WO2018233696A1 - 作为mek抑制剂的类香豆素环类化合物及其应用 - Google Patents
作为mek抑制剂的类香豆素环类化合物及其应用 Download PDFInfo
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- WO2018233696A1 WO2018233696A1 PCT/CN2018/092457 CN2018092457W WO2018233696A1 WO 2018233696 A1 WO2018233696 A1 WO 2018233696A1 CN 2018092457 W CN2018092457 W CN 2018092457W WO 2018233696 A1 WO2018233696 A1 WO 2018233696A1
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- 0 CC(N1C2CC2)=CC(OC(C(C)=C2*)=O)=C2C1=O Chemical compound CC(N1C2CC2)=CC(OC(C(C)=C2*)=O)=C2C1=O 0.000 description 2
- OPKAGVRBWHZYKM-UHFFFAOYSA-N CN(S(C)(=O)=O)S(C)(=O)=O Chemical compound CN(S(C)(=O)=O)S(C)(=O)=O OPKAGVRBWHZYKM-UHFFFAOYSA-N 0.000 description 2
- FYFFNYBMNIHCRO-UHFFFAOYSA-N CC(C(OC(C(Br)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(cccc1)c1F Chemical compound CC(C(OC(C(Br)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(cccc1)c1F FYFFNYBMNIHCRO-UHFFFAOYSA-N 0.000 description 1
- QXAHMUXWCXYICS-UHFFFAOYSA-N CC(C(OC(C(c1cc(NC(C2COC2)=O)ccc1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I Chemical compound CC(C(OC(C(c1cc(NC(C2COC2)=O)ccc1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I QXAHMUXWCXYICS-UHFFFAOYSA-N 0.000 description 1
- SIFPUZQVIMKREA-UHFFFAOYSA-N CC(C(OC(C(c1cccc(CN(C)C)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(ccc(I)c1)c1F Chemical compound CC(C(OC(C(c1cccc(CN(C)C)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(ccc(I)c1)c1F SIFPUZQVIMKREA-UHFFFAOYSA-N 0.000 description 1
- OTQIKEDORUUWTH-UHFFFAOYSA-N CC(C(OC(C(c1cccc(CNC)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I Chemical compound CC(C(OC(C(c1cccc(CNC)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I OTQIKEDORUUWTH-UHFFFAOYSA-N 0.000 description 1
- ZJCSHNYFRYFHPL-UHFFFAOYSA-N CC(C(OC(C(c1cccc(CS(C)(=O)=O)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I Chemical compound CC(C(OC(C(c1cccc(CS(C)(=O)=O)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I ZJCSHNYFRYFHPL-UHFFFAOYSA-N 0.000 description 1
- TWIQUYYJAHOIFR-UHFFFAOYSA-N CC(C(OC(C(c1cccc(CS(C)=O)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I Chemical compound CC(C(OC(C(c1cccc(CS(C)=O)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I TWIQUYYJAHOIFR-UHFFFAOYSA-N 0.000 description 1
- WATUSBUSEMWLBY-UHFFFAOYSA-N CC(C(OC(C(c1cccc(N(S(C)(=O)=O)S(C)(=O)=O)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I Chemical compound CC(C(OC(C(c1cccc(N(S(C)(=O)=O)S(C)(=O)=O)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I WATUSBUSEMWLBY-UHFFFAOYSA-N 0.000 description 1
- VPIDAPHRGWCODY-UHFFFAOYSA-N CC(C(OC(C(c1cccc(NC(C(OC)OC)=O)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I Chemical compound CC(C(OC(C(c1cccc(NC(C(OC)OC)=O)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I VPIDAPHRGWCODY-UHFFFAOYSA-N 0.000 description 1
- CGAZDXBJRNLOCQ-UHFFFAOYSA-N CC(C(OC(C(c1cccc(NC(COC)=O)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I Chemical compound CC(C(OC(C(c1cccc(NC(COC)=O)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I CGAZDXBJRNLOCQ-UHFFFAOYSA-N 0.000 description 1
- AOPASZQTZIEOJS-UHFFFAOYSA-N CC(C(OC(C(c1cccc(NS(C)(=O)=O)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I Chemical compound CC(C(OC(C(c1cccc(NS(C)(=O)=O)c1)=C(C)N1C2CC2)=C2C1=O)=O)=C2Nc(c(F)c1)ccc1I AOPASZQTZIEOJS-UHFFFAOYSA-N 0.000 description 1
- XRNPIIZKEOJUAP-UHFFFAOYSA-N CC(N1CCCOC)=CC(OC(C(C)=C2Nc(c(F)c3)ccc3I)=O)=C2C1=O Chemical compound CC(N1CCCOC)=CC(OC(C(C)=C2Nc(c(F)c3)ccc3I)=O)=C2C1=O XRNPIIZKEOJUAP-UHFFFAOYSA-N 0.000 description 1
- KINCONDIDKPIDN-UHFFFAOYSA-N CC(N1CCOC)=CC(OC(C(C)=C2Nc(c(F)c3)ccc3I)=O)=C2C1=O Chemical compound CC(N1CCOC)=CC(OC(C(C)=C2Nc(c(F)c3)ccc3I)=O)=C2C1=O KINCONDIDKPIDN-UHFFFAOYSA-N 0.000 description 1
- MQAKBIIVRARTHD-UHFFFAOYSA-N CC(NCc1cccc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(C2CC2)C3=O)c1)=O Chemical compound CC(NCc1cccc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(C2CC2)C3=O)c1)=O MQAKBIIVRARTHD-UHFFFAOYSA-N 0.000 description 1
