***性硬化病、皮肌炎、多肌炎、关节炎、骨质疏松、溃疡、神经***功能减低、男性***功能障碍、佩罗尼氏病、杜普伊特伦氏挛缩、阿尔茨海默氏病、雷诺氏综合征、辐射-诱发的纤维化、血栓形成、肿瘤转移性生长、多发性骨髓瘤、黑素瘤、神经胶质瘤、胶质母细胞瘤、白血病、肉瘤、平滑肌瘤、间皮瘤、乳腺癌、***、肺癌、胃癌、直肠癌、结肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、***癌、骨癌、肾癌、卵巢癌、膀胱癌和肝癌,其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物。
本发明进一步涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物,其用作药物。
本发明进一步涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、
外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物,其用作TGF-β受体激酶抑制剂。
本发明进一步涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物,其用于治疗、预防或减少肿瘤细胞(特别是人类肿瘤细胞)转移。
本发明进一步涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物,其用于治疗、预防或减少由TGF-β过度表达介导的癌症,特别是通过抑制TGF-β信号传导途径来治疗、预防或减少由TGF-β过度表达介导的癌症。
本发明进一步涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物,其用于治疗、预防或减轻(特别是人类的)选自下述的疾病:血管损伤、肾小球性肾炎、糖尿病性肾病、狼疮性肾炎、高血压-诱发的肾病、肾间质性纤维化、由药物暴露并发症所致肾纤维化、与HIV有关的肾病、移植物肾病、各种病因的肝纤维化、可归因于感染的肝功能障碍、酒精-诱发的肝炎、囊性纤维化病、间质性肺病、急性肺损伤、成人呼吸窘迫综合征、特发性肺纤维化、慢性阻塞性肺病、由感染性或毒性因子引起的肺病、梗塞后心纤维化、充血性心力衰竭、扩张型心肌病、心肌炎、内膜增厚、血管狭窄、高血压引起的血管重构、肺动脉高压、冠状动脉再狭窄、周围动脉再狭窄、颈动脉再狭窄、支架诱导的再狭窄、动脉粥样硬化、眼部瘢痕形成、角膜瘢痕形成、增生性玻璃体视网膜病变、青光眼、眼内压高、发生在由创伤或手术伤口所致伤口愈合期间的过度性或肥厚性真皮瘢痕或瘢痕疙瘩形成、腹膜与皮下粘连、硬皮病、纤维硬化、进行性***性硬化病、皮肌炎、多肌炎、关节炎、骨质疏松、溃疡、神经***功能减低、男性***功能障碍、佩罗尼氏病、杜普伊特伦氏挛缩、阿尔茨海默氏病、雷诺氏综合征、辐射-诱发的纤维化、血栓形成、肿瘤转移性生长、多发性骨髓瘤、黑素瘤、神经胶质瘤、胶质母细胞瘤、白血病、肉瘤、平滑肌瘤、间皮瘤、乳腺癌、***、肺癌、胃癌、直肠癌、结肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、***癌、骨癌、肾癌、卵巢癌、膀胱癌和肝癌。
含活性成分的药物组合物可以是适用于口服的形式,例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊,或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物,此类组合物可含
有一种或多种选自以下的成分:甜味剂、矫味剂、着色剂和防腐剂,以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。
油混悬液可通过使活性成分悬浮于植物油中配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂,以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
通过加入水可使适用于制备水混悬的可分散粉末和颗粒提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油。适宜的乳化剂可以是天然产生的磷脂。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本发明的药物组合物可以是无菌注射水溶液形式。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。
本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术,用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外,可方便地用无菌固定油作为溶剂或悬浮介质。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体,因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
如本领域技术人员所熟知的,药物的给药剂量依赖于多种因素,包括但并非限定于以下因素:所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行被、患者的饮食、给药时间、给药方式、***的速率、药物的组合等;另外,最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
发明的详细说明
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至12个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁
基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基,及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基,非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR8R9和-C(O)NR8R9中的一个或多个取代基所取代。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,优选包含3至12个碳原子,更优选包含3至10个碳原子,最优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等;多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基,优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括:
术语“稠环烷基”指5至20元,***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***。优选为6至14元,更优选为7至10元。
根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括:
术语“桥环烷基”指5至20元,任意两个环共用两个不直接连接的碳原子的全碳多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,优选为双环、三环或四环,更有选为双环或三环。桥环烷基的非限制性实例包括:
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上,其中与母体结构连接在一起的环为环烷基,非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的,当被取代时,取代基优选为独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR8R9和-C(O)NR8R9中的一个或多个取代基所取代。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1~4个是杂原子;更优选环烷基环包含3至10个环原子。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2.3.6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。其可以含有一个或多个双键,但没有一个环具有完全共轭
的π电子***。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括:
术语“稠杂环基”指5至20元,***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基,优选为双环或三环,更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括:
术语“桥杂环基”指5至14元,任意两个环共用两个不直接连接的原子的多环杂环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基,优选为双环、三环或四环,更优选为双环或三环。桥杂环基的非限制性实例包括:
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基,其非限制性实例包括:
杂环基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR8R9和-C(O)NR8R9中的一个或多个取代基所取代。
术语“芳基”指6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,其为具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团,优选为6至10元,例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环,其非限制性实例包括:
芳基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR8R9和-C(O)NR8R9中的一个或多个取代基所取代。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。杂芳基优选为5至10元,更优选为5元或6元,例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、吡唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,其非限制性实例包括:
杂芳基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR8R9和-C(O)NR8R9中的一个或多个取代基所取代。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基),其中烷基的定义如上所述。烷氧基的非限制性实例包括:甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、氨基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR8R9和-C(O)NR8R9中的一个或多个取代基所取代。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“氧代基”指=O。
术语“羟烷基”指被羟基取代的烷基,其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代,其中烷基如上所定义。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个
氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐,这类盐用于哺乳动物体内时具有安全性和有效性,且具有应有的生物活性。
m和R7~R9如通式(I)化合物中所定义。
本发明化合物的合成方法
为了完成本发明的目的,本发明采用如下技术方案:
方案一
本发明通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐的制备方法,包括以下步骤:
通式(I-A)的化合物和通式(I-B)的化合物在碱性条件下,在催化剂存在下经Suzuki反应,得到通式(I)的化合物;
提供碱性条件的试剂包括有机碱和无机碱类,所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠或叔丁醇钾,所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂;
催化剂包括但不限于钯/碳、雷尼镍、四-三苯基膦钯、二氯化钯、醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯或三(二亚苄基丙酮)二钯,优选为[1,1'-双(二苯基膦基)二茂铁]二氯化钯;
上述反应优选在溶剂中进行,所用溶剂包括但不限于:醋酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物;
其中:
X为卤素,优选为溴;
环A、环B、G1、G2、R1~R3、r、p、n、s和q如通式(I)中所定义。
本发明通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐的制备方法,包括以下步骤:
方案二
第一步反应为式(III-a)和(III-b)的化合物在高温条件下,亲核取代得到式(III-c)化合物;
第二步反应为式(III-c)化合物和醋酸铵在酸性条件下,关环得到式(III-d);
第三步反应为式(III-d)化合物酸性条件下,进行卤代反应得到式(III-e)化合物;
第四步反应为式(III-e)的化合物和(III-f)的化合物,在碱性条件下,进行Suzuki偶联,得到通式(III)化合物;
提供酸性条件的试剂包括但不限于吡啶氢溴酸盐、三氟乙酸、甲酸、乙酸、盐酸、硫酸或甲磺酸,优选为乙酸;
提供碱性条件的试剂包括有机碱和无机碱类,所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠或叔丁醇钾,所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂;
提供卤代反应的试剂包括但不限于液溴、溴化氢、N-溴代丁二酰亚胺(NBS)、PBr3、POBr3、过溴化吡啶氢溴酸盐(PHP)、四溴环酮(TBCO)、溴代丙二酸二乙酯和四丁基溴化铵,N-氯代琥珀酰亚胺,PCl3和POCl3;
催化剂包括但不限于钯/碳、雷尼镍、四-三苯基膦钯、二氯化钯、醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯或三(二亚苄基丙酮)二钯,优选为[1,1'-双(二苯基膦基)二茂铁]二氯化钯;
上述反应优选在溶剂中进行,所用溶剂包括但不限于:醋酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物;
其中:
X为卤素,优选为溴;
环B、R1、R2、r和s如通式(Ⅰ)中所定义。
方案三
本发明通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐的制备方法,包括以下步骤:
第一步反应为式(IV-a)和式(IV-b)的化合物在酸性条件下,反应得到式(IV-c)的化合物,或为式(IV-a)和式(IV-bb)的化合物在酸性条件下,反应得到式(IV-cc)的化合物;
第二步反应为式(IV-c)或式(IV-cc)的化合物在碱性条件下,关环得到式(IV-d);
第三步反应为式(IV-d)化合物酸性条件下,进行卤代反应得到式(IV-e)化合物;
第四步反应为式(IV-e)的化合物和(IV-f)的化合物,在碱性条件下,进行Suzuki偶联,得到通式(IV)化合物;
提供酸性条件的试剂包括但不限于吡啶氢溴酸盐、三氟乙酸、甲酸、乙酸、盐酸、硫酸或甲磺酸,优选为乙酸。
提供碱性条件的试剂包括有机碱和无机碱类,所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠或叔丁醇钾,所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂。
提供卤代反应的试剂包括但不限于液溴、溴化氢、N-溴代丁二酰亚胺(NBS)、PBr3、POBr3、过溴化吡啶氢溴酸盐(PHP)、四溴环酮(TBCO)、溴代丙二酸二乙酯和四丁基溴化铵,N-氯代琥珀酰亚胺,PCl3和POCl3;
催化剂包括但不限于钯/碳、雷尼镍、四-三苯基膦钯、二氯化钯、醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯或三(二亚苄基丙酮)二钯,优选为[1,1'-双(二苯基膦基)二茂铁]二氯化钯。
上述反应优选在溶剂中进行,所用溶剂包括但不限于:醋酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
其中:
R13选自烷基、环烷基和杂环基,优选为烷基,更优选为乙基;
X为卤素,优选为溴;
环B、R1、R2、r和s如通式(Ⅰ)中所定义。
方案四
本发明通式(IV)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐的制备方法,包括以下步骤:
第一步反应为式(IV-aa)和式(IV-b)的化合物在酸性条件下,反应得到式(IV-g)的化合物;
第二步反应为式(IV-g)的化合物在碱性条件下,关环得到式(IV);
提供酸性条件的试剂包括但不限于吡啶氢溴酸盐、三氟乙酸、甲酸、乙酸、盐酸、硫酸或甲磺酸,优选为乙酸。
提供碱性条件的试剂包括有机碱和无机碱类,所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠或叔丁醇钾,所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂。
上述反应优选在溶剂中进行,所用溶剂包括但不限于:醋酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
其中:
环B、R1、R2、r和s如通式(Ⅰ)中所定义。
以下结合实施例用于进一步描述本发明,但这些实施例并非限制着本发明的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号:Finnigan LCQ advantage MAX)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
手性HPLC分析测定使用LC-10A vp(Shimadzu)或者SFC-analytical(Berger Instruments Inc.)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
手性制备柱层析使用Prep Star SD-1(Varian Instruments Inc.)或SFC-multigram(Berger Instruments Inc.)
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自ABCR GmbH&Co.KG,Acros Organics,Aldrich Chemical Company,韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明,反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空,充入氢气,反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温,为20℃~30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC),反应所使用的展开剂的体系有:A:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:二氯甲烷和丙酮体系,D:石油醚和乙酸乙酯体系,溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括:A:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:二氯甲烷和丙酮体系,D:石油醚和乙酸乙酯体系,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
6-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-甲酰胺1
第一步
3-甲氧基-2-氮杂双环[2.2.1]庚-2-烯1b
将2-氮杂双环[2.2.1]庚烷-3-酮1a(2.5g,22.494mmol,采用公知的方法“Angewandte Chemie,International Edition,2005,44(35),5710-5713”制备而得)溶于40mL二氯甲烷中,加入三甲基四氟硼酸盐(3.66g,24.744mmol),搅拌反应12小时。反应液中加入饱和碳酸氢钠溶液,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题化合物1b(2.5g),产品不经纯化直接进行下一步反应。
第二步
2-(2-(6-甲基吡啶-2-基)-2-氧代乙基)-2-氮杂双环[2.2.1]庚烷-3-酮1d
将化合物1c(600mg,2.802mmol)和粗品化合物1b(702mg,5.606mmol)溶于5mL N,N-二甲基甲酰胺中,升温至55℃搅拌反应5小时。反应液冷却至室温,加入水,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题化合物1d(685mg),产品不经纯化直接进行下一步反应。
第三步
2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶1e
将粗品化合物1d(685mg,2.8mmol)和醋酸铵(2.16g,2.8mmol)溶于3mL乙酸中,升温至100℃搅拌反应12小时。反应液冷却至室温,减压浓缩后,向所得残余物中滴加饱和碳酸氢钠溶液至pH为7,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系A纯化所得残余物,得到标题化合物1e(600mg,产率:95%)。
第四步
3-溴-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶1f
将化合物1e(500mg,2.22mmol)溶于20mL二氯甲烷中,加入液溴(390mg,2.44mmol),搅拌反应2小时。反应液中加入饱和碳酸氢钠溶液,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题化合物1f(600mg),产品不经纯化直接进行下一步反应。
第五步
6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉-4-甲腈1h
将6-溴喹啉-4-甲腈1g(550mg,2.36mmol,采用专利申请“WO2014022128”公开的方法制备而得)、联硼酸频那醇酯(898.91mg,3.54mmol)、醋酸钾(926.41mg,9.44mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(350.11mg,0.47mmol)溶于10mL 1,4-二氧六环中,升温至90℃搅拌反应12小时。反应液冷却至室温,减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物1h(520mg,产率:78.66%)。
第六步
6-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-甲腈1i
将化合物1f(300mg,0.968mmol)、化合物1h(414mg,1.479mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(72mg,0.099mmol)和碳酸钾(408mg,2.958mmol)溶于10mL 1,4-二氧六环和水(V/V=4:1)的混合溶剂中,升温至85℃搅拌反应12小时。反应液冷却至室温,减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物1i(160mg,产率:43%)。
第七步
将化合物1i(30mg,0.079mmol)溶于3mL二甲亚砜中,加入0.2mL过氧化氢溶液(30%)和碳酸钾(33mg,0.283mmol),室温搅拌反应2小时。反应液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物1(15mg,产率:48.4%)。
MS m/z(ESI):396.2[M+1]
1H NMR(400MHz,CDCl3)δ8.97(d,1H),8.49(d,1H),8.12(d,1H),8.00(dd,1H),7.64-7.54(m,3H),6.99(d,1H),6.18(s,1H),5.95(s,1H),4.97(s,1H),3.69(d,1H),2.39(s,3H),2.37(s,1H),2.09-2.02(m,1H),1.99-1.91(m,2H),1.56-1.55(m,1H),1.46-1.42(m,1H).
实施例1-1
6-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-甲酰胺1-1
第一步
(1S,4R)-3-甲氧基-2-氮杂双环[2.2.1]庚-2-烯1b-1
将(1S,4R)-2-氮杂双环[2.2.1]庚烷-3-酮1a-1(50g,449.88mmol,采用专利申请“US20150284362”公开的方法制备而得)溶于400mL二氯甲烷中,加入三甲基四氟硼酸盐(86.5g,584.85mmol),室温搅拌反应48小时。反应液中加入饱和碳酸氢钠溶液,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题化合物1b-1(47g),产品不经纯化直接进行下一步反应。
第二步
(1S,4R)-2-(2-(6-甲基吡啶-2-基)-2-氧代乙基)-2-氮杂双环[2.2.1]庚烷-3-酮1d-1
将2-溴-1-(6-甲基吡啶-2-基)乙酮1c(40g,186.86mmol,采用专利申请“WO2013009140”公开的方法制备而得)和粗品化合物1b-1(46.78g,373.73mmol)溶于300mL N,N-二甲基甲酰胺中,升温至50℃搅拌反应12小时。反应液冷却至室温,减压浓缩,得到粗品标题化合物1d-1(45.649g),产品不经纯化直接进行下一步反应。
第三步
(5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶1e-1
将粗品化合物1d-1(35g,143.27mmol)和醋酸铵(110.43g,1432.7mmol)溶于250mL乙酸中,升温至110℃搅拌反应12小时。反应液冷却至室温,减压浓缩后,向所得残余物中滴加饱和碳酸氢钠溶液至pH为7,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物1e-1(12g,产率:37.18%)。
第四步
(5S,8R)-3-溴-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶1f-1
将化合物1e-1(6.g,26.63mmol)溶于100mL二氯甲烷中,加入液溴(4.26g,26.63mmol),室温搅拌反应1小时。反应液中加入饱和碳酸氢钠溶液,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系A纯化所得残余物,得到标题化合物1f-1(6.6g,产率:81.47%)。
第五步
6-溴喹啉-4-甲酸甲酯1k
将6-溴喹啉-4-甲酸1j(3.5g,13.89mmol)溶于50mL甲醇中,加入氯化亚砜(1.65g,13.89mmol),升温至回流搅拌反应12小时。反应液冷却至室温,减压浓缩,得到粗品标题化合物1k(3.7g),产品不经纯化直接进行下一步反应。
第六步
6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉-4-甲酸甲酯1l
将粗品化合物1k(3.69g,13.87mmol),联硼酸频那醇酯(5.28g,20.8mmol),醋酸钾(2.72g,27.73mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(1014.8mg,1.39mmol)溶于30mL 1,4-二氧六环中,升温至80℃搅拌反应12小时。反应液冷却至室温,减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物1l(4.3g,产率:99.02%)。
第七步
6-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-甲酸甲酯1m-1
将化合物1l(2.32g,7.4mmol)、化合物1f-1(1.5g,4.93mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.36g,0.49mmol)和碳酸钾(1.36g,9.86mmol)溶于24mL1,4-二氧六环和水(V/V=5:1)的混合溶剂中,升温至80℃搅拌反应12小时。反应液冷却至室温,减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物1m-1(1g,产率:49.41%)。
第八步
6-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-甲酰胺1-1
将化合物1m(1.g,2.44mmol)溶于80mL 7M的氨的甲醇溶液中,升温至100℃封管搅拌反应12小时。反应液冷却至室温,减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物1-1(750mg,产率:77.85%)。
MS m/z(ESI):396.4[M+1]
1H NMR(400MHz,CDCl3)δ8.98(d,1H),8.48(d,1H),8.11(d,1H),8.01(dd,1H),7.62(d,1H),7.58-7.53(m,2H),6.99(d,1H),6.26(s,1H),6.00(s,1H),4.97(s,1H),3.68(d,1H),2.39(s,3H),2.37(s,1H),2.12-2.08(m,1H),2.01-1.98(m,1H),1.91(d,1H),1.56-1.52(m,1H),1.46-1.43(m,1H).
实施例1-2
6-((5R,8S)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-甲酰胺1-2
将化合物1i(100mg,0.424mmol)溶于3mL二甲亚砜中,加入0.5mL过氧化氢溶液(30%)和碳酸钾(117mg,0.848mmol),室温搅拌反应1小时。反应液减压浓缩,用手性制备方法纯化所得残余物(分离条件:手性制备柱CHIRALPAK OD 21.5×250mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=20/80(v/v);流速:15mL/分钟),收集其相应组分,减压浓缩,得到标题化合物1-2(52mg,产率:31%)。
MS m/z(ESI):396.4[M+1]
手性HPLC分析方法:保留时间23.287分钟,(色谱柱:CHIRALPAK OD 4.6×150mm 5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=10/90(v/v));
1H NMR(400MHz,CDCl3)δ8.99(d,1H),8.49(d,1H),8.12(d,1H),8.02(dd,1H),7.64-7.54(m,3H),6.99(d,1H),6.17(s,1H),5.95(s,1H),4.97(s,1H),3.69(d,1H),2.39(s,3H),2.37(s,1H),2.12-2.09(m,1H),2.01-1.98(m,1H),1.91(d,1H),1.59-1.54(m,1H),1.47-1.42(m,1H).
实施例2
6-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)[1,2,4]***[4,3-a]吡啶-3-甲酰胺2
第一步
6-溴-[1,2,4]***[4,3-a]吡啶-3-甲酸乙酯2b
将5-溴-2-肼基吡啶2a(4g,21.27mmol,采用专利申请“US20140134133”公开的方法制备而得)和2-氧代乙酸乙酯(2.17g,21.27mmol)溶于60mL甲醇中,升温至60℃搅拌反应1小时。反应液冷却至室温,减压浓缩,所得残余物中加入60mL1,4-二氧六环,缓慢加入二乙酰氧基碘代苯(7.81g,24.24mmol),室温搅拌反应18小时。反应液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物2b(500mg,产率:8.7%)。
第二步
6-溴-[1,2,4]***[4,3-a]吡啶-3-甲酰胺2c
将化合物2b(4.5g,17.57mmol)溶于33.75mL 7M氨的甲醇溶液中,升温至50℃封管搅拌反应2小时。反应液冷却至室温,减压浓缩,得到粗品标题化合物2c(4.2g),产品不经纯化直接进行下一步反应。
第三步
(3-氨甲酰基-[1,2,4]***[4,3-a]吡啶-6-基)硼酸2d
将粗品化合物2c(4.2g,17.42mmol),联硼酸频那醇酯(6.64g,26.14mmol),醋酸钾(4.28g,43.56mmol)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(1.29g,1.74mmol)溶于80mL 1,4-二氧六环中,升温至80℃搅拌反应3小时。反应液冷却至室温,减压浓缩,用硅胶柱色谱法以洗脱剂体系A纯化所得残余物,得到标题化合物2d(2.6g,产率:72.4%)。
第四步
6-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)-[1,2,4]***[4,3-a]吡啶-3-甲酰胺2
将化合物1f(60mg,0.2mmom)、化合物2d(60.94mg,0.3mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(14.63mg,0.02mmol)和碳酸钾(54.52mg,0.39mmol)溶于5mL 1,4-二氧六环和水(V/V=4:1)的混合溶剂中,升温至80℃搅拌反应12小时。反应液冷却至室温,过滤,滤液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物2(19mg,产率:26.3%)。
MS m/z(ESI):386.5[M+1]
实施例2-1
6-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)[1,2,4]***[4,3-a]吡啶-3-甲酰胺2-1
采用实施例2的合成路线,将第三步原料化合物1f替换为化合物1f-1制得标题化合物2-1(20mg,产率:26.31%)。
MS m/z(ESI):386.5[M+1]
1H NMR(400MHz,CDCl3)δ9.57(t,1H),7.86(dd,1H),7.76(dd,2H),7.62(t,1H),7.46(s,1H),7.01(d,1H),5.77(s,1H),4.89(s,1H),3.73(d,1H),2.42(d,1H),2.37(s,3H),2.15-2.12(m,1H),2.05-2.02(m,1H),1.93(d,1H),1.59-1.54(m,1H),1.47-1.42(m,1H).
实施例2-2
6-((5R,8S)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)[1,2,4]***[4,3-a]吡啶-3-甲酰胺2-2
采用实施例2的合成路线,通过手性制备(分离条件:手性制备柱CHIRALPAK AS 20×250mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=20/80(v/v),流速:
15mL/分钟),收集相应组分,减压浓缩,制得标题化合物2-2(30mg)。
MS m/z(ESI):386.5[M+1]
手性HPLC分析方法:保留时间7.486分钟,手性纯度99.5%,(色谱柱:CHIRALPAK AD 4.6×150mm,5μm;流动相:甲醇/乙醇(含0.1%二乙胺)/正己烷=10/10/80(v/v/v));
1H NMR(400MHz,CD3OD)δ9.56(s,1H),7.87(d,1H),7.68(t,2H),7.60(d,1H),7.10(d,1H),5.00(s,1H),3.65(d,1H),2.37(d,1H),2.31(s,3H),2.23-2.16(m,1H),2.10-1.98(m,2H),1.42-1.35(m,2H).
实施例3
2-(6-甲基吡啶-2-基)-3-(2-(4-(甲磺酰基)苯基)吡啶-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶3
第一步
4-溴-2-(4-(甲磺酰基)苯基)吡啶3c
将2,4-二溴吡啶3a(1g,4.22mmol)、(4-(甲磺酰基)苯基)硼酸3b(844mg,4.22mmol,采用公知的方法“Journal of Organic Chemistry,2008,3(2),4662-4670”)、四(三苯基膦)钯(487.6mg,0.422mmol)和碳酸钠(894.6mg,8.44mmol)溶于21mL甲苯、乙醇和水(V/V/V=4:2:1)的混合溶剂中,升温至100℃微波反应2小时。反应液冷却至室温,减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物3c(300mg,产率:23%)。
第二步
2-(4-(甲磺酰基)苯基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶3d
将化合物3c(300mg,0.96mmol)、联硼酸频那醇酯(230mg,1.15mmol)、醋酸钾(188.4mg,1.92mmol)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(70.2mg,0.096mmol)溶于10mL 1,4-二氧六环中,升温至90℃搅拌反应3小时。反应液冷却至室
温,减压浓缩,用硅胶柱色谱法以洗脱剂体系A纯化所得残余物,得到标题化合物3d(350mg,产率:100%)。
第三步
(5S,8R)-2-(6-甲基吡啶-2-基)-3-(2-(4-(甲磺酰基)苯基)吡啶-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶3
将化合物1f(50mg,0.16mmol)、化合物3d(91.09mg,0.254mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(24.385mg,0.0329mmol)和碳酸钾(68.153mg,0.4931mmol)溶于5mL 1,4-二氧六环和水(V/V=4:1)的混合溶剂中,升温至100℃搅拌反应12小时。反应液冷却至室温,用硅藻土过滤,滤饼用乙酸乙酯洗涤,滤液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物3(21mg,产率:24.5%)。
MS m/z(ESI):457.4[M+1]
1H NMR(400MHz,CD3OD)δ8.70(d,1H),8.18(d,2H),8.08(d,3H)7.73(t,1H),7.58-7.52(m,2H),7.19(d,1H),5.10(s,1H),3.66(s,1H),3.19(s,3H),2.45(d,1H),2.35(s,3H),2.25-2.15(m,1H),2.04-2.02(m,2H),1.45-1.25(m,2H).
实施例3-1
(5S,8R)-2-(6-甲基吡啶-2-基)-3-(2-(4-(甲磺酰基)苯基)吡啶-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶3-1
采用实施例3的合成路线,将第三步原料化合物1f替换为化合物1f-1制得标题化合物3-1(20mg,产率:24.52%)。
MS m/z(ESI):457.4[M+1]
1H NMR(400MHz,CD3OD)δ8.70(d,1H),8.18(d,2H),8.08(d,3H)7.73(t,1H),7.58-7.52(m,2H),7.19(d,1H),5.10(s,1H),3.66(s,1H),3.19(s,3H),2.45(d,1H),2.35(s,3H),2.25-2.15(m,1H),2.04-2.02(m,2H),1.45-1.25(m,2H).
实施例3-2
(5R,8S)-2-(6-甲基吡啶-2-基)-3-(2-(4-(甲磺酰基)苯基)吡啶-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶3-2
将化合物3进行手性制备(分离条件:手性制备柱CHIRALPAK OD 21.5×250mm,5μm;流动相:乙醇=100(v/v),流速:7.0mL/分钟),收集相应组分,减压浓缩,得标题化合物3-2(51mg)。
MS m/z(ESI):457.4[M+1]
手性HPLC分析方法:保留时间8.488分钟,(色谱柱:CHIRALPAK OD 4.6×150mm,5μm;流动相:乙醇/正己烷=60/40(v/v));
1H NMR(400MHz,CD3OD)δ8.70(d,1H),8.18(d,2H),8.08(d,3H)7.73(t,1H),7.58-7.52(m,2H),7.19(d,1H),5.10(s,1H),3.66(s,1H),3.19(s,3H),2.45(d,1H),2.35(s,3H),2.25-2.15(m,1H),2.04-2.02(m,2H),1.45-1.25(m,2H).
实施例4
4-(4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)苯甲酰胺4
第一步
4-(4-溴代吡啶-2-基)苯甲酸甲酯4b
将化合物3a(1g,4.22mmol)、(4-(甲氧羰基)苯基)硼酸4a(759.72mg,4.22mmol)、四(三苯基膦)钯(487.8mg,0.422mmol)和碳酸钠(894.85mg,8.44mmol)溶于14mL甲苯、乙醇和水(V/V/V=4:2:1)的混合溶剂中,升温至100℃微波反应1小时。反应液冷却至室温,减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物4b(220mg,产率:17.84%)。
第二步
(2-(4-(甲氧羰基)苯基)吡啶-4-基)硼酸4c
将化合物4b(310mg,1.06mmol)、联硼酸频那醇酯(404.21mg,1.59mmol)、醋酸钾(208.29mg,2.12mmol)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(78.716mg,0.106mmol)溶于10mL 1,4-二氧六环中,升温至90℃搅拌反应2小时。反应液冷却至室温,减压浓缩,得到粗品标题化合物4c(272mg),产品不经纯化直接进行下一步反应。
第三步
4-(4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)苯甲酸甲酯4d
将化合物1f(200mg,0.658mmol)、粗品化合物4c(202.81mg,0.789mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(48.771mg,0.0657mmol)和碳酸钾(272.61mg,1.972mmol)溶于12mL 1,4-二氧六环和水(V/V=5:1)的混合溶剂中,升温至100℃搅拌反应12小时。反应液冷却至室温,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物4d(180mg,产率:62.72%)。
第四步
4-(4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)
苯甲酰胺4
将化合物4d(30mg,0.07mmol)溶于10mL 7M的氨的甲醇溶液中,升温至110℃封管搅拌反应12小时。反应液冷却至室温,减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物4(10mg,产率:33.4%)。
MS m/z(ESI):422.6[M+1]
1H NMR(400MHz,CD3OD)δ8.68(d,1H),8.04-8.02(m,1H),8.00(s,4H)7.75(t,1H),7.56(d,1H),7.52-7.49(dd,1H),7.20(d,1H),5.10(s,1H),3.68(m,1H),2.42(d,1H),2.36(s,3H),2.25-2.15(m,1H),2.10-2.00(m,2H),1.45-1.35(m,2H).
实施例4-1,4-2
4-(4-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)苯甲酰胺4-1
4-(4-((5R,8S)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)苯甲酰胺4-2
将化合物4(150.mg,0.344mmol)溶于10mL 7M的氨的甲醇溶液中,升温至110℃封管搅拌反应12小时。反应液冷却至室温,减压浓缩,通过手性制备纯化所得残余物,(分离条件:手性制备柱CHIRALPAK OD 21.5×250mm,5μm;流动相:乙醇(含0.1%二乙胺)=100(v);流速:7mL/分钟),收集其相应组分,减压浓缩,得到标题化合物(30mg、35mg)。
单一构型化合物(较短保留时间):
MS m/z(ESI):422.2[M+1]
手性HPLC分析方法:保留时间4.058分钟,(色谱柱:CHIRALPAK OD 4.6×150mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=40/60(v/v));
1H NMR(400MHz,CD3OD)δ8.68(d,1H),8.03-8.00(m,5H),7.74(t,1H),7.57-7.50(m,2H),7.20(d,1H),5.11(s,1H),3.68(s,1H),2.42(d,1H),2.36(s,3H),2.21(s,1H),2.03(d,2H),1.41-1.31(m,2H).
单一构型化合物(较长保留时间):
MS m/z(ESI):422.2[M+1]
手性HPLC分析方法:保留时间7.204分钟,(色谱柱:CHIRALPAK OD 4.6×150mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=40/60(v/v));
1H NMR(400MHz,CD3OD)δ8.68(d,1H),8.03-8.00(m,5H),7.74(t,1H),7.57-7.50(m,2H),7.20(d,1H),5.11(s,1H),3.68(s,1H),2.42(d,1H),2.36(s,3H),2.21(s,1H),2.03(d,2H),1.41-1.31(m,2H).