- NZSGPUKPTAVDOW-UHFFFAOYSA-N CC(Nc1cc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(C2CCOCC2)C3=O)ccc1)=O Chemical compound CC(Nc1cc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(C2CCOCC2)C3=O)ccc1)=O NZSGPUKPTAVDOW-UHFFFAOYSA-N 0.000 description 1
- JHKLOUSHBNJEDR-UHFFFAOYSA-N CC(Nc1cc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(CC(CO)O)C3=O)ccc1)=O Chemical compound CC(Nc1cc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(CC(CO)O)C3=O)ccc1)=O JHKLOUSHBNJEDR-UHFFFAOYSA-N 0.000 description 1
- LXGQYUBKOYGUTH-UHFFFAOYSA-N CC(Nc1cc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(CCCOC)C3=O)ccc1)=O Chemical compound CC(Nc1cc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(CCCOC)C3=O)ccc1)=O LXGQYUBKOYGUTH-UHFFFAOYSA-N 0.000 description 1
- JFZYKLLFGMGBQC-UHFFFAOYSA-N CC(Nc1cc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(CCN(C)C(C)=O)C3=O)ccc1)=O Chemical compound CC(Nc1cc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(CCN(C)C(C)=O)C3=O)ccc1)=O JFZYKLLFGMGBQC-UHFFFAOYSA-N 0.000 description 1
- JNZSXVYPQMJBCI-UHFFFAOYSA-N CC(Nc1cc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(CCN(C)S(C)(=O)=O)C3=O)ccc1)=O Chemical compound CC(Nc1cc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(CCN(C)S(C)(=O)=O)C3=O)ccc1)=O JNZSXVYPQMJBCI-UHFFFAOYSA-N 0.000 description 1
- VAJYKZSEOBOART-UHFFFAOYSA-N CC(Nc1cc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(CCNC)C3=O)ccc1)=O Chemical compound CC(Nc1cc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(CCNC)C3=O)ccc1)=O VAJYKZSEOBOART-UHFFFAOYSA-N 0.000 description 1
- VEPVDDYNBLUXCQ-UHFFFAOYSA-N CC(Nc1cc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(CCOC)C3=O)ccc1)=O Chemical compound CC(Nc1cc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(CCOC)C3=O)ccc1)=O VEPVDDYNBLUXCQ-UHFFFAOYSA-N 0.000 description 1
- AINMTRNMOZEJSP-UHFFFAOYSA-N CC(Nc1cccc(CC(C(O2)=C3C(Nc(ccc(I)c4)c4F)=C(C)C2=O)=C(C)N(C2CC2)C3=O)c1)=O Chemical compound CC(Nc1cccc(CC(C(O2)=C3C(Nc(ccc(I)c4)c4F)=C(C)C2=O)=C(C)N(C2CC2)C3=O)c1)=O AINMTRNMOZEJSP-UHFFFAOYSA-N 0.000 description 1
- VZLKIPIRAJPXMD-UHFFFAOYSA-N CC(Nc1nc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(C2CC2)C3=O)cnc1)=O Chemical compound CC(Nc1nc(C(C(O2)=C3C(Nc(c(F)c4)ccc4I)=C(C)C2=O)=C(C)N(C2CC2)C3=O)cnc1)=O VZLKIPIRAJPXMD-UHFFFAOYSA-N 0.000 description 1
- MXJMSZOCWKUIOP-UHFFFAOYSA-N CCN(C)S(C)(=O)=O Chemical compound CCN(C)S(C)(=O)=O MXJMSZOCWKUIOP-UHFFFAOYSA-N 0.000 description 1
- PZVFQOBASICMME-UHFFFAOYSA-N CCNS(C)(=O)=O Chemical compound CCNS(C)(=O)=O PZVFQOBASICMME-UHFFFAOYSA-N 0.000 description 1
- WCFDSGHAIGTEKL-UHFFFAOYSA-N CN(C)S(C)(=O)=O Chemical compound CN(C)S(C)(=O)=O WCFDSGHAIGTEKL-UHFFFAOYSA-N 0.000 description 1
- NRVCJRHYKFYMDJ-UHFFFAOYSA-N CNCCCC(CO)O Chemical compound CNCCCC(CO)O NRVCJRHYKFYMDJ-UHFFFAOYSA-N 0.000 description 1
- DUHAOXIKDKRWHH-UEJVZZJDSA-N C[C@@H]1C(C2OCCN(C)C2)OC1 Chemical compound C[C@@H]1C(C2OCCN(C)C2)OC1 DUHAOXIKDKRWHH-UEJVZZJDSA-N 0.000 description 1
- HSMRNVBIWWWKJF-UHFFFAOYSA-N Cc(cc1F)ccc1NC(C(C(N(C1CC1)C(C)=C1c2cc(N)ncc2)=O)=C1O1)=C(C)C1=O Chemical compound Cc(cc1F)ccc1NC(C(C(N(C1CC1)C(C)=C1c2cc(N)ncc2)=O)=C1O1)=C(C)C1=O HSMRNVBIWWWKJF-UHFFFAOYSA-N 0.000 description 1
- HJFZAYHYIWGLNL-UHFFFAOYSA-N Cc1nc(C)cnc1 Chemical compound Cc1nc(C)cnc1 HJFZAYHYIWGLNL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- 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
- A61K31/4427—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
- A61K31/495—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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to a class of coumarin-like compounds as MEK inhibitors and pharmaceutical compositions comprising such compounds, and their use in the manufacture of a medicament for the treatment of MEK-related diseases. Specifically, it relates to a compound of the formula (I) and a pharmaceutically acceptable salt thereof.