实施例5
2-((4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)氨基)乙醇5
第一步
(5S,8R)-3-(2-氟吡啶-4-基)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶5b
将(2-氟吡啶-4-基)硼酸5a(48.64mg,0.35mmol,采用专利申请“WO2015103137”公开的方法制备而得)、化合物1f(70mg,0.23mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(17.07mg,0.023mmol)和碳酸钾(63.61mg,0.46mmol)溶于5mL 1,4-二氧六环和水(V/V=4:1)的混合溶剂中,升温至80℃搅拌反应12小时。反应液冷却至室温,减压浓缩,用硅胶柱色谱法以洗脱剂体系A纯化所得残余物,得到标题化合物5b(70mg,产率:94.95%)。
第二步
2-((4-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)氨基)乙醇5
将化合物5b(50mg,0.16mmol)和氨基乙醇(476.65mg,7.8mmol)加入反应瓶中,升温至110℃搅拌反应2小时。反应液冷却至室温,减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物5(15mg,产率:26%)。
MS m/z(ESI):362.5[M+1]
1H NMR(400MHz,CDCl3)δ8.04(d,1H),7.49(t,1H),7.19(d,1H),6.97(d,1H),
6.51(d,1H),6.30(s,1H),4.75(s,1H),3.87-3.85(m,2H),3.77-3.75(m,1H),3.59(d,1H),3.51-3.48(m,1H),2.47(t,3H),2.22(d,1H),1.97-1.90(m,2H),1.81-1.77(m,2H),1.13-1.11(m,1H),0.93-0.90(m,1H).
实施例5-1
2-((4-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)氨基)乙醇5-1
采用实施例5的合成路线,将第一步原料化合物1f替换为1f-1得到标题化合物5-1(20mg,产率:35.45%)。
MS m/z(ESI):362.3[M+1]
1H NMR(400MHz,CDCl3)δ8.06(d,1H),7.48(t,1H),7.15(d,1H),6.97(d,1H),6.48(d,1H),6.24(s,1H),4.75(s,1H),3.87-3.83(m,3H),3.60(d,1H),3.44-3.40(m,1H),2.47(s,3H),2.26(d,1H),1.90-1.72(m,4H),1.05-1.02(m,1H),0.79-0.76(m,1H).
实施例6
2-(6-甲基吡啶-2-基)-3-(喹喔啉-6-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶6
将化合物1f(900mg,2.959mmol)、6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹喔啉6a(985mg,3.846mmol,采用专利申请“WO2010059943”公开的方法制
备而得)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(216mg,0.296mmol)和碳酸钠(941mg,8.877mmol)溶于18mL乙二醇二甲醚和水(V/V=5:1)的混合溶剂中,升温至80℃搅拌反应24小时。反应液冷却至室温,加入水,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系A纯化所得残余物,得到标题化合物6(560mg,产率:54%)。
MS m/z(ESI):354.3[M+1]
1H NMR(400MHz,CD3OD)δ9.01(d,2H),8.37(d,1H),8.30(d,1H),8.01(d,1H),7.83(t,1H),7.43(d,1H),7.36(d,1H),5.16(s,1H),3.98(d,1H),2.69(s,3H),2.56(d,1H),2.39-2.36(m,1H),2.20-2.16(m,2H),1.60-1.55(m,2H).
实施例6-1,6-2
((5S,8R)-2-(6-甲基吡啶-2-基)-3-(喹喔啉-6-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶6-1
((5R,8S))-2-(6-甲基吡啶-2-基)-3-(喹喔啉-6-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶6-2
将化合物6(560mg,1.58mmol)进行手性制备(分离条件:色谱柱:Superchiral S-OZ(Chiralway),2cm I.D.×25cm Length,5μm;流动相:二氧化碳/乙醇=50/50(v/v);流速:50g/分钟),收集其相应组分,减压浓缩,得到标题化合物(240mg、245mg)。
单一构型化合物(较短保留时间):
MS m/z(ESI):354.4[M+1]
手性HPLC分析方法:保留时间3.747分钟,(色谱柱:CHIRALPAK IB 4.6×150mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=30/70(v/v));
1H NMR(400MHz,CDCl3)δ8.91(t,2H),8.20(d,1H),8.08(d,1H),7.92-7.88(dd,1H),7.70(t,1H),7.52(d,1H),7.15(d,1H),5.08(s,1H),3.69(d,1H),2.42(d,1H),2.33(s,3H),2.23-2.21(m,1H),2.05-2.02(m,2H),1.44-1.38(m,2H).
单一构型化合物(较长保留时间):
MS m/z(ESI):354.4[M+1]
手性HPLC分析方法:保留时间5.327分钟,(色谱柱:CHIRALPAK IB 4.6×150mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=30/70(v/v));
1H NMR(400MHz,CDCl3)δ8.91(t,2H),8.20(d,1H),8.08(d,1H),7.92-7.88(dd,1H),7.70(t,1H),7.52(d,1H),7.15(d,1H),5.08(s,1H),3.69(d,1H),2.42(d,1H),2.33(s,3H),2.23-2.21(m,1H),2.05-2.02(m,2H),1.44-1.38(m,2H).
实施例7
2-((7-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹喔啉-2-基)氧基)乙醇7
第一步
2-((7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹喔啉-2-基)氧基)乙醇7b
将2-((7-溴喹喔啉-2-基)氧基)乙醇7a(400mg,1.48mmol,采用专利申请“WO2005092894”公开的方法制备而得)、联硼酸频那醇酯(451mg,1.78mmol)、醋酸钾(290mg,2.96mmol)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(54mg,0.074mmol)溶于5mL 1,4-二氧六环中,升温至90℃搅拌反应2小时。反应液冷却至室温,加入50mL水,用乙酸乙酯萃取(50mL×2),合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物7b(249mg,产率:53%)。
第二步
2-((7-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹喔啉-2-基)氧基)乙醇7
将化合物7b(103mg,0.328mmol)、化合物1f(50mg,0.164mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(24mg,0.033mmol)和碳酸钾(67mg,0.442mmol)溶于6mL 1,4-二氧六环和水(V/V=5:1)的混合溶剂中,升温至100℃搅拌反应1小时。反应液冷却至室温,用硅藻土过滤,滤液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物7(20mg,产率:29.8%)。
MS m/z(ESI):414.4[M+1]
1H NMR(400MHz,CD3OD)δ8.51(d,1H),7.96(d,2H),7.70-7.60(m,2H),7.44(d,1H),7.15(d,1H),5.10(s,1H),4.59(t,2H),3.98(t,2H),3.68(s,1H),2.43(d,1H),2.37(s,3H),2.25-2.15(m,1H),2.10-2.00(m,2H),1.45-1.35(m,2H).
实施例8
2-(6-甲基吡啶-2-基)-3-(1'-(甲磺酰基)-1',2',3',6'-四氢-[2,4'-联吡啶]-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶8
第一步
4-溴-5',6'-二氢-[2,4'-联吡啶]-1'(2'H)-甲酸叔丁酯8b
将化合物3a(1g,4.22mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯8a(1.305g,4.22mmol)、四(三苯基膦)钯(487mg,0.422mmol)和碳酸钠(894.85mg,8.44mmol)溶于14mL甲苯、乙醇和水(V/V/V=4:2:1)的混合溶剂中,升温至100℃微波反应1小时。反应液冷却至室温,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物8b(220mg,产率:15.36%)。
第二步
(1'-(叔丁氧羰基)-1',2',3',6'-四氢-[2,4'-联吡啶]-4-基)硼酸8c
将化合物8b(350mg,1.03mmol)、联硼酸频那醇酯(314.4mg,1.24mmol)、
醋酸钾(202.51mg,2.064mmol)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(76.53mg,0.103mmol)溶于10mL 1,4-二氧六环中,升温至90℃搅拌反应12小时。反应液冷却至室温,过滤,滤液减压浓缩,得到粗品标题化合物8c(240mg),产品不经纯化直接进行下一步反应。
第三步
4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)-5',6'-二氢--[2,4'-联吡啶]-1'(2'H)-甲酸叔丁酯8d
将粗品化合物8c(239.97mg,0.789mmol)、化合物1f(240mg,0.789mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(58.53mg,0.0789mmol)和碳酸钾(218.09mg,1.578mmol)溶于16.5mL 1,4-二氧六环和水(V/V=10:1)的混合溶剂中,升温至100℃搅拌反应12小时。反应液冷却至室温,用硅藻土过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物8d(300mg,产率:78.63%)。
第四步
2-(6-甲基吡啶-2-基)-3-(1',2',3',6'-四氢-[2,4'-联吡啶]-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶8e
将化合物8d(200mg,0.414mmol)溶于10mL二氯甲烷中,加入6mL三氟乙酸,室温搅拌反应12小时。反应液用饱和碳酸钠溶液调pH为8左右,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题化合物8e(150mg),产品不经纯化直接进行下一步反应。
第五步
2-(6-甲基吡啶-2-基)-3-(1'-(甲磺酰基)-1',2',3',6'-四氢-[2,4'-联吡啶]-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶8
将粗品化合物8e(20mg,0.0522mmol)溶于5mL二氯甲烷中,加入0.03mL N,N-二异丙基乙胺,再加入甲磺酰氯(8.96mg,0.08mmol),室温搅拌反应1小时。反应液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物8(4mg,产率:15.95%)。
MS m/z(ESI):462.2[M+1]
1H NMR(400MHz,CD3OD)δ8.52(d,1H),7.73(t,1H),7.62(s,1H),7.51(d,1H),7.38-7.21(m,1H),7.20(d,1H),6.58(s,1H),5.05(s,1H),4.64(s,1H),4.01-3.99(m,2H),3.66(s,1H),3.51(t,2H),2.92(s,3H),2.72(s,2H),2.41(s,3H),2.21-2.20(m,1H),2.06-1.97(m,2H),1.39-1.23(m,2H).
实施例9
6-(2-(5-氟吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)-[1,2,4]三氮唑并[4,3-a]吡啶-3-甲酰胺9
第一步
2-(2-(5-氟吡啶-2-基)-2-氧代乙基)-2-氮杂双环[2.2.1]庚烷-3-酮9b
将2-溴-1-(5-氟吡啶-2-基)乙酮9a(5.56g,44.41mmol,采用公知的方法“Molecules,2014,19(10),15653-15672”制备而得)溶于15mL N,N-二甲基甲酰胺中,加入化合物1b(4.2g,19.26mmol),氩气氛下,于50℃搅拌反应18小时。反应液减压浓缩得粗品标题化合物9b(4g),产品不经纯化直接进行下一步反应。
第二步
2-(5-氟吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶9c
将粗品化合物9b(4g,16.11mmol)和醋酸铵(12.42g,161.13mmol)加入到20mL醋酸中,于110℃搅拌反应4小时。反应结束后,将反应液减压浓缩,用乙酸乙酯溶解所得残余物,饱和碳酸氢钠溶液洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得标题化合物9c(1.4g,产率:37.90%)。
第三步
3-溴-2-(5-氟吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶9d
将化合物9c(1.4g,6.11mmol)加入25mL二氯甲烷中,降温至0℃,滴加液溴(0.35mL,6.72mmol),于25℃反应1.5小时。反应结束后,加入20mL饱和亚硫酸钠溶液搅拌10分钟淬灭反应,用二氯甲烷萃取,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物9d(1g,产率:53.14%)。
第四步
6-(2-(5-氟吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)-[1,2,4]三氮唑并[4,3-a]吡啶-3-甲酰胺9
将化合物2d(60.16mg,0.29mmol),化合物9d(90mg,0.29mmol)和碳酸钾(237.9mg,0.73mmol)溶于10mL 1,4-二氧六环和1.5mL水中,反应体系用氩气置换三次,加入[1,1'-双(二叔丁基膦基)二茂铁]二氯化钯(19.33mg,0.3mmol),氩气氛下,升温至100℃搅拌反应1小时。反应结束后,加入水搅拌淬灭,用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物9(25mg,产率:20.71%)。
MS m/z(ESI):390.4[M+1]
1H NMR(400MHz,CDCl3)δ9.62-9.60(m,1H),8.25(d,1H),8.03-8.00(m,1H),7.89(dd,1H),7.65(dd,1H),7.53(br,1H),7.48-7.43(m,1H),5.89(br,1H),4.87(br,1H),3.73-3.72(m,1H),2.41(d,1H),2.19-2.12(m,1H),2.05-1.96(m,1H),1.94(d,1H),1.56-1.51(m,1H),1.43-1.36(m,1H).
实施例9-1,9-2
6-((5S,8R)-2-(5-氟吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)-[1,2,4]三氮唑并[4,3-a]吡啶-3-甲酰胺9-1
6-((5R,8S)-2-(5-氟吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)-[1,2,4]三氮唑并[4,3-a]吡啶-3-甲酰胺9-2
将化合物9(17mg,0.044mmol)进行手性制备(分离条件:手性制备柱LuxAmylose-1(AD)21.2×250mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=50/50(v/v),流速:15.0mL/分钟),收集其相应组分,减压浓缩,得到标题化合物(8mg、8mg)。
单一构型化合物(较短保留时间):
MS m/z(ESI):390.4[M+1]
手性HPLC分析方法:保留时间6.631分钟,(色谱柱:AD Phenomenex Lux Amylose-1 150×4.6mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷(含0.1%二乙胺)=40/60(v/v));
MS m/z(ESI):390.4[M+1]
1H NMR(400MHz,CDCl3)δ9.60-96.2(m,1H),8.25(d,1H),8.03-8.00(m,1H),7.89(dd,1H),7.65(dd,1H),7.53(br,1H),7.48-7.43(m,1H),5.89(br,1H),4.87(br,1H),
3.73-3.72(m,1H),2.41(d,1H),2.19-2.12(m,1H),2.05-1.96(m,1H),1.94(d,1H),1.56-1.51(m,1H),1.43-1.36(m,1H)。
单一构型化合物(较长保留时间):
MS m/z(ESI):390.4[M+1]
手性HPLC分析方法:保留时间13.001分钟,(色谱柱:AD Phenomenex Lux Amylose-1 150×4.6mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷(含0.1%二乙胺)=40/60(v/v));
MS m/z(ESI):390.4[M+1]
1H NMR(400MHz,CDCl3)δ9.62-9.60(m,1H),8.25(d,1H),8.03-8.00(m,1H),7.89(dd,1H),7.65(dd,1H),7.53(br,1H),7.48-7.43(m,1H),5.89(br,1H),4.87(br,1H),3.73-3.72(m,1H),2.41(d,1H),2.19-2.12(m,1H),2.05-1.96(m,1H),1.94(d,1H),1.56-1.51(m,1H),1.43-1.36(m,1H).
实施例10
2-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)噻吩并[3,2-c]吡啶10
采用实施例1的合成路线,将第五步原料化合物1h替换为噻吩并[3,2-c]吡啶-2-基硼酸(采用专利申请“WO2013101974”公开的方法制备而得),制得标题化合物10(25mg)。
MS m/z(ESI):359.3[M+1]
1H NMR(400MHz,CDCl3)δ9.65(s,1H),8.66(d,1H),8.32(d,1H),8.09-7.90(m,2H),7.75(d,1H),7.40(d,1H),5.18(s,1H),4.07(t,1H),2.76(s,3H),2.54(d,1H),2.32-2.30(m,1H),2.21-2.18(m,1H),2.09(d,1H),1.69-1.66(m,1H),1.59-1.57(m,1H).