- the MAPK pathway exists in a series of cellular processes such as cell proliferation, differentiation, apoptosis and stress response.
- MAPK pathways There are currently four known MAPK pathways: ERK1/2, JNK, p38 and ERK5.
- One of the most important and well-known MAPK pathways is the Ras/Raf kinase pathway. This pathway is firstly combined with a transmembrane receptor (ie, PDGFR or EGFR or ErbB2, etc.) by an extracellular growth factor (ie, PDGF or EGF, etc.) to activate the receptor, and the activated receptor passes a guanylate exchange factor (such as SOS).
- Ras binds to GTP and activates in the membrane; activated Ras further phosphorylates indirectly and activates Raf (MAPKKK in this pathway); then, two serines of activated Raf in MEK1/2 (MAPKK in this pathway) Phosphorylation was performed on the residues (MEK1 corresponds to S218 and S222; MEK2 corresponds to S222 and S226) (Ahn et al., Methods in Enzymology, 2001, 332, 417-431). Phosphorylated ERK dimerizes and migrates into the nucleus and accumulates (Khokhlatchev et al., Cell, 1998, 93, 605-615).
- ERK in the nucleus involves many cellular functions including, but not limited to, nuclear transport, signal transduction, DNA repair, nucleosome assembly and migration, and mRNA processing and translation (Ahn et al., Molecular Cell, 2000, 6, 1343). -1354).
- the RAF-MEK-ERK pathway can transmit proliferation and anti-apoptotic signals from growth factors and oncogenic factors, thereby promoting cell growth, development and metastasis; if the pathway involves gene mutations or growth factors, downstream signaling proteins or protein kinases Overexpression will result in uncontrolled cell proliferation and ultimately tumor formation.
- cancer cell mutations cause overexpression of growth factors, resulting in sustained activation of the internal MAPK pathway; or the inability to deactivate the activated Ras complex due to mutations, which also contributes to the continued activation of the MAPK pathway; bRaf mutations have been identified from more than 60% of melanomas (Davies, H. et al., Nature, 2002, 417, 949-954).
- MAPK pathway is at the central position in cell proliferation and differentiation, inhibition of this pathway will facilitate the treatment of a variety of hyperproliferative diseases, and MEK downstream of Ras and Raf in this pathway becomes a key player in this pathway.
- MEK downstream of Ras and Raf in this pathway becomes a key player in this pathway.
- the substrate that can be phosphorylated and activated by MEK has only MAPK, namely ERK1 and ERK2. This strict selectivity and the unique ability of its bifunctional kinase make it an attractive drug target. Potential and wide range of therapeutic applications, such as malignant and benign hyperproliferative diseases, immune regulation and inflammation.
- Raf and MEK inhibitors are currently in clinical and market stages for the MAPK signaling pathway.
- Sorafenib (Bay 43-9006), approved by the FDA in December 2005, is a non-specific silk/threonine and tyrosine kinase inhibitor that targets Raf, MEK, VEGFR2/3, and Flt-3. , PDGFR, c-Kit, etc.
- B-Raf-specific inhibitors such as dabrafenib (GSK21 18436) and vemurafenib (PLX4032) have good clinical outcomes, but have a short duration, and clinical studies have found that long-term treatment with B-Raf inhibitors leads to patient acquiredness. Drug resistance.
- MEK inhibitors are often used in combination with B-Raf inhibitors clinically.
- Specific inhibition of the MEK1/2 inhibitor Trametiniib (GSK-1 120212) was approved by the FDA in May 2013 and was approved in March 2014 for treatment with advanced melanoma in combination with dabrafenib; specific inhibition of the MEK1/2 inhibitor cobimetinib Approved by the FDA in 2015 for use in combination with vemurafenib for melanoma treatment.
- Binimetinib applied to the FDA for the registration of melanoma treatment for N-RAS mutations.
- MEK1/2 inhibitors such as Selumetinib and reametinibd in the clinical stage.