实施例11
3-([1,2,4]***[1,5-a]吡啶-6-基)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶11
采用实施例1的合成路线,将第五步原料化合物1h替换为6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-[1,2,4]***[1,5-a]吡啶(采用专利申请“WO2013009140”公开的方法制备而得)制得标题化合物11(10mg)。
MS m/z(ESI):343.3[M+1]
1H NMR(400MHz,CDCl3)δ9.14(d,1H),8.42(s,1H),7.80-7.71(m,3H),7.59(t,1H),6.99(d,1H),4.84(s,1H),3.72(d,1H),2.41(s,3H),2.34(d,1H),2.14-2.11(m,1H),2.04-1.92(m,2H),1.55-1.54(m,1H),1.41-1.40(m,1H).
实施例12
3-(2-(1-甲基-1H-吡唑-4-基)吡啶-4-基)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶12
第一步
4-溴-2-(1-甲基-1H-吡唑-4-基)吡啶12b
将化合物3a(1g,4.22mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑12a(0.79g,0.90mmol,采用专利申请“WO2009155527”公开的方法制备而得)、四(三苯基膦)钯(0.49g,0.42mmol)和碳酸钠(0.89mg,8.44mmol)溶于7mL甲苯、乙醇和水(V/V/V=4:2:1)的混合溶剂中,升温至100℃微波反应1小时。反应结束后,将反应液减压浓缩,乙酸乙酯溶解残余物,用水洗涤,有机
相用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物12b(530mg,产率:52.74%)。
第二步
2-(1-甲基-1H-吡唑-4-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶12c
将化合物12b(250mg,1.05mmol)、联硼酸频那醇酯(319.98mg,1.26mmol)、醋酸钾(206.11mg,2.10mmol)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(77.89mg,0.11mmol)溶于10mL 1,4-二氧六环中,升温至80℃搅拌反应5小时。反应结束后得标题化合物12c的反应液,不作处理直接进行下一步反应。
第三步
3-(2-(1-甲基-1H-吡唑-4-基)吡啶-4-基)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶12
将化合物1f(80mg,0.263mmol),上步化合物12c的反应液,[1,1’-双(二苯基膦基)二茂铁]二氯化钯(19.25mg,0.026mmol)和碳酸钾(109.05mg,0.79mmol)溶于5mL 1,4-二氧六环和水(V/V=4:1)的混合溶剂中,升温至80℃搅拌反应12小时。反应液冷却至室温,用硅藻土过滤,滤饼用乙酸乙酯洗涤,滤液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物12(60mg,产率:59.65%)。
MS m/z(ESI):383.5[M+1]
1H NMR(400MHz,CDCl3)δ8.58(d,1H),7.96(s,1H),7.91(s,1H),7.78(s,1H),7.61-7.58(m,2H),7.26(d,1H),7.02(d,1H),4.88(s,1H),4.00(s,3H),3.70(d,1H),2.44(s,3H),2.37(d,1H),2.12-2.09(m,1H),2.00-1.98(m,1H),1.92(d,1H),1.57-1.51(m,1H),1.41-1.39(m,1H).
实施例12-1,12-2
(5S,8R)-3-(2-(1-甲基-1H-吡唑-4-基)吡啶-4-基)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶12-1
(5R,8S)-3-(2-(1-甲基-1H-吡唑-4-基)吡啶-4-基)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶12-2
将化合物12(60mg,0.157mmol)进行手性制备(分离条件:手性制备柱CHIRALPAK OD 21.5×250mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=50/50(v/v),流速:12mL/分钟),收集其相应组分,减压浓缩,得到标题化合物(20mg、20mg)。
单一构型化合物(较短保留时间):
MS m/z(ESI):383.5[M+1]
手性HPLC分析方法:保留时间2.955分钟,(色谱柱:CHIRALPAK OD 4.6×150mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=60/40(v/v));
1H NMR(400MHz,CDCl3)δ8.58(d,1H),7.96(s,1H),7.91(s,1H),7.78(s,1H),7.61-7.58(m,2H),7.26(d,1H),7.02(d,1H),4.88(s,1H),4.00(s,3H),3.70(d,1H),2.44(s,3H),2.37(d,1H),2.12-2.09(m,1H),2.00-1.98(m,1H),1.92(d,1H),1.57-1.51(m,1H),1.41-1.39(m,1H).
单一构型化合物(较长保留时间):
MS m/z(ESI):383.5[M+1]
手性HPLC分析方法:保留时间4.695分钟,(色谱柱:CHIRALPAK OD 4.6×150mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=60/40(v/v));
1H NMR(400MHz,CDCl3)δ8.58(d,1H),7.96(s,1H),7.91(s,1H),7.78(s,1H),7.61-7.58(m,2H),7.26(d,1H),7.02(d,1H),4.88(s,1H),4.00(s,3H),3.70(d,1H),2.44(s,3H),2.37(d,1H),2.12-2.09(m,1H),2.00-1.98(m,1H),1.92(d,1H),1.57-1.51(m,1H),1.41-1.39(m,1H).
实施例13-1
4-(4-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)苯磺酰胺13-1
采用实施例3的合成路线,将第一步原料化合物3b替换为4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯磺酰胺(采用公知的方法“Tetrahedron Letters,2013,54(2),166-169”制备而得)制得标题化合物13-1(10mg)。
MS m/z(ESI):458.4[M+1]
1H NMR(400MHz,CD3OD)δ8.70-8.68(d,1H),8.09-8.01(m,5H),7.76-7.74(m,1H),7.71-7.58(m,2H),7.21-7.19(d,1H),5.11(s,1H),3.68(m,1H),2.42-2.40(d,1H),2.35(s,3H),2.25-2.15(m,1H),2.05-2.02(m,2H),1.37-1.31(m,2H).
实施例14
4-((4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)氨基)苯磺酰胺14
第一步
4-((4-氯吡啶-2-基)氨基)苯磺酰胺14c
将2-溴-4-氯吡啶14a(576mg,2.993mmol)、4-氨基苯磺酰胺14b(515.42mg,2.99mmol,采用专利申请“CZ105175294”公开的方法制备而得)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(173.19mg,0.299mmol)、碳酸铯(1.462g,4.49mmol)和醋酸钯(67.199mg,0.299mmol)溶于10mL 1,4-二氧六环中,升温至90℃搅拌反应12小时。反应液冷却至室温,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系A纯化所得残余物,得到标题化合物14c(230mg,产率:27.08%)。
第二步
(2-((4-氨磺酰基苯基)氨基)吡啶-4-基)硼酸14d
将化合物14c(50mg,0.176mmol)、醋酸钾(25.94mg,0.264mmol)、2-二环己基膦-2’,6’-二甲氧基-联苯(7.235mg,0.0176mmol)、联硼酸频那醇酯(89.5mg,0.352mmol)和三(二亚苄基丙酮)二钯(8.6mg,0.0088mmol)溶于5mL 1,4-二氧六环中,升温至100℃搅拌反应3小时。反应液冷却至室温,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系A纯化所得残余物,得到标题化合物14d(35mg,产率:67.76%)。
第三步
4-((4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)氨基)苯磺酰胺14
将化合物14d(35mg,0.119mmol)、化合物1f(36mg,0.119mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(8.86mg,0.0119mmol)和碳酸钾(33mg,0.239mmol)溶于6mL 1,4-二氧六环和水(V/V=5:1)的混合溶剂中,升温至100℃搅拌反应12小时。反应液冷却至室温,用硅藻土过滤,滤液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物14(10mg,产率:17%)。
MS m/z(ESI):473.4[M+1]
1H NMR(400MHz,CD3OD)δ8.40(d,1H),7.95(t,1H),7.83(s,4H),7.51-7.47(m,2H),7.02-7.00(m,2H),5.15(s,1H),3.91(s,1H),2.71(s,3H),2.48-2.31(m,2H),2.19-2.14(m,2H),1.55-1.52(m,2H).
实施例15
2-(6-甲基吡啶-2-基)-3-(4-(哌啶-4-基氧基)喹啉-6基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶15
第一步
4-((6-溴喹啉-4-基)氧基)哌啶-1-羧酸叔丁酯15c
将4-羟基哌啶-1羧酸叔丁酯15b(166mg,0.826mmol)和氢化钠(99mg,2.48mmol,60%)溶于5mL N,N-二甲基甲酰胺中,室温搅拌反应30分钟后,加入6-溴-4-氯喹啉15a(200mg,0.826mmol),室温搅拌反应2小时。反应液中加入10mL水,用乙酸乙酯(20mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题化合物15c(230mg),产品不经纯化直接进行下一步反应。
第二步
4-((6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉-4-基)氧基)哌啶-1-羧酸叔丁酯15d
将粗品化合物15c(302mg,0.746mmol)、醋酸钾(146mg,1.492mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(27mg,0.037mmol)和联硼酸频那醇酯(227mg,0.896mmol)溶于5mL 1,4-二氧六环中,升温至90℃搅拌反应2小时。反应液冷却
至室温,加入20mL水,用乙酸乙酯(50mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物15d(100mg,产率:29.4%)。
第三步
4-((6-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-基)氧基)哌啶-1-羧酸叔丁酯15e
将化合物15d(100mg,0.22mmol)、化合物1f(44.6mg,0.147mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(21mg,0.03mmol)和碳酸钾(60mg,0.441mmol)溶于5mL 1,4-二氧六环和水(V/V=4:1)的混合溶剂中,升温至100℃搅拌反应1小时。反应液冷却至室温,加入50mL乙酸乙酯,用水(30mL)洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物15e(30mg,产率:37.5%)。
第四步
2-(6-甲基吡啶-2-基)-3-(4-(哌啶-4-基氧基)喹啉-6基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶15
将化合物15e(30mg,0.054mmol)溶于4mL二氯甲烷中,加入1mL三氟乙酸,室温搅拌反应2小时。反应液中加入饱和碳酸氢钠溶液,用乙酸乙酯(50mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物15(8mg,产率:33.3%)。
MS m/z(ESI):452.5[M+1]
1H NMR(400MHz,CDCl3)δ9.13(d,1H),8.70(s,1H),8.29-8.24(dd,2H),8.02(t,1H),7.75(d,1H),7.70(d,1H),7.68(d,1H),5.45-5.32(m,2H),5.12(s,1H),3.98(s,1H),3.55-3.42(m,2H),2.66(s,3H),2.56(d,1H),2.43-2.32(m,3H),2.31-2.20(m,2H),2.16(d,2H),1.61-1.52(m,2H),1.35-1.27(m,2H).
实施例16-1
4-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)-N-(2-吗啉乙基)吡啶-2-胺16-1
采用实施例5的合成路线,将第二步原料氨基乙醇替换为2-吗啉乙胺制得标
题化合物16-1(10mg)。
MS m/z(ESI):431.3[M+1]
1H NMR(400MHz,CDCl3)δ8.13(d,1H),7.46-7.54(m,2H),7.02(d,1H),6.69(d,2H),5.16(s,1H),4.85(s,1H),3.75(t,4H),3.68(d,1H),3.39-3.34(m,2H),2.65(t,2H),2.53-2.51(m,7H),2.33(d,1H),2.10-2.07(m,1H),1.98-1.95(m,2H),1.57-1.54(m,2H).
实施例17
4-(4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺17
第一步
4-(4-溴吡啶-2-基)苯甲酸17a
将化合物4b(100mg,0.342mmol)溶于7mL甲醇和水(V/V=5:2)的混合溶剂中,加入氢氧化钠(68.46mg,1.712mmol),室温搅拌反应12小时。反应液用2M盐酸调节pH为酸性,用二氯甲烷萃取三次,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题化合物17a(90mg),产品不经纯化直接进行下一步反应。
第二步
4-(4-溴吡啶-2-基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺17b
将粗品化合物17a(100.mg,0.36mmol)和氯化亚砜(2138.98mg,17.98mmol)
加入反应瓶中,升温至80℃搅拌反应2小时,反应液冷却至室温,减压浓缩,所得残余物中加入10mL二氯甲烷,将4-氨基四氢吡喃(54.56mg,0.54mmol)溶于3mL二氯甲烷中,缓慢加入到上述反应液中,室温搅拌反应2小时。反应液减压浓缩,得到粗品标题化合物17b(129mg),产品不经纯化直接进行下一步反应。
第三步
(2-(4-((四氢-2H-吡喃-4-基)氨甲酰基)苯基)吡啶-4-基)硼酸17c
将双三苯基膦二氯化钯(21.37mg,0.03mmol)、醋酸钾(59.77mg,0.61mmol)、粗品化合物17b(110.mg,0.3mmol)和联硼酸频那醇酯(92.79mg,0.37mmol)溶于5mL 1,4-二氧六环中,升温至90℃搅拌反应2小时。反应液冷却至室温,减压浓缩,所得残余物中加入10mL水,用乙酸乙酯(20mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物17c(70mg,产率:70.48%)。
第四步
4-(4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺17
将化合物17c(48.25mg,0.148mmol)、化合物1f(30mg,0.099mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(7.32mg,0.001mmol)和碳酸钾(27.26mg,0.197mmol)溶于5mL 1,4-二氧六环和水(V/V=4:1)的混合溶剂中,升温至90℃搅拌反应12小时。反应液冷却至室温,加入10mL水,用乙酸乙酯(20mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物17(23mg,产率:26.29%)。
MS m/z(ESI):506.5[M+1]
1H NMR(400MHz,CD3OD)δ8.68(d,1H),8.02-7.93(m,5H),7.73(t,1H),7.57(d,1H),7.50(d,1H),7.20(d,1H),5.11(s,1H),4.20-4.10(m,1H),4.01(d,2H),3.68(s,1H),3.55(t,2H),2.48(d,1H),2.36(s,3H),2.25-2.15(m,1H),2.10-2.00(m,2H),1.96-1.85(m,2H),1.75-1.65(m,2H),1.45-1.30(m,2H).
实施例17-1,17-2
4-(4-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺17-1
4-(4-((5R,8S)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺17-2
将化合物17(23mg,0.045mmol)进行手性制备(分离条件:手性制备柱CHIRALPAK OD 21.5×250mm,5μm;流动相:乙醇/正己烷=50/50(v/v),流速:10mL/分钟),收集其相应组分,减压浓缩,得到标题化合物(8mg、10mg)。
单一构型化合物(较长保留时间):
MS m/z(ESI):506.5[M+1]
手性HPLC分析方法:保留时间9.196分钟,(色谱柱:CHIRALPAK OD 4.6×150mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=30/70(v/v));
1H NMR(400MHz,CD3OD)δ8.68(d,1H),8.02-7.93(m,5H),7.73(t,1H),7.57(d,1H),7.50(d,1H),7.20(d,1H),5.11(s,1H),4.20-4.10(m,1H),4.01(d,2H),3.68(s,1H)3.55(t,2H),2.48(d,1H),2.36(s,3H),2.25-2.15(m,1H),2.10-2.00(m,2H),1.96-1.85(m,2H),1.75-1.65(m,2H),1.45-1.30(m,2H).
单一构型化合物(较短保留时间):
MS m/z(ESI):506.5[M+1]
手性HPLC分析方法:保留时间5.418分钟,(色谱柱:CHIRALPAK OD 4.6×150mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=30/70(v/v));
1H NMR(400MHz,CD3OD)δ8.68(d,1H),8.02-7.93(m,5H),7.73(t,1H),7.57(d,1H),7.50(d,1H),7.20(d,1H),5.11(s,1H),4.20-4.10(m,1H),4.01(d,2H),3.68(s,1H)3.55(t,2H),2.48(d,1H),2.36(s,3H),2.25-2.15(m,1H),2.10-2.00(m,2H),1.96-1.85(m,2H),1.75-1.65(m,2H),1.45-1.30(m,2H).
实施例18-1
(S)-1-((4-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)氨基)丙烷-2-醇18-1
采用实施例5的合成路线,将第二步原料氨基乙醇替换为(S)-1-氨基丙烷-2-醇(采用专利申请“JP2011079782”公开的方法制备而得)制得标题化合物18-1(20mg)。
MS m/z(ESI):376.5[M+1]
1H NMR(400MHz,CDCl3)δ8.05(d,1H),7.51(t,1H),7.32(d,1H),6.99(d,1H),6.61(dd,1H),6.48(s,1H),5.65(s,1H),4.78(s,1H),4.08-4.12(m,1H),3.63(d,1H),3.48-3.52(m,1H),3.35-3.38(m,1H),2.50(s,3H),2.52(d,2H),1.98-2.02(m,2H),1.82-1.86(m,2H),1.28(d,3H).