- the present invention provides a compound of the formula (I), a pharmaceutically acceptable salt thereof or a tautomer thereof:
- n is selected from: 0, 1 or 2;
- r is selected from: 0, 1, 2 or 3;
- n is selected from: 0 or 1; when m is selected from 0, Is H;
- Ring A is selected from the group consisting of: phenyl or 5- to 6-membered heteroaryl;
- R 1 is selected from H or is selected from the group consisting of: 1, 2, or 3 R: NH 2 , C 1-6 alkyl, 3 to 6-membered heterocycloalkyl, C 3-6 cycloalkyl, C 1- 3 heteroalkyl;
- R 2 is selected from H or is selected from C 1 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 5-6 hexavalent optionally substituted by 1, 2 or 3 R. Cycloalkyl;
- R 3 is selected from the group consisting of: H, F, Cl, Br, I, or selected from, optionally substituted by 1, 2 or 3 R: C 1-3 alkyl, C 1-3 alkoxy, C 1-4 Alkynyl, C 1-4 alkenyl, phenyl;
- R 4 and R 5 are each independently selected from H, F, Cl, Br, I, NH 2 , OH, or selected from the group consisting of 1, 2 or 3 R: C 1-6 alkyl, C 1 -3 alkoxy;
- R 3 and R 4 are bonded to form one: a 5- to 7-membered cycloalkyl group, a 5- to 7-membered heterocycloalkyl group, a 5- to 7-membered aryl group or a 5- to 7-membered heteroaryl group;
- R 6 and R 7 are each independently selected from the group consisting of: H, F, Cl, Br, I, CH 3 , Et, CH 3 -O-, CH 3 -CH 2 -O-;
- R is selected from the group consisting of: F, Cl, Br, I, OH, or selected from the group consisting of 1, 2 or 3 R's substituted: NH 2 , C 1-3 alkyl, C 1-3 heteroalkyl; R 'selected from F, Cl, Br, I, NH 2 or C 1-3 alkyl;
- the number of heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
- R ' is selected from F, Cl, Br, I, NH 2 or CH 3.
- the above R is selected from the group consisting of: F, Cl, Br, I, OH, or selected from the group consisting of 1, 2 or 3 R' substitutions: NH 2 , CH 3 ,
- the above R is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CH 3 ,
- the A ring is selected from the group consisting of phenyl, pyridyl or pyrazinyl.
- the A ring is selected from the group consisting of:
- the above L is selected from the group consisting of: a single bond, -NH-, -N(CH 3 )-,
- R 1 is selected from H or is selected from the group consisting of: 1, 2, or 3 R: NH 2 , methyl, ethyl, isobutyl, acetonyl, Alkyl group, cyclopropyl group, CH 3 -O-.
- R 1 is selected from H or is selected from the group consisting of: 1, 2, or 3 R: NH 2 , Me, Et,
- R 1 is selected from the group consisting of: H, NH 2 , CH 3 , CF 3 , Et,
- R 2 is selected from H or is selected from the group consisting of: 1, 2 or 3, R: methyl, ethyl, propyl, cyclopropyl, tetrahydropyranyl.
- R 2 is selected from H or is selected from: CH 3 optionally substituted by 1, 2 or 3 R,
- R 2 is selected from the group consisting of: H, CH 3 ,
- R 3 is selected from the group consisting of H, F, Cl, Br, I, CH 3 , CF 3 or CH 3 -O-.
- R 4 and R 5 are each independently selected from the group consisting of H, F, Cl, Br, I, CH 3 , CH 3 CH 2 -, CH 3 -O-.
- the structural unit From:
- R ' is selected from F, Cl, Br, I, NH 2 or CH 3, the other variables are as defined in the present invention.
- R is selected from the group consisting of: F, Cl, Br, I, OH, or selected from the group consisting of 1, 2 or 3 R' substitutions: NH 2 , CH 3 , Other variables are as defined by the present invention.
- the above R is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CH 3 , Other variables are as defined by the present invention.
- the A ring is selected from the group consisting of phenyl, pyridyl or pyrazinyl, and other variables are as defined above.
- the A ring is selected from the group consisting of: Other variables are as defined by the present invention.
- the above L is selected from the group consisting of: a single bond, -NH-, -N(CH 3 )-, Other variables are as defined by the present invention.
- R 1 is selected from H or is selected from the group consisting of: 1, 2, or 3 R: NH 2 , methyl, ethyl, isobutyl, acetonyl, morpholinyl, cyclopropyl, CH 3 -O-, the other variables are as defined in the present invention.
- R 1 is selected from H or is selected from the group consisting of: 1, 2, or 3 R: NH 2 , Me, Et, Other variables are as defined by the present invention.
- R 1 is selected from the group consisting of: H, NH 2 , CH 3 , CF 3 , Et, Other variables are as defined by the present invention.
- R 2 is selected from H or is selected from the group consisting of: 1, 2 or 3 R substituted: methyl, ethyl, propyl, cyclopropyl, tetrahydropyranyl, others Variables are as defined by the present invention.
- R 2 is selected from H or is selected from: CH 3 optionally substituted by 1, 2 or 3 R, Other variables are as defined by the present invention.
- R 2 is selected from the group consisting of: H, CH 3 , Other variables are as defined by the present invention.
- R 3 is selected from the group consisting of: H, F, Cl, Br, I, CH 3 , CF 3 or CH 3 -O-, and other variables are as defined herein.
- R 4 and R 5 are each independently selected from the group consisting of: H, F, Cl, Br, I, CH 3 , CH 3 CH 2 -, CH 3 -O-, and other variables such as the present invention definition.
- the above compounds, pharmaceutically acceptable salts thereof, and isomers thereof are selected from the group consisting of:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L, r and n are as defined in the present invention.
- the present invention also provides a compound of the formula: a pharmaceutically acceptable salt thereof or a tautomer thereof, the compound of which is selected from the group consisting of:
- the above compound is selected from the group consisting of
- the salt is selected from the group consisting of a hydrochloride or a formate.
- the hydrochloride salt is selected from the group consisting of
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
- the invention also provides the use of a compound as described above, or a pharmaceutically acceptable salt thereof, or a composition as described above, for the manufacture of a medicament for the treatment of a MEK related disorder.
- pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
- a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
- an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
- pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
- the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
- the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
- a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
- pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
- Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
- non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
- such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
- a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
- Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
- wedge-shaped dashed keys Represents the absolute configuration of a stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Straight solid key And straight dashed keys Indicates the relative configuration of the stereocenter.
- the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.
- “Enriched in one isomer” means that the content of one of the isomers is ⁇ 100%, and ⁇ 60%, preferably ⁇ 70%, more preferably ⁇ 80%, more preferably ⁇ 90%, more preferably ⁇ 95%, More preferably ⁇ 96%, more preferably ⁇ 97%, more preferably ⁇ 98%, more preferably ⁇ 99%, more preferably ⁇ 99.5%, more preferably ⁇ 99.6%, more preferably ⁇ 99.7%, more preferably ⁇ 99.8%, more preferably ⁇ 99.9%.
- An excess of isomer refers to the difference between the relative percentages of the two isomers. For example, if one of the isomers is 90% and the other isomer is 10%, the isomer excess is 80%.
- (+) means right-handed, (-) means left-handed, and ( ⁇ ) means racemic.
- the compounds of the invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
- Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
- optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
- a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
- the diastereomers are resolved and the pure enantiomer is recovered.
- the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
- radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
- substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
- Oxygen substitution does not occur on the aromatic group.
- optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
- any variable eg, R
- its definition in each case is independent.
- the group may optionally be substituted with at most two R, and each case has an independent option.
- combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
- one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
- a substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A.
- the substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
- substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
- the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
- ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
- 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
- ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
- heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a hetero atom which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
- the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
- the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
- the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
- the nitrogen atom in the heterocycle is optionally quaternized.
- a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred option is that the total number of S and O atoms in the heterocycle does not exceed one.
- aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
- the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
- the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
- bridged rings are also included in the definition of heterocycles.
- a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
- Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
- heterocyclic compounds include, but are not limited to, acridinyl, anthracycline, benzimidazolyl, benzofuranyl, benzofurylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl, ind
- hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
- the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
- C 1-12 is selected from C 1
- Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
- An aromatic hydrocarbon group such as benzene, naphthalene or the like.
- hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
- saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
- a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
- the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
- heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
- heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
- the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
- the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
- Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
- cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
- a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
- cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
- heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
- alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
- alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
- alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
- alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.
- alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
- alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
- a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or polyvalent.
- Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
- halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
- haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
- halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
- examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
- alkoxy represents attached through an oxygen bridge
- C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
- alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
- aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
- heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
- a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
- aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
- aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
- aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
- alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
- the solvent used in the present invention is commercially available.
- the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
- the compounds of the invention have good MEK biological activity and tumor cell growth inhibition ability associated with this signaling pathway.
- reaction methods commonly used in the present invention are as follows:
- the substrate (1.00 eq) and boron ester/boric acid (1.00-2.00 eq) were dissolved in a solvent, and Pd(dppf)Cl 2 .CH 2 Cl 2 (0.10 eq) and base (2.00-) were added under nitrogen at 20 ° C under nitrogen. 3.00 eq), the temperature was raised to 85-100 ° C to stir the reaction. After completion of the reaction, it was cooled to room temperature, water was added, and then extracted with dichloromethane / ethyl acetate. The organic phase was collected, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated The crude product was purified by column chromatography to give the title compound.
- the substrate (1.00 eq) and boron ester/boric acid (1.00-2.00 eq) were added to the solvent, and Pd(dppf)Cl 2 .CH 2 Cl 2 (0.10 eq) and base (2.00-5.00 eq) were added under nitrogen.
- the reaction was stirred by heating to 60-110 °C. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate / methylene chloride. The organic phase was combined and dried over anhydrous sodium sulfate, filtered and evaporated to dryness
- the substrate (1.00 eq) was added to the solvent at 15 ° C, and boron ester/boric acid (1.20 eq), Pd 2 (dba) 3 (0.10 eq), RuPhos (0.10 eq), base (2.00 eq) was added.
- the reaction was stirred by raising the temperature to 130 °C. After completion of the reaction, it was cooled to room temperature, water was added, and ethyl acetate / dichloromethane was evaporated. The organic phase was collected, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate The crude product was purified by column chromatography to give the title compound.
- the substrate (1.00 eq) and boron ester/boric acid (2.00 eq) were dissolved in a solvent, and SPhos (0.10 eq), Pd 2 (dba) 3 (0.05 eq), base (2.00-2.50 eq) was added under a nitrogen atmosphere. .