实施例19
4-(4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-3-基)吡啶-2-基)苯甲酸19
将化合物4d(30mg,0.069mmol)溶于10mL甲醇中,加入4mL水和氢氧化钠(27.5mg,0.687mmol),室温搅拌反应12小时。反应液调pH为酸性,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物19(10mg)。
MS m/z(ESI):423.2[M+1]
1H NMR(400MHz,CD3OD)δ8.86(d,1H),7.90-8.17(m,6H),7.61(d,1H),7.46(d,2H),5.16(s,1H),3.90(s,1H),2.68(s,3H),2.32-2.51(m,2H),2.14(d,2H),1.51(s,2H).
实施例20
1-甲基-5-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2(1H)-酮20
采用实施例7的合成路线,将第二步原料化合物7b替换为1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2(1H)-酮(采用专利申请“WO2014210255”公开的方法制备而得)制得标题化合物20(40mg)。
MS m/z(ESI):333.4[M+1]
1H NMR(400MHz,CDCl3)δ8.06(d,1H),7.72-7.70(dd,1H),7.59(t,1H),7.52(dd,1H),7.00(d,1H),6.65(d,1H),4.74(br,1H),3.68(s,3H),2.48(s,3H),2.33-2.31(m,1H),2.13-2.07(m,1H),2.02-1.96(m,1H),1.92-1.89(d,1H),1.53-1.48(m,1H),1.40-1.29(m,2H).
实施例21
2-(6-甲基吡啶-2-基)-3-(吡啶-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶21
采用实施例7的合成路线,将第二步原料化合物7b替换为吡啶-4-基硼酸(采用专利申请“CN104177390”公开的方法制备而得)制得标题化合物21(30mg)。
MS m/z(ESI):303.2[M+1]
1H NMR(400MHz,CD3OD)δ8.54(d,2H),7.72(t,1H),7.53-7.49(m,3H),7.20(d,1H),5.06(s,1H),3.65(s,1H),2.42-2.36(m,4H),2.19-2.01(m,3H),1.39-1.31(m,2H).
实施例22
3-(2-氟吡啶-4-基)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶22
采用实施例7的合成路线,将第二步原料化合物7b替换为化合物8a,制得标题化合物22(30mg)。
MS m/z(ESI):321.1[M+1]
1H NMR(400MHz,CD3OD)δ8.19(d,1H),7.73(t,1H),7.54(t,1H),7.37(d,1H),7.27(s,1H),7.20(d,1H),5.07(s,1H),3.66(s,1H),2.41(s,3H),2.38(d,1H),2.21-2.17(m,1H),2.06-2.00(m,2H),1.38-1.29(m,2H).
实施例23-1
(S)-3-((4-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)氨基)丙烷-1,2-二醇23-1
采用实施例5的合成路线,将第二步原料氨基乙醇替换为(S)-3-异丙胺-1,2-二醇(采用专利申请“US20120095075”公开的方法制备而得)制得标题化合物23-1(20mg)。
MS m/z(ESI):392.5[M+1]
1H NMR(400MHz,CDCl3)δ8.06(d,1H),7.51(t,1H),7.33(d,1H),6.99(d,1H),6.61(dd,1H),6.49(s,1H),5.81(s,1H),4.78(s,1H),4.13-4.09(m,1H),3.64(d,1H),3.50(d,1H),3.39-3.32(m,1H),2.50(s,3H),2.27(d,1H),2.05-1.99(m,4H),1.90-1.83(m,3H).
实施例24-1
N1,N1-二甲基-N2-(4-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)乙烷-1,2-二胺24-1
采用实施例5的合成路线,将第二步原料氨基乙醇替换为N1,N1-二甲基乙烷-1,2-二胺制得标题化合物24-1(20mg)。
MS m/z(ESI):389.5[M+1]
1H NMR(400MHz,CDCl3)δ8.09(d,1H),7.54(t,1H),7.45(d,1H),7.02(d,1H),
6.68(dd,1H),6.63(s,1H),5.43(s,1H),4.85(s,1H),3.67(d,1H),3.42(t,2H),2.64(t,2H),2.53(s,3H),2.33(s,6H),2.07-2.05(m,2H),1.95-1.87(m,4H).
实施例25
4-((4-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)氨基)环己醇25
将化合物22(30mg,0.094mmol)、4-氨基环己醇(32mg,0.281mmol)和碳酸铯(91mg,0.281mmol)溶于5mL二甲亚砜中,升温至120℃搅拌反应12小时。反应液冷却至室温,减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物25(6mg,产率:15%)。
MS m/z(ESI):416.3[M+1]
1H NMR(400MHz,CDCl3)δ8.09(d,1H),7.53(t,1H),7.44(d,1H),7.02(d,1H),6.68(dd,1H),6.51(s,1H),4.85(s,1H),4.51(s,1H),3.67-3.72(m,2H),3.48-3.46(m,1H),2.54(s,3H),2.35(d,1H),2.10-1.87(m,5H),1.58-1.55(m,1H),1.41-1.26(m,8H).
实施例26
2-((4-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)氧基)乙醇26
采用实施例25的合成路线,将原料4-氨基环己醇替换为乙二醇制得标题化合物26(10mg)。
MS m/z(ESI):363.5[M+1]
1H NMR(400MHz,CD3OD)δ8.09(d,1H),7.71(t,1H)7.43(d,1H),7.19(d,1H),6.96(d,1H),6.91(d,1H),5.10(s,1H),4.37(t,2H),3.88(t,2H),3.68(s,1H),2.44(t,3H),2.35(d,1H),2.20-2.15(m,1H),2.10-1.98(m,2H),1.49-1.30(m,2H).
实施例27
2-((6-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-基)氧基)乙酰胺27
第一步
2-((6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉-4-基)氧基)乙酸乙酯27b
将2-((6-溴喹啉-4-基)氧基)乙酸乙酯27a(200mg,0.647mmol,采用公知的方法“Heteroatom Chemistry,2012,23(4),399-410”制备而得)、联硼酸频那醇酯(146mg,0.776mmol)、醋酸钾(126mg,1.294mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(23mg,0.032mmol)溶于5mL 1,4-二氧六环中,升温至90℃搅拌反应2小时。反应液冷却至室温,减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物27b(90mg,产率:38.9%)。
第二步
2-((6-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-基)氧基)乙酸乙酯27c
将化合物1f(72mg,0.238mmol)、化合物27b(170mg,0.476mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(34mg,0.047mmol)和碳酸钾(98mg,0.714mmol)溶于5mL 1,4-二氧六环和水(V/V=4:1)的混合溶剂中,升温至100℃微波反应1小
时。反应液冷却至室温,用硅藻土过滤,滤液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物27c(52mg,产率:48.5%)。
第三步
2-((6-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-基)氧基)乙酰胺27
将化合物27c(20mg,0.044mmol)溶于10mL7M氨的甲醇溶液中,升温至110℃搅拌反应12小时。反应液冷却至室温,减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物27(10mg,产率:53.4%)。
MS m/z(ESI):426.4[M+1]
1H NMR(400MHz,CDCl3)δ8.50(s,1H),8.01(s,1H),7.82(d,1H),7.68(t,1H),7.55(d,1H),7.46(d,1H),7.12(d,1H),6.38(d,1H),5.06(s,1H),4.62(s,2H),3.66(s,1H),2.39(d,1H),2.36(s,3H),2.21-2.10(m,1H),2.06-1.95(m,2H),1.42-1.30(m,2H).
实施例28
4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-6-甲酸叔丁酯28
第一步
4-溴喹啉-6-甲酸叔丁酯28b
将4-溴喹啉-6-甲酸28a(1.8g,7.141mmol)溶于10mL N,N-二甲基甲酰胺中,加入N,N-羰基二咪唑(1.158g,7.141mmol),升温至40℃搅拌反应1小时,加入叔丁醇(1.058g,14.282mmol)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(2.177g,14.282mmol),升温至80℃搅拌反应12小时。反应液冷却至室温,加入水,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物28b(900mg,产率:41%)。
第二步
4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉-6-甲酸叔丁酯28c
将化合物28b(900mg,2.92mmol)、联硼酸频那醇酯(1.11g,4.381mmol)、醋酸钾(858mg,8.76mmol)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(214mg,0.292mmol)溶于10mL二甲亚砜中,升温至60℃搅拌反应12小时。反应液冷却至室温,减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物28c(900mg,产率:90%)。
第三步
4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-6-甲酸叔丁酯28
将化合物28c(61mg,0.171mmol)、化合物1f(40mg,0.131mmol)、碳酸钠(42mg,0.393mmol)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(15mg,0.013mmol)溶于6mL乙二醇二甲醚和水(V/V=5:1)的混合溶剂中,升温至80℃搅拌反应12小时。反应液冷却至室温,减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物28(10mg,产率:17%)。
MS m/z(ESI):453.4[M+1]
1H NMR(400MHz,CD3OD)δ9.01(dd,1H),8.36(d,1H),8.24-8.11(m,2H),7.77-7.59(m,3H),6.95(dd,1H),5.17(s,1H),3.76(s,1H),2.69(s,3H),2.48-2.41(m,2H),2.25-2.21(m,2H),2.09-2.01(m,2H),1.50(d,9H).
实施例29
4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-6-甲酰胺29
第一步4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-6-甲酸29a
将化合物28(80mg,0.177mmol)溶于5mL二氯甲烷中,加入1.5mL三氟乙酸,室温搅拌反应12小时。反应液减压浓缩,所得残余物中加入水,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题化合物29a(50mg),产品不经纯化直接进行下一步反应。
第二步
4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-6-甲酰胺29
将粗品化合物29a(50mg,0.126mmol)、氯化铵(67mg,1.201mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(36mg,0.189mmol)、1-羟基苯丙三氮唑(26mg,0.189mmol)和N,N-二异丙基乙胺(49mg,0.378mmol)溶于3mL N,N-二甲基甲酰胺中,室温搅拌反应12小时。反应液用高效液相色谱法纯化,得到标题化合物29(10mg,产率:20%)。
MS m/z(ESI):396.4[M+1]
1H NMR(400MHz,CD3OD)δ8.91(t,2H),8.37(d,1H),8.30(d,1H),8.01(dd,1H),7.82(t,1H),7.43(d,1H),7.34(d,1H),5.17(s,1H),3.98(d,1H),2.69(s,3H),2.56(d,1H),2.39-2.35(m,1H),2.20-2.16(m,2H),1.60-1.55(m,2H).
实施例30
4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)烟酰胺30
第一步
4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)烟腈30b
将4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)烟腈30a(90.76mg,0.39mmol,采用专利申请“WO2012086735”公开的方法制备而得)、化合物1f(60mg,0.2mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(14.43mg,0.02mmol)和碳酸钾(81.78mg,0.59mmol)溶于5mL 1,4-二氧六环和水(V/V=4:1)的混合溶剂中,升温至80℃搅拌反应12小时。反应液冷却至室温,减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物30b(15mg,产率:23.23%)。
第二步
4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)烟酰胺30
将化合物30b(15mg,0.05mmol)、过氧化氢(15.58mg,0.46mmol)和碳酸钾(19mg,0.14mmol)溶于1mL二甲亚砜中,室温搅拌反应2小时。反应液用高效液相色谱法纯化,得到标题化合物30(2mg,产率:12.39%)。
MS m/z(ESI):346.5[M+1]
1H NMR(400MHz,CDCl3)δ8.98(dd,2H),8.57(t,1H),7.71(d,1H),7.59(t,1H),6.99(d,1H),6.46(s,1H),5.93(s,1H),4.81(s,1H),3.70(d,1H),2.39(s,3H),2.36(d,1H),2.08-2.20(m,1H),1.81-1.97(m,2H),1.50-1.52(m,1H),1.34-1.35(m,1H)。
实施例30-1
4-((5S,8R)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)烟酰胺30-1
采用实施例30的合成路线,将第一步原料化合物1f替换为化合物1f-1制得标题化合物30-1(15mg)。
MS m/z(ESI):346.5[M+1]
1H NMR(400MHz,CDCl3)δ8.99(dd,2H),8.58(t,1H),7.72(d,1H),7.59(t,1H),6.99(d,1H),6.42(s,1H),5.86(s,1H),4.82(s,1H),3.70(d,1H),2.39(s,3H),2.37(d,1H),2.15-2.09(m,1H),1.99-1.99(m,2H),1.54-1.51(m,1H),1.39-1.36(m,1H).
实施例31
(4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)氨基甲酸叔丁酯31
采用实施例8的合成路线,将第三步原料化合物8c替换为(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-基)氨基甲酸叔丁酯(采用专利申请
“WO2015039172”公开的方法制备而得)制得标题化合物31(30mg)。
MS m/z(ESI):418.2[M+1]
1H NMR(400MHz,CD3OD)δ8.17(d,1H),8.02(s,1H),7.71(t,1H),7.46(d,1H),7.19(d,1H),7.04-7.02(m,1H),5.12(s,1H),3.65(s,1H),2.44(s,3H),2.39-2.02(m,4H),1.53(s,9H),1.42-1.31(m,2H).
实施例32
4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-胺32
将化合物31(50mg,0.12mmol)溶于10mL二氯甲烷中,加入3mL三氟乙酸,100℃搅拌反应16小时。反应液用饱和碳酸氢钠溶液调节pH为碱性,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用高效液相色谱法纯化所得残余物,制得标题化合物32(20mg)。
MS m/z(ESI):318.2[M+1]
1H NMR(400MHz,CD3OD)δ7.86(d,1H),7.70(t,1H),7.41(t,1H),7.18(d,1H),6.69(d,1H),6.61(t,1H),5.22(s,1H),3.64(s,1H),2.68(s,3H),2.47-2.46(m,1H),2.34-2.32(m,1H),2.07-1.99(m,2H),1.39-1.32(m,2H).