- the reaction was stirred by raising the temperature to 110-120 °C. After completion of the reaction, it was diluted with water and extracted with dichloromethane / ethyl acetate. The organic phase was collected, dried, and purified by column chromatography to give the title compound.
- the substrate (1.00 eq) was dissolved in N,N-dimethylformamide and trifluoroacetic acid and N-iodosuccinimide (1.50-3.00 eq) were added under nitrogen at 0 °C.
- the reaction was stirred at 30 °C.
- the reaction mixture was dried with EtOAc EtOAc m.
- Step 1 Synthesis of compound BA-1-2.
- Step 2 - Method A Synthesis of compound BA-1-3.
- Step 2 - Method B Synthesis of compound BA-1-3.
- Step 4 Synthesis of compound BA-1-5.
- Step 5 Synthesis of compound BA-1.
- Step 1 Synthesis of Compound BA-2.
- Step 1 Synthesis of Compound BA-3-1.
- Step 1 Synthesis of Compound BA-4-1.
- Step 1 Synthesis of compound BA-5-2.
- Step 4 Synthesis of compound BA-5-5.
- Step 5 Synthesis of compound BA-5.
- Step 1 Synthesis of compound BA-6-2.
- Step 1 Synthesis of Compound BB-1.
- Step 1 Synthesis of compound BB-2-2.
- Step 2 Synthesis of compound BB-2.
- Step 1 Synthesis of compound BB-3-2.
- Step 2 Synthesis of compound BB-3.
- Step 1 Synthesis of compound BB-4-2.
- Step 2 Synthesis of compound BB-4.
- Step 1 Synthesis of compound BB-6-2.
- Step 2 Synthesis of compound BB-6-3.
- Step 3 Synthesis of compound BB-6.
- Step 1 Synthesis of compound BB-7-2.
- Step 2 Synthesis of compound BB-7-3.
- Step 3 Synthesis of compound BB-7-4.
- Step 4 Synthesis of compound BB-7.
- Step 1 Synthesis of compound BB-8.
- Step 1 Synthesis of compound BB-9-2.
- Step 2 Synthesis of compound BB-9.
- Step 1 Synthesis of compound BB-10-2.
- the organic phase was washed sequentially with saturated sodium bicarbonate solution (100 mL*2) and water (100 mL).
- the aqueous phase was extracted with dichloromethane (100 mL*2).
- the organic phase was dried over anhydrous sodium sulfate and dried to dryness.
- the crude product was triturated with methyl tert-butyl ether (10 mL) and petroleum ether (10 mL) to afford compound BB-10-2.
- Step 2 Synthesis of compound BB-10-3.
- the crude material was diluted with ethyl acetate (200 mL) and washed with hydrochloric acid (3M, 100mL*3).
- the aqueous phase was extracted with additional ethyl acetate (100 mL).
- the organic phases were combined, dried over anhydrous sodium sulfate and evaporated to dryness.
- Step 3 Synthesis of compound BB-10.
- Step 1 Synthesis of compound BB-12-2.
- Step 2 Synthesis of compound BB-12.
- Step 1 Synthesis of compound BB-13-2.
- Step 2 Synthesis of compound BB-13.
- Step 1 Synthesis of Compound BB-14-2
- Methyl chloroformate (22.90 g, 242.33 mmol, 5.21 eq) was dissolved in dichloromethane (100.00 mL), and compound BB-10-1 (8.00) dissolved in dichloromethane (60.00 mL) was added at -10 °C. g, 46.51 mmol, 1.00 eq) and triethylamine (14.12 g, 139.53 mmol, 3.00 eq). The reaction was stirred at -10 ° C for 2 hours.
- reaction mixture was evaporated to dryness eluting with ethyl acetate (50mL), and then washed with water (30mL*2) and saturated sodium chloride solution (20mL). The organic phase was dried over anhydrous sodium sulfate, filtered and dried then evaporated. The crude product was slurried with methyl tert-butyl ether (20 mL).
- Step 1 Synthesis of compound BB-15-2.
- Step 1 Synthesis of Compound BB-16.
- Step 1 Synthesis of compound BB-17-2.
- Step 2 Synthesis of compound BB-17.
- Step 1 Synthesis of Compound BB-18-2.
- BB-18-1 (15.00 g, 74.60 mmol, 1.00 eq) was dissolved in dichloromethane (300.00 mL) and PBr 3 (13.13 g, 48.49 mmol, 4.61 mL, 0.65 eq) was added dropwise to the solution at 0 ° C. ), stirring at 25 ° C for 15 hours. After completion of the reaction, it was cooled to 0 ° C and then quenched with methanol (20 mL). It was washed successively with a saturated sodium hydrogen carbonate solution (100 mL*3) and water (100 mL*2). The organic phase was collected, dried over anhydrous sodium sulfate and dried to give compound br.
- Step 2 Synthesis of compound BB-18-3.
- Step 3 Synthesis of compound BB-18-4.
- Step 4 Synthesis of compound BB-18.