实施例33
2-(6-甲基吡啶-2-基)-3-(2-(4-(甲磺酰基)苯基)吡啶-4-基)-4,5,6,7-四氢-4,7-乙桥吡唑并[1,5-a]吡啶33
第一步
2-(4-(甲氧羰基)环己基)肼基甲酸叔丁酯33b
将4-环己酮甲酸甲酯33a(2g,12.806mmol),肼基甲酸叔丁酯(1.86g,14.286mmol)和三乙酰氧基硼氢化钠(5.4g,25.612mmol)溶于30mL二氯甲烷中,加入0.5mL乙酸,室温搅拌反应12小时。反应液中加入水,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物33b(1.5g,产率:43%)。
第二步
4-(2-(叔丁氧羰基)肼基)环己烷羧酸33c
将化合物33b(900mg,3.203mmol)溶于10mL甲醇中,加入4mL 2M氢氧化钠溶液,室温搅拌反应3小时。向反应液中滴加2M盐酸至pH为5~6,用二氯甲烷和甲醇(V/V=10:1)的混合溶剂萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题化合物33c(750mg),产品不经纯化直接进行下一步反应。
第三步
2-氮杂双环[2.2.2]辛烷-2-基氨基甲酸叔丁酯33d
将粗品化合物33c(750mg,2.903mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(832mg,4.355mmol)、1-羟基苯丙***(588mg,4.355mmol)和三乙胺
(633mg,5.806mmol)溶于10mL N,N-二甲基甲酰胺中,室温搅拌反应12小时。反应液中加入饱和碳酸氢钠溶液,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物33d(490mg,产率:70%)。
第四步
2-氮杂双环[2.2.2]辛烷-2-胺盐酸盐33e
将化合物33d(490mg,2.039mmol)溶于5mL 4M氯化氢的1,4二氧六环溶液中,室温搅拌反应3小时。反应液减压浓缩,得到粗品标题化合物33e(300mg),产品不经纯化直接进行下一步反应。
第五步
3-(2-氮杂双环[2.2.2]辛烷-2-基亚氨基)-3-(6-甲基吡啶-2-基)丙酸乙酯33g
将粗品化合物33e(350mg,1.981mmol)、3-(6-甲基吡啶-2-基)-3-氧代丙酸乙酯33f(452mg,2.179mmol,采用专利申请“WO2006052568”公开的方法制备而得)和对甲苯磺酸(34mg,0.198mmol)溶于10mL吡啶中,加入100mg分子筛,室温搅拌反应12小时。反应液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物33g(300mg,产率:46%)。
第六步
2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-乙桥吡唑并[1,5-a]吡啶-3-羧酸33h
将化合物33g(1.3g,3.95mmol)溶于20mL甲苯中,加入乙醇钠(537.14mg,7.89mmol),升温至100℃搅拌反应12小时。反应液冷却至室温,减压浓缩,所得残余物中加入50mL乙酸乙酯,依次用水和饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题化合物33h(1.1g),产品不经纯化直接进行下一步反应。
第七步
3-溴-2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-乙桥吡唑并[1,5-a]吡啶33i
将粗品化合物33h(1.1g,3.88mmol)溶于15mL N,N-二甲基甲酰胺中,加入N-溴代丁二酰亚胺(1.38g,7.76mmol),升温至40℃搅拌反应12小时。反应液冷却至室温,减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物33i(550mg,产率:44.52%)。
第八步
2-(6-甲基吡啶-2-基)-3-(2-(4-(甲磺酰基)苯基)吡啶-4-基)-4,5,6,7-四氢-4,7-乙桥吡唑并[1,5-a]吡啶33
将化合物33i(50mg,0.157mmol)、化合物3d(112.9mg,0.314mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(11.5mg,0.0157mmol)和碳酸钾(65.15mg,0.47mmol)溶于2mL 1,4-二氧六环和水(V/V=3:1)的混合溶剂中,升温至100℃微波反应1小时。反应液冷却至室温,减压浓缩,用高效液相色谱法纯化所得残余物,得到
标题化合物33(15mg,产率:20.08%)。
MS m/z(ESI):471.4[M+1]
1H NMR(400MHz,CDCl3)δ8.69(d,1H),8.12(d,2H),8.05(d,2H),7.80(s,1H),7.60(t,1H),7.42(d,1H),7.29(d,1H),7.13(d,1H),4.92(s,1H),3.54(s,1H),3.13(s,3H),2.52(s,3H),2.04-1.19(m,6H),1.76-1.71(m,2H).
实施例34
第一步
4-(2-(2-氮杂双环[2.2.2]辛烷-2-基亚氨基)-2-(6-甲基吡啶-2-基)乙基)喹啉-6-甲腈34b
将化合物33e(200mg,1.132mmol)、4-(2-(6-甲基吡啶-2-基)-2-氧代乙基)喹啉-6-甲腈34a(358mg,1.245mmol,采用专利申请“WO2007018818”公开的方法制备而得)和对甲苯磺酸(50mg,0.291mmol)溶于5mL吡啶中,加入200mg分子筛,室温搅拌反应12小时。反应液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物34b(200mg,产率:43%)。
第二步
4-(2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-乙桥吡唑并[1,5-a]吡啶-3-基)喹啉-6-甲腈34c
将化合物34b(150mg,0.366mmol)溶于4mL N,N-二甲基甲酰胺中,加入氢化钠(44mg,1.099mmol,60%),室温搅拌反应1小时后,升温至100℃搅拌反应12小时。反应液冷却至室温,加入水,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题化合物34c(70mg),产品不经纯化直接进行下一步反应。
第三步
4-(2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-乙桥吡唑并[1,5-a]吡啶-3-基)喹啉-6-甲酰胺34
将粗品化合物34c(70mg,0.179mmol)溶于3mL二甲亚砜中,加入0.3mL过氧化氢溶液(30%)和碳酸钾(74mg,0.536mmol),室温搅拌反应2小时。反应液中加入水,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物34(20mg,产率:27%)。
MS m/z(ESI):410.4[M+1]
1H NMR(400MHz,CDCl3)δ9.00(d,1H),8.26(d,1H),8.19(d,1H),8.13(dd,1H),7.56(d,1H),7.38(dd,1H),7.00(dd,2H),5.98(s,1H),5.50(s,1H),4.99(s,1H),3.28(s,1H),2.38(s,3H),2.09-1.93(m,6H),1.78-1.76(m,2H).
实施例35
4-(2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-甲桥吡唑并[1,5-a]吡啶-3-基)喹啉-6-甲酰胺35
第一步
2-氨基-2-氮杂双环[2.2.1]庚烷-3-酮乙酸盐35b
将2-亚硝基-2-氮杂双环[2.2.1]庚烷-3-酮35a(15g,107mmol,采用专利申请“WO2010132509”公开的方法制备而得)溶于75mL乙酸中,冷却至0℃,加入锌粉(10.2g,159mmol),缓慢升至室温,搅拌反应至反应液呈灰色,停止反应。反应液用硅胶过滤,滤液减压浓缩,得到粗品标题化合物35b(22g),产品不经纯化直接进行下一步反应。
第二步
3-(6-甲基吡啶-2-基)-3-((3-氧代双环[2.2.1]庚烷-2-基)氨亚基)丙酸乙酯35c
将粗品化合物35b(5g,25.9mmol),化合物33f(7.2g,38.9mmol)溶于100mL
甲苯中,加入对甲苯磺酸(445mg,25.9mmol),升温至130℃搅拌反应18小时。反应液冷却至室温,加入饱和碳酸氢钠溶液,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物35c(5.9g,产率:72.8%)。
第三步
2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-甲桥吡唑并[1,5-a]吡啶-3-羧酸35d
将化合物35c(2g,6.9mmol)溶于50mL甲苯中,加入乙醇钠(1.4g,20.9mmol),升温至100℃搅拌反应16小时。反应液冷却至室温,加入水,滴加1N盐酸至pH为5-6,用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题化合物35d(1.4g),产品不经纯化直接进行下一步反应。
第四步
3-溴-2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-甲桥吡唑并[1,5-a]吡啶35e
将粗品化合物35d(600mg,2.23mmol)溶于5mL N,N-二甲基甲酰胺中,加入N-溴代丁二酰亚胺(422mg,2.45mmol),室温搅拌反应4小时。反应液中加入饱和碳酸氢钠溶液,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物35e(610mg,产率:90.3%)。
第五步
4-(2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-甲桥吡唑并[1,5-a]吡啶-3-基)喹啉-6甲腈35g
将化合物35e(250mg,0.18mmol),4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉-6-甲腈35f(278mg,0.989mmol,采用专利申请“US20100160280”公开的方法制备而得),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(30mg,0.041mmol)和碳酸钾(342mg,2.475mmol)溶于5.5mL 1,4-二氧六环和水(V/V=10:1)的混合溶剂中,升温至80℃搅拌反应1小时。反应液冷却至室温,加入水,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物35g(250mg,产率:80%)。
第六步
4-(2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-甲桥吡唑并[1,5-a]吡啶-3-基)喹啉-6-甲酰胺35
将化合物35g(250.mg,0.66mmol)溶于3mL二甲亚砜中,加入0.5mL过氧化氢溶液(30%)和碳酸钾(273mg,1.98mmol),室温搅拌反应1小时。反应液中加入水,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物35(98mg,产率:37.6%)。
MS m/z(ESI):396.4[M+1]
1H NMR(400MHz,CD3OD)δ8.88-8.87(d,1H),8.40(s,1H),8.16-8.09(m,2H),
7.60-7.56(m,1H),7.69-7.46(m,2H),7.05-7.03(d,1H),5.08(s,1H),6.65-3.63(m,1H),3.37(s,1H),2.68(s,3H),2.44-2.41(d,1H),2.16-2.12(m,2H),2.06-2.03(m,1H),1.56-1.51(m,1H),1.45-1.40(m,1H),0.92-0.90(m,1H).
实施例35-1,35-2
4-((4S,7R)-2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-甲桥吡唑并[1,5-a]吡啶-3-基)喹啉-6-甲酰胺35-1
4-((4R,7S)-2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-甲桥吡唑并[1,5-a]吡啶-3-基)喹啉-6-甲酰胺35-2
将化合物35(98mg,0.247mmol)进行手性制备(分离条件:色谱柱:Superchiral S-OJ(Chiralway),2cm I.D.×25cm Length,5μm;流动相:二氧化碳/甲醇=80/20(v/v),流速:50g/分钟),收集其相应组分,减压浓缩,得到标题化合物(45mg、45mg)。单一构型化合物(较短保留时间):
MS m/z(ESI):396.4[M+1]
手性HPLC:保留时间7.153分钟,手性纯度:99.9%,(色谱柱:CHIRALPAK OD4.6×150mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=20/80(v/v));
1H NMR(400MHz,CDCl3)δ9.01-9.00(d,1H),8.20-8.18(m,2H),8.14-8.11(m,1H),7.44-7.43(d,1H),7.39-7.35(m,1H),7.14-7.12(d,1H),6.97-6.95(d,1H),5.95-5.90(br,1H),5.97-5.51(br,1H),5.09(s,1H),3.65(s,1H),2.42-2.40(d,1H),2.27(s,3H),2.18-2.08(m,2H),1.98-1.96(m,1H),1.69-1.68(m,1H),1.53-1.50(m,1H)。
单一构型化合物(较长保留时间):
MS m/z(ESI):396.4[M+1]
手性HPLC:保留时间7.992分钟,手性纯度:99.1%,(色谱柱:CHIRALPAK OD4.6×150mm,5μm;流动相:乙醇(含0.1%二乙胺)/正己烷=20/80(v/v));
1H NMR(400MHz,CDCl3)δ9.01-9.00(d,1H),8.20-8.18(m,2H),8.14-8.11(m,1H),7.44-7.43(d,1H),7.39-7.35(m,1H),7.14-7.12(d,1H),6.97-6.95(d,1H),5.94-5.90(br,1H),5.97-5.51(br,1H),5.09(s,1H),3.65(s,1H),2.42-2.40(d,1H),2.27(s,3H),2.18-2.08(m,2H),1.98-1.96(m,1H),1.69-1.68(m,1H),1.53-1.50(m,1H).
实施例36
6-(2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-乙桥吡唑并[1,5-a]吡啶-3-基)喹啉-4-甲酰
胺36
第一步
6-(2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-乙桥吡唑并[1,5-a]吡啶-3-基)喹啉-4-甲腈36a
将化合物1h(66mg,0.236mmol)、化合物33i(50mg,0.157mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(12mg,0.016mmol)和碳酸钾(65mg,0.471mmol)溶于5mL 1,4-二氧六环和水(V/V=4:1)的混合溶剂中,升温至85℃搅拌反应12小时。反应液冷却至室温,减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物36a(30mg,产率:50%)。
第二步
6-(2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-乙桥吡唑并[1,5-a]吡啶-3-基)喹啉-4-甲酰胺36
将化合物36a(30mg,0.077mmol)溶于2mL二甲亚砜中,加入30%过氧化氢溶液(26.063mg,0.766mmol)和碳酸钾(21.183mg,0.153mmol),室温搅拌反应1小时。反应液过滤,滤液用高效液相色谱法纯化,得到标题化合物36(15mg,产率:47.8%)。
MS m/z(ESI):410.4[M+1]
1H NMR(400MHz,CDCl3)δ8.95(d,1H),8.29(d,1H),8.09(d,1H),7.72(dd,1H),7.49-7.57(m,2H),7.32(dd,1H),7.08(d,1H),6.04(s,1H),5.92(s,1H),4.91(s,1H),3.57(s,1H),2.52(s,3H),1.91-2.02(m,6H),1.72-1.76(m,2H).
实施例37
2-((4-(2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-乙桥吡唑并[1,5-a]吡啶-3-基)吡啶-2-基)氨基)乙醇37
采用实施例5的合成路线,将第一步原料化合物1f替换为化合物33i制得标题产物37(20mg)。
MS m/z(ESI):376.5[M+1]
1H NMR(400MHz,CDCl3)δ7.99(d,1H),7.52(t,1H),7.14(d,1H),7.18(d,1H),6.47(dd,1H),6.24(s,1H),5.62(s,1H),4.83(s,1H),3.83(t,2H),3.58-3.53(m,2H),3.40(s,1H),2.58(s,3H),1.94-1.88(m,4H),1.77-1.74(m,2H),1.59-1.57(m,2H).
实施例38
3-([1,2,4]***并[1,5-a]吡啶-6-基)-2-(6-甲基吡啶-2-基)-4,5,6,7-四氢-4,7-乙桥吡唑并[1,5-a]吡啶38
将6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-[1,2,4]***[1,5-a]吡啶38a(90mg,0.368mmol)溶于5mL 1,4-二氧六环和水(V/V=4:1)的混合溶剂,加入化合物33i(78mg,0.245mmol),碳酸钾(225mg,1.632mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(20mg,0.027mmol),升温至85℃搅拌反应12小时。反应液冷却至室温,减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物38(10mg,产率:11.5%)。
MS m/z(ESI):357.5[M+1]
1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.37(s,1H),7.72(d,1H),7.57-7.54(m,
2H),7.46(d,1H),7.08(d,1H),4.90(s,1H),3.45(s,1H),2.49(s,3H),1.93-2.03(m,6H),1.69-1.73(m,2H).
实施例39-1
6-((5S,8R)-2-(5-氟吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-甲酰胺39-1
第一步
(1S,4R)-2-(2-(5-氟吡啶-2-基)-2-氧代乙基)-2-氮杂双环[2.2.1]庚烷-3-酮39a-1
将化合物9a(4.5g,20.64mmol)溶于50mL N,N-二甲基甲酰胺中,加入粗品化合物1b-1(5.19g,41.28mmol),氩气氛下,于50℃搅拌反应18小时。反应液减压浓缩得粗品标题化合物39a-1(5.1g),产物不经纯化直接进行下一步反应。
第二步
(5S,8R)-2-(5-氟吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶39b-1
将粗品化合物39a-1(5g,20.14mmol)和醋酸铵(1.71g,22.16mmol)溶于50mL乙酸中,升温至100℃搅拌反应18小时。反应液冷却至室温,减压浓缩后,向所得残余物中滴加饱和碳酸氢钠溶液至pH为7,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系B纯化所得残余物,得到标题化合物39b-1(1.5g,产率:29.24%)。
第三步
(5S,8R)-3-溴-2-(5-氟吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶39c-1
将化合物39b-1(1.5g,6.54mmol)溶于10mL二氯甲烷中,冷却至0℃,滴加液溴(1.15g,7.2mmol),室温搅拌反应1.5小时。反应液中加入15mL饱和亚硫酸氢钠溶液,用二氯甲烷萃取(20mL×3),合并有机相,用无水硫酸钠干燥,过滤,
滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系A纯化所得残余物,得到标题化合物39c-1(1.3g,产率:58.03%)。
第四步
6-((5S,8R)-2-(5-氟吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-甲酸甲酯39d-1
将化合物1l(121.9mg,0.39mmol),化合物39c-1(0.1g,0.32mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(12mg,0.016mmol)和碳酸钾(112.1g,0.811mmol)溶于11mL 1,4-二氧六环和水(V/V=20:1)的混合溶剂中,升温至100℃搅拌反应16小时。反应液冷却至室温,硅藻土过滤。滤液减压浓缩,用高效液相色谱法纯化所得残余物,得到标题化合物39d-1(50mg,产率:33.4%)。
第五步
6-((5S,8R)-2-(5-氟吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-甲酰胺39-1
将化合物39d-1(60mg,0.14mmol)溶于3mL 7M的氨的甲醇溶液中,密封条件下升温至50℃搅拌反应3小时。反应液冷却至室温,减压浓缩,用硅胶柱色谱法以洗脱剂体系A纯化所得残余物,得到标题化合物39-1(30mg,产率:51.42%)。
MS m/z(ESI):400.5[M+1]
1H NMR(400MHz,CDCl3)δ9.01-9.00(m,1H),8.56-8.55(m,1H),8.27-8.26(m,1H),8.17-8.15(m,1H),7.95-7.90(m,2H),7.60(d,1H),7.45-7.40(m,1H),6.23(br,1H),5.98(br,1H),4.96(br,1H),3.70(br,1H),2.42-2.40(m,1H),2.13-2.10(m,1H),2.00-1.93(m,2H),1.58-1.55(m,1H),1.44-1.42(m,1H).