- Step 1 Synthesis of Compound BB-19-2
- Step 2 Synthesis of Compound BB-19-3
- Step 1 Synthesis of Compound BB-20
- Step 1 Synthesis of Compound BB-21-2
- Step 1 Synthesis of Compound BB-22-2
- the compound WX059-3 (700 mg, 3.35 mmol, 1.00 eq) was dissolved in diphenyl ether, and the compound methyl malonate (700.24 mg, 4.02 mmol, 686.51 ⁇ L, 1.20 eq) was added, and the mixture was heated to 250 ° C and stirred. Reaction for 2 hours. After completion of the reaction, petroleum ether (20 mL) was added, and a solid precipitated, which was filtered and washed with petroleum ether (5 mL) to give the title compound WX059-4.
- WX118-2 was subjected to supercritical fluid chromatography (separation condition chromatography column: Chiralpak AD-3 100 ⁇ 4.6 mm ID, 3 ⁇ m; mobile phase: A: CO 2 B: ethanol (0.05% DEA); gradient: 5% B in 4.5 minutes After the internal constant velocity was increased to 40% B, 40% B was maintained for 2.5 minutes, and then 5% B was eluted for 1 minute; flow rate: 2.8 mL/min; column temperature: 40 ° C), and the rotamers WX118 and WX119 were obtained.
- the retention time was 5.934 min, 4.958 min, and the ratio was 6:7.
- HT29 and A375 cells were plated in 96-well cell culture plates at 40,000 cells per well and 20,000 cells per well, respectively, and cultured overnight.
- the compounds were serially diluted in a 1:3 ratio, diluted and added to the cell culture medium, and incubated with the cells for 3 days in a 37 ° C incubator.
- the 96-well cell culture plate was taken out from the incubator, equilibrated at room temperature for 30 min, and Cell Titer-Glo reagent (Promega Cat #G7573) was added at a ratio of 1:2, and mixed for 2 min on a shaker to promote cell lysis.
- the cell culture plates were incubated for 10 min at room temperature and read on an Envision plate reader (PerkinElmer). Data analysis and mapping were performed using XLfit5 software. The experimental results are shown in Table 5.
- Human colon cancer HT-29 cells (ATCC-HTB-38) were cultured in vitro in a single culture in the condition of McCoy's 5a medium (Gibco, 1835937) plus 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin. Cultured at 37 ° C 5% CO 2 . Passage was routinely digested with trypsin-EDTA twice a week. When the cell saturation is 80%-90%, the cells are collected, counted, and inoculated. 0.1 mL (5 x 10 6 ) of HT-29 cells were subcutaneously inoculated into the right back of each nude mouse.
- TGI (%) [(1 - mean tumor volume at the end of administration of a treatment group - mean tumor volume at the start of administration of the treatment group)) / (average tumor at the end of treatment of the solvent control group) Volume-solvent control group average tumor volume at the start of treatment)] ⁇ 100%.
- the experimental results are shown in Table 6.
- the compounds of the present invention have a good tumor growth inhibitory effect.
- Intravenous and oral vehicles are a proportion of DMSO, PEG and water or Solutol, HPMC and SLS aqueous solutions. Collect whole blood samples within 24 hours, centrifuge at 3000 rpm for 15 minutes, separate the supernatant to obtain plasma samples, add 4 times volume of acetonitrile solution containing internal standard to precipitate protein, centrifuge to remove the supernatant, add equal volume of water and centrifuge.
- the supernatant was injected, and the plasma concentration was quantitatively analyzed by LC-MS/MS analysis, and the pharmacokinetic parameters such as peak concentration, peak time, clearance rate, half-life, area under the curve of the drug, and bioavailability were calculated.
- the compounds of the invention have good pharmacokinetic indices in rats.
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Abstract
Description
Claims (25)
- 式(Ⅰ)所示化合物、其药学上可接受的盐或其互变异构体:其中,n选自:0、1或2;r选自:0、1、2或3;A环选自:苯基或5~6元杂芳基;L选自单键、-S(=O)-、-S(=O) 2-、-C(=O)-,或选自任选被1、2或3个R取代的:-NH-、-NH-C(=O)-、-NH-C(=O)-O-、-NH-S(=O) 2-、-NH-S(=O)-、-NH-C(=O)-NH-;R 1选自H,或选自任选被1、2、或3个R取代的:NH 2、C 1-6烷基、3~6元杂环烷基、C 3-6环烷基、C 1- 3杂烷基;R 2选自H,或选自任选被1、2或3个R取代的:C 1-6烷基、C 1-6杂烷基、C 3-6环烷基、5~6元杂环烷基;R 3选自:H、F、Cl、Br、I,或选自任选被1、2或3个R取代的:C 1-3烷基、C 1-3烷氧基、C 1-4炔基、C 1-4烯基、苯基;R 4、R 5分别独立地选自H、F、Cl、Br、I、NH 2、OH,或选自任选被1、2或3个R取代的:C 1-6烷基、C 1-3烷氧基;或者,R 3和R 4连接形成一个:5~7元环烷基、5~7元杂环烷基、5~7元芳基或5~7元杂芳基;R 6、R 7分别独立地选自:H、F、Cl、Br、I、CH 3、Et、CH 3-O-、CH 3-CH 2-O-;R选自:F、Cl、Br、I、OH,或选自任选被1、2或3个R'取代的:NH 2、C 1-3烷基、C 1-3杂烷基;R'选自F、Cl、Br、I、NH 2或C 1-3烷基;所述5~6元杂芳基、5~6元杂环烷基、3~6元杂环烷基、C 1-3杂烷基、5~7元杂环烷基、5~7元杂环烷基、5~7元芳基、5~7元杂芳基之“杂”分别独立地选自:-NH-、N、-O-、-S(=O) 2-、-S(=O) 2-NH-、-NH-S(=O) 2-NH-、-C(=O)-NH-、-S(=O)-、-C(=O)-、-S(=O)-NH-、-O-C(=O)-NH-;以上任何一种情况下,杂原子或杂原子团的数目分别独立地选自1、2、3或4。
- 根据权利要求1所述的化合物、其药学上可接受的盐及其异构体,其中,R'选自F、Cl、Br、I、NH 2 或CH 3。
- 根据权利要求1所述的化合物、其药学上可接受的盐及其异构体,其中,R选自:F、Cl、Br、I、OH,或选自任选被1、2或3个R'取代的:NH 2、甲基、乙基、C 1-3烷基-S(=O) 2-NH-、C 1-3烷基-S(=O) 2-、C 1- 3烷基-C(=O)-NH-、C 1-3烷基-O-。
- 根据权利要求1~5任意一项所述的化合物、其药学上可接受的盐及其异构体,其中,A环选自:苯基、吡啶基或吡嗪基。
- 根据权利要求1~5任意一项所述的化合物、其药学上可接受的盐及其异构体,其中,R 1选自H,或选自任选被1、2、或3个R取代的:NH 2、甲基、乙基、异丁基、噁丁环基、吗啉基、环丙基、CH 3-O-。
- 根据权利要求1~5任意一项所述的化合物、其药学上可接受的盐及其异构体,其中,R 2选自H,或选自任选被1、2或3个R取代的:甲基、乙基、丙基、环丙基、四氢吡喃基。
- 根据权利要求1~5任意一项所述的化合物、其药学上可接受的盐及其异构体,其中,R 3选自:H、F、Cl、Br、I、CH 3、CF 3或CH 3-O-。
- 根据权利要求1~5任意一项所述的化合物、其药学上可接受的盐及其异构体,其中,R 4、R 5分别独立地选自:H、F、Cl、Br、I、CH 3、CH 3CH 2-、CH 3-O-。
- 根据权利要求1~20任意一项所述的化合物、其药学上可接受的盐或其互变异构体,其中,所述的盐选自盐酸盐或甲酸盐。
- 一种药物组合物,包括治疗有效量的根据权利要求1~23任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
- 根据权利要求1~23任意一项所述的化合物或其药学上可接受的盐或根据权利要求24所述的组合物在制备治疗MEK相关病症的药物上的应用。
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KR1020207002346A KR102580179B1 (ko) | 2017-06-23 | 2018-06-22 | Mek억제제로서의 쿠마린 고리계 화합물 및 이의 용도 |
JP2019571352A JP6774578B2 (ja) | 2017-06-23 | 2018-06-22 | Mek阻害剤としてのクマリン環系化合物およびその応用。 |
CN201880041369.3A CN111201225B (zh) | 2017-06-23 | 2018-06-22 | 作为mek抑制剂的类香豆素环类化合物及其应用 |
BR112019027292-5A BR112019027292A2 (pt) | 2017-06-23 | 2018-06-22 | composto cíclico semelhante a cumarina como inibidor de mek e uso do mesmo |
MX2019015431A MX2019015431A (es) | 2017-06-23 | 2018-06-22 | Compuesto cíclico tipo cumarina como inhibidor de mek y su uso. |
EP18819636.4A EP3643308B1 (en) | 2017-06-23 | 2018-06-22 | Coumarin-like cyclic compound as mek inhibitor and use thereof |
CA3067941A CA3067941C (en) | 2017-06-23 | 2018-06-22 | Coumarin-like cyclic compound as mek inhibitor and use thereof |
AU2018289864A AU2018289864B2 (en) | 2017-06-23 | 2018-06-22 | Coumarin-like cyclic compound as MEK inhibitor and use thereof |
US16/625,258 US11021486B2 (en) | 2017-06-23 | 2018-06-22 | Coumarin-like cyclic compound as MEK inhibitor and use thereof |
SG11201912997TA SG11201912997TA (en) | 2017-06-23 | 2018-06-22 | Coumarin-like cyclic compound as mek inhibitor and use thereof |
ES18819636T ES2876293T3 (es) | 2017-06-23 | 2018-06-22 | Compuesto cíclico similar a la cumarina como inhibidor de MEK y uso del mismo |
RU2020100608A RU2742234C1 (ru) | 2017-06-23 | 2018-06-22 | Кумариноподобное циклическое соединение в качестве ингибитора мек и его применение |
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CN116036080A (zh) * | 2023-04-03 | 2023-05-02 | 江西省林业科学院 | 吡喃并吡啶酮类化合物在制备治疗肝癌药物中的应用 |
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CN116036080B (zh) * | 2023-04-03 | 2023-06-06 | 江西省林业科学院 | 吡喃并吡啶酮类化合物在制备治疗肝癌药物中的应用 |
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