实施例40-1
(5S,8R)-2-(5-氟吡啶-2-基)-3-(2-(1-甲基-1H-吡唑-4-基)吡啶-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶40-1
采用实施例12的合成路线,将第三步原料化合物1f替换为化合物39c-1,制得标题化合物40-1(10mg)。
MS m/z(ESI):387.5[M+1]
1H NMR(400MHz,CDCl3)δ8.59(d,1H),8.33(d,1H),7.96(s,1H),7.93(s,1H),7.89-7.87(m,1H),7.70(s,1H),7.43(t,1H),7.22-7.20(m,1H),4.86(s,1H),4.00(s,
3H),3.70(d,1H),2.39(d,1H),2.13-2.10(m,1H),1.98-1.92(m,2H),1.56-1.54(m,1H),1.51-1.42(m,1H).
实施例41-1
4-(4-((5S,8R)-2-(5-氟吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)吡啶-2-基)苯甲酰胺41-1
采用实施例4的合成路线,将化合物1f替换为化合物39c-1,制得标题化合物41-1(30mg)。
MS m/z(ESI):424.0[M+1]
1H NMR(400MHz,CDCl3)δ8.78(d,1H),8.33(br,1H),8.12-8.10(m,2H),8.06(s,1H),7.98-7.94(m,3H),7.48-7.41(m,2H),6.23(br,1H),5.84(br,1H),4.89(br,1H),3.75(br,1H),2.42-2.38(m,1H),2.18-2.11(m,1H),2.04-2.00(m,2H),1.57-1.52(m,1H),1.38-1.35(m,1H).
实施例42-1
(5S,8R)-2-(5-氟吡啶-2-基)-3-(2-(4-(甲磺酰基)苯基)吡啶-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶42-1
采用实施例3的合成路线,将化合物1f替换为化合物39c-1,制得标题化合物42-1(30mg)。
MS m/z(ESI):461.5[M+1]
1H NMR(400MHz,CDCl3)δ8.78(d,1H),8.30(d,1H),8.21-8.19(m,2H),8.09-8.07(m,3H),7.98-9.98(m,1H),7.48-7.43(m,2H),4.88(br,1H),3.74(br,1H),3.10(s,3H),2.41-2.39(m,1H),2.22-2.14(m,1H),2.01-1.93(m,2H),1.55-1.50(m,1H),1.40-1.35(m,1H).
实施例43
2-(6-甲基吡啶-2-基)-3-(2-(1-(甲磺酰基)-1H-吡唑-4-基)吡啶-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶43
第一至三步
2-(6-甲基吡啶-2-基)-3-(2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡啶-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶43d
采用实施例12的合成路线,将原料化合物12a替换为1-(四氢-2H-吡喃-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑43a(采用专利申请“WO20140005183”公开的方法制备而得),制得标题化合物43d(100mg)。
第四步
3-(2-(1H-吡唑-4-基)吡啶-4-基)-2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶43e
将化合物43d(15mg,0.03mmol)溶于2mL的1M氯化氢1,4-二氧六环溶液,搅拌反应1小时。反应液减压浓缩,得粗品标题化合物43e(10mg),产物不经纯化直接进行下一步反应。
第五步
2-(6-甲基吡啶-2-基)-3-(2-(1-(甲磺酰基)-1H-吡唑-4-基)吡啶-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶43
将粗品化合物43e(10mg,0.03mmol)溶于5mL二氯甲烷,冷却至0℃,加入三乙胺(8.24mg,0.08mmol)和甲烷磺酰氯(4.66mg,0.04mmol),搅拌反应1小时。
反应液减压浓缩,用高效液相色谱法纯化所得残余物,得标题化合物43(10mg,产率:82.51%)。
MS m/z(ESI):447.2[M+1]
1H NMR(400MHz,CDCl3)δ8.81(d,1H),8.67(s,1H),8.36(s,1H),7.87(s,1H),7.82(t,1H),7.58(d,1H),7.39(d,1H),7.27(d,1H),4.98(s,1H),4.10(s,1H),3.45(t,3H),2.71(s,3H),2.52(d,1H),2.25-2.30(m,1H),2.05-2.11(m,2H),1.61-1.69(m,1H),1.41-1.49(m,1H).
实施例44
2-(6-甲基吡啶-2-基)-3-(2-(1-(甲基磺酰基)哌啶-4-基)吡啶-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶44
第一步
4-(2-(6-甲基吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)-5',6'-二氢-[2,4'-联吡啶]-1'(2'H)-甲酸叔丁酯44a
将化合物1f(240mg,0.79mmol),化合物8c(237.97mg,0.79mmol),碳酸钾(218.09mg,1.58mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(58.53mg,0.08mmol)溶于15mL 1,4-二氧六环和1.5mL水中,氩气氛下,升温至100℃搅拌反应
12小时。反应液冷却至室温,减压浓缩,用combiflash以洗脱剂体系A纯化所得残余物,得到标题化合物44a(300mg,产率:78.63%)。
第二步
2-(6-甲基吡啶-2-基)-3-(1',2',3',6'-四氢-[2,4'-联吡啶]-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶44b
将化合物44a(200mg,0.41mmol),三氟乙酸(6mL)加入10mL二氯甲烷中,室温下搅拌反应12小时。停止搅拌,用饱和碳酸氢钠溶液调节反应液pH至碱性,用二氯甲烷萃取,合并有机相,减压浓缩得粗品标题化合物44b(150mg,产率94.58%)。
第三步
2-(6-甲基吡啶-2-基)-3-(2-(哌啶-4-基)吡啶-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶44c
将化合物44b(80mg,0.210mmol)溶于10mL甲醇中,加入10%钯碳(16mg,0.470mmol),氢气置换三次,室温搅拌反应0.5小时。反应液过滤,滤液减压浓缩得到粗品标题化合物44c(80mg,黄色固体),产品不经纯化直接进行下一步反应。
第四步
2-(6-甲基吡啶-2-基)-3-(2-(1-(甲基磺酰基)哌啶-4-基)吡啶-4-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶44
将粗品化合物44c(30mg,0.08mmol)溶于5mL二氯甲烷中,0℃加入N,N-二异丙基乙胺(30.17mg,0.23mmol)和甲磺酰氯(17.83mg,0.16mmol),0℃搅拌反应2小时。减压浓缩,用combiflash以洗脱剂体系A纯化所得残余物,得到标题化合物44(2mg,产率:5.16%)。
MS m/z(ESI):464.5[M+1]
1H NMR(400MHz,CD3OD)δ8.49(d,1H),7.76-7.72(m,1H),7.49(d,1H),7.38(d,2H),7.21(d,1H),3.86(d,2H),3.66(s,1H),2.92-2.86(m,5H),2.43-2.37(m,4H),2.21-2.18(m,2H),2.07-2.00(m,4H),1.83-1.80(m,2H),1.39-1.23(m,3H).
实施例45-1
6-((5S,8R)-2-(吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-甲酰胺45-1
第一步
(5S,8R)-3-溴-2-(吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶45b-1
采用实施例1第1-4步的的合成方法,将化合物1c替换为2-溴-1-(吡啶-2-基)乙酮45a,得到标题化合物45b-1(5g)。
第二步
6-((5S,8R)-2-(吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)喹啉-4-甲酰胺45-1
采用实施例36第2-3步的的合成方法,将化合物33i替换为化合物45b-1,得到标题化合物45-1(15mg)。
MS m/z(ESI):382.4[M+1]
1H NMR(400MHz,CD3OD)δ8.94(d,1H),8.43-8.38(m,2H),8.07(d,1H),7.83-7.80(m,2H),7.73(d,1H),7.66(d,1H),7.30-7.29(m,1H),5.08(d,1H),3.68(d,1H),2.40(d,1H),2.24-2.19(m,1H),2.08-2.02(m,2H),1.47-1.36(m,2H).
实施例46-1
(5S,8R)-3-(2-(4-(甲磺酰基)苯基)吡啶-4-基)-2-(吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶46-1
采用实施例3的合成方法,将化合物1f替换成化合物45b-1,得到标题化合物46-1(10mg)。
MS m/z(ESI):443.1[M+1]
1H NMR(400MHz,CD3OD)δ8.72(d,1H),8.44(d,1H),8.20-8.18(m,2H),8.09-8.06(m,3H),7.89-7.82(m,2H),7.52-7.51(m,1H),7.34-7.33(d,1H),5.10(d,1H),3.69(d,1H),3.19(s,3H),2.42(d,1H),2.24-2.19(m,1H),2.08-2.01(m,2H),1.42-1.35(m,2H).
实施例47-1
7-((5S,8R)-2-(吡啶-2-基)-5,6,7,8-四氢-5,8-甲桥咪唑并[1,2-a]吡啶-3-基)-[1,2,4]***[4,3-a]吡啶-3-甲酰胺47-1
采用实施例2的合成方法,将原料化合物1f替换成化合物45b-1,得到标题化合物47-1(10mg)。
MS m/z(ESI):372.1[M+1]
1H NMR(400MHz,CD3OD)δ8.37(d,1H),7.90-7.84(m,4H),7.66-7.63(m,1H),7.28-7.25(m,1H),5.02(s,1H),3.68(d,1H),2.40-2.38(m,1H),2.25-2.19(m,1H),2.12-2.02(m,2H),1.44-1.31(m,2H).
测试例:
生物学评价
测试例1、本发明化合物对TGFβRI激酶活性的抑制作用的测定
体外TGFβRI激酶活性的抑制作用通过以下的方法进行测试。
本发明化合物对TGFβRI激酶ALK5活性的抑制作用采用如下实验方法测定:
酶活性检测使用TGFβRI激酶检测试剂盒(V4093,Promega),在384孔板(4514,Corning)中依次加入2μl用反应缓冲液(40mM Tris pH7.5,20mM MgCl2,0.1mg/ml BSA)配制的酶溶液(反应体系中酶终浓度为2ng/μL),1μl溶于5%DMSO的3倍梯度稀释的化合物,2μl ATP和TGFβRI底物多肽的混合溶液(ATP终浓度为50μM,底物终浓度为0.2μg/μL),27℃反应2.5小时后,每孔加入5μl试剂盒中的ADP-Glo溶液,27℃放置40分钟,每孔再加入10μl激酶检测试剂,27℃放置30分钟。使用Victor 3(PerkinElmer)多功能酶标仪检测化学发光信号值。用Graphpad prism软件根据化合物各浓度与相应的信号值计算化合物对酶抑制作用的IC50值。
本发明化合物的生物活性通过以上的试验进行测定,测得的IC50值见下表1。
表1本发明化合物对TGFβRI激酶ALK5活性抑制的IC50
实施例编号 | IC50(nM) |
1-1 | 9 |
1-2 | 16 |
2-1 | 3 |
3-1 | 4 |
4 | 29 |
4-1、4-2中保留时间4.058分钟对应的化合物 | 2 |
4-1、4-2中保留时间7.204分钟对应的化合物 | 18 |
5-1 | 46 |
6 | 26 |
6-1、6-2中保留时间3.747分钟对应的化合物 | 7 |
6-1、6-2中保留时间5.327分钟对应的化合物 | 8 |
7 | 20 |
9 | 43 |
10 | 25 |
11 | 16 |
12 | 9 |
13-1 | 11 |
14 | 31 |
15 | 60 |
16-1 | 77 |
17 | 38 |
17-1、7-2中保留时间9.196分钟对应的化合物 | 28 |
17-1、7-2中保留时间5.418分钟对应的化合物 | 28 |
18-1 | 80 |
5 | 59 |
19 | 87 |
9-1、9-2中保留时间6.631分钟对应的化合物 | 13 |
9-1、9-2中保留时间13.001分钟对应的化合物 | 13 |
29 | 85 |
3-2 | 23 |
1 | 14 |
31 | 55 |
32 | 9 |
33 | 34 |
34 | 12 |
35 | 12 |
35-1、35-2中保留时间7.153分钟对应的化合物 | 39 |
35-1、35-2中保留时间7.992分钟对应的化合物 | 25 |
36 | 21 |
37 | 52 |
38 | 9 |
39-1 | 26 |
40-1 | 10 |
41-1 | 28 |
2-2 | 3 |
43 | 21 |
12-1、12-2中保留时间2.955分钟对应的化合物 | 6 |
12-1、12-2中保留时间4.695分钟对应的化合物 | 7 |
45-1 | 29 |
46-1 | 34 |
47-1 | 39 |
结论:本发明实施例化合物对TGFβRI激酶ALK5活性均有明显地抑制作用。
测试例2、本发明化合物对VEGFR2激酶活性的的抑制作用的测定
体外VEGFR2激酶活性的的抑制作用通过以下的方法进行测试。
以下所述实验方法用来测定本发明化合物对VEGFR2激酶活性的抑制作用:
酶活性检测使用Kinase Assay Kit-Tyrosine 1Peptide(PV3190,Invitrogen)试剂盒,在384孔板(4513,Corning)中依次加入5μl用反应缓冲液(50mM HEPES pH7.5,10mM MgCl2,1mM EGTA,0.05%BRIJ-35)配制的重组人VEGFR2酶(PV3660,Invitrogen)和VEGFR2底物多肽(反应体系中酶终浓度为0.14ng/μL,底物终浓度为2μM),2.5μl溶于5%DMSO的2倍梯度稀释的化合物,2.5μL ATP溶液(ATP终浓度为50μM),25℃反应2小时后,每孔加入5μL检测试剂,25℃放置1小时后,用NOVOstar(BMG)多功能酶标仪检测发射波长445nm和520nm的荧光信号值。用Graphpad prism软件根据化合物各浓度与相应的信号值计算化合物对酶抑制作用的IC50值。
本发明化合物的生物活性通过以上的试验进行测定,测得的IC50值见下表2。
表2本发明化合物对VEGFR2激酶活性的抑制作用的IC50
实施例编号 | IC50(nM) |
1-1 | 3048 |
2-1 | 1156 |
3-1 | 2890 |
4 | 4055 |
4-1、4-2中保留时间4.058分钟对应的化合物 | 1052 |
5-1 | 3709 |
14 | 1001 |
16-1 | >10000 |
17 | 919 |
17-1、7-2中保留时间9.196分钟对应的化合物 | 871 |
17-1、7-2中保留时间5.418分钟对应的化合物 | 960 |
9-1、9-2中保留时间6.631分钟对应的化合物 | >10000 |
9-1、9-2中保留时间13.001分钟对应的化合物 | 1346 |
3-2 | 928 |
32 | 1122 |
34 | 1243 |
35-1、35-2中保留时间7.153分钟对应的化合物 | 1711 |
36 | 1008 |
37 | 2910 |
39-1 | 6305 |
40-1 | 2083 |
42-1 | 9736 |
43 | 551 |
结论:本发明实施例化合物对VEGFR2激酶活性未表现出明显的抑制作用,说明本发明实施例化合物对TGFβRI激酶具有选择性抑制作用。
测试例3、本发明化合物对p38α激酶活性的抑制作用的测定
体外p38α激酶活性的抑制通过以下的方法进行测试。
以下所述实验方法用来测定本发明化合物对p38α激酶活性的抑制作用:
酶活性检测使用p38α激酶检测试剂盒(V9591,Promega),在384孔板(4514,Corning)中依次加入2μl用反应缓冲液(40mM Tris pH7.5,20mM MgCl2,0.1mg/ml BSA)配制的酶溶液(反应体系中酶终浓度为0.5ng/μL),1μl溶于5%DMSO的3倍梯度稀释的化合物,2μl ATP和p38底物多肽的混合溶液(ATP终浓度为50μM,底物终浓度为0.2μg/μL),27℃反应2.5小时后,每孔加入5μl试剂盒中的ADP-Glo溶液,27℃放置40分钟,每孔再加入10μl激酶检测试剂,27℃放置30分钟。使用Victor 3(PerkinElmer)多功能酶标仪检测化学发光信号值。用Graphpad prism软件根据化合物各浓度与相应的信号值计算化合物对酶抑制作用的IC50值。
本发明化合物的生物活性通过以上的试验进行测定,测得的IC50值见下表3。
表3本发明化合物对p38α激酶活性的抑制作用的IC50
实施例编号 | IC50(nM) |
1-1 | 618 |
2-1 | 1710 |
3-1 | 686 |
4 | 638 |
6-1、6-2中保留时间3.747分钟对应的化合物 | 515 |
12 | 454 |
9-1、9-2中保留时间6.631分钟对应的化合物 | 5798 |
9-1、9-2中保留时间13.001分钟对应的化合物 | 2456 |
3-2 | 654 |
33 | 563 |
36 | 598 |
39-1 | 4734 |
40-1 | 1362 |
42-1 | 7782 |
结论:本发明实施例化合物对p38α激酶活性未表现出明显的抑制作用,说明本发明实施例化合物对TGFβRI激酶具有选择性抑制作用。
测试例4、本发明化合物对NIH3T3细胞增殖的抑制测定
下面的体外试验是用来测定本发明化合物对NIH3T3细胞增殖的抑制活性。
以下所述实验方法用来测定本发明化合物对NIH3T3细胞增殖的抑制作用:
在96孔透明底白板(3903,Corning)中用含10%FBS的DMEM培养基(SH30243.01,GE)每孔接种100μL NIH3T3细胞(GNM6,中国科学院典型培养物保藏委员会细胞库),接种密度为2000细胞/孔,细胞在37℃,5%CO2条件下培养过夜。过夜培养后,每孔更换为90μL含0.5%FBS的DMEM培养基,然后加入10μL用含0.5%FBS的DMEM培养基3倍梯度稀释的化合物,放置37℃,5%CO2细胞培养箱中培养72小时。最后每孔加入50μL CellTiter-Glo(G7573,Promega),室温孵育10分钟后使用Victor3酶标仪(PerkinElmer)读取化学发光信号值。用Graphpad Prism软件根据化合物各浓度与相应的信号值计算化合物的IC50值。
本发明化合物生物活性由上述分析所得,计算所得的IC50值如下表4:
表4本发明化合物对NIH3T3细胞增殖的抑制的IC50
实施例编号 | IC50(nM) |
1-1 | 89 |
2-1 | 44 |
3-1 | 28 |
4-1、4-2中保留时间4.058分钟对应的化合物 | 39 |
6 | 22 |
6-1、6-2中保留时间3.747分钟对应的化合物 | 40 |
6-1、6-2中保留时间5.327分钟对应的化合物 | 18 |
7 | 23 |
9 | 91 |
10 | 41 |
11 | 37 |
12 | 13 |
17-1、7-2中保留时间9.196分钟对应的化合物 | 84 |
9-1、9-2中保留时间6.631分钟对应的化合物 | 69 |
1 | 80 |
32 | 19 |
35-1、35-2中保留时间7.153分钟对应的化合物 | 71 |
38 | 33 |
39-1 | 88 |
40-1 | 42 |
43 | 33 |
12-1、12-2中保留时间2.955分钟对应的化合物 | 37 |
12-1、12-2中保留时间4.695分钟对应的化合物 | 41 |
45-1 | 51 |
结论:本发明化合物对NIH3T3细胞增殖有明显的抑制活性。
测试例5、本发明化合物对TGFβRI的Smad信号通路的抑制活性的测定
下面的体外试验是用来测定本发明化合物对TGFβRI的Smad信号通路的抑制活性。
以下所述实验方法用来测定本发明化合物对TGFβRI的Smad信号通路的抑制活性:
在96孔板中用含10%FBS的EMEM培养液(42360-099,Gibco)每孔接种100μl HepG2(TCHu 72,中国科学院典型培养物保藏委员会细胞库)细胞,接种密度为2.5x104细胞/孔,细胞在37℃,5%CO2条件下培养过夜。更换含10%FBS的EMEM新鲜培养液,每孔转染0.1μg 3TP-lux质粒(11767,普如汀生物技术(北京)有限公司),细胞继续在37℃,5%CO2条件下培养24小时。每孔更换90μl含0.5%FBS的EMEM培养液,饥饿6小时。将化合物配置成20mM的储存
液,用100%DMSO梯度稀释成400×的浓度,再用含0.5%FBS的EMEM稀释40倍。取出细胞培养板,每孔分别加入10μl稀释后的化合物或对照(0.25%DMSO),轻轻振荡混匀,放置37℃,5%CO2培养箱中培养18小时,最后每孔加入100μl检测试剂ONE-GloTM Luciferase Assay(E6110,Promega),室温避光放置10分钟,采用Victor3.0(PerkinElmer)读取化学发光信号值。用Graphpad Prism软件根据化合物各浓度与相应的信号值计算化合物的IC50值。
本发明化合物生物活性由上述分析所得,计算所得的IC50值如下表5:
表5本发明化合物对TGFβRI的Smad信号通路抑制的IC50
实施例编号 | IC50(nM) |
1-1 | 36 |
1-2 | 15 |
2-1 | 21 |
3-1 | 19 |
4 | 86 |
4-1、4-2中保留时间4.058分钟对应的化合物 | 27 |
4-1、4-2中保留时间7.204分钟对应的化合物 | 60 |
5-1 | 75 |
6 | 21 |
6-1、6-2中保留时间3.747分钟对应的化合物 | 4 |
6-1、6-2中保留时间5.327分钟对应的化合物 | 3 |
7 | 6 |
9 | 82 |
10 | 23 |
11 | 26 |
12 | 33 |
13-1 | 37 |
14 | 81 |
17 | 96 |
17-1、7-2中保留时间9.196分钟对应的化合物 | 38 |
17-1、7-2中保留时间5.418分钟对应的化合物 | 71 |
18-1 | 88 |
5 | 39 |
3 | 58 |
20 | 53 |
26 | 86 |
9-1、9-2中保留时间6.631分钟对应的化合物 | 29 |
9-1、9-2中保留时间13.001分钟对应的化合物 | 94 |
3-2 | 31 |
1 | 57 |
32 | 8 |
33 | 87 |
35-1、35-2中保留时间7.153分钟对应的化合物 | 56 |
35-1、35-2中保留时间7.992分钟对应的化合物 | 87 |
36 | 18 |
37 | 61 |
38 | 11 |
39-1 | 24 |
40-1 | 18 |
42-1 | 31 |
2-2 | 36 |
43 | 11 |
12-1、12-2中保留时间2.955分钟对应的化合物 | 9 |
12-1、12-2中保留时间4.695分钟对应的化合物 | 13 |
45-1 | 32 |
46-1 | 79 |
47-1 | 53 |
结论:本发明化合物均对TGFβRI的Smad信号通路具有明显的抑制活性。
药代动力学评价
测试例6、本发明化合物的药代动力学测试
1、摘要
以大鼠为受试动物,应用LC/MS/MS法测定了大鼠灌胃给予实施例1-1化合物、实施例1-2化合物、实施例2-1化合物、实施例3-1化合物、实施例9-1、9-2中保留时间6.631分钟对应的化合物、实施例33化合物和实施例39-1化合物后不同时刻血浆中的药物浓度。研究本发明化合物在大鼠体内的药代动力学行为,评价其药动学特征。
2、试验方案
2.1试验药品
实施例1-1化合物、实施例1-2化合物、实施例2-1化合物、实施例3-1化合物、实施例9-1、9-2中保留时间6.631分钟对应的化合物、实施例33化合物、实施例39-1化合物。
2.2试验动物
健康成年SD大鼠28只,雌雄各半,平均分成7组,每组4只,购自上海西普尔-必凯实验动物有限公司,动物生产许可证号:SCXK(沪)2008-0016。
2.3药物配制
称取一定量药物,加5%体积的DMSO、5%体积的吐温80和90%体积的生理盐水配制成0.2mg/mL的无色澄清透明液体。
2.4给药
SD大鼠禁食过夜后灌胃给药,给药剂量均为2.0mg/kg,给药体积均为10.0mL/kg。
3、操作
大鼠灌胃给药实施例1-1化合物、实施例1-2化合物、实施例2-1化合物、实施例3-1化合物、实施例9-1、9-2中保留时间6.631分钟对应的化合物、实施例33化合物和实施例39-1化合物,于给药前及给药后0.5,1.0,2.0,4.0,6.0,8.0,11.0,24.0小时由眼眶采血0.2mL,置于肝素化试管中,4℃、3500转/分钟离心10分钟分离血浆,于-20℃保存,给药后2小时进食。
测定不同浓度的药物灌胃给药后大鼠血浆中的待测化合物含量:取给药后各时刻的大鼠血浆25μL,加入内标溶液喜树碱50μL(100ng/mL),乙腈175μL,涡旋混合5分钟,离心10分钟(4000转/分钟),血浆样品取上清液3.0μL进行LC/MS/MS分析。
4、药代动力学参数结果
表6、本发明化合物的药代动力学参数如下:
结论:本发明化合物的药代吸收良好,具有明显的药代动力学优势。
Claims (22)
- 一种通式(I)所示的化合物:或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,其中:G1和G2为N或C,且当G1为N时,G2为C;当G1为C时,G2为N;环A为芳基或杂芳基;环B选自芳基、杂芳基和杂环基;R1相同或不同,且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基;R2相同或不同,且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、氧代基、-OR4、-C(O)R4、-C(O)OR4、-NHC(O)OR4、-O(CH2)xOR4、-NH(CH2)xOR4、-NR5R6、-O(CH2)xC(O)NR5R6、-NH(CH2)xNR5R6和-C(O)NR5R6,其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氢原子、烷基、烷氧基、卤素、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-S(O)mNR8R9、-NR8R9和-C(O)NR8R9中的一个或多个取代基所取代;R3相同或不同,且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氨基、氰基和硝基;R4选自氢原子、烷基、卤代烷基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、烷氧基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代;R5和R6各自独立地选自氢原子、烷基、卤代烷基、烷氧基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、烷氧基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-NR8R9、-C(O)R7、-C(O)OR7、-S(O)mNR8R9和-S(O)mR7中的一个或多个取代基所取代;R7选自氢原子、烷基、卤代烷基、羟烷基、氨基、烯基、炔基、环烷基、杂 环基、芳基和杂芳基;R8和R9各自独立地选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基;n为0、1或2;s为0、1或2;r为1或2;p为0、1或2;q为0、1或2;m为0、1或2;且x为0、1、2、3或4。
- 根据权利要求1-3中任一项所述的通式(I)所示的化合物,其中R1为烷 基或卤素,优选为甲基、乙基、氯原子、溴原子或氟原子。
- 一种药物组合物,所述药物组合物含有治疗有效量的根据权利要求1~9中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
- 根据权利要求1~9中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求15所述的药物组合物在制备用于治疗、预防或减少肿瘤细胞转移的药物中的用途。
- 一种治疗、预防或减少肿瘤细胞转移的方法,其包括向患者施用治疗有效剂量的根据权利要求1~9任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐或根据权利要求15所述的药物组合物。
- 根据权利要求1~9中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求15所述的药物组合物在制备用于治疗、预防或减少由TGF-β过度表达介导的癌症的药物中的用途。
- 一种治疗、预防或减少由TGF-β过度表达介导的癌症的方法,其包括向患者施用治疗有效剂量的根据权利要求1~9任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐或根据权利要求15所述的药物组合物。
- 根据权利要求1~9中任一项所述的通式(I)所示的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求15所述的药物组合物,其用作TGF-β受体激酶抑制剂。
- 根据权利要求1~9中任一项所述的通式(I)所示的化合物或根据权利要求15所述的药物组合物在制备用于治疗、预防或减轻选自下述疾病的药物中的用途:血管损伤、肾小球性肾炎、糖尿病性肾病、狼疮性肾炎、高血压-诱发的肾病、肾间质性纤维化、由药物暴露并发症所致肾纤维化、与HIV有关的肾病、移植物肾病、各种病因的肝纤维化、可归因于感染的肝功能障碍、酒精诱发的肝炎、囊性纤维化病、间质性肺病、急性肺损伤、成人呼吸窘迫综合征、骨髓增生异常综合征、特发性肺纤维化、慢性阻塞性肺病、由感染性或毒性因子引起的肺病、梗塞后心纤维化、充血性心力衰竭、扩张型心肌病、心肌炎、内膜增厚、血管狭窄、高血压引起的血管重构、肺动脉高压、冠状动脉再狭窄、周围动脉再狭窄、颈动脉再狭窄、支架诱导的再狭窄、动脉粥样硬化、眼部瘢痕形成、角膜瘢痕形成、增生性玻璃体视网膜病变、青光眼、眼内压高、发生在由创伤或手术伤口所致伤口愈合期间的过度性或肥厚性真皮瘢痕或瘢痕疙瘩形成、腹膜与皮下粘连、硬皮病、纤维硬化、进行性***性硬化病、皮肌炎、多肌炎、关节炎、骨质疏松、溃疡、 神经***功能减低、男性***功能障碍、佩罗尼氏病、杜普伊特伦氏挛缩、阿尔茨海默氏病、雷诺氏综合征、辐射-诱发的纤维化、血栓形成、肿瘤转移性生长、多发性骨髓瘤、黑素瘤、神经胶质瘤、胶质母细胞瘤、白血病、肉瘤、平滑肌瘤、间皮瘤、乳腺癌、***、肺癌、胃癌、直肠癌、结肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、***癌、骨癌、肾癌、卵巢癌、膀胱癌和肝癌。
- 一种治疗、预防或减轻选自下述疾病的方法:血管损伤、肾小球性肾炎、糖尿病性肾病、狼疮性肾炎、高血压-诱发的肾病、肾间质性纤维化、由药物暴露并发症所致肾纤维化、与HIV有关的肾病、移植物肾病、各种病因的肝纤维化、可归因于感染的肝功能障碍、酒精-诱发的肝炎、囊性纤维化病、间质性肺病、急性肺损伤、成人呼吸窘迫综合征、骨髓增生异常综合征、特发性肺纤维化、慢性阻塞性肺病、由感染性或毒性因子引起的肺病、梗塞后心纤维化、充血性心力衰竭、扩张型心肌病、心肌炎、内膜增厚、血管狭窄、高血压引起的血管重构、肺动脉高压、冠状动脉再狭窄、周围动脉再狭窄、颈动脉再狭窄、支架诱导的再狭窄、动脉粥样硬化、眼部瘢痕形成、角膜瘢痕形成、增生性玻璃体视网膜病变、青光眼、眼内压高、发生在由创伤或手术伤口所致伤口愈合期间的过度性或肥厚性真皮瘢痕或瘢痕疙瘩形成、腹膜与皮下粘连、硬皮病、纤维硬化、进行性***性硬化病、皮肌炎、多肌炎、关节炎、骨质疏松、溃疡、神经***功能减低、男性***功能障碍、佩罗尼氏病、杜普伊特伦氏挛缩、阿尔茨海默氏病、雷诺氏综合征、辐射-诱发的纤维化、血栓形成、肿瘤转移性生长、多发性骨髓瘤、黑素瘤、神经胶质瘤、胶质母细胞瘤、白血病、肉瘤、平滑肌瘤、间皮瘤、乳腺癌、***、肺癌、胃癌、直肠癌、结肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、***癌、骨癌、肾癌、卵巢癌、膀胱癌和肝癌,其包括给予所需患者治疗有效量的根据权利要求1~9任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物。
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CN108779115A (zh) | 2018-11-09 |
EP3527570A4 (en) | 2020-04-15 |
EP3527570A1 (en) | 2019-08-21 |
US10906905B2 (en) | 2021-02-02 |
JP2019534266A (ja) | 2019-11-28 |
